ESMO Supporter 2018

Displaying One Session

Hall A3 - Poster Area Networking Hub Poster Display session
Date
21.10.2018
Time
12:45 - 13:45
Location
Hall A3 - Poster Area Networking Hub
Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session
Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

6P - Molecular characterization and search for founding effects in Canarian families with Hereditary Breast and Ovarian Cancer Syndrome

Presentation Number
6P
Lecture Time
12:45 - 12:45
Speakers
  • Elisenda Llabres Valenti (Las Palmas, ES)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The Hereditary Breast and Ovarian Cancer Syndrome (HBOC) is an autosomal dominant disease caused by germline mutations in BRCA1 (17q21) and BRCA2 (13q12) genes. The identification of BRCA1/2 genes has represented a great advance in the management of families with HBOC allowing carriers to follow up personalized and early detection of tumors at a very early stage.

Methods

Descriptive study of the Canarian families with mutation in BRCA1/2, analyzing clinical, anatomopathological and resulting parameters of the genetic analysis. The screening of point mutations was performed in all exons encoders and adjacent intron sequences by HRM (High Resolution Melting) and subsequent characterization of the patterns altered by sequencing direct. The study of large genomic rearrangements was carried out by MLPA (Multiplex Ligation-dependent Probe Amplification).

Results

Of the 611 families evaluated in the hereditary cancer clinic, 385 have genetic test completed. 55 families have been identified with a pathogenic mutation (14.2%); 36 different mutations (19 in BRCA1 (32 families) and 17 in BRCA2 (23 families). The spectrum of pathogenic mutations identified in the BRCA1 gene suggested strong founder effects on the island of Gran Canaria, where we have detected a recurrent mutation [c.3582-3589del8] (p.His1195PhefsTer21)] that explains more than 70% of families with mutation in BRCA1.

Conclusions

The percentage of pathogenic mutations in Canary HBOC families was 14.2%, similar to that detected in other populations. However, our data showed the presence of a founding mutation which explains more than 70% of our families in Gran Canaria with mutation in BRCA1, which could help us to optimize the algorithms for the study of mutations in these genes.

Legal entity responsible for the study

Elisenda Llabrés Valentí.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

7P - Effect of the polymorphism rs2066844 of the NOD2 gene on colon cancer incidence in a high cardiovascular risk population. Modulation by gender

Presentation Number
7P
Lecture Time
12:45 - 12:45
Speakers
  • Judith Begona Ramirez Sabio (Sagunt, ES)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The nucleotide-binding oligomerization domain containing 2 (NOD2) gene is located on chromosome 16q21. It is expressed in monocytes, macrophages, epithelium of the digestive tract, breast, lung and in the kidney and is associated with the chronic inflammatory process and regulating apoptosis. A crucial role has been described in the maintenance of immune homeostasis and in the relationship with the microbiota. This gene has been linked to diseases such as Crohn's disease but also to gastric cancer, colon, endometrium, breast, ovary, bladder, lung or larynx. Our aim has been to estimate the association between polymorphism rs2066844 of the NOD2 gene on colon cancer by gender in a Mediterranean population.

Methods

We have carried out an observational study at baseline and longitudinally in the PREDIMED-Valencia study including 1094 participants (696 women) at high cardiovascular risk aged 67±6 years. We prospectively analyzed cancer incidence as a secondary outcome in this study. Lifestyle, clinical and biochemical variables were assessed by standardized methods. DNA was isolated from blood and the selected polymorphisms were determined.

Results

We detected 21 new cases of colon cancer from 2003 to 2014, representing 1.9% of all cancers and 10% of all cancer cases in men and 11% in women respectively. In our study it was observed that the variant rs2066844 was related to the new cases of colon cancer in women but not in men. The allelic frequency of the T allele was 0.054, for which the carriers of the T allele were grouped in front of the CC carriers. When assessing the risk of having suffered colon cancer according to the genotype of this variant, it was observed that the individuals carrying the T allele presented a higher risk OR = 8.7: CI 95% (2.2-23.4); P = 0.002 after adjustment for sex, age, intervention group, tobacco smoking, alcohol drinking and intake of omega-3 fatty acids.

Conclusions

rs2066844 of the NOD2 gene could be associated with colon cancer in women in a high cardiovascular risk population.

Clinical trial identification

ISRCTN35739639.

Legal entity responsible for the study

University of Valencia.

Funding

Instituto de Salud Carlos III.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

8P - Effect of the polymorphisms rs1476413, rs1801131, rs4846052 and rs6541003 of the MTHFR gene on prostate cancer in a high cardiovascular risk population

Presentation Number
8P
Lecture Time
12:45 - 12:45
Speakers
  • Judith Begona Ramirez Sabio (Sagunt, ES)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Some genetic variants of the Methylenetetrahydrofolate Reductase (MTHFR) gene can lead to high levels of homocysteine and hinder the ability to process folate. Some genetic variants of this gene are related to susceptibility of many diseases such as cancer. Our aim has been to estimate the association between polymorphisms rs1476413, rs1801131, rs4846052 and rs6541003 of the MTHFR gene on prostate cancer in a Mediterranean population.

Methods

We have carried out an observational study at baseline and longitudinally in the PREDIMED-Valencia study including 398 men at high cardiovascular risk. We prospectively analyzed cancer incidence as a secondary outcome in this study. Lifestyle, clinical and biochemical variables were assessed by standardized methods. DNA was isolated from blood and the selected polymorphisms were determined.

Results

We detected 21 new cases of prostate cancer from 2003 to 2014, representing 1.9% of all cancers and 5.3% of all cancer cases in men. The analysis of the risk of prostate cancer in the variants described was carried out grouping the carriers of the allele less frequent. The allelic frequency of the rs1476413 was 0.219 for not affected participants while it was 0.074 in the cases. The crude OR = 0.24 (95%CI 0.08-0.74) p = 0.013 and OR = 0.23 (95%CI 0.08-0.71) p = 0.010 after adjustment (by age, intervention group and smoking habit). For the rs1801131, the allelic frequency was 0.271 for not affected participants while it was 0,148 in the cases. The crude OR = 0.33 (95%CI 0.13-0.83) p = 0.019 and OR = 0.33 (95%CI 0.13-0.84) p = 0.020 after adjustment. For the rs4846052, the allelic frequency was 0.390 for not affected participants while it was 0.278 in the cases. The crude OR = 0.43 (95%CI 0.19-0.95) p = 0.038 and OR = 0.43 (95%CI 0.19-0.97) p = 0.043 after adjustment. For the rs6541003 was the allelic frequency was 0.380 for not affected participants while it was 0.259 in the cases. The crude OR = 0.39 (95%CI 0.17-0.87) p = 0.021 and OR 0.39 (95%CI 0.17-0.88) p = 0.023 after adjustment.

Conclusions

The rs1476413, rs1801131, rs4846052 and rs6541003 of the MTHFR gene were protective against the development of prostate cancer in a high cardiovascular risk population.

Clinical trial identification

ISRCTN35739639.

Legal entity responsible for the study

University of Valencia.

Funding

Instituto de Salud Carlos III.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

9P - Association of a genetic variant in cyclin-dependent kinase Inhibitor 2A gene with the increased risk of breast cancer

Presentation Number
9P
Lecture Time
12:45 - 12:45
Speakers
  • Soodabeh Shahid Sales (Mashhad, IR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Breast cancer is second leading cause of cancer-related-deaths in women, supporting the need for the detection of novel prognostic biomarkers for risk stratification. There is growing body of evidence showing the association of common genetic variants on chromosome 9p21 with an increased risk of developing different tumors and metabolic disorders. Here we investigated the association of a genetic variant in CDKN2A/B, rs1333049, for the first time in 303 subjects with and without breast cancer.

Methods

Method: Genotyping was carried out using TaqMan real time PCR method in case and control groups. The associations of this genetic variant were evaluated with breast cancer risk and pathological information of patients.

Results

We observed that the minor allele homozygote situation of this genetic variant in total population was 10%, while this condition in heterozygote was 38%. the logistic regression under recessive genetic model revealed that breast cancer patients with GG genotype had higher risk of breast cancer, compared to CC/CG genotypes (e.g., OR = 2.8, 95% CI:1.4-5.4, p = 0.001), after adjusted for age, and BMI.

Conclusions

We demonstrated that patients carrying the GG genotype for CDKN2A/B rs1333049 polymorphism had an increased risk of breast cancer susceptibility, indicating further studies in a larger and prospective setting to show the value of emerging marker as a risk stratification biomarker in breast cancer.

Legal entity responsible for the study

Mashhad University of Medical Sciences, Mashhad, Iran.

Funding

Mashhad University of Medical Sciences, Mashhad, Iran.

Editorial Acknowledgement

Mashhad University of Medical Sciences, Mashhad, Iran.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

10P - Investigating the role of HAT protein TIP60 in regulating functional dynamics of nuclear receptor PXR

Presentation Number
10P
Lecture Time
12:45 - 12:45
Speakers
  • KARISHMA BAKSHI (Greater Noida, UP, IN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

PXR (Pregnane Xenobiotic Receptor) belongs to the class II family of nuclear receptor (NR). PXR is considered as a master regulator of xenobiotic metabolism. PXR gets activated in a ligand-dependent manner and then heterodimerizes with RXR. PXR can also get activated via post-translational modifications and leads to crosstalk between signaling pathways. PXR is shown to be acetylated in vivo and this acetylation regulates its selective functions independent of ligands. However, the molecular players behind this acetylation and the impact of this acetylation in intracellular dynamics of PXR is not known. TIP60 is a lysine acetyltransferase which acetylates histones as well as non-histone proteins like ATM/ATR kinases and p53, and plays a role in DNA damage and repair pathway and in apoptosis. TIP60 is shown to interact with class I of NR. Thus, it might be interesting to reveal the role of TIP60 in acetylation of class II NR PXR.

Methods

We performed in vitro and in vivo co-immunoprecipitation assay and live cell imaging to show interaction as well as domain mapping. We found the site of acetylation in PXR by in silico and in vitro assay. To examine whether TIP60-PXR complex has any influence on these cellular processes, we performed cell migration, cell adhesion, cell proliferation and cell invasion assays.

Results

In this study, we are trying to dissect the mechanism of PXR activation and functional dynamics by TIP60 dependent acetylation. We found the sites of interaction as LBD of PXR with NR box of TIP60 and thus TIP60 mediated subcellular dynamics of PXR. Also, we have found TIP60 mediated the acetylation site of PXR at lysine 170. This novel complex is independent of ligand and does not form a complex with RXR. Also, this complex does not activate ligand dependent PXR target genes. Interestingly, PXR augments TIP60 acetylation on histones. We further discovered TIP60-PXR complex promotes cell migration and adhesion, which might lead to their involvement in physiological or pathophysiological conditions.

Conclusions

This is the first report demonstrating the exclusive interaction of TIP60 with unliganded PXR and uncovers a potential role for the TIP60-PXR complex in cell migration and cell adhesion.

Legal entity responsible for the study

ICMR and Shiv Nadar University.

Funding

ICMR.

Disclosure

The author has declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

11P - The role of downregulated SIRT3 expression in patients with hepatocellular carcinoma

Presentation Number
11P
Lecture Time
12:45 - 12:45
Speakers
  • Hanhee Jo (Incheon, KR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Hepatocellular carcinoma (HCC) is the fifth leading cause of cancer-related deaths worldwide. The only drug currently approved for clinical use in the treatment of advanced HCC is sorafenib, a tyrosine kinase inhibitor. However, many patients with HCC are resistant to sorafenib and sensitivity to sorafenib differs according to the progression of liver cancer. SIRT3, a member of the mammalian sirtuin family, is localized to the mitochondria and regulates metabolic activity. To date, a few studies have investigated the effects of SIRT3 on prognosis and drug resistance in patients with HCC.

Methods

A correlation study between SIRT3 and other genes was conducted through the TCGA online data portal site (http://cancergenome.nih.gov). To determine the protein expression of SIRT3, immunohistochemistry (IHC) was performed with liver cancer tissue using various antibodies. To investigate whether the expression of SIRT3 in HCC is related to the resistance to sorafenib, we treated sorafenib after the modulation of SIRT3 levels in HCC cell lines (overexpression in Huh7, knockdown in HepG2 and Hep3B cells) and conducted functional assays.

Results

We identified that SIRT3 expression is downregulated in patients with HCC and high GLUT1 (glucose metabolism index) and Ki67 (proliferation index) expression. In addition, analysis of Cancer Imaging Archive data (TCGA) revealed a negative correlation between GLUT1 and SIRT3 mRNA expression and also HIF1a and SIRT3 mRNA expression. There was also a negative correlation between Ki67 and SIRT3 mRNA expression. After sorafenib treatment, SIRT3 protein expression was highly downregulated in various HCC cell lines (HepG2/Hep3B/SK-Hep1/Huh7). These cells altered their therapeutic resistance to sorafenib via SIRT3 modulation through a 2 dimensional (D)/3D cell culture system.

Conclusions

Taken together, our results show that SIRT3 acts as a tumor suppressor and plays an important role in therapy resistance for HCC.

Legal entity responsible for the study

Misu Lee.

Funding

The National Research Foundation of Korea (Seoul, Korea; Grant Nos. NRF-2015R1D1A1A01057737, NRF-2018R1C1B6003894).

Editorial Acknowledgement

This research was supported by the National Research Foundation of Korea (Seoul, Korea; Grant Nos. NRF-2015R1D1A1A01057737, and NRF-2018R1C1B6003894)

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

12P - Prediction and Intervention of Colorectal Cancer Risk with Artificial Intelligent System

Presentation Number
12P
Lecture Time
12:45 - 12:45
Speakers
  • Yang Ge (Fuyang, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Colorectal cancer is the third most common cancer worldwide, with nearly 1.4 million new cases diagnosed in 2012. It is also one of the most common cancers in China, with nearly 200,000 people dying annually as a result of colorectal cancer. Prediction and intervention of colorectal cancer risk would save millions of lives worldwide. The purpose of this study is to provide a simple, effective and economic method to help people predict and intervene in colorectal cancer risk.

Methods

A total of 720182 subjects including 18406 colorectal cancer patients and 701776 normal people (see the table for details) were involved in the study. The data were used in the study including demographic, CBC, CMP, lipids and urinalysis data. Analysis of covariance, logistic analysis and discriminant analysis were used to identify the significant factors and to build the colorectal cancer risk prediction model and the significant level was set at p < 0.05. SAS was used as the primary statistical analysis tool.

Subject by gender

Subject2012-2015
2016
MaleFemaleTotal% of MalesMaleFemaleTotal% of Males
Colorectal cancer patients8,0025,22413,22660.5%3,1152,0655,18060.1%
Healthy individuals335,021205,678540,66962.0%99,34961,728161,07761.7%
Total343,023210,902553,92561.9%102,46463,793166,25761.6%

Results

The analysis showed that CBC, CMP, lipids and urinalysis data can significantly distinguish healthy individuals from colorectal cancer patients and those data can be used to build colorectal cancer risk prediction models. The predicting accuracy was 96.1% and the clinical verification rate was 95.7%. Top parameters were selected through the discriminant analysis and logistic analysis. Some parameters, such as red cell distribution width, red cell count, leukocyte percentage and age are positively correlated with colorectal cancer risk, and others, such as albumin, platelet count, hematocrit and platelet distribution width are negatively correlated with colorectal cancer risk.

Conclusions

This research shows that the routine blood and urine test results can be used to predict colorectal cancer risks and the accuracy of the prediction is over 95%. The research would provide an effective, convenient and economical method to help people predict and intervene in colorectal cancer risk.

Legal entity responsible for the study

Fuyang No2. Hospital and Beijing Yiwang Data Technology.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

13P - Measuring the Efficiency of Cancer Care in Europe

Presentation Number
13P
Lecture Time
12:45 - 12:45
Speakers
  • Rikard Althin (Lund, SE)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The rationale of this study is to develop the use of Data Envelopment Analysis (DEA) to measure and compare the efficiency of breast and lung cancer care in Europe in order to inform related policy discussions. In the wake of the increasing prevalence of cancer and pressures on constrained healthcare budgets, understanding how to make the most of available resources is essential to sustainable cancer care. DEA is a well-established instrument capable of identifying best practice in a complex production process such as cancer care with rapid change in technologies. DEA could be used to compare different production units such as e.g., countries, regions, or hospitals. In this study, we use real life data to evaluate the country specific performance of cancer care in Europe.

Methods

DEA is capable of handling many inputs and many outputs simultaneously to estimate the best practice of cancer care. The method is independent of unit of measurement allowing for the use of input and output quantities measured in different units. No data on prices are needed. For this application publicly available, aggregate, retrospective, and comparable data on breast cancer (BC) and lung cancer (LC) from Eurostat, WHO, and OECD was used in the analysis. In the model input variables such as number of radiation units, number of oncologists, and oncology drugs was used to produce survival and quality of life.

Results

The data displayed large differences in both inputs and outputs between countries and over time (2001-2015) and this was reflected in the performance measures. The efficiency base case in 2015 in BC identified 6 efficient countries out of the 23 included with a mean inefficiency of 80% and a minimum of 0.49%, i.e. the same outcome could have been produced with 49% of the inputs used. In the 2015 LC base case there were 8 efficient countries with a mean inefficiency of 82% (minimum 0.51%).

Conclusions

DEA is a policy relevant approach to measure and improve cancer care efficiency in Europe in order to provide information for decisions aimed at reducing waste and ensure better outcomes for patients. The research highlights key inefficiencies and opportunities to improve resource allocation in European cancer care.

Legal entity responsible for the study

The Swedish Institute for Health Economics.

Funding

Bristol-Myers Squibb.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

14P - Circulating cell-free DNA isolated from plasma of mesenteric veins predicts prognosis in stage II colorectal cancer patients

Presentation Number
14P
Lecture Time
12:45 - 12:45
Speakers
  • Chih-Yung Yang (Taipei, TW)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

It is difficult to predict relapse in patients with stage II colorectral cancer (CRC). In recent years, circulating cell-free DNA (cfDNA) from peripheral blood represents a promising biomarker for detection, monitoring and survival prediction of metastatic colorectal cancer (CRC). However, its prognostic significance in patients with stage II CRC remains uncertain.

Methods

In this study, the blood samples were drawn from mesenteric vein (MV) and peripherial vein (PV). MV and PV cfDNA level was quantified by real-time quantitative PCR of ALU repeats. The cfDNA from MV and PV was quantified and the correlation among the cfDNA concentration, clinicopathological features and multivariate survival was analyzed in CRC patients.

Results

Our results showed the MV cfDNA concentrations were lower in early stage than late stage CRC. We also found that MV cfDNA level was positively correlated with tumor size. Stage II CRC patients with higher cfDNA concentrations have better prognosis than those with lower cfDNA concentrations.

Conclusions

These results indicated that MV cfDNA concentration has prognostic value in stage II CRC patients and may act as an additional biomarker in stage II CRC patients for receiving chemotherapy criteria.

Legal entity responsible for the study

Chih-Yung Yang.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

15P - _lonality of uterine carcinosarcoma as a factor of clinical prognosis.

Presentation Number
15P
Lecture Time
12:45 - 12:45
Speakers
  • Natalia Levitskaya (Moscow, RU)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Uterine carcinosarcoma is a malignant mixed Mullerian tumour, composed of epithelial and stromal components. Most uterine carcinosarcomas are monoclonal tumours, but a small proportion of them is a collision of carcinoma and sarcoma.

Methods

This research is based on the investigation of formalin‐fixed, paraffin‐embedded tissue blocks from 13 women undergoing primary surgical treatment between 1961–2010, that were retrieved from the archival collections of the pathoanatomical department of the Institute of Oncology named after N.N. Petrov. Mutations of TP53, PTEN and K-RAS genes were analyzed to determine clonality of uterine carcinosarcoma. DNAs were extracted by proteinase K digestion («Fisher» US) by the method of Herrington, C.S. & McGee, J.O. Mutations of TP53, PTEN and K-RAS were defined by single-strand conformation polymorphism with the next sequence. The found mutations in the TP53 (exons 5-9), PTEN (exons 5, 8), K-RAS (exon 1) genes were compared in epithelial and stromal components of 13 uterine carcinosarcomas. The tumours were classified as monoclonal in the presence of identical mutations in epithelial and stromal components, in the presence of different mutations - as biclonal. Of 13 cases 7 (53.8%) were monoclonal, 6 (46.2%) – biclonal.

Results

We evaluated clinical and histopathologic features of monoclonal and biclonal uterine carcinosarcomas. Monoclonal tumours showed worse prospects than the biclonal ones: 1-yr overall survival - 20% vs 37% (p = 0.0078). In all cases (100%) of monoclonal tumors the average length of full remission was three times shorter than in cases of biclonal tumours.

Comparison of monoclonal and biclonal carcinosarcomas

Clinical and morphological features of uterine carcinosarcomaMonoclonal tumoursBiclonal tumoursp ≦
Tumours invades the serosa of the corpus uteri, %100 %50 %p < 0.0001
Lymphovascular invasion80%0p < 0.0001
Average size of the tumour (cm3)1305.8131.5p < 0.05
Length of full remission7.7524.6p < 0.05

Conclusions

Clonality of the uterine carcinosarcomas may be a clinical marker as it determines the prospects of the disease, influencing the overall survival rate. Biclonal carcinosarcomas have a lesser potential for malignant development and are characterized by stronger survival capacity compared with the monoclonal tumours.

Legal entity responsible for the study

Department of Oncology of the Russian Medical Academy of Continuous Vocational Training.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

16P - ODM-207 - a novel BET bromodomain inhibitor with antitumor activity in nonclinical models of ER+ breast cancer

Presentation Number
16P
Lecture Time
12:45 - 12:45
Speakers
  • Anu Moilanen (Turku, FI)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The bromodomain and extraterminal (BET) family of proteins are chromatin readers that promote the transcription of several important cell identity genes. BET inhibitors have shown promising antitumor activity in a variety of pre-clinical cancer models, as BET inhibition abrogates the transcription of several key oncogenes in a cell type-specific manner. Hence, the purpose of this study was to determine the anticancer activity of the novel BET inhibitor ODM-207 in ER+ breast cancer models and to look for cancer-associated signaling pathways suppressed by BET inhibitors.

Methods

ER+ breast cancer cell lines were studied for sensitivity to ODM-207 and the in vivo efficacy was assessed using the ER+ Ma3366 patient-derived xenograft model. For gene expression analyses, breast cancer cells were treated with ODM-207 or reference BET inhibitor JQ1 and differentially expressed genes were analysed by RNA-sequencing. The ability of ODM-207 to regulate anticancer signaling pathways was validated by western blotting. Synergistic drug interactions were profiled using five-concentration dose response matrices.

Results

ODM-207 is a novel BET inhibitor structurally distinct from JQ1 and its benzodiazepine-related derivatives. In this study, we show that ODM-207 effectively inhibits the proliferation of ER+ breast cancer cell lines as well as suppresses the growth of patient-derived xenograft tumors. Furthermore, ODM-207 and the JQ1 targeted several pathways important for cancer progression such as the DNA damage and repair pathways.

Conclusions

Our results indicate that ODM-207, which is currently in Phase I clinical trials for treating solid tumors, causes significant growth inhibition in pre-clinical models of ER+ breast cancer, and regulates signaling pathways involved in breast cancer cell survival.

Legal entity responsible for the study

Orion Corporation, Orion Pharma.

Funding

Orion Corporation, Orion Pharma.

Disclosure

A. Moilanen, M. Björkman, R. Riikonen, D. Nicorici, E. Mattila, P. Kallio: Employee: Orion Corporation, Orion Pharma. J. Lindqvist: Employee: Orion Corporation, Orion Pharma, Åbo Akademi University. C. Abbineni, M. Jaleel: Employee: Aurigene Discovery Technologies Limited. J. Eriksson: Employee: Åbo Akademi.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

17P - HER2-positive breast cancer resistance to trastuzumab is associated with metabolic switch.

Presentation Number
17P
Lecture Time
12:45 - 12:45
Speakers
  • Roman Dubianski (Warsaw, PL)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Overexpression of the HER2 (ErbB2 or HER2/neu) receptor occurs in 20-25% of breast cancer patients population and is related to more aggressive disease. Implementation of trastuzumab to the treatment of HER2-positive breast cancer improved the results of the treatment in this subgroup of patients. However, the resistance to trastuzumab occurs in some patients. The presence of the nuclear localization of HER2 was also noticed. The aim of this work was to verify the molecular basis of resistance to transtuzumab and correlation between the resistance and the nuclear localization of HER2 protein.

Methods

Among more than 650 patients treated with trastuzumab in MSCMCC 50 patients with resistance to trastuzumab, and 50 well responding to the treatment were chosen. The percentage of the cells with HER2 localized in the nucleus were counted. Additionally, the transcriptomic analysis of HER2 positive breast cancer cell line resistant to trastuzumab was performed. The HER2 ChIP seq and Co-IP from SK-BR3 cell nuclei followed by mass spectrometry analysis were obtained.

Results

In breast cancer with HER2 overexpression nuclear staining was present in immunochemistry. The comparative transcriptomic reanalysis of GEO datasets performed on trastuzumab resistant cell lines and sensitive cell lines revealed that in trastuzumab resistant cell lines the reprogramming of cell metabolism takes place. The most common disturbances were detected in the expression of genes involved in the lipids metabolism, glycolysis and vitamin A metabolism. Moreover, among 308 genes upregulated in trastuzumab resistant breast cancer cells the 216 genes were directly bound/regulated by BRG1 ATPase-the core subunit of SWI/SNF chromatin remodeling complex which is known regulator of metabolism related genes. Among 151 downregulated genes 67 were directly targeted by BRG1. Similarly, the another SWI/SNF ATPase (BRM) – directly targeted 151 of 308 upregulated and 32 of 151 downregulated genes. These results strongly suggested the direct regulation or interdependence of HER2 and SWI/SNF complex.

Conclusions

In HER2 cancer cells resistant to transtuzumab treatment the strong metabolic switch is observed. Moreover, the SWI/SNF complex and nuclear HER2 can be involved in this process.

Legal entity responsible for the study

Maria Sklodowska - Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

Funding

Maria Sklodowska - Curie Memorial Cancer Center and Institute of Oncology, Warsaw, Poland.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

18P - Combination treatment with the PARP inhibitor niraparib and chemotherapeutics in a preclinical model of KRAS/BRAF mutated colorectal cancer cell lines across the four Consensus Molecular Subtypes.

Presentation Number
18P
Lecture Time
12:45 - 12:45
Speakers
  • Pietro Paolo Vitiello (Napoli, IT)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

DNA damage response (DDR) is crucial in a variety of tumours. Colorectal cancer (CRC) shows some features of dependency upon DDR such as frequent activation of RAS-MAPK pathway, that is strongly associated with mitotic stress. Moreover, several approved chemotherapeutics in CRC are typical DNA damaging agents that require active DDR systems in cancer cells to be tolerated (e.g. irinotecan and oxaliplatin). It has been recently shown that PARP inhibitors are able to potentiate the anti-proliferative effect of irinotecan and oxaliplatin, particularly in MSI tumours. However, there is still no correlation between niraparib response and Consensus Molecular Subtypes (CMS).

Methods

We analysed the sensitivity using MTT proliferation assay to the PARP-inhibitor niraparib used alone or in combination with either 5-fluorouracil (5FU), irinotecan (active metabolite SN38) or oxaliplatin in a panel of 8 KRAS (HCT15, LOVO, LS1034, SW1116, SW948, HCT116, SW480) or BRAF (WiDr) mutated CRCs, from the four CMS clusters. Combination index analysis was performed in order to evaluate the synergism between niraparib and the chemotherapeutics. Further characterization of sensitive cell lines was performed using western blot, cell cycle and apoptosis analyses.

Results

Niraparib showed synergistic activity when used in combination with chemotherapeutics in most cell lines used. In particular, the combination with SN38 exhibited the strongest synergism, while synergism with 5FU was only evident in a minority of the analysed cell lines. Synergistic effect between niraparib and chemotherapy was evidenced across all the four CMS. Cell cycle and apoptosis assays revealed differences in sensitive cell lines in terms of increased induction of apoptosis.

Conclusions

Combination of niraparib and chemotherapy in RAS/BRAF mutated CRC is synergistic irrespectively of CMS. SN38 is the best candidate for combination. Further analyses are needed in order to find other markers predictive of good response to PARP inhibitors and chemotherapy in this model.

Legal entity responsible for the study

Department of Precision Medicine, Università della Campania Luigi Vanvitelli.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

19P - Exosomal microRNA-32-5p induces multidrug resistance in hepatocellular carcinoma via the PI3K/Akt pathway.

Presentation Number
19P
Lecture Time
12:45 - 12:45
Speakers
  • Xiao Fu (Xi'an, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Multidrug resistance is the main obstacle for hepatocellular carcinoma (HCC) treatment. Through bioinformatics prediction, literature review, and real-time PCR, we found that elevated miR-32-5p was associated with tumorigenesis in different cancer types, including HCC. miR-32-5p also contributes to castration resistance, radioresistance and chemoresistance in prostate cancer, but its function in multidrug resistance is still unclear. Exosomes are the most abundant type of extracellular vehicles (EVs), containing RNAs (especially miRs), proteins and other bioactive molecules. Recently, exosomes generated from chemoresistant cells have been proven to deliver miRs and transfer malignant phenotype to sensitive cells. Here we aim to find out the function of miR-32-5p in inducing multidrug resistance and the possible underlying mechanisms.

Methods

We detected the expression of miR-32-5p and PTEN in the cells and exosomes from both the multidrug-resistant and the sensitive cell lines, HCC and para-carcinoma liver tissues through real-time PCR. Dual-luciferase reporter assay verified PTEN is the target of miR-32-5p. Exosomes were obtained and confirmed through ultracentrifuge and Nano Analyzer. Gain- and loss-of-function experiments, rescue experiments, an exosome biogenesis inhibitor, and nude mice xenograft models were used to determine the underlying mechanisms of miR-32-5p and PTEN, as well as exosomal miR-32-5p in inducing multidrug resistance in vitro and in vivo.

Results

miR-32-5p was significantly elevated in multidrug-resistant HCC cell line, Bel/5-FU as well as the exosomes derived from Bel/5-FU. An inverse correlation between miR-32-5p and PTEN was confirmed in HCC cell lines and patients; moreover, high expression of miR-32-5p and low expression of PTEN were positively associated with poor prognosis. Both in vitro and in vivo expriments reveal that exosomal miR-32-5p leads to multidrug resistance by targeting PTEN and activating the PI3K/Akt pathway through promoting EMT and angiogenesis.

Conclusions

Our study demonstrated that the multidrug-resistant cell, Bel/5-FU delivers miR-32-5p to sensitive cell, Bel7402 by exosome and activates the PI3K/Akt pathway to further induce multidrug resistance by modulating angiogenesis and EMT.

Legal entity responsible for the study

The First Affiliated Hospital of Xi'an Jiaotong University.

Funding

National Natural Science Foundation of China (No. 81301909 and 81672810). International cooperation project in science and technology of Shaanxi province (No. 2016KW-017). Natural Science Foundation of Shaanxi Province (No.2017JM8019).

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

20P - Effect of the polymorphism rs2470893 of the CYP1A1 gene on ovarian and endometrial cancer in Mediterranean women

Presentation Number
20P
Lecture Time
12:45 - 12:45
Speakers
  • Judith Begona Ramirez Sabio (Sagunt, ES)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The CYP1A1 gene is located on chromosome 15 (15q22-q24.1) and is part of the cytochrome P450 family. This catabolizing enzyme has an important role in the activation / deactivation of various chemical agents, including xenobiotics and sex hormones. It is related to the synthesis of cholesterol and steroids, and to the metabolism of drugs, coffee, or different metabolites such as those of tobacco. It is found mainly in extrahepatic tissues such as lung, breast or ovarian follicles, and participates in the metabolism of a large number of xenobiotics as well as one of endogenous substrates. Human cytochrome P450 1A 1 is one of the most important enzymes involved in the human carcinogenesis because it metabolizes several procarcinogens to active carcinogens. There are previous studies that have linked rs2470893 with ovarian cancer. Our aim has been to estimate the association between polymorphism rs2470893 of the CYP1A1 gene on ovarian and endometrial cancer in a Mediterranean population.

Methods

We have carried out an observational study at baseline and longitudinally in the PREDIMED-Valencia study including 696 women at high cardiovascular risk. We prospectively analyzed cancer incidence as a secondary outcome in this study. Lifestyle, clinical and biochemical variables were assessed by standardized methods. DNA was isolated from blood and the selected polymorphisms were determined

Results

We detected 8 new cases of ovarian and endometrial cancer from 2003 to 2014, representing 0.6% and 0.1% respectively, of all cancers. In our study it was observed that the variant rs2470893 was related to ovarian and endometrial cancer. The allelic frequency of the A allele was 0.246. The carriers of the G allele were grouped in front of the AA carriers. When assessing the risk of having suffered from ovarian or endometrial cancer according to the genotype of this variant, it was observed that the individuals carrying the AA allele presented a higher risk OR = 8.7: CI 95% (2.4-31.9); P = 0.001 after adjustment for age, intervention group, tobacco smoking and obesity (BMI ≥ 30 Kg/m2).

Conclusions

rs2470893of the CYP1A1 gene could be associated with ovarian and endometrial cancer in a high cardiovascular risk population.

Clinical trial identification

ISRCTN35739639.

Legal entity responsible for the study

University of Valencia.

Funding

Instituto de Salud Carlos III.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

21P - Cisplatin in NIPEC or HIPEC?

Presentation Number
21P
Lecture Time
12:45 - 12:45
Speakers
  • Ivan K. Alvovsky (Saint-Petersburg, RU)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Eliminating minimal residual disease in patients with advanced ovarian cancer (AOC) is necessary to prevent recurrencies and could be achieved with hyperthermic intraperitoneal chemoperfusion (HIPEC). Cisplatin comprises the majority of HIPEC regimens due to its known synergic efficacy with hyperthermia. However, emerging report are impugning its role. Our goal was to compare the survival of rats treated with cisplatin by hyperthermic and normothermic intraperitoneal chemoperfusion (HIPEC and NIPEC) and to evaluate, whether the outcome of HIPEC would depend on its opened (oHIPEC) or closed (cHIPEC) delivery.

Methods

A rodent model of ascitic ovarian cancer was used. 1*107 tumor cells were inoculated i.p. 48 hours prior to the treatment to 48 female Wistar rats. As indicated by our previous research, this time limit of tumor progression reflects the biological pattern of optimally debulked AOC in women. Each 12 rats were randomized into four groups to receive either cisplatin at a maximum tolerated dose of 20 mg/kg in NIPEC, cHIPEC, and oHIPEC or i.p. 20 mg/kg saline as a control without treatment.

Results

The mean survival in the untreated control was 31.8 days. Cisplatin in NIPEC increased the mean survival by 22 days (P = 0.0007), while in cHIPEC and oHIPEC by 19.9 (P = 0.003) and 31.5 (P = 0.003) days, respectively. Cisplatin in oHIPEC was shown to be the most effective combination. The differences between NIPEC and cHIPEC with cisplatin were not statistically significant.

Conclusions

Our results prompt that NIPEC with cisplatin might be just as effective as cHIPEC in increasing survival in AOC.

Legal entity responsible for the study

Vladimir Bespalov.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

22P - Matrix metalloproteinase-mediated regulation of programmed-death ligand in the human head and neck squamous cell carcinoma microenvironment

Presentation Number
22P
Lecture Time
12:45 - 12:45
Speakers
  • MARIKO HIRAI (Kanazawa, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. According to recent clinical studies, tumour growth can be effectively reduced and survival can be improved by blocking the programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway. However, anti-PD-1 treatment is beneficial only for certain patients. Therefore, the mechanisms controlling PD-L1 expression warrant further investigation in order to provide a better understanding of the predicting efficacy of and optimising anti-PD-1 therapy, alone or in combination.

Methods

MMP-mediated regulation of PD-L1 expression was examined in three human HNSCC cell lines (OSC-20, OSC-19 and HOC313). Enzymatic activity of MMP against PD-L1 was evaluated in vitro using purified recombinant proteins or MMP synthetic inhibitors.

Results

PD-L1 protein extracted from the cell membrane was found to be downregulated in OSC-20 cells compared with OSC-19 cells, despite a higher PD-L1 expression in the total cell lysate of the OSC-20 compared with the OSC-19 cells. Several matrix metalloproteinases (MMPs) were found to be upregulated in HNSCC; in particular, MMP-7 and -13 were upregulated in the OSC-20 compared with the OSC-19 cells. Purified PD-L1 was degraded by recombinant MMP-13 and -7. The expression of PD-L1 was significantly restored by a specific inhibitor of MMP-13 (CL82198), which suggested the involvement of MMP-13 in the shedding/cleavage of PD-L1 in the OSC-20 cells. Among the anti-cancer drugs conventionally used in the treatment of patients with HNSCC, paclitaxel increased MMP-13 expression in R/M HNSCC cells (HOC313 cells) co-cultured without/with dendritic cells (DCs).

Conclusions

These results suggest that the shedding/cleavage of PD-L1 by MMP-13 is one of the mechanisms behind the protective effect against invasion and metastasis. Thus, MMP-13 has potential value as a marker predictive of the decreased efficacy of anti-PD-1 therapy. In addition, paclitaxel is a particularly promising candidate for combination therapy in R/M HNSCC with anti-PD-1 therapy.

Legal entity responsible for the study

Graduate School of Medical Science, Kanazawa University.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

24P - Trametinib synergizes with dexamethasone in KRAS-mutant myeloma cell lines through modulation of NDRG1 and induction of apoptosis

Presentation Number
24P
Lecture Time
12:45 - 12:45
Speakers
  • Priya Sriskandarajah (Orpington, GB)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Multiple myeloma (MM) remains incurable despite advances in available therapy. Mutations within the RAS-MAPK pathway are frequently associated with relapsed/refractory disease, with KRAS being particularly prevalent. Increased efforts to target this pathway with the MEK inhibitor, trametinib (Tr) have been limited by toxicities and the development of resistance due to adaptive signalling networks. Dexamethasone (Dex) is a corticosteroid commonly used in clinical practice, to synergistically enhance efficacy of anti-myeloma therapy. Therefore, we hypothesised that the combination of Tr and Dex would yield synergistic activity in KRAS-mutant MM.

Methods

Sensitivity to Tr and Dex was determined via CellTiter-Blue (CTB) assay in the KRAS-mutant multiple myeloma cell lines (MMCLs): MM1R (Dex-refractory) & MM1S (Dex-sensitive). Apoptosis and cell cycle were evaluated by flow cytometry. Reverse phase protein array (RPPA) was employed for quantitative analysis of 60 proteins and validated by Western blotting.

Results

CTB assay demonstrated a dose-dependent reduction in cell proliferation with Tr and Dex individually in MM1S, while MM1R was resistant to both treatments. TrDex demonstrated synergistic cytotoxicity in MM1S using CTB and annexin V staining. An accumulation of sub-G1 cells was observed during cell cycle analysis in MM1S, confirming increased cell death. These effects were accompanied by activation of pro-apoptotic proteins, such as cleaved PARP and increased BIM. RPPA revealed the following phospho-proteins were downregulated with TrDex in MM1S compared to MM1R: FAK, PYK2, FLT3, NDRG1 and 4EBP1. Changes in phospho-NDRG1 were statistically significant (P < 0.001; 2-way ANOVA). This was confirmed by Western blotting, where expression levels were downregulated by TrDex in MM1S but unaffected in the resistant cell line MM1R.

Conclusions

TrDex demonstrates synergistic activity in KRAS-mutant MMCLs by suppression of pro-survival signalling and engagement of apoptotic pathways. Our data support further investigation of this combination in KRAS-mutant MM.

Legal entity responsible for the study

Institute of Cancer Research.

Funding

Cancer Research UK.

Disclosure

P. Sriskandarajah: CRUK funding grant awarded in 2016. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

25P - Functional inhibition of TGF-_ in colorectal cancer cells and its interaction with AXL receptor

Presentation Number
25P
Lecture Time
12:45 - 12:45
Speakers
  • Davide Ciardiello (Napoli, IT)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

AXL and transforming growth factor β (TGF-β) are correlated with epithelial to mesenchymal transition, invasiveness, angiogenesis and immune modulation in colorectal cancer (CRC). We have previously demonstrated that targeting AXL caused a significant blockade of cancer cell proliferation and migration. Here we have evaluated the role of TGF-β signalling and the potential interaction between TGF- β and AXL in human CRC cell lines.

Methods

We assessed the expression and activation of TGF-β and AXL in a panel of human CRC cell lines (HCT116, SW480, LOVO, LIM 1215 and SW48) by Western Blot (WB) and Real time PCR. We tested the sensitivity of Galunisertib (LY21209761), a TGF-β R1 inhibitor, in HCT116 and LOVO cells the treatment by using MTT, soft-agar colony forming, cell invasion and wound healing assays. To study the correlation between these two pathways, we generated stable LOVO short hairpin RNA (shRNA)-sh-AXL cells clones, in which AXL expression was decreased, and stimulated both parental and shAXL LOVO cells with TGF-β1.

Results

TGF-β receptors 1 and 2 were expressed in all cell lines, whereas AXL was expressed only in HCT116, SW480, LOVO cells. Treatment with Galunisertib had a modest effect on cancer cell growth, whereas it significantly decreased TGF-β induced cell migration, invasion and colony formation in HCT116 and LOVO cells (that co-expressed both TGF-β receptors and AXL). The stimulation of HCT116 and LOVO cells with TGF-β1 resulted in increased levels of phosphorylated (p) AXL, pAKT, and p38 MAPK proteins. However, in contrast to parental LOVO cells, no increase in p38 MAPK was found in LOVO shAXL clones, upon TGF-β stimulation.

Conclusions

In HCT116 and LOVO cells, TGF-β mediated cell migration, invasion and soft agar colony growth formation were significantly inhibited by Galunisertib treatment. Furthermore, a functional potential cross talk between TGF-β induced signalling and AXL could converge on p38 MAPK activation. In this respect, combined treatments with Galunisertib and AXL inhibitors are ongoing to evaluate their antitumor effects in CRC cells.

Legal entity responsible for the study

Dipartimento di Medicina di Precisione, Università degli Studi della Campania Luigi Vanvitelli.

Funding

AIRC (Associazione Italiana per la Ricerca sul Cancro) MFAG-2015-ID:7778.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

26P - Isoform-specific AKT Inhibition Differentially Affects Cell Functions in Pancreatic Adenocarcinoma

Presentation Number
26P
Lecture Time
12:45 - 12:45
Speakers
  • Hugo Arasanz (Pamplona, ES)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

AKT/PKB is a protein kinase that plays a key role in cancer, as different oncogenic pathways on it. Three isoforms with a similar structure have been described: AKT1/PKBα, AKT2/PKBβ and AKT3/PKBγ. Although there is evidence that each isoform yields specific functions, which may vary depending on the cell type, the data available about downstream pathways is scarce. Our project evaluates the consequences of the individual inhibition of each isoform in pancreatic adenocarcinoma cells.

Methods

We have individually silenced each AKT isoform short hairpin RNAs (shRNAs) delivered by lentiviral transduction. Cells transduced with an unspecific shRNA were used as controls. Then, high-throughput quantitative proteomic analyses were performed to evaluate the differential signaling routes altered by silencing of each AKT isoform. Lastly, Western Blot and proliferation, apoptosis and chemosensitivity experiments have been completed.

Results

3930 proteins were identified with a false discovery rate (FDR) lower than 1%. Proteome pairwise comparisons were performed with the cells lines. The specific silencing of each isoform lead to differential protein expression profiles, although KEGG pathway analysis tools revealed that many of the pathways altered were common. Individual silencing of any AKT isoform caused an inhibition of glycolysis and a subsequent increase of mitochondrial activity, as seen by fluorescent mitochondrial staining. AKT silencing increased gemcitabine sensitivity for all isoforms. AKT1 and AKT2 increased 5-FU sensitivity, while AKT3 had a comparable value. Western Blot demonstrated an increase in mTOR expression after AKT1 and AKT2 silencing. p-EIF4B expression was decreased after AKT2 and AKT3 silencing. No differences were observed in ERK expression.

Conclusions

AKT isoforms have specific functions in pancreatic adenocarcinoma. Its silencing drives cancer cells from aerobic glycolysis to mitochondrial dependent metabolism. A deeper knowledge of its downstream molecular pathways might give the rationale for individual pharmacological inhibition and combination with other therapies, thus improving the efficacy of the available treatments.

Legal entity responsible for the study

Immunomodulation Group. Navarrabiomed / Fundación Miguel Servet.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

27P - Lymphocytes express receptor tyrosine kinases in patients with renal cell carcinoma and healthy donors

Presentation Number
27P
Lecture Time
12:45 - 12:45
Speakers
  • Ilya Tsimafeyeu (Moscow, RU)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Very little is known about receptor tyrosine kinases (RTK) expression on peripheral blood mononuclear cells (PBMC) in humans including renal cell carcinoma (RCC) patients. The primary objective of study was to evaluate expression levels of major RTKs on PBMC and tumor infiltrating lymphocytes (TIL) isolated from RCC patients. The secondary aim was to compare levels of RTK expression in RCC patients before surgery and on the 180th day after surgery (lymphocyte lifetime) and to compare with expression in healthy donors (HD). In addition, we compared RTK and PD-L1 expression in TIL.

Methods

Tumor and blood samples were obtained from 20 patients with primary RCC immediately after surgical resection. Blood samples were collected from 10 HD. Tumors were harvested into RPMI1640 medium (Gibco) and processed within 4 h. TIL isolation was performed under modified protocol [Baldan 2015]. Isolated TIL and PBMC were prepared for flow cytometry. Cells were double stained with anti-CD45 FITC-conjugated mouse antibody and with PE-conjugated mouse antibodies to VEGFR1-2, PDGFRα-β, FGFR2 (all Sony Biotech) and were analyzed on NovoCyte 2000R flow cytometer (ACEA Biosciences). Expression of RTK was evaluated with NovoExpress Software. 20 tumors from same patients were stained with PD-L1 IHC assay (clone SP142 (Ventana).

Results

PBMC/TIL express RTKs (Table). In HD PBMC express all RTKs in 2-3 times higher than PBMC of RCC patients (all P < 0.05). TIL also had lower expression of RTK (all P < 0.05). There was no significant recovery of RTK expression on 180th day except of VEGFR2. Level of FGFR2 was lower on TIL (P = 0.03). 50% of patients had PD-L1 expression (1-11% of positive TIL). We found negative correlation of PDGFRα, β and PD-L1 expression (P = 0.04).

Expression of RTK, %, meanPBMC, HDPBMC, RCC, before surgeryPBMC, RCC, 180 days after surgeryTIL, RCC
VEGFR178.128.843.428.1
VEGFR279.627.157.844.3
PDGFRα80.144.949.152.3
PDGFRβ75.562.647.452.3
FGFR272.141.435.123.2

Conclusions

PBMC and TIL had similar low RTK expression levels in RCC patients. Lymphocytes of healthy humans had significantly higher expression of RTK. PD-L1 and PDGFRa-b expression could correlate.

Clinical trial identification

KCRB11022016.

Legal entity responsible for the study

Ministry of Health.

Funding

Kidney Cancer Research Bureau.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

28P - Oncogenes analysis using GO-based clustering

Presentation Number
28P
Lecture Time
12:45 - 12:45
Speakers
  • Dmitriy Babenko (Karaganda, KZ)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

New technology, including next-generation sequencing, has been contributing to discover novel genes and a genetic mechanism connected to oncology. Oncogenes are of particular interest to biologists, as they can provide a direct target for small molecule inhibitors. However, recent studies show that tumor suppressors and oncogenes are separable using rates of truncating mutations, mutation clustering, and copy number data. At the same time, existing literature suggested a higher intensity of purifying selection on cancer-related genes. This has led to hypothesize those oncogenes and tumor suppressor genes are more closely related physically, than noncancer-related genes. The aim of this study was to carry out clustering protein genes based on GO-terms and determine cluster structure and oncogene positions on it.

Methods

List of protein-coding genes was obtained with biomaRt Bioconductor package. ClusterProfiler Bioconductor package was used to get gene ontology data of the genes. The association of genes to cancer was calculated with OncoScore Bioconductor package. Data associated with biological processes, cellular components, and molecular functions were presented in a binary format that was used for clustering analysis. SeqSphere software used for generating minimum spanning trees (MST).

Results

15521 out 19295 protein-coding genes (85.5%) had full information about biological processes, cellular components, and molecular functions. Among 15521 genes (1.5%), 226 genes were high associated with cancer (75 and higher oncoscore). 1441 protein-coding genes had a medium association with cancer (50-74 oncoscore). 5694 genes were between 21 and 49 oncoscores. 7345 genes were not oncogenes (based on oncoscore). In 815 cases it was not possible to determine the oncoscore. MST created on 206 unique GO terms (10% cutoff) of 15521 genes revealed grape-like structure with many clusters. High associated gene to cancer (oncogenes with high oncoscore) was distributed across different clusters and located on the outer layer of clusters.

Conclusions

Cluster analysis of protein-coding genes based on GO-terms (on biological process, molecular functions, and cell localization data) demonstrated cluster (grape-like) structure. Oncogenes were located mostly outside the cluster center.

Legal entity responsible for the study

Dmitriy Babenko, Karaganda State Medical University.

Funding

Ministry of Education and Science of Republic of Kazakhstan.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

29P - PNU-74654 enhances the antiproliferative effects of 5-FU in breast cancer and antagonizes thrombin induced cell growth via the Wnt Pathway

Presentation Number
29P
Lecture Time
12:45 - 12:45
Speakers
  • Soodabeh Shahid Sales (Mashhad, IR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The Wnt/beta-catenin pathway is one of the main pathways that are dysregulated in several malignancies, including breast cancer, and may therefore be a potential therapeutic target. We have investigated the anticancer activity of PNU-74654 in breast cancer, as a Wnt/ β-catenin inhibitor, either alone or in combination with 5-FU in vitro and in vivo.

Methods

Cell viability was assessed in 2 and 3-dimensional (D) cell culture models. The ability of PNU-74654 to inhibit the chemotaxis of cells was investigated using an in vitro migration assay, and the expression of several candidate genes involved in the cell cycle, migration, as well as the markers of Wnt/b-catenin pathway were investigated by qRT-PCR and/or Western blotting as well as cell cycle analysis by flow cytometry. The effect of PNU-74654 on oxidative balance was evaluated by determining the malondialdehyde (MDA) and concentration of total thiols (T-SH), and the activity of catalase (CAT) and superoxide dismutase (SOD). We reconstructed a Boolean network in order to understand dynamic behavior of genes, while the robustness of this model was assessed by Hamming distance.

Results

PNU-74654 suppressed cell growth at an IC50 of 122±0.4 umol/L and synergistically enhanced the antiproliferative activity of gemcitabine by modulating the Wnt pathway. The 3-D cell culture model showed that PNU-74654 caused tumor shrinkage. It reduced the migration of MCF-7 cells (by an 18% reduction in invasive behavior) after treatment with PNU-74654 through perturbation of E-cadherin and MMP3/9. PNU-74654/5-FU combination enhanced the percentages of cells in S-phase, and significantly increased apoptosis. Moreover, our data showed that this agent was able to inhibit the growth of tumor in a xenograft model, although this effect was more pronounced in the animals treated with PNU-74654 plus 5-FU.

Conclusions

The antitumor activity of PNU-74654 were shown in breast cancer.

Legal entity responsible for the study

Mashhad University of Medical Sciences, Mashhad, Iran.

Funding

Mashhad University of Medical Sciences, Mashhad, Iran.

Editorial Acknowledgement

Mashhad University of Medical Sciences, Mashhad, Iran

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

30P - P21 has the potential to become the monitoring marker for the CDK4/6 inhibitors resistance in breast cancer

Presentation Number
30P
Lecture Time
12:45 - 12:45
Speakers
  • Masafumi Iida (Sendai, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

CDK4/6 inhibitors have been widely used around the world for advanced estrogen receptor positive breast cancer patients in the past several years. However, the benefit offered by CDK4/6 inhibitors is individually different, therefore it is imperative need to identify the biomarker and/or monitoring marker.

Methods

We established CDK6 over expression cell lines (MCF7-C6) from MCF-7 by stably transfected CDK6 expression vector. We also established Ribociclib-resistant cell lines (RIBR) after long-term culture under the condition of sufficient doses of Ribociclib from estrogen deprivation-resistant cell lines (EDR) which established from MCF-7 cultured with steroid depleted medium as aromatase inhibitor resistance models. We further established RIBR(-R) cell lines from RIBR by long-term cultured without Ribociclib.

Results

First, we assessed IC50 of Ribociclib in several cell lines. Luminal cell lines exhibited lower Ribociclib IC50 than non-luminal cell lines. Immunoblot analysis of Luminal cell lines showed extremely lower levels of CDK6 compared with others. Then we established MCF7-C6. MCF7-C6 reduced Ribociclib sensitivity equivalent to non-luminal cell lines. Next, we established RIBR to understand the characteristics in acquired resistance. We confirmed RIBR showed higher Ribociclib IC50 than EDR. Surprisingly the expression levels of CDK6 were not reduced in RIBR, indicating that the mechanism of resistance to Ribociclib would be different between MCF-7-C6 and RIBR. Then, we explored the efficacy of other CDK4/6 inhibitors on MCF7-C6 and RIBR. MCF7-C6 and RIBR cells showed cross-resistant not only to Palbociclib but Abemaciclib. The expression levels of p21 were reduced in both cell lines though the mechanisms of resistance to CDK4/6 inhibitors were different. Finally, we established RIBR(-R). RIBR(-R) showed more sensitive to Ribociclib than RIBR. In addition, p21 levels of RIBR(-R) were restored to the same degree as EDR.

Conclusions

Ribociclib sensitivity was proportional to the expression levels of p21, suggesting that p21 levels might be the monitoring marker for the CDK4/6 inhibitors resistance in breast cancer.

Legal entity responsible for the study

Shin-ichi Hayashi.

Funding

Grant-in-aid for scientific research from the Ministry of Education, Science, Sports, Science and Technology of Japan; Grant-in-aid for cancer research from the Ministry of Health, Labour and Welfare of Japan; Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation (NIBIO); Grant from the Smoking Research Foundation.

Disclosure

S-I. Hayashi: Research grants: Novartis Pharma K.K, AstraZeneca K.K. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

31P - Overexpression of NAMPT in adult T-cell leukemia/lymphoma patients and anti-tumor activity of a NAMPT inhibitor in vivo

Presentation Number
31P
Lecture Time
12:45 - 12:45
Speakers
  • Tomohiro Kozako (Fukuoka, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of mature T lymphocytes induced by human T-cell leukemia virus (HTLV) that has poor outcomes. New molecular targets for prevention and treatment of ATL are urgently needed. We reported that SIRT1, a nicotinamide adenine dinucleotide (NAD+)-dependent histone/protein deacetylase, is highly expressed in primary acute-type ATL cells. NAD+ biosynthesis via nicotinamide phosphoribosyltransferase (NAMPT) modulates SIRT1 activity. We examined the expression and inhibition of NAMPT, a rate-limiting enzyme in NAD+ biosynthesis, in ATL cells.

Methods

Peripheral blood mononuclear cells from ATL patients were carried out in accordance with the guidelines of the Committees for Ethical Review of Research involving Human Subjects at Kagoshima University Hospital. Cell viability was evaluated in the S1T cell line derived from an ATL patient, MT-2 cell line derived from normal human leukocytes transformed by leukemic T-cells from an ATL patient, and primary ATL cells. Animal experiments were approved by the Animal Care and Use Committee of Rakuno Gakuen University in accordance with the Guide for the Care and Use of Laboratory Animals.

Results

Peripheral blood mononuclear cells from acute-type ATL patients expressed significantly higher NAMPT protein levels than cells from healthy controls. FK866, a NAMPT inhibitor, induced apoptosis in cell lines and fresh ATL cells, accompanied by caspase activation, DNA fragmentation, and mitochondrial transmembrane potential disruption in vitro. A pan-caspase inhibitor failed to prevent the FK866-induced cell death, while FK866 increased endonuclease G, a caspase-independent cell death mediator. Intriguingly, FK866 activated autophagy, revealed by increased LC3-II protein levels. Thus, FK866 simultaneously activated apoptosis and autophagy. Finally, FK866 treatment markedly decreased human ATL tumor xenograft growth in immunodeficient mice.

Conclusions

These results demonstrate that NAMPT inhibition induces autophagy and caspase-dependent and -independent cell death in ATL cells, suggesting a novel therapeutic strategy for patients with this fatal disease.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

32P - 9-ING-41, a clinically relevant inhibitor of Glycogen Synthase Kinase-3 (GSK-3), is active pre-clinically in human bladder and renal cell cancers

Presentation Number
32P
Lecture Time
12:45 - 12:45
Speakers
  • Hiroo Kuroki (Niigata, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Glycogen Synthase Kinase-3b (GSK-3b) is a serine/threonine protein kinase that has been established as a therapeutic target in a broad spectrum of human malignancies. We have previously identified aberrant GSK-3b nuclear expression in urothelial cancer (UC) and renal cell carcinoma (RCC), and demonstrated that GSK-3b positively regulated UC and RCC cell survival and proliferation. Our objective was to evaluate the antitumor effects of clinically viable agent 9-ING-41, a maleimide-based ATP-competitive GSK-3 inhibitor, which demonstrated broad spectrum antitumor activity and marked activity in reversing chemoresistance in a variety of human cancers.

Methods

We used flow cytometry, Western immunoblotting, quantitative RT-PCR, BrDU incorporation and MTS assays to examine the pre-clinical antitumor activity of 9-ING-41 in UC (T24, HT1376 and RT4 cell lines) and RCC (ACHN, Caki2, A498 and KRC/Y cell lines).

Results

A dose-dependent decrease in cancer cell proliferation was observed by MTS assay and BrdU incorporation assay with GI50 ranging from 0.7 to 4.7 mM (UC) and 7.2 to 11.5 mM (RCC). Treatment with 9-ING-41 induced prominent cell cycle arrest (predominantly G2 arrest) in UC and RCC cell lines. Expression of cell cycle related proteins, including Cyclin D, and anti-apoptotic proteins, such as XIAP and Bcl-2, were decreased as detected by Western immunoblotting and real time RT-PCR. Treatment with 9-ING-41 significantly potentiated the growth inhibitory effect of cisplatin and gemcitabine in both UC and RCC cell lines.

Conclusions

Our data provide a rationale for the inclusion of patients with advanced and/or chemo-refractory UC or RCC in 9-ING-41 clinical studies.

Legal entity responsible for the study

Hiroo Kuroki.

Funding

D. Schmitt: President, CEO, equity interest: Actuate Therapeutics, Inc. A. Mazar: Equity interest, scientific advisor: Actuate Therapeutics, Inc. A. Ugolkov: Equity interest, consulting scientific Director: Actuate Therapeutics, Inc.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

33P - A new natural compound identified with metabolomic approach has cytotoxic activity against human colorectal cancer cell lines with acquired resistance to cetuximab

Presentation Number
33P
Lecture Time
12:45 - 12:45
Speakers
  • Vincenzo De Falco (Napoli, IT)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The discovery of bioactive compounds from natural sources is an important resource to develop new weapons against cancer. In a previous study, we have used a rapid NMR-based metabolomic approach to select plant species belonging to Fabaceae family with anti-proliferative properties. Fourteen species of this family were studied with high-resolution 2D NMR spectroscopy and then several molecules were purified from plant extracts. The family of Fabaceae is widely distributed in the Northern hemisphere and putative pharmacologic effects are described in traditional Chinese pharmacopoeia.

Methods

We analysed the cytotoxic activity of an Astragalus boeticus compound on a panel of human colon cancer cell lines sensitive (SW48, GEO and CACO-2) and with acquired resistance to anti-EGFR inhibitors such as cetuximab (SW48-CR, GEO-CR and CACO-2-CR).

Results

Among a panel of human CRC cell lines, three with acquired resistance to cetuximab (SW48-CR, GEO-CR and Caco-2-CR) were highly sensitive to the Astragalus compound. The treatment with this compound determines a transition to an epithelial phenotype in all three cell lines with reduction of vimentin and an increase of E-cadherin expression. Moreover, Astragalus treatment determines an induction of apoptosis and a significant increase in cell death in SW48-CR, GEO-CR and Caco-2-CR cells, but not in the parental cell lines. These findings were confirmed by western blot assay with activation of caspase cascade only in cetuximab-resistant cells. Moreover, the antiproliferative effect of Astragalus compound on cetuximab-resistant cells is mediated by the inhibition of AKT/mTOR signalling pathway. In particular, western blot analyses have shown a significant reduction in the expression of 4-EBP1 and p-4EBP1 in cetuximab-resistant cell lines following Astragalus treatment. Moreover, the combined treatment with cetuximab and Astragalus induced a synergistic antiproliferative and apoptotic effects with blockade in AKT/mTOR pathway in h cetuximab-resistant cells.

Conclusions

Astragalus compound induces antiproliferative activity in a panel of human CRC with acquired resistance to cetuximab by inhibiting AKT/mTOR pathway.

Legal entity responsible for the study

Università degli Studi della Campania Luigi Vanvitelli.

Funding

Università degli Studi della Campania Luigi Vanvitelli.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

34P - Multiple Myeloma Metal Levels and Proteasome Activity

Presentation Number
34P
Lecture Time
12:45 - 12:45
Speakers
  • Kai Uwe Stumpf (Würzburg, DE)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The biologically active metal-based compounds are of interest in both prevention and treatment of cancer. Metal-containing complexes are essential for the normal biochemical processes, and due to their reactivity, imbalance in the metal concentration is linked to the development of diverse malignancy. Several proteasome inhibitors contain metal complexes. Bortezomib (a boron complex) is the first successfully used therapeutic proteasome inhibitor in multiple myeloma (MM). However, major clinical limitations of the drug are the severe side effects caused by the inhibition of proteasomal and non-proteasomal activity in normal cells. Here we analyze the associations between individual metals and proteasome activity.

Methods

The study was performed on MM cell lines MM.1S and L363. Chymotrypsin–like (CT-like) proteasome activity is the primary measure of the degradation potential of the proteasome. In order to determine how metals are linked to proteasome activity, we expose MM cells to bortezomib or 5-amino-8-hydroxyquinoline dihydrochloride (5AHQ) proteasome inhibitors. The CT-like activities of β5 and β5i subunit were measured and evaluated based on a cumulative inhibition of β5 and β5i CT-like sites. Metal content analysis of MM.1S and L363 cells was performed by total reflection X-ray fluorescence spectrometer.

Results

The metal content analysis demonstrated rigorous imbalances for calcium, phosphorus and potassium, moderate to no imbalances for iron and zinc accompanied by 65% MM.1S (54% L363) reduction of CT-like activity under bortezomib. However, under 5AHQ treatment, a decrease in the concentration of phosphorus and potassium was accompanied by minor to no change of iron and zinc levels and an increase of calcium. As metals may positively correlate or be antagonistic to one another, we evaluated the correlations between metals and proteasome activity.

Conclusions

Overall, our analysis suggests that the modulation of metal interactions specific to the proteasome activity is a strategy worth exploring to improve the efficacy of proteasome inhibition therapies.

Legal entity responsible for the study

AG Hematology.

Funding

Wilhelm Sander Foundation.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

35P - A translational drug-screening tool for interrogating the effect of anti-TGF-_ therapy on fibroblast activity and the desmoplastic reaction

Presentation Number
35P
Lecture Time
12:45 - 12:45
Speakers
  • Neel I. Nissen (Herlev, DK)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Numerous clinical trials are currently evaluating anti-transforming growth factor beta (TGF-β) therapy for treating lung cancer patients. However, interrogating stromal reactivity, and enhancing the mechanistic understanding of desmoplasia in relation to TGF-β signaling represents unmet medical needs and may allow for discovery of novel TGF-β associated biomarkers for use in the clinical setting. Cancer associated fibroblasts are major contributors to the desmoplastic reaction (ECM deposition) upon TGF-β stimulation. Applying the “Scar-in-a-jar” (SiaJ) model, we evaluated the impact of TGF-β, and inhibitors, on lung fibroblasts’ expression of different collagens.

Methods

Primary human healthy lung fibroblasts were cultured for up to 15 days in the presence of ficoll and TGF-β, with or without addition of 1nM-10µM ALK-5/type I TGF-β receptor kinase inhibitor (iTGFβ. ELISAs quantified pro-peptides from type I (PINP), type III (PRO-C3) and type VI (PRO-C6) collagen in cell supernatant as surrogate measures of the TGF-β induced ECM deposition. Cytotoxicity (lactate dehydrogenase (LDH) release) and metabolic activity (AlamarBlue) were evaluated.

Results

Stimulating lung fibroblasts with TGF-β induced PINP, PRO-C3 and PRO-C6 increase up to 8-fold compared to TGF-β (p < 0.001). iTGFβ dose-dependently reduced the PINP, PRO-C3 and PRO-C6 increase induced by TGF-β. No cytotoxicity could be detected. The metabolic activity was decreased at 1uM iTGFβ.

Conclusions

The SiaJ model can be used to evaluate the impact of TGF-β, and inhibitors, on lung fibroblasts’ viability and expression of different collagens. The findings suggest that SiaJ together with PINP, PRO-C3 and PRO-C6 can be used as a translational drug screening tool for interrogating the effect of anti-TGF-β therapy on fibroblast activity and the desmoplastic reaction.

Legal entity responsible for the study

Nordic Bioscience A/S.

Funding

Nordic Bioscience A/S.

Disclosure

N.I. Nissen, N. Willumsen, N. Gudmann, S. Rønnow, J. Sand: Employee: Nordic Bioscience A/S. M. Karsdal, D. Leeming: Employee and stocks: Nordic Bioscience A/S.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

36P - Eribulin demonstrate selectively high sensitivity to recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) cells and xenograft tumors

Presentation Number
36P
Lecture Time
12:45 - 12:45
Speakers
  • Hiroko Kitahara (Kanazawa, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Recurrent and/or metastatic head and neck squamous cell carcinoma (R/M HNSCC) is a devastating malignancy with a poor prognosis. Eribulin (a microtubule inhibitor) reportedly renders breast cancer less aggressive, and less likely to metastasise, by triggering the mesenchymal-to-epithelial (MET) transition. Previously we reported that eribulin-induced MET was associated with re-sensitization of resistant HNSCC cell lines to cetuximab. In this study, we evaluated eribulin activity in preclinical R/M HNSCC models.

Methods

In vitro antiproliferative activities (IC50) were determined in three human HNSCC cell lines (OSC-20, OSC-19 and OLC01) treated with eribulin or other microtubule inhibitors (paclitaxel and vinblastine). The effects of eribulin were evaluated in eribulin-sensitive and -resistant HNSCC xenograft tumors.

Results

Eribulin demonstrate selectively high sensitivity to OLC01 cells (R/M HNSCC) in comparison with other cell lines. Eribulin has sub-0.1 nM growth inhibitory activities in vitro against OLC01 cells as well as marked in vivo activities at 0.1–0.5 mg/kg against OLC01 cells xenografts. Inducible TUBB3 correlates with lower sensitivity to eribulin in HNSCC cells and xenograft tumors.

Conclusions

Understanding the mechanisms involved in the overall drug response to eribulin may help in the design of therapeutic strategies that enhance drug activity and improve benefits of eribulin in R/M HNSCC patients.

Legal entity responsible for the study

Graduate School of Medical Science, Kanazawa University.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

37P - Tranilast inhibits TGF-beta-induced EMT and invasion/metastasis via the suppression of Smad4 in lung cancer cell lines.

Presentation Number
37P
Lecture Time
12:45 - 12:45
Speakers
  • Koji Takahashi (Kyoto, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Epithelial-mesenchymal transition (EMT) is a key event in cancer metastasis and promotes cancer cell migration and invasion. Transforming growth factor-beta (TGF-β), a well-known inducer of fibroblast proliferation, plays a crucial role in cancerous EMT via regulating E-cadherin or vimentin expression through TGF-β/Smad signaling. Tranilast is an anti-allergic drug clinically used for the treatment of keloids and hypertrophic scars to inhibit tissue fibrosis. We investigated whether trainlast could inhibit TGF-β-induced EMT in non-small cell lung cancer (NSCLC) cell lines.

Methods

We used A549 and PC14 NSCLC cell lines which are epithelial type cultured under normal conditions, but changes their phenotype into mesenchymal type with TGF-β stimulation. Western blottings were applied to examine epithelial or mesenchymal markers, and signal transductions of TGF-β/Smad pathway in these cell lines exposed to tranilast. To downregulate Smad signaling, siRNA methods were applied. Next, to investigate the capability of in vitro invasion, matrigel invasion assays were performed in which TGF-β was used as a chemoattractant. To develop orthotopic in vivo cancer models, A549 cells mixed with matrigel were injected into left lung of nude mice. Subsequently, mice were treated with or without tranilast for one month, then, the number of micrometastasis in both lungs were counted and compared between the two groups.

Results

In mesenchymal phenotype of A549 and PC14 stimulated with TGF-β, tranilast reinstated EMT via suppressing Smad4. The downregulation of Smad4 by siRNA methods also induced the recovery of EMT in these cell lines, resulting in the inhibition of in vitro invasion. The number of tumor spread through air space (STAS) in lung parenchyma was more suppressed in the tranilast administerd mice group.

Conclusions

Tranilast suppressed TGF-β-induced EMT via the downregulation of Smad4 resulting in the inhibition of in vitro and in vivo invasion/metastasis in lung cancer cell lines.

Legal entity responsible for the study

Kyoto University Graduate School, Thoracic Surgery.

Funding

Has not received any funding.

Editorial Acknowledgement

Kissei Pharmaceutical Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

38P - Integrin beta-like 1 overexpression stimulates invasiveness of ovarian cancer cells in vitro

Presentation Number
38P
Lecture Time
12:45 - 12:45
Speakers
  • Alexander J. Cortez (Gliwice, PL)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

In our previous microarray study we analyzed gene expression profile of over 100 ovarian cancer samples [1]. We identified two molecular subgroups of high grade serous ovarian cancers (HG-SOC) with distinct gene expression profiles and survival [2]. Among differentially expressed genes was an Integrin beta-like1 gene (ITGBL1). ITGBL1 is a poorly characterized protein, structurally cognate with integrin β. Our aim was to study whether and how ITGBL1 can influence the phenotype of ovarian cancer cells.

Methods

ITGBL1 coding sequence was PCR-amplified from cDNA and cloned into pLNCX2 vector. Retroviral system was used to obtain two ovarian cancer cell lines: OAW42/ITGBL1(+) and SKOV3/ITGBL1(+) with overexpression of ITGBL1. Control cell lines were obtained by transduction with empty vector. A Matrigel cell invasion assay was performed using 24-well transwell inserts (coated with fibronectin and matrigel). Crystal violet staining of invaded cells was performed, then the dye was solubilized with 10% acetic acid and the absorbance was measured at a wavelength of 595 nm.

Results

We compared invasion rate of control OAW42 and SKOV3 cells with that of isogenic cell lines containing ITGBL1 construct. The results indicate that ITGBL1 overexpression increases invasiveness of ovarian cancer cells.

Conclusions

Our results indicate that ITGBL1 may increase ovarian cancer cell invasion rate. Along with our previous reported results that overexpression of ITGBL1 may increase migration, decrease adhesion [3] and has no effect on proliferation rate [4], these results suggests that ITGBL1 may play an important role in ovarian cancer progression enabling easier spreading of the cells within peritoneal cavity. [1]K.M.Lisowska, et al. (2014),Front.Oncol. DOI:10.3389/fonc.2014.00006. [2]K.M.Lisowska,et al.(2016),J.Cancer Res.Clin.Oncol.DOI:10.1007/s00432-016-2147-y. [3] A.J.Cortez, et al. (2016), Int. J. Gynecol. Cancer. Vol 26, sup. 3, p. 665 [4] A.J.Cortez, et al. (2017), Int. J. Gynecol. Cancer. Vol 27, sup. 4, p. 1931.

Legal entity responsible for the study

Maria Skłodowska-Curie Institute - Oncology Center, Gliwice Branch.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

39P - MiR-449a suppresses endometrial cancer invasion and metastasis by targeting NDRG1

Presentation Number
39P
Lecture Time
12:45 - 12:45
Speakers
  • Lihua Qiu (Shanghai, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Endometrial cancer (EC) is the most common gynecologic malignancy in western counties. Generally, a five-year survival of patients with localized disease remains at approximately 96% and this rate drops to 67% and 17% for the patients suffering from regional and distant metastasis, respectively. Therefore, an improved understanding of the molecular mechanisms in metastasis of endometrial cancer has the potential to significantly impact the outcomes for this disease. Studies has outlined the essential roles for miR-449a in regulating pathogenesis of cancers. A number of reports have identified the role of microRNAs in EC, but little is known about miR-449a in it.

Methods

FISH was used to detect the expression of miR-449a in the 55 tissues and IHC was performed to measure the NDRG1 expression in the above samples. The alterations of NDRG1 gene were analyzed by cBioPortal for Cancer Genomics online. The human EC cell lines were cultured in DMEM/F12 medium supplemented with 10% fetal bovine serum and Penicillin/Streptomycin in a humid atmosphere incubator with 5% CO2 at 37 °C. The expression of miR-449a and NDRG1 were assayed by quantitative real time-PCR Wound healing assay, migration and invasion assays were performed to detect the ability of migration and invasion in EC cells. NDRG1 and PTEN/AKT pathway were detected by immunoblotting.

Results

In this study, our analysis found that miR-449a expression is inversely correlated with the stage of endometrial cancer. Overexpression of miR-449a in human EC cells alleviated cell invasion and metastasis in vitro. Conversely, miR-449a knock-down promoted migration and invasion of EC cells. Moreover, we identified N-myc Downstream-Regulated Gene 1 (NDRG1) as a direct and functional target gene of miR-449a in EC cells, and the expression NDRG1 in 55 endometrial cancer specimens were inversely correlated with that of miR-449a. In addition to this, further studies show that down-regulation of NDRG1 inhibited migration and invasion of EC cells through PTEN/AKT pathway.

Conclusions

miR-449a suppresses metastasis of EC cells by directly targeting NDRG1 gene and activation of miR-449a may represent an effective therapeutic strategy in endometrial cancer.

Legal entity responsible for the study

Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai JiaoTong University, China.

Funding

National Natural Science Foundation of China (81272884).

Disclosure

The author has declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

40P - Cancer-associated fibroblasts-derived VEGFA mediates the migration of gastric cancer cells through VEGFR1

Presentation Number
40P
Lecture Time
12:45 - 12:45
Speakers
  • Xiaoxun Wang (Shenyang, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Cancer-associated fibroblasts (CAFs) are major components of the tumor stroma and regulators of tumor progression. CAFs are also involved in the intraperitoneal dissemination of gastric cancer cells. However, the molecular mechanism by which CAFs promote gastric cancer peritoneal dissemination should be further explored.

Methods

1. Cell migration ability was measured using Transwell assay. 2. Protein expression was analyzed by western blot. 3. Mouse model detects peritoneal metastasis of gastric cancer cells. 4. Affymetrix scanner 3000 was used to analyse the microarray genome-wide expression. 5. Statistical analysis. All values are expressed as means ± SD. The differences of the results between two groups were evaluated by Student’s t-test. P<0.05 was considered to be statistically significant.

Results

In our study, we found CAFs enhance the migration of gastric cancer cells through the expression of VEGFA. While VEGFA neutralizing antibody bevacizumab markedly attenuated these CAFs-induced phenotypes in gastric cancer cells. Moreover, VEGFA enhances the gastric cancer cells' ability to diffuse and metastasize in the peritoneum. And the Bevacizumab could inhibit peritoneal metastatic nodules. We further found the migration of MGC-803 was increased with VEGFA stimulation, mainly through VEGFR1 but not VEGFR2.

Conclusions

Taken together, these results revealed that the activation of VEGFR1 by CAFs-derived VEGFA enhances the migration of gastric cancer cells. And VEGFA enhances the peritoneal metastasis capacity of gastric cancer cells. Our results suggested that inhibition of VEGFA and its receptor VEGFR1 to control downstream signaling may provide a promising therapeutic target for the treatment of tumors.

Legal entity responsible for the study

Academic Group.

Funding

National Natural Science of Foundation.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

41P - Risk prediction of metastasis through study of circulating tumor cells

Presentation Number
41P
Lecture Time
12:45 - 12:45
Speakers
  • Panagiotis Apostolou (Filotas, GR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The study of circulating tumor cells (CTCs) has rapidly increased in the last decade, as this entity of cells is implicated in cancer prognosis and progression. CTCs constitute a non-homogeneous population of cells, with metastatic ability. The present study tested the gene expression profile of genes involved in metastasis in particular organs, in CTCs from cancer patients representing different cancer types and stages.

Methods

Blood samples were randomly collected from 35 patients, suffering from breast, prostate, ovarian, lung, colorectal, peritoneal, bladder, endometrial and stomach cancer. CTCs were isolated using enrichment protocols and cellular-molecular based assays were used to enumerate and study their expression profiles. qRT-QPCR for genes correlated with risk metastasis in principle (TGFBR2, ITGB5, ITGB6), risk of metastasis to pleura (CCR6), skin (CCR7), lung (IGF2R, ERK1, ERK2), bone (BMPR1A, BMPR1B, BMPR2, CXCR4, BST2), liver (CXCR4, TRAILR2, FAS, MET) and brain metastasis (STAT3, CX3CR1, DSC2) performed by using ACTB as housekeeping gene. All the reactions were performed in triplicates. A normal and a reference cancer RNA was used as control.

Results

Samples mainly from prostate, breast and squamous cancer overexpressed markers involved in general metastasis. These samples were at stage III and IV, and CTCs were 6.7±2.35/ml. For pleura and skin, overexpression was observed in samples with higher CTCs number (8.2±1.3/ml) than in prostate and ovarian cancer, respectively. Markers correlated with liver metastasis were expressed higher in breast and ovarian samples at stage IV. The majority of breast and prostate cancer samples also expressed markers correlated with bone metastasis, while squamous and ovarian cancer samples expressed genes involved in brain metastasis. By contrast, samples with lower CTCs exhibited expression in markers correlated with metastasis to lung (5.8±2.3/ml), involving breast, prostate and ovarian cancer.

Conclusions

Among same cancer type samples, different metastasis profiles were revealed, demonstrating that analysis of CTCs and particularly, their enumeration in comparison with their expression profile might be useful to focus the follow up and screening to specific organs.

Legal entity responsible for the study

Research Genetic Cancer Centre Group Ethic Committee.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

42P - First step to metastasis: miRNAome abnormalities impair cell-cell adhesion and facilitate detachment of breast cancer cells

Presentation Number
42P
Lecture Time
12:45 - 12:45
Speakers
  • Volodymyr Halytskiy (Kiev, UA)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

In order to metastasize, cancer cells must detach from neighboring cells and extracellular matrix. With regard to data that microRNAs (miRNAs) miR-18, miR-19, miR-21, miR-23, miR-29, miR-155, miR-181, miR-206, miR-210, miR-221/222 and miR-375 are usually overexpressed in breast cancer cells, this research aims to identify in what way the abnormality in miRNA signature can contribute to the disintegration of cell-cell contacts.

Methods

MiRNA targets within gene transcripts were predicted in silico using the TargetScan software.

Results

Targets of overexpressed miRNAs miR-18, miR-23, miR-25, miR-150, miR-181, miR-221/222 and miR-372/373 were found in transcript of CDH1 gene encoding E-cadherin. Transcripts of genes F11R and JAM3 encoding junctional adhesion molecules JAM-A and JAM-C carry targets of miRNAs miR-23, miR-29, miR-155, miR-181 and miR-221/222. Binding sites for miRNAs miR-23 and miR-150 were revealed in transcripts of TJP1 and TJP2 genes encoding tight junction proteins ZO-1 and ZO-2. MiRNAs miR-21, miR-29, miR-155 and miR-375 can silence CLDN1 gene encoding claudin 1. Up-regulated miRNAs miR-19, miR-21 and miR-155 can target transcript of CGN gene encoding cingulin. MiRNAs miR-18, miR-29, miR-155, miR-181 and miR-375 suppress OCLN gene coding occludin. Overexpressed miRNAs miR-21, miR-23, miR-29, miR-155, and miR-221/222 can target transcripts of PVRL1 and PVRL3 genes encoding nectin 1 and 3. In addition, up-regulated miRNAs can silence other genes responsible for cell-cell adhesion - CADM1/3 (encoding nectin-like molecules 2/1), CTNNA1 (alpha-catenin), CTNND1 (p120-catenin) as well as genes encoding tropomyosin 1, vinculin, alpha-actinins.

Conclusions

MiRNAs, hyperexpressed in breast cancer cells, can silence genes encoding E-cadherin and numerous other epithelial junction components. This causes disruption of cell-cell adhesion, and, in addition, affects cell polarity and contact inhibition, predetermines epithelial-mesenchymal transition, detachment, movement and invasiveness of the breast cancer cells.

Legal entity responsible for the study

Palladin Institute of Biochemistry of the National Academy of Sciences of Ukraine.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

43P - Extracellular matrix of normal brain tissue is affected by temozolomide during anti-glioblastoma treatment

Presentation Number
43P
Lecture Time
12:45 - 12:45
Speakers
  • Alexandra Tsidulko (Novosibirsk, RU)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Temozolomide (TMZ) is a main drug for chemotherapy of glioblastoma multiforme (GBM). During the treatment, both GBM tumour and surrounding normal brain are exposed to the drug, and its effects on the normal brain tissue are not investigated. Survival and invasion of GBM cells depend not only on their characteristics but also on the structure of extracellular matrix (ECM) of brain tissue, which consists mainly of glycosylated molecules such as proteoglycans (PGs) and glycosaminoglycans (GAGs). Here, we aimed to investigate the effects of TMZ on PGs and GAGs expression in normal brain tissue.

Methods

Two-month-old Wistar rats were used in the study, and effects of TMZ treatment on PGs (syndecan-1, glypican-1, perlecan, decorin, biglycan, lumican, brevican, neurocan, CSPG4/NG2, aggrecan) were studied using real-time RT-PCR and IHC analyses.

Results

Treatment with TMZ had almost no effects on the overall transcriptional activity of the PGs core proteins in normal brain tissue but resulted in a 2-fold increase of GAGs content (both heparin sulfates and chondroitin sulfates). Different TMZ-based drugs demonstrated different effects on the PGs core proteins expression - treatment with some of them resulted in significant decrease in syndecan-1, glypican-1, perlecan and lumican expression. Moreover, treatment with combination of TMZ and dexamethasone, commonly used to treat glioma-induced edema, led to the most dramatic changes in PGs composition in the brain tissue at both core protein and GAG levels.

Conclusions

The obtained results demonstrate that chemotherapy with temozolomide affects proteoglycan composition and ECM structure in normal brain tissue. These changes might be involved in the formation of the tumourigenic niche for the expansion of the residual glioma cells and the disease progression.

Legal entity responsible for the study

Federal Research Center of Fundamental and Translational Medicine.

Funding

Russian Science Foundation (RSF grant 16-15-10243). Tsidulko A. was funded by individual scholarship of Russian Federation President for young scientists (SP-5435.2018.4).

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

44P - Study of the activation of TLR receptors in neurospheres from glioblastoma cells in vitro

Presentation Number
44P
Lecture Time
12:45 - 12:45
Speakers
  • David Albert Bellver (Valencia, ES)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Glioblastoma (GB) is the most aggressive brain tumor known. GB stem cells (GSC) are resistant to ordinary therapy and contribute to the development of recurrences. Toll-like receptors (TLR) are expressed in immunity cells to recognize multiple ligands from multiple infectious agents to unleash the immune response. TLRs are also expressed in neural cells, such as GB and neural stem cells, where its activation may imply cell differentiation. The aim of this study was to prove whether the stimulation of GSC TLRs induces a phenotype more sensitive to therapy and less aggressive.

Methods

Two GB cell lines were used: U-87 and U-118 (ATCC), cultured in the presence of Neurobasal® medium and in the absence of fetal bovine serum. The culture obtained was formed by neurospheres, which include a high proportion of GSC. On the one hand, the enrichment in GSC was confirmed by flow cytometry by the expression of stem cell markers CD133 and CD44. On the other hand, the analysis of TLR expression was performed by RT-PCR. According to its TLR expression, neurosphere cells were exposed to the pertinent TLR ligands for 24 hours in vitro and cultured in the presence or absence of temozolomide (TMZ). After stimulation, the expression of CD133 and CD44 was measured by flow cytometry.

Results

Flow cytometry results showed a higher proportion of GSC in the culture with Neurobasal®. RT-PCR results demonstrated expression in stem cells of the genes corresponding to TLR2, TLR3, TLR4 and TLR6 receptors. Flow cytometry post-stimulation proved a decrease of stem cell markers in the ligands of the TLR2 and TLR4 in both lines. Cultures with TMZ did not show significantly altered expression of GSC, although survival was lower than cultures without TMZ.

Conclusions

These results show a relation between the activation of the TLR and the increase of the differentiation rate in GSCs, especially through TLR2 and TLR4. Based on the results obtained, a new therapy for GB treatment, might be possible, which would include the differentiation of GSC by the exposition to TLR2 and TLR4 ligands, previous or concomitant to chemotherapy.

Legal entity responsible for the study

University of Valencia.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

45P - 5-Fluorouracil induced up-regulation of exosomal PD-L1 causing immunosuppression in gastric cancer patients

Presentation Number
45P
Lecture Time
12:45 - 12:45
Speakers
  • Zhang Min (Shenyang, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Although 5-fluorouracil chemotherapy has been thought to directly kill cancer cells and even play an immunostimulatory role, accumulating evidence indicates 5-fluorouracil also damages function of T cells through up-regulating programmed death-1-ligand 1(PD-L1), which is a negative regulator of T cell immune ability. Previous study has shown that PD-L1 has exosomal forms secreted in the microenvironment, except for membrane bound forms and extracellular soluble forms. In addition, exosomal PD-L1 retains stronger immunosuppressive activity. However, whether 5-fluorouracil can change the expression of exosomal PD-L1 and induce immunosuppression is unknown.

Methods

We retrospectively detected exosomal PD-L1, by ELISA, in 17 stage III/IV gastric cancer patients before and after 2,4,6,8 repeated cycles of 5-fluorouracil chemotherapy treatment.

Results

Compared with the expression at baseline, exosomal PD-L1 was up-regulated gradually in the plasma of patients when 2,4,6,8 repeated cycles of 5-fluorouracil were administered, accompanied with the decreased amounts of CD4+ and CD8+ T cells. Mechanistically, 5-fluorouracil up-regulated PD-L1 and exosomal PD-L1 in gastric cancer cell lines. Moreover, exosomal PD-L1 derived from gastric cancer cells induced apoptosis of T cells after 48h treatment, which could be reversed by nivolumab.

Conclusions

5-Fluorouracil up-regulated exosomal PD-L1 which induced apoptosis of T cells and caused immunosuppression in gastric cancer patients.

Legal entity responsible for the study

Academic Group.

Funding

National Natural Science Foundation of China.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

46P - Thrombocytosis and leukocytosis: are they negative prognostic factors in solid tumours?

Presentation Number
46P
Lecture Time
12:45 - 12:45
Speakers
  • Filip Kohutek (Trencin, SK)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Induction of thrombocytosis and leukocytosis by tumour is a part of complex propagative strategy of malignancy. Activated leukocytes and thrombocytes produce several cytokines and enzymes that are crucial for tumour growth, invasion and dissemination. Therefore, leukocytosis and thrombocytosis might be a negative prognostic factor in malignancies.

Methods

Thrombocyte and leukocyte count were determined before the beginning of treatment. Patients with recent bleeding, elevated CRP or treated with best-supportive care were excluded. Relationship between thrombocytosis, leukocytosis and known negative prognostic factors was assessed. The impact of thrombocytosis and leukocytosis on progression-free survival (PFS) was determined. Chi- squared test, Kaplan- Meier and Cox- regression statistical analysis were used.

Results

500 patients with breast cancer (BC), ovarian cancer (OC), colorectal cancer (CrC), head and neck tumours (H&N) or lung cancer (LC) were included to our retrospective study. Thrombocytosis was more frequent in patients with metastatic cancer (whole population of patients) (17.4%, 95%CI :8.1125-26.7381, p = 0.0001); in patients with CrC (27%, 95% CI: 4.1554-47.9434, p = 0.0111); in patients with OC (27.7%, 95%CI: 6.5334- 46.4296, p = 0.0063) and in patients with H&N (46.9%, 95%CI: -9.5975-72.7755, p = 0.0459). Grading, estrogen- receptor (ER) progesteron- receptor (PR) and her2 status had no impact on frequency of thrombocytosis. Thrombocytosis had no impact on PFS. Leukocytosis was more frequent among patients with metastatic malignancies (10.6 %, 95%CI: 1.4352- 19.9713, p = 0.0174). This result reflected only in the subgroup of patients with H&N (46.9%, 95%CI: -9.5975- 72.7755, p = 0.0459). Grading, PR and her2 status had no impact on frequency of leukocytosis. Leukocytosis was more frequent in BC patients with negative ER status (18.7%, 95%CI: 1.0068- 40.1859, p = 0.0158). Leukocytosis shortened PFS in patients with LC (hazard ratio 2.1126, 95%CI:1.2712- 3.5109, p = 0.0014).

Conclusions

Leukocytosis might be a negative prognostic factor in patients with LC. More studies are needed to identify the subpopulation of leukocytes responsible for this effect.

Legal entity responsible for the study

Faculty Hospital Trencin, Department of Oncology.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

47P - Evaluation of stemness and proliferation of human breast cancer stem cells (ALDH+) supplemented with heat-activated TGF-beta1 in the secretomes of stem cells from human exfoliated deciduous teeth (SHED)

Presentation Number
47P
Lecture Time
12:45 - 12:45
Speakers
  • Septelia I. Wanandi (Jakarta, ID)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Our previous studies have reported that the secretomes of umbilical cord- and adipose-derived mesenchymal stem cells (MSCs) affected the stemness properties of human breast CSCs (BCSCs). However, little is known about specific factors in MSC secretomes, particularly those from human exfoliated deciduous teeth, which involved in tumor aggressiveness such as stemness and proliferation of CSCs. This study aimed to evaluate the stemness and proliferation of human BCSCs after supplemented with heated secretomes of stem cells from human exfoliated deciduous teeth (SHED) to activate latent TGF-β1.

Methods

To collect SHED conditioned medium (SHED-CM) containing secretomes, SHED were grown in serum-free a-MEM for 24 and 48 hours, respectively. SHED-CM 24-h was then heated at 800C for 10 min. Human BCSCs (ALDH+) cultured in DMEM-F12 were supplemented with 50% (v/v) non-heated SHED-CM 24- and 48-h, as well as with heated SHED-CM 24-h followed by 72-h incubation. Control was BCSCs supplemented with non-heated 50% (v/v) a-MEM/DMEM-F12. Following the supplementation, we measured the mRNA expression of TGF-β1 receptor (TβRI), as well as stemness genes ALDH1A1 and OCT4 of BCSCs using qRT-PCR. BCSC proliferation was determined using trypan blue dye.

Results

This study demonstrates that relative mRNA expression levels of TβRI, OCT4 and ALDH1A1 in BCSCs supplemented with non-heated SHED-CM 24- and 48-h were increased compared to their control. Interestingly, the increase of TβRI, OCT4 and ALDH1A1 expressions after TGF-β1 heat activation was significantly higher than in non-heated SHED-CM. Conversely, BCSC proliferation was significantly reduced after supplemented with non-heated SHED-CM 24- and 48-h, but drastically increased higher than control when treated with heated SHED-CM 24-h, suggesting the involvement of other factors in SHED-CM that restrain TGF-β1 signaling and suppress cell proliferation.

Conclusions

Heated SHED secretomes contained activated TGF-β1 that increased the expression of stemness genes, OCT4 and ALDH1A1, as well as proliferation of human BCSCs (ALDH+) via TGF-β1 paracrine signaling.

Legal entity responsible for the study

Septelia Inawati Wanandi.

Funding

Directorate of Research and Community Service, Universitas Indonesia.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

48P - Estrogen-related receptor _ as a potential molecular target for endometrial cancer therapy

Presentation Number
48P
Lecture Time
12:45 - 12:45
Speakers
  • TETSUYA KOKABU (Kyoto, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Estrogen-related receptor α (ERRα) is considered to be a potential molecular target against several cancer types. We previously demonstrated that ERRα knockdown regulated tumor progression in uterine endometrial cancer. The purpose of this study was to elucidate the effects of XCT790, a selective inverse agonist of ERRα, on endometrial cancer.

Methods

HEC-1A and KLE cells, endometrial cancer cells with high expression of ERRα, and HEC-1A-derived xenograft mouse model were treated with XCT790. Cell proliferation was evaluated with WST-8 and colony formation assays. The cell cycle was examined with flow cytometry, fluorescent immunocytochemistry. The apoptotic effect was determined with TUNEL assay and caspase-3/7 assay. Proteins and mRNA levels were detected by western blotting and real-time PCR.

Results

XCT790 significantly inhibited ERRα-induced transcriptional activity in a dose-dependent manner (P < 0.01) without reduction of mRNA level of ERRα. XCT790 suppressed colony formation and cell proliferation in a concentration- and time-dependent manner (P < 0.01), without cytotoxicity. Flow cytometry, fluorescence immunocytochemistry, and western blotting indicated that XCT790 induced apoptosis (P < 0.01), and caused cell cycle arrest at the mitotic phase. Western blotting revealed that XCT790 inhibited Akt/mTOR signaling pathway without the alteration of the expression level of PI3K. Additionally, XCT790 significantly suppressed tumor progression in the xenograft mouse model (P < 0.05). XCT790 induced apoptosis and decreased Ki-67 positive cells in tissue sections (P < 0.01).

Conclusions

The findings of the present study suggested that XCT790 could be a novel therapeutic agent in uterine endometrial cancer.

Legal entity responsible for the study

Tetsuya Kokabu.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

49P - Good tolerability and limited target-specific tissue distribution of an anti-L1CAM antibody administered to cynomolgus monkey indicates favorable safety profile of L1CAM-targeting therapies

Presentation Number
49P
Lecture Time
12:45 - 12:45
Speakers
  • Jacques Gaudreault (Schlieren, CH)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

L1 cell adhesion molecule (L1CAM) is a ∼200 kDa transmembrane protein which is overexpressed in several tumor types. Its expression has been shown to be a predictor of poor outcome in several independent publications. Anti-L1CAM antibody therapy, is expected to lead to tumor regression through inhibition of tumor growth, inhibition of migration/cell adhesion, reversal of chemoresistance and cell killing via ADCC. In addition to tumors, L1CAM is expressed in a restricted set of healthy tissues, including the nervous system and kidney tubules. The current study was conducted to investigate the acute tolerability and tissue distribution of an antibody directed against L1CAM and inform about the potential target organs which might be affected by anti-L1 CAM therapy.

Methods

The acute tolerability and biodistribution of an antibody that binds with high affinity to cynomolgus monkey L1CAM was evaluated. The antibody was administered in two IV bolus injections of 20 mg/kg, 24 hours apart to a single cynomolgus monkey. Clinical signs were recorded and the animal was sacrificed 48 hours after administration of the second dose, followed by macropathological inspection and tissue collection. A second untreated control animal was used as control for subsequent analyses. Tissues from both animals were collected, paraffin-blocked, and the presence of tissue-bound anti-L1CAM antibody was detected by immunohistochemistry.

Results

Administration of the anti-L1CAM antibody was well tolerated with no signs of acute local or systemic intolerance observed. In cynomolgus monkey, specific binding was observed in kidney tubules and Kupffer’s cells of the liver, while no binding was observed in the central nervous system, peripheral nerves, or any other tissues.

Conclusions

Administration of L1CAM antibody was well tolerated and the observed tissue distribution was consistent with the known expression profile of L1CAM. These data support the safety of anti-L1CAM therapy using an antibody approach.

Legal entity responsible for the study

Elthera AG.

Funding

Elthera AG.

Disclosure

J. Gaudreault, A. Schmidt, P. Altevogt, G. Spohn: Stock ownership: Elthera AG.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

Tumour biology and pathology

Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

451P - Pharmacokinetic drug-drug interaction between mitotane and etoposide in the treatment of adrenocortical carcinoma

Presentation Number
451P
Lecture Time
12:45 - 12:45
Speakers
  • Anne Jouinot (Paris, FR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Association between mitotane and platinum-etoposide chemotherapy is the front-line treatment in metastatic adrenocortical carcinoma (ACC), although this regimen shows limited efficacy. Drug-drug interaction between mitotane -which is a strong pharmacokinetic inductor of CYP3A4 and BRCP- and etoposide –which is a substrate of CYP3A4 and BRCP- may contribute to chemoresistance in ACC. The aim of this study was to evaluate the pharmacokinetic interaction between mitotane and etoposide.

Methods

From December 2016 to October 2017, this observational study included 5 consecutive ACC patients treated with platinum-etoposide (120 to 150 mg/m2 J1-J2-J3 at cycle 1) chemotherapy in referral center for rare adrenal diseases and oncology department of Cochin hospital, Paris. Plasma etoposide concentrations were measured using liquid chromatography at 0, 4 and 24h after each etoposide infusion. In the absence of dose-limiting toxicity, a dose escalation of etoposide was proposed from cycle 2.

Results

Patients received a median of 3 [2 to 6] chemotherapy cycles, in association with mitotane (4 patients, median mitotane plasma concentration of 14.2 mg/L) or after mitotane discontinuation (1 patient, plasma concentration 1 mg/L). Etoposide clearance was higher in association with mitotane (4.95 L/h [2.67 to 6.20]) than after discontinuation (2.53 L/h [2.02 to 2.78], Wilcoxon p = 0.014) or in a reference population not treated with mitotane (1.81 L/h)1. Etoposide dose escalation was performed in 4 patients treated with mitotane, resulting in 2 minor tumor response at 300mg/m2 and 1 febrile neutropenia.

Conclusions

Drug-drug interaction between mitotane and etoposide may partly explain the low efficacy of platinum-etoposide chemotherapy in ACC. Given the elimination half-life of mitotane is extremely long (18-159 days), this observation suggests further a potential benefit of increasing etoposide dosage in patients receiving mitotane than stopping mitotane before chemotherapy initiation in ACC patients.

Legal entity responsible for the study

Blanchet Benoit and Jouinot Anne.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

Gastrointestinal tumours, colorectal

Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

463P - Real-world dosing of regorafenib (REG) in metastatic colorectal cancer (mCRC): final results from the prospective, observational CORRELATE study

Presentation Number
463P
Lecture Time
12:45 - 12:45
Speakers
  • Juan Manuel O'Connor (Buenos Aires, AR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

REG 160 mg/day 3 weeks on/1 week off is approved for the treatment of patients with treatment-refractory mCRC. This final analysis of the prospective, observational CORRELATE study describes REG real-world dosing in mCRC.

Methods

CORRELATE (NCT02042144) was conducted in 13 countries across Europe, Latin American, and Asia and enrolled patients with mCRC for whom the decision to treat with REG was made by the treating physician. The primary aim was to assess safety.

Results

Of 1037 patients, 57% started treatment at 160 mg, 30% at 120 mg, and 13% at ≤ 80 mg. The mean and median percent of the approved dose was 75%. At baseline, median age was 65 years, most patients were ECOG performance status (PS) 0–1 (87%), and 56% had KRAS mutations; age and ECOG PS was similar between dose groups (160 vs 120 mg; Table). Dose reductions were more frequent in the 160 versus 120 mg group, while the proportion of patients having an interruption/delay or treatment modification was similar. Treatment modifications were most commonly due to treatment-emergent adverse events (TEAEs) (66%). Overall, most discontinuations (49%) were due to radiologic disease progression, whereas 19% were due to REG-related TEAEs. Overall, TEAEs of any grade occurred in 95% of patients, and were deemed REG related in 80%. Grade ≥3 TEAEs occurred in 62% of patients, and were attributed to REG in 36%. The most common REG-related grade ≥3 TEAEs were fatigue (9%), hand–foot skin reaction (7%), and hypertension (6%). Grade 5 TEAEs occurred in 17% of patients and were considered REG related in 1%. Median overall survival (OS) was 7.6 months (95% CI 7.1–8.2) and the estimated 1-year OS was 34%.

%Starting dose 160 mgStarting dose 120 mgTotal
(N = 591)(N = 315)(N = 1037)
Median age*64 (24–85)65 (33–89)65 (24–93)
Sex, male/female58/4266/3461/39
ECOG PS 0–1/2–489/485/987/6
Metastatic site at study entry, liver/lung73/5769/5772/57
Median treatment duration2.6 (0.03–29.5)2.4 (0.03–20.6)2.5 (0.03–29.5)
Treatment modification656365
Dose reduction473440
Treatment interruption/delay504748
Treatment modification due to AEs765866

years (range);

months (range)

Conclusions

In this real-world, observational study, the starting dose of REG for nearly half of patients was less than 160 mg/day. Common TEAEs were generally consistent with the known safety profile of REG in mCRC.

Clinical trial identification

NCT02042144.

Legal entity responsible for the study

Bayer.

Funding

Bayer.

Editorial Acknowledgement

Editorial assistance in the preparation of this abstract was provided by Katrin Gudmundsdottir of SuccinctChoice Medical Communications (London, UK), with financial support from Bayer.

Disclosure

J.M. O’Connor: Advisory board attendance: Merck Serono, Bayer, Servier; Speaker's bureau: Merck Serono, Bayer, Servier. M. Ducreux: Grants/research support: Roche, Merck Serono; Advisory board attendance: Roche, Merck Serono, Celgene, Bayer, Servier, Amgen, Ipsen; Honoraria: Bayer, Roche, Merck Serono, Servier, Amgen, Novartis, Ipsen and Lilly; Travel, accommodations, expenses: Roche, Ipsen, Merck Serono, Merck Sharp & Dohme, Lilly, Amgen. J-P. Metges: Honoraria from Lilly, Sanofi, Novartis, Merck Serono. J.W. de Groot: Advisory board attendance, Bayer, Bristol-Myers Squibb, Celgene, Merck Sharp & Dohme, Servier, Roche. J-Y. Wang: Grants/research support: Roche; Advisory board attendance: Bayer; Speaker's bureau: Bayer, Merck Serono, Pfizer, Roche. B. García Paredes: Advisory board: Sanofi. E. Dochy: Full-time employment: Bayer. S. Fiala-Buskies: Full-time employee, Stock ownership: Bayer. A. Cervantes: Grants, Research support: Roche, Merck Serono, Servier; Advisory board: Bayer, Roche and Merck Serono; Honoraria: Bayer, Amgen, Roche, Lilly, Merck Serono, Servier, Novartis, Takeda, BeiGene, Astellas Pharma. A. Falcone: Grants, Research support: Amgen, Roche, Merck Serono, Servier, Bayer Merck Sharp & Dohme; Advisory board: Amgen, Roche, Merck Serono, Servier, Bayer Bristol-Myers Squibb; Honoraria: Amgen, Roche, Merck Serono, Servier, Bayer. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

464P - Safety and efficacy of trifluridine/tipiracil (FTD/TPI) in metastatic colorectal cancer (mCRC) patients according to previous treatment with regorafenib in the international phase 3b PRECONNECT study

Presentation Number
464P
Lecture Time
12:45 - 12:45
Speakers
  • Julien Taieb (Paris, FR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The oral chemotherapy trifluridine/tipiracil (FTD/TPI or TAS-102) is approved for treatment of previously treated mCRC patients (pts) beyond the second line, in the same setting as regorafenib. Optimal treatment sequencing between the two at this stage is not established. Here, a descriptive post hoc sub-group analysis assessed safety and efficacy of FTD/TPI in mCRC pts according to previous treatment with regorafenib in a preliminary analysis of the phase 3b PRECONNECT study (NCT03306394).

Methods

PRECONNECT is enrolling pts with histologically confirmed mCRC previously treated with available therapies, with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0/1. Pts receive oral FTD/TPI (35 mg/m2 bid) on days 1–5 and 8–12 of each 28-day cycle. Of the 462 patients who received at least one dose at cutoff (1 Nov 2017), 166 (36%) were pretreated with regorafenib.

Results

Patient subgroups pretreated (n = 166) and non-pretreated (n = 296) with regorafenib were broadly similar, with a slight imbalance for RAS mutant status (61% vs 47%), left-sided tumour (58% vs 65%) and treatment line (12% vs 36% receiving FTD/TPI third line), respectively. There was no difference in rate of emergent or drug-related any grade adverse events (AEs), or drug-related grade ≥3 AEs in pts treated with FTD/TPI between the regorafenib pretreated and regorafenib non-pretreated subgroups (98% vs 96%; 77% vs 79%; and 54% vs 51%, respectively). The most common drug-related grade ≥3 AEs were neutropenia (43% vs 40%) and anemia (8% vs 7%). Median FTD/TPI treatment duration were 2.7 and 3.1 months, with a median PFS of 2.7 (95% CI 2.2-3.3) and 3.3 months (95% CI 2.8-3.7), disease control rate was 38% (95% CI 30–46) and 43% (95% CI 37-49) and median time to ECOG-PS ≥2 was 8.5 and 8.7 months in the regorafenib pretreated and regorafenib non-pretreated, respectively.

Conclusions

FTD/TPI may be used either before or after regorafenib with similar efficacy results making treatment safety profile and patient quality of life major points to determine treatment option in third-line for mCRC patients.

Clinical trial identification

EudraCT: 2016-002311-18.

Legal entity responsible for the study

Laboratoires Servier.

Funding

Laboratoires Servier.

Editorial Acknowledgement

Not applicable

Disclosure

J. Taieb: Honoraria speaker or advisory role: Servier, Roche, Lilly, Celgene, Shire, Amgen, Sanofi, Merck, Lilly, Sirtex. A. Falcone: Compensation for participation Advisory Boards, Research Grants to institution: Amgen, Bayer, Merck, MSD, Roche, Lilly, Servier, Bristol. S. Lonardi: Consulting or advisory role: Amgen, Bayer, Merck, Lilly; Speakers' bureau: Lilly; Roche, BMS; Research funding: Amgen. T.J. Price: Advisory board: Amgen (paid self), Merck, Roche, Takeda (paid self). J-B. Bachet: Honoraria: Amgen, Bayer, Celgene, Merck Serono, Roche, Shire, Servier. L. Wyrwicz: Funding or fees: Halozyme, Eisai, Merck. F. Ciardiello: Advisory board role: Servier, Merck, Roche, Amgen, Bayer, Symphogen. M. Becquart, N. Mounedji: Employee: Servier. E. Van Cutsem: Grants: Amgen, Bayer, BMS, Boehringer, Celgene, Ipsen, Lilly, Merck, MSD, Novartis, Roche, Servier; Honoraria: Bayer, BMS, Celgene, Lilly, Novartis, Servier.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

465P - Treatment pattern and outcomes of trifluridine/tipiracil therapy for metastatic colorectal cancer in the real-world data from the JFMC50 study

Presentation Number
465P
Lecture Time
12:45 - 12:45
Speakers
  • Takeshi Kawakami (Shizuoka, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Randomized phase 3 trials, RECOURSE and TERRA, established trifluridine/tipiracil (FTD/TPI) as a salvage-line therapy for patients with metastatic colorectal cancer (mCRC). This retrospective, large cohort study, JFMC50, aims to assess the treatment pattern and outcomes of FTD/TPI for mCRC in routine clinical practice.

Methods

We collected data of patients with mCRC who received FTD/TPI during July 2014-September 2016 in Japanese institutions. However, we examined patients who fulfilled the eligibility criteria, through their backgrounds, treatment course, clinical outcomes, including the OS, time to treatment failure (TTF), disease control rate (DCR), and safety. The main eligibility criteria were the ECOG performance status (PS) 0-2 and the starting dose of FTD/TPI close to the standard dose.

Results

From 127 Japanese institutions, we collected data of 2030 patients and assessed 1770 patients. Patients’ backgrounds were the median age [67 (23-92) years], males (60.1%), ECOG PS 0/1/2 (33.7%/56.7%/9.5%), right-sided tumor (25.4%), and prior regorafenib treatment (23.3%). The median OS and TTF were 8.1 and 2.7 months, respectively; the DCR was 21.0%. Major grade 3 or 4 adverse events were leukopenia, neutropenia, and anemia (25.9%, 39.3%, and 17.7%, respectively). At the data cutoff date, 1756 patients discontinued FTD/TPI therapy. The median OS because of treatment termination due to disease progression was 11.6 months in the progression after progressive disease (PD) by RECIST (n = 122), 9.2 months in PD by RECIST (n = 930), 7.8 months in the elevation of tumor marker (n = 109), and 4.9 months in clinical PD (n = 206).

Conclusions

Both efficacy and safety of FTD/TPI in the clinical practice were compatible with clinical trials. The continuous use of FTD/TPI after PD by RECIST could contribute to longer survival; however, further investigation is warranted.

Clinical trial identification

UMIN000027585.

Legal entity responsible for the study

Japanese Foundation for Multidisciplinary Treatment of Cancer.

Funding

Taiho Pharmaceutical Co., Ltd.

Editorial Acknowledgement

The authors would like to thank Enago for the English language review.

Disclosure

T. Kawakami: Honoraria: Takeda, Chugai Pharma, Merck Serono, Lilly Japan, Taiho Pharmaceutical. K. Yamazaki: Speaker's bureau: Chugai, Takeda, Taiho, Yakult, Merck Serono, Lili, Sanofi, Bayer. E. Oki: Speakers' bureau: Taiho Pharmaceutical, Chugai. M. Shimokawa: Statistical consulting fee: Sysmex. T. Esaki: Speakers' bureau from Taiho, Bristol, Eli Lilly, Eisai, Daiichi-Sankyo, Merck Serono, Chugai, Ono, Takeda; Research funding: Daiichi-Sankyo, Merck Serono, Taiho, MSD, Novartis, Dainippon Sumitomo, Ono; Honoraria: Eli Lilly, Kyowa Kirin. Y. Tsuji: Honoraria: Merck Serono, Eli Lilly Japan, Chugai, Taiho, Ono, Daiichi Sankyo, Yakult Honsha, Eisai and Medicon outside the submitted work. Y. Shimada, Y. Komatsu: Research funding, Honoraria: Taiho Pharmaceutical. M. Ohue: Speakers' bureau: Taiho Pharmaceutical; Research funding: Taiho Pharmaceutical, Chugai. Y. Maehara: Speakers' bureau, Research funding: Taiho Pharmaceutical. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

466P - Phase II trial to evaluate efficacy and tolerance of regorafenib monotherapy in patients (pts) over 70 with previously treated metastatic colorectal adenocarcinoma (mCRC) FFCD 1404 - REGOLD

Presentation Number
466P
Lecture Time
12:45 - 12:45
Speakers
  • Thomas Aparicio (Bobigny, FR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Regorafenib (REG) significantly increases overall survival (OS) in previously treated mCRC pts. However, no prospective trial specific to elderly population including geriatric parameter evaluation has evaluated the safety and efficacy of REG in its registered indication.

Methods

Multicenter one-arm phase II that enrolled pts ≥70 years, ECOG performance status ≤1, with mCRC after failure of fluoropyrimidine-based chemotherapy, anti-VEGF and anti-EGFR treatment. Primary endpoint was tumor control rate 2 months after initiation of REG administered at 160mg/day (3weeks on/1 week off).

Results

43 pts were enrolled from January 2016 to April 2017, median age 77 (range 70 – 91), ECOG 0: 37.2%, ECOG 1: 60.5%, altered activities of daily living (ADL) in 37.5%. Median time from diagnosis of metastases to enrolment: 27.7 months, median number of previous lines: 3. At the time of analysis, the median follow-up was 13.3 months and 62.8% pts had died. One patient never started treatment. The median duration of REG treatment was 45.0 days [5 to 440]. 8 patients were not evaluable for the primary endpoint. Tumor control rate at 2 months in the 35 evaluable pts was 31.4% [18.7% – 46.6%]. Among the 11 pts with tumor control, 9 (81.8%) were < 80 yrs. In the 42 treated pts, median progression free survival (PFS) and OS were 2.2 [1.9-3.3] and 7.5 [5.5-14.6] months, respectively. Modification of the initial dose was performed in 54.3% of the 116 cycles delivered. A grade 3-4 adverse event was observed in 37 (88.1%) pts notably: asthenia (45.2%), hand foot syndrome (21.4%), arterial hypertension (21.4%), and diarrhea (7.1%). Treatment was stopped for toxicity without progression in 12 (28.6%) pts. Among them, 10 (83.3%) pts were ECOG 1, 6 (50%) were over 80 years and 6 (50%) had abnormal baseline ADL. No toxic death was observed.

Conclusions

Treatment with REG in heavily pretreated elderly pts gives a tumor control at 2 months in around 30% of pts. The median PFS and OS are comparable to those observed in the pivotal study. With caution due to small number, drop-out rate for treatment toxicity seems higher in pts with ECOG 1, age over 80 yrs and abnormal ADL.

Clinical trial identification

EudraCT: 2015-002086-29.

Legal entity responsible for the study

Fédération Francophone de Cancérologie Digestive.

Funding

Bayer.

Disclosure

T. Aparicio: Consulting or advisory role: Pierre Fabre, Ipsen, Halio DX, Bristol-Myers Squibb; Travel, accommodations, expenses: Ipsen, Novartis, Ipsen, Roche, Hospira; Honoraria: Pfizer, Roche, Sanofi, Léo Pharma, Amgen, Bristol-Myers Squibb, Servier; Research funding: Bayer. A. Darut Jouve: Travel, accommodations, expenses: Novartis, Bayer. F. Khemissa: Travel, accommodations, expenses: Ipsen, Roche, Sanofi, Bayer; Honoraria: Sanofi, Roche, Bayer; Speakers' bureau: Sanofi, Roche. P. Artru: Consulting or advisory role: Roche, Merck; Travel, accommodations, expenses: Roche, Merck, Bayer; Honoraria: Roche, Amgen, Bayer, Servier, Lilly, Merck; Speakers' bureau: Roche, Merck, Servier. L. Cany: Travel, accommodations, expenses: Novartis. O. Romano: Consulting or advisory role: Roche, Sanofi, Pierre Fabre; Travel, accommodations, expenses: Novartis; Honoraria: Roche, Sanofi, Pierre Fabre; Research funding: Sanofi. C. Falandry: Consulting or advisory role: Pfizer, AstraZeneca, Novartis, Teva, Pierre Fabre, Roche; travel, accommodations, expenses: AstraZeneca, Roche, Pfizer; Honoraria: Pfizer, AstraZeneca, Novartis. M. Duluc: ravel, accommodations, expenses: Ipsen. J.L. Legoux: Consulting or advisory role: Lilly, Novartis; Travel, accommodations, expenses: Merck Serono, Lilly, Ipsen, Novartis; Honoraria: Novartis Research funding: Sanofi/Regeneron. M. Ben Abdelghani: Consulting or advisory role: Amgen, Sanofi, Merck Serono, Bayer, Ipsen, Novartis/Pfizer Travel, accommodations, expenses: Roche, Amgen, Novartis/Pfizer, Ipsen, Bayer, Sandoz, Sanofi. E. Assenat: Consulting or advisory role: Ipsen, Sanofi; Travel, accommodations, expenses: Bayer, Ipsen; Honoraria: Bayer, Sirtex Medical. M. Dhooge: Travel, accommodations, expenses: Norgine SAS. C. Lepage: Consulting or advisory role: Advanced Accelerator Applications; Travel, accommodations, expenses: Amgen, Novartis, Ipsen, Bayer; Honoraria: Novartis. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

467P - Prospective Evaluation of Regorafenib Dose Escalation Strategy with Low Starting Dose in Patients with Colorectal Cancer

Presentation Number
467P
Lecture Time
12:45 - 12:45
Speakers
  • Toshiki Masuishi (Nagoya, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Regorafenib is the first small-molecule multikinase inhibitor with survival benefit as a salvage line therapy for metastatic colorectal cancer (mCRC). However, severe toxicities often occur early and require dose reduction and/or interruption. To improve dose intensity and treatment outcome, we investigated regorafenib dose escalation strategy with low starting dose. The association between systemic exposure and tolerability was also analyzed.

Methods

In this phase II, single arm, multicenter study, we enrolled patients with refractory mCRC. Regorafenib was initiated at 120 mg/day. In patients who experienced neither hand-foot skin reaction nor grade ≥2 adverse reactions without dose reduction or interruption until day 15 in the first cycle, the dose of regorafenib was escalated to standard dose of 160 mg/day at day 15. The primary endpoint was disease control rate (DCR). With power of 80% and two-sided alpha of 5%, 67 patients were required to reject 30% of DCR expecting 45% of DCR. Serum concentrations of regorafenib and its active metabolites (M-2, N-oxide metabolite; M-5, N-oxide/N-desmethyl metabolite) at days 8, 15 and 22 in the first cycle were assessed.

Results

From September 2016 to December 2017, 68 patients were enrolled. The DCR was 32.4% (95% CI, 21.5-44.8) with no patients achieving complete or partial response. The dose of regorafenib was escalated to 160 mg at day 15 in only six patients of 39 patients without dose reduction or interruption until day 15. In 55 patients without dose reduction or interruption due to adverse reactions until day8, the serum concentrations of regorafenib at day 8 in the six patients whose dose was escalated to 160 mg were significantly lower than those in the other 49 patients (median, 3978 nM; range, 2487-13614 nM vs. 6951 nM; 2822-17621 nM; P = 0.028). The serum concentrations of sum of regorafenib and active metabolites (M-2 and M-5) at day 8 showed similar tendency (6582 nM; 2913-21388 nM vs. 11730 nM; 4596-33211 nM; P = 0.064).

Conclusions

This dose escalation strategy with low starting dose for regorafenib did not improve DCR. Lower systemic exposure was associated with better tolerability.

Legal entity responsible for the study

Hiromasa Takaishi.

Funding

Keio University.

Disclosure

T. Masuishi: Honoraria: Bayer. H. Satake: Honoraria: Bayer, Chugai Pharma, Eli Lilly Japan, Merck Serono, Takeda, Taiho Pharmaceutical, Yakult Honsha. N. Boku: Investigator initiated trial funded by Bayer. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

468P - Regorafenib for metastatic colorectal carcinoma: a registry-based analysis

Presentation Number
468P
Lecture Time
12:45 - 12:45
Speakers
  • Katerina Kopeckova (Prague, CZ)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Regorafenib is a multikinase inhibitor approved for the therapy of patients with metastatic colorectal carcinoma (mCRC) previously treated with a fluoropyrimidine, oxaliplatin, irinotecan, anti-VEGF therapy, and (in wild-type RAS tumours) anti-EGFR therapy. The aim of the present study was to analyse the outcomes of treatment with regorafenib in real-world clinical practice based on data from a national registry.

Methods

The CORECT registry (http://corect.registry.cz) is a non-interventional database of patients with colorectal cancer treated with targeted agents. The analysis included 451 evaluable patients treated with regorafenib for mCRC.

Results

The median age at diagnosis was 61.1 years. The primary tumor was in the left colon or rectum in 343 patients (76.1%), right colon in 81 patients (18.0%), data on location were not available for 27 patients (6.0%). KRAS mutation was detected in 202 patients (44.8%) and NRAS mutation in 40 patients (8.9%). The median duration of treatment was 2.7 months (range 0.0-23.4 months). Partial response was seen in 12 patients (3.2%). Progression of the disease was reported in 170 patients (44.7%) and disease stabilisation for at least 6 weeks in 110 patients (28.9%). Progression-free and overall survival data are shown in the table. Improved outcomes were observed in patients with longer interval from diagnosis of mCRC and in those without liver metastases. Age, tumor sidedness, and RAS status were not associated with outcome of regorafenib therapy. The main cause of treatment discontinuation was disease progression (71.3%) followed by general deterioration in the absence of radiological progression in 93 patients (24.5%), and adverse events related to regorafenib in (4.2%).

Progression-free survival and overall survival of patients treated with regorafenib

Median (95% CI)3-month survival (95% CI)6-month survival (95% CI)
Progression-free survival3.5 months (3.2–3.7)57.6% (52.5–62.4)25.2% (20.9–29.9)
Overall survival9.3 months (7.9–10.7)88.8% (85.2–91.5)68.7% (63.6–73.3)

Conclusions

Overall survival of patients treated with regorafenib in real-world clinical practice exceeded that achieved in randomised trials.

Legal entity responsible for the study

Katerina Kopeckova and Tomas Buchler.

Funding

The Institute of Biostatistics and Analysis, Faculty of Medicine, Masaryk University, Brno received financial support for the CORECT registry from Bayer, Amgen, Merck and Roche. Supported by Grant AZV 15-26535A from the Czech Health Research Council.

Disclosure

K. Kopeckova: Research support: Bayer. B. Melichar: Consulting fees: Roche, Novartis, Astellas, Bristol-Myers Squibb, MSD, Merck, Pfizer, Janssen; Travel: Roche, Novartis, Astellas, Bristol-Myers Squibb; Provision of writing assistance: Roche, Bristol-Myers Squibb Payment for lectures: Roche, Novartis, Astellas, Bristol-Myers Squibb, MSD, Merck, Pfizer, Janssen. J. Finek: Lecture honoraria, travel grants: Roche, Merck, Pfizer, Novartis, Amgen. O. Fiala, T. Buchler: Research funding, travel grants, honoraria: Roche, Merck, Bayer, Servier, BMS, MSD, Sanofi, Amgen. J. Tomasek: Grants, consulting fees, travel: Bayer. I. Kiss: Speakers’ honoraria: Roche, Merck, Amgen. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

469P - The Combination of TAS-102 and Bevacizumab as the third line chemotherapy for metastatic colorectal cancer (TAS-CC3 Study)

Presentation Number
469P
Lecture Time
12:45 - 12:45
Speakers
  • Hirohiko Kamiyama (Tokyo, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

TAS-102 improved overall survival of refractory colorectal cancer patients with median progression free survival (PFS) of 2.0 months (RECOURSE trial). Subsequently, the combination of TAS-102 and Bevacizumab has been shown to extend median PFS with 3.7 months (C-TASK FORCE). However, this study included patients with 2nd line and 3rd line chemotherapy. Our study was planned exclusively for patients receiving this combination as the 3rd line chemotherapy to investigate clinical impact of this combination beyond cytotoxic doublet.

Methods

This phase II study was conducted in investigator-initiated, open-label, single-arm, multicentered manner in Japan. Eligible patients were 20-80 years old, and had to have an Eastern Cooperative Oncology Group performance status of 0 or 1; had confirmed unresectable metastatic colorectal cancer (mCRC) with histologically diagnosed adenocarcinoma; were refractory or intolerant to fluoropyrimidine, irinotecan, and oxaliplatin in the 1st and the 2nd line chemotherapy; and had no previous treatment with regorafenib. TAS-102 (35 mg/ m²) was given orally twice daily on days 1–5 and 8–12 in a 4-weeks cycle, and bevacizumab (5 mg/ kg) was administered by intravenous infusion for 30 minutes in every 2 weeks. The primary endpoint was progression free survival (PFS), and the secondary endpoints were time to treatment failure (TTF), response rate (RR), overall survival (OS), and safety.

Results

Between June 1, 2016, and August 31, 2017, 32 patients with mCRC were enrolled in this study. The median PFS was 4.5 months. Partial response was observed in 2 patients. The most common adverse events above grade 3 were neutropenia (15 patients) followed by thrombocytopenia (4 patients). Treatment-related serious adverse events were reported in one patient. There were no non-hematologic adverse events above grade 3. No treatment-related deaths occurred.

Conclusions

This is the first study which involves the combination of TAS-102 and Bevacizumab as the 3rd line chemotherapy in the setting beyond cytotoxic doublet, and showed to improve PFS for the patients with mCRC. This combination has a potential to be one of therapeutic options of the 3rd line chemotherapy for mCRC.

Clinical trial identification

University Hospital Medical Information Network UMIN#000022438.

Legal entity responsible for the study

TAS-CC3 Study Group.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

470P - Safety run-in evaluation of the phase I trial of trifluridine/tipiracil (FTD/TPI) in combination with oxaliplatin and a monoclonal antibody (bevacizumab or nivolumab) in patients (pts) with metastatic colorectal cancer (mCRC)

Presentation Number
470P
Lecture Time
12:45 - 12:45
Speakers
  • Aitana Calvo Ferrandiz (Madrid, ES)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The addition of the monoclonal antibody bevacizumab to chemotherapy has shown survival benefits in pts with mCRC. Another potential strategy is to combine chemotherapy with immunotherapies to enhance antitumor effect of the immune system. In vivo studies have shown an increase in anti-tumor activity when combining FTD/TPI with oxaliplatin or bevacizumab; and an increase in tumor immunogenicity after treatment with FTD/TPI and oxaliplatin, leading to a better tumor response to anti-PD-1 exposure.

Methods

Further to the dose-escalation part (24 pts), the recommended dose (RD) was defined as FTD/TPI 35 mg/m² bid, days 1–5 q14, together with oxaliplatin 85 mg/m² (day 1). Safety data were collected during expansion part from 12 evaluable pts treated with the doublet at the RD with either nivolumab 3 mg/kg (n = 6) or bevacizumab 5 mg/kg (n = 6) administered at day 1. Pts were monitored for safety for the first 2 months of treatment before allowing further enrollment. Eligibility criteria included measurable disease, performance status (PS) 0-1, normal organ function, and progression after >1 prior anti-tumor therapy (excluding oxaliplatin).

Results

Baseline characteristics were median age of 67 years (range 52 to 75 years); PS 0/1 (3/9 pts), male/female (8/4 pts); and colon/rectum (5/7 pts). Drugrelated adverse events (AEs) reported in ≥ 2 pts were neutropenia, diarrhoea, asthenia, and nausea; mainly (93%) grade 1-2. The most common grade 3 or 4 drugrelated event was neutropenia. Grade 1 neurotoxicity attributed to oxaliplatin was observed in 2 pts. No immune-related AE due to nivolumab were reported. Best overall response included 2 partial responses after 2 months of treatment (1 pt in bevacizumab cohort, 1 MSI-H pt in nivolumab cohort). Pharmacokinetics parameters for FTD/TPI were aligned with historical data.

Conclusions

The safety data showed that the two triplets were well tolerated. Expansion enrollment is continuing in both cohorts to confirm preliminary evidence of activity in a larger number of patients.

Clinical trial identification

NCT02848443.

Legal entity responsible for the study

Institut de Recherches Internationales Servier (I.R.I.S.).

Funding

Institut de Recherches Internationales Servier (I.R.I.S.).

Disclosure

A. Hollebecque: Lilly, Amgen; Travel expenses: Servier, Amgen. G. Prager: Advisory boards, Speakers fee: Servier, Roche, BMS, Taiho. T. Andre: Consulting, advisory fees, travel expenses: Roche/Genentech, Amgen, Bristol-Myers Squibb, Honoraria: Roche/Genentech, Sanofi, Baxter, Bayer, Bristol-Myers Squibb, Amgen, MSD Oncology, Servier, XBiotech, Novartis. R. Bordonaro: Honoraria, consulting or advisory role: Proacta, Sanofi; Speakers' bureau: Novartis, Roche, Sanofi; Travel, accommodations, expenses: Novartis, Roche, Bayer, Astellas. A. Stein: Consulting or advisory role: Amgen, Bristol-Myers Squibb, Merck KGaA, Roche; Speakers' bureau: Amgen, Bayer, Celgene, Lilly, Merck KGaA, Roche, Sanofi; Servier research funding: Merck KGaA (Inst), Roche (Inst), Sanofi (Inst); Travel, accommodations, expenses: Roche. G. Tortora: Consulting or advisory role: Celgene; Merck Serono; Travel, accommodations, expenses: Merck Serono; Roche. C. Leger, N. Amellal: Employee: Servier. J. Tabernero: Advisory boards: Bayer, Boehringer Ingelheim, Genentech/Roche, Lilly, MSD, Merck Serono, Merrimack, Novartis, Peptomyc, Roche, Sanofi, Symphogen, Taiho. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

471P - A phase I study to determine the maximum tolerated dose of trifluridine/tipiracil and oxaliplatin in patients with refractory metastatic colorectal cancer: LUPIN study

Presentation Number
471P
Lecture Time
12:45 - 12:45
Speakers
  • Mitsukuni Suenaga (Tokyo, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The effectiveness of reintroduction of oxaliplatin for metastatic colorectal cancer (mCRC) refractory to both oxaliplatin and irinotecan was previously reported in a single arm, open-label phase II study (RE-OPEN, Suenaga, 2015). We conducted a phase I study to determine the maximum tolerated dose (MTD) and the safety of oxalipatin plus trifluridine/tipiracil (FTD/TPI, also known as TAS-102) in patients with refractory mCRC (UMIN000015764).

Methods

Three dosages of intravenous oxaliplatin (50, 65 and 85 mg/m2) on days 1 and 15 and a fixed dose of FTD/TPI 35 mg/m2 bid on days 1–5, 15–19 every 4 weeks were investigated in patients with refractory mCRC by using a 3 + 3 design. Eligible patients had received prior oxaliplatin-based treatment that achieved a response or stable disease followed by confirmed disease progression at least 6 months before entering the study.

Results

12 patients were enrolled in the study. Characteristics of patients were as follows: median age, 62 (range, 47–68) years; male/female, 6/6; ECOG PS 0, 75%; number of prior regimens ≥3, 33.3%; and median oxaliplatin-free interval, 24.3 (range, 6.2–71.4) months. 3 of 6 patients of the oxaliplatin 85mg/m2 cohort had dose-limiting toxicities (DLTs): treatment delay on 2nd cycle ≥8 days due to grade ≥2 neutropenia or grade 2 AST/ALT increased. No DLTs were observed in the other cohorts. The median number of treatment cycles was 3 (range, 1–9): 9 patients continued the treatment until disease progression; and 3 patients discontinued due to toxicity or patient’s refusal. In safety, grade ≥3 adverse events were neutropenia (n = 3), thrombocytopenia (n = 1), anorexia (n = 1) and nausea (n = 1). There was no evidence of allergic reaction to oxaliplatin and severe peripheral sensory neuropathy.

Conclusions

According to the results of this phase I study, a combination of trifluridine/tipiracil 35 mg/m2 bid on days 1–5, 15–19 and oxaliplatin 85 mg/m2 on days 1 and 15 every 4 weeks could be a candidate for recommended dose of the trifluridine/tipiracil+oxaliplatin regimen in patients with refractory mCRC.

Clinical trial identification

UMIN000015764 (release date, 1/12/2014).

Legal entity responsible for the study

Cancer Institute Hospital of the Japanese Foundation for Cancer Research.

Funding

Japanese Foundation for Cancer Research.

Editorial Acknowledgement

Not applicable

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

472P - Sidedness of the Primary Tumor on the Effect of TAS-102 for Refractory metastatic colorectal cancer

Presentation Number
472P
Lecture Time
12:45 - 12:45
Speakers
  • Shinya Ueda (Nara, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

TAS-102 study was shown to have clinical activity in a large population of Japanese and Western patientswith heavily pretreated metastatic colorectal cancer, including those whose disease was refractory to fluorouracil.But we know few date of TAS-102 in daily medical practice. So we assessed efficacy and safety of TAS-102 for refractory metastatic colorectal cancer.

Methods

We retrospectively reviewed the data of 86 patientswho received TAS-102 treatment in our institution between June2014 and October2017.TAS-102 (with each dose consisting of 35 mg per square meter) was administered twice daily, 5 days on and 2 days off for 2 weeks, followed by 2 weeksrest period. The regimen was repeated every 4 weeks.

Results

The median age was 69 years (range, 27–87). Performance status of 1 and 2 were 39 and 47 patients. RAS wild and mutant were 39 and 47 patients. Primary tumor site of right and left were 25 and 61 patients. All patients had received prior chemotherapy regimens containing a fluoropyrimidine, oxaliplatin, and irinotecan. 41 patients received 4 or more prior chemotherapy. Response rate and disease control rate of all were 1% and 24%. Right and left-sided of response rate were 4% and 0%. Right and left-sided of disease control rate were 32% and 19%. Median PFS was 62 days, right and left-sided were 55 and 64 days. Median OS was 216 days, right and left-sided were 262 and 200 days. OS was longer than previously reported. 40 patientsreceived subsequent chemotherapy. Adverse events were mild with 18% of Grade 4 neutropenia and 4% of Grade 3 febrile neutropenia.

Conclusions

TAS-102 was active and tolerable for heavily treated refractory metastatic colorectal cancer. There were no significant difference of PFS and OS in primary tumor site.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Editorial Acknowledgement

This publication is not Acknowledgement.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

473P - Influence of the proton pump inhibitor esomeprazole on the bioavailability of regorafenib

Presentation Number
473P
Lecture Time
12:45 - 12:45
Speakers
  • Femke M. De Man (Rotterdam, NL)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The multikinase inhibitor regorafenib (REG) is currently registered for the treatment of colorectal cancer (CRC), gastrointestinal stromal tumors (GIST), and hepatocellular carcinoma. REG exhibits a pH-dependent solubility, and therefore acid reducing drugs such as proton pump inhibitors (PPIs, e.g. esomeprazole) might reduce REG absorption by increasing the stomach pH as was shown for many other kinase inhibitors (van Leeuwen, Lancet Oncol, 2014). We performed a randomized, 3-phase, cross-over trial to compare the exposure of REG alone to REG with esomeprazole (concomitantly or 3 hours prior to REG intake) in CRC and GIST patients.

Methods

Patients were randomized into 2 sequence groups consisting of 3 phases: REG intake alone, REG with concomitant esomeprazole (for 5 days), and REG 3 hours preceded by esomeprazole (for 5 days). Pharmacokinetic (PK) blood sampling was performed at the 21th, 49th and 77th day of the trial. All patients were treated with REG 120 mg at steady-state. Primary endpoint was the relative difference (RD) in geometric means for REG AUC0-24h. A linear mixed model was used to analyze log-transformed area under the curve (AUC). For multiple testing a Bonferroni correction was applied.

Results

A total of 14 patients were evaluable for the primary endpoint. Exposure (AUC0-24h) to REG alone was: 55.9 µg*h/mL (CV: 40.3%). For REG with concomitant esomeprazole or with esomeprazole 3 hours prior AUC0-24h was: 53.7 µg*h/mL (CV: 33.5%) and 53.6 µg*h/mL (CV: 42.6%) respectively. No significant differences were identified when REG alone was compared to REG with concomitant esomeprazole (RD: -3.9%, 95% CI: -20.5-16.1%, p = 1.0) or REG with esomeprazole 3 hours prior (RD: -4.1%, 95% CI: -22.8-19.2%, p = 1.0). Furthermore, no significant differences were observed in other PK parameters of REG and its active metabolites M-2 and M-5 (i.e. Cmax, Tmax). Most common adverse events ≥ grade 2 were hypertension (71%), fatigue (43%) and hand foot skin reaction (36%).

Conclusions

The use of esomeprazole concomitantly or 3 hours prior to REG intake did not alter REG pharmacokinetics. Our results indicate that PPIs like esomeprazole can be combined with REG without the appearance of a significant drug interaction.

Clinical trial identification

NCT02800330, 01-05-2016.

Legal entity responsible for the study

Erasmus University Medical Center.

Funding

Bayer.

Disclosure

R.H.J. Mathijssen: Research support: Astellas, Bayer, Boehringer Ingelheim, Cristal Therapeutics, Novartis, Pamgene, Pfizer, Roche Sanofi; Consultation fees: Novartis, Servier, Travel support: Astellas, Pfizer. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

474P - A novel biomarker combination and its association with resistance to chemotherapy combinations with bevacizumab: First results of the PERMAD trial.

Presentation Number
474P
Lecture Time
12:45 - 12:45
Speakers
  • Thomas Seufferlein (Ulm, DE)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Antiangiogenic agents are frequently used in the systemic treatment of metastatic colorectal cancer (mCRC). Since these strategies target not the tumor but the tumor associated endothelium establishing positive or negative predictive biomarkers is challenging. Recent research indicated a potentially predictive value of cytokines and angiogenic factors (CAF) for early detection of progression during treatment with chemotherapy and bevacizumab. The PERMAD trial is a two-phase trial with the primary objective to evaluate of the impact of a personalized, marker-driven treatment approach with early detection of progression and modification of treatment. The aim of the first phase is to establish a combination of CAFs that allows early detection/prediction of disease progression (PD) under a treatment with FOLFOX plus bevacizumab (Bev). The second phase is a randomized part with marker-driven switch of anti-angiogenic agent and maintenance of the chemotherapy backbone until definite radiological PD compared to a conventional treatment approach of changing chemotherapy and antiangiogenic agent at time of radiologic PD. Here we report the results from the first phase examining samples of 50 patients.

Methods

During the run-in phase 102 CAFs were established in blood samples taken prior to treatment and q2w thereafter until PD. Using machine learning we aimed at establishing a combination of 5 out of the 102 CAFs that fulfilled these criteria: cytokines should be affected by PD, but not by treatment itself and should indicate PD at least 2 months prior to the time of PD as determined by MD-CT which was performed every 2 months.

Results

Using our machine learning approach we could establish a combination of markers from 30 patients that is associated with > 80% accuracy with PD 2 months prior to radiological PD under a treatment with FOLFOX plus Bev. This combination will be corroborated in another 20 patients (data presented at the meeting) and used for the second, randomized part of the trial.

Conclusions

Using advanced bioinformatics we have identified a biomarker combination that is associated with subsequent PD with a high accuracy under a treatment with FOLFOX plus Bev.

Clinical trial identification

NCT02331927.

Legal entity responsible for the study

Ulm University Hospital.

Funding

Sanofi-Aventis.

Disclosure

T. Seufferlein: Research funding: Celgene, Sanofi; Consulting or advisory role: Celgene, Lilly Pharma, Boehringer Ingelheim, Merck Serono, Amgen. A. Stein: Consulting or advisory role: Merck KGaA, Bristol-Myers Squibb, Amgen, Roche, MSD; Speakers' bureau: Roche, Sanofi, Bayer, Lilly, Celgene, Amgen, Merck KGaA, Servier, Bristol-Myers Squibb; Travel, accommodations, expenses: Roche, Bristol-Myers Squibb; Research funding: Roche, Sanofi, Merck KGaA, Bristol-Myers Squibb. A.W. Berger: Consulting or advisory role: Sanofi; Travel, accommodations, expenses: Taiho Pharmaceutical. D. Arnold: Consulting or advisory role: Roche, Bayer, Merck Serono, Servier, Biocompatibles, Terumo, Helsinn Therapeutics; Travel, accommodations, expenses: Roche/Genentech, Bayer, Merck Serono; Honoraria: Bayer, Merck Serono, Roche/Genentech, Servier, Terumo; Research funding: Roche/Genentech, Sanofi. T.J. Ettrich: Research grants: Baxalta/Shire; Consulting fees, other remuneration (payment): Merck-Serono, Sanofi, Sirtex, Medical, Novartis, Bayer, Bristol-Myers Squibb, Pfizer. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

475P - Updated analysis and exploratory analysis of primary tumor location in the TRICOLORE trial: A randomized phase 3 trial of S-1 and irinotecan plus bevacizumab versus mFOLFOX6 or CapeOX plus bevacizumab as first-line treatment for metastatic colorectal cancer

Presentation Number
475P
Lecture Time
12:45 - 12:45
Speakers
  • Masato Nakamura (Matsumoto, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The TRICOLORE trial previously demonstrated that S-1 and irinotecan (IRI) plus bevacizumab (Bmab) was non-inferior to mFOLFOX6 or CapeOX plus Bmab in terms of progression-free survival (PFS) as first-line treatment for metastatic colorectal cancer (mCRC), irrespective of RAS status (Komatsu Y, et al. ESMO 2017, and Yamada Y, et al. Ann Oncol. 2018). We now report the final overall survival (OS) after a median follow-up of more than 3 years. The results of this trial were subjected to an exploratory analysis to determine if primary tumor location (TL) influenced the response to S-1 and IRI plus Bmab.

Methods

This trial was a randomized, open-label, phase 3 trial. Chemotherapy-naïve patients with mCRC were randomly assigned to receive either mFOLFOX6 or CapeOX plus Bmab (arm A) or S-1 and IRI plus Bmab (arm B, given as a 3-week regimen [7.5 mg/kg Bmab, 150 mg/m2 IRI on day 1, and 40 − 60 mg S-1 twice daily for 2 weeks, followed by a 1-week rest] or a 4-week regimen [5 mg/kg Bmab, 100 mg/m2, IRI on days 1 and 15, and 40 − 60 mg S-1 twice daily for 2 weeks, followed by a 2-week rest). Patients’ data were finally updated in September 2017.

Results

At this final analysis, the median overall survival (mOS) was 32.6 months with arm A and 34.3 months with arm B (median follow-up, 48.7 months). The hazard ratio (HR) for OS was 0.89 (95% CI: 0.72 − 1.10). Median progression-free survival (mPFS) in arm A/B were 10.8/14.0 months (HR 0.86, 95% CI: 0.71–1.04, p < 0.0001 for non-inferiority). In right-sided TL, mOS and mPFS in arm A/B were 25.6/28.1 months (HR 0.82, 95% CI 0.56-1.21) and 9.6 /11.4 months (HR 0.85, 95% CI 0.60-1.22), respectively. In left-sided TL, mOS and mPFS in arm A/B were 35.5/36.8 months (HR 0.89, 95% CI 0.68-1.15) and 11.3/15.0 months (HR 0.82, 95% CI 0.66-1.03), respectively.

Conclusions

Our updated analysis reconfirmed that S-1 and IRI plus Bmab is non-inferior to mFOLFOX6 or CapeOX plus Bmab in terms of PFS. S-1 and IRI plus Bmab is now recommended as a 1st-line treatment for mCRC irrespective of primary TL and RAS status.

Clinical trial identification

UMIN000007834.

Legal entity responsible for the study

Tokyo Cooperative Oncology Group (TCOG).

Funding

Taiho Pharmaceutical Co. Ltd.

Disclosure

A. Takashima: Corporate-sponsored research: Taiho, Takeda. T. Denda: Corporate-sponsored research: Sanofi, Boehringer Ingelheim, MSD. M. Gamoh: Corporate-sponsored research: Chugai, Taiho, Daiichi Sankyo, Yakult. Y. Komatsu: Other substantive relationships: Taiho Pharmaceutica, Lilly, MSD, Ono Pharmaceutical, Novartis, Chugai Pharma, Yakult, Merck Serono, Pfizer, Bayer. M. Takahashi: Corporate-sponsored research: Ono Yakuhin, MSD; Other substantive relationships: Ono Yakuhin, Chugaim Merck-Serono, Daiichi-Sankyo, Nihon-kayaku, Yakult, Taiho, Eli Lilly, Kyowa-Kirin. C. Ishioka: Corporate-sponsored research: Mochida, Kyowa-Kirin, Eizai, Chugai, Tsumura, Novartis, Merck-Serono, Daiichi-Sankyo, Takeda, Nihon-Kayaku, Yakult, Taiho, Ono, Astellas, Asahikasei-Parma, Kissei, Bristol other substantive relationships: Mochida, Chugai, Novartis, Merck-Serono, Daiichi-Sankyo, Takeda, Nihon-Kayaku, Yakult, Taiho, Ono, Asahikasei-Parma, Eli Lilly, Bayer. A. Sato: Membership on an advisory board or board of directors: Taiho Pharmaceutical Co., Ltd., Chugai Pharma Co., Ltd., Sumitomo Dainippon Pharma Co., Ltd.; Corporate-sponsored research: Taiho Pharmaceutical Co., Ltd., Chugai Pharma Co., Ltd. S. Yuki: Honoraria: Chugai Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Bayer Yakuhin, Ltd., Taiho Pharmaceutical Co. Ltd., Takeda Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Merck Serono Co., Ltd., Sanofi Co. Ltd. S. Morita: Corporate-sponsored research: Taiho; Honorarium: Taiho. T. Yamaguchi: Honorarium: Taiho. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

476P - Aflibercept in combination with Irinotecan, fluorouracil and leucovorin (FOLFIRI) as first-line chemotherapy in metastatic colorectal cancer (mCRC) patients : a phase II multicentric study.

Presentation Number
476P
Lecture Time
12:45 - 12:45
Speakers
  • Alexandra Lapeyre-Prost (Paris, FR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

FOLFIRI (5FU/leucovorin/irinotecan) + aflibercept significantly improves median overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients (pts) with previously treated metastatic colorectal cancer (mCRC). The aim of this study was to investigate efficacy and tolerability of adding aflibercept to FOLFIRI in the first line setting.

Methods

Pts with untreated documented mCRC received aflibercept plus FOLFIRI every 14 days until progression or unacceptable toxicity in an open, phase II single arm, multicenter trial. The primary endpoint was the 6-months PFS rate. Secondary endpoints were overall PFS, OS and tolerability. A two- steps Simon design was used with H0: 55% and H1= 75%, respectively (one-sided α = 5%, 1-β=90%). Data were analyzed in intention to treat population. The study was stopped at the first stage.

Results

41 patients were included and 40 analyzed (1 consent withdrawal) in 9 French centers between 10/2014 and 02/2017. Median age was 65 y (46-81), 42% were men, 53% had two or more metastatic sites. Eighteen patients (54.5%, IC [38.940; 69.509]) were alive and non-progressive at 6 months. Treatment with FOLFIRI plus aflibercept was therefore considered ineffective, inclusions were stopped. Median follow-up was 20.5 months (95% CI (15,11 ; 27,86)). ORR was 54% and disease control rate was 80%. Median duration of treatment was 5.2 months, median PFS and OS were 8,3 and 21.9 months respectively. Grade 3-4 adverse events were mainly gastrointestinal (18 pts, 45% : mucositis (15%), diarrhea (12,5%), abdominal pain (10%)) and vascular (13 pts, 32,5% : hypertension (17,5%) and venous thromboembolism (15%)). Severe hematological toxicities occurred in 7,5% of pts. 87.5% of patients had at least one dose modification during treatment. 37 pts received a second line therapy.

Conclusions

First line FOLFIRI+ aflibercept for mCRC pts is feasible but with significant toxicities leading to dose reduction in the majority of patients. Median PFS and OS were close to those reported with classical doublet and targeted agents in this setting.

Clinical trial identification

EudraCT: 2013-004081-33.

Legal entity responsible for the study

Fédération Francophone de Cancérologie Digestive.

Funding

Sanofi.

Disclosure

S. Pernot: Honoraria: Amgen, Sanofi; Travel, accomodations, expenses: Amgen, Merck, Servier, Bayer T. Aparicio: Conference: Pfizer, Roche, Sanofi, Léo Pharma, Amgen, BMS, Servier, Shire, Ipsen; Board: Pierre Fabre Ipsen, HalioDX, BMS; Travels: Ipsen, Novartis, Roche, Hospira; Research: Novartis. L. Dahan: Honoraria: Sanofi, Amgen. T. Lecomte: Consultant, expert: Sanofi; Courses, trainings: Lilly, Merck, Amgen; Invitations to national or international congresses: Amgen C. Lepage: Clinical research: Ipsen, Novartis Oncology; Courses: Advanced Accelerator Applications; Invitations to national or international congresses: Amgen, Ipsen, Novartis Oncology, Bayer. J. Taieb: Consultancy: Roche, Merck KGaA, Amgen, Celgene, Lilly, Baxalta, Servier, Sirtex Medical; Speaker's bureau: Servier, Amgen, Baxalta, Roche/Genentech, Sanofi, Merck, Lilly. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

477P - Folfiri-Aflibercept vs Folfiri-Bevacizumab as Second Line Treatment of RAS Mutated Metastatic Colorectal Cancer in Real Practice.

Presentation Number
477P
Lecture Time
12:45 - 12:45
Speakers
  • Alessandro Ottaiano (Napoli, IT)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

To date the treatment of RAS mutated (-M) metastatic colorectal cancer (mCRC) patients (pts) relies on the administration of oxaliplatin-based chemotherapy and bevacizumab as first line. Intensive debate is open about second-line treatments.

Methods

This is a real practice study; consecutive RAS-M unresectable mCRC were treated at the oncologist discretion at progression to FOLFOX/BEVA (fluorouracil, folinic acid, oxaliplatin, bevacizumab) with FOLFIRI/BEVA (fluorouracil, folinic acid, irinotecan, bevacizumab) (arm A) or FOLFIRI/AFLI (FOLFIRI, aflibercept) (arm B). We have analyzed differences in outcome and response between the two therapy sequences.

Results

Seventy-four patients were treated from January 2014 to January 2018; 31 treated with arm A, 43 with arm B. Among clinical factors there was a predominance of more extended disease (>two metastatic sites) in arm B (25/31 [51.2%] vs 40/43 [32.3 %] arm A; p = 0.0414). Fifty-nine pts were evaluable for response through RECIST: arm A, 5 PR, 15 SD, 8 PD; arm B, 5 PR, 16 SD, 10 PD. Second-line chemotherapy doses were reduced in 32.3% of pts in arm A and 38.1% in arm B. There were no grade 4 toxic events (NCI-CTC v4.0). The mean distance from first-line discontinuation to second-line start was 0.8 months in arm A and 2.4 months in arm B. Duration of first-line chemotherapy was significantly shorter in pts treated in arm B (12 pts < 6 months arm B vs 1 pt in arm A; p = 0.0278). Analysis of overall survival (OS) was done excluding these 13 pts to avoid prognostic interferences. Median OS were 22.7 in arm A vs 25.5 months in arm B (+ 2.8 months; P = 0.6855, HR: 1.12; 95% CI: 0.62 to 2.03). No maintenance treatment was done in arm B while in arm A BEVA with or without fluorouracil and folinic acid was done; censoring the analysis of OS at the end of the induction phase of both arms favored arm B (P = 0.0425; HR: 0.42; 95% CI: 0.15 to 1.15).

Conclusions

In our real practice, oncologists tend to administer FOLFIRI/AFLI in more extended RAS-M mCRC and to delay start of therapy. FOLFIRI/BEVA and FOLFIRI/AFLI are equally effective second-lines albeit FOLFIRI/AFLI, during the induction phase (6 months), is associated with a lower risk of death.

Legal entity responsible for the study

Istituto Nazionale Tumori di Napoli, IRCCS “G. Pascale”.

Funding

Has not received any funding.

Editorial Acknowledgement

Not applicable.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

478P - In the pathway to response: Is aflibercept an optimal treatment for RASwt mCRC patients after progression to 1st line containing anti-EGFR?

Presentation Number
478P
Lecture Time
12:45 - 12:45
Speakers
  • Elena Mata Velasco (Pamplona, ES)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

VELOUR trial compared FOLFIRI+/-aflibercept in 1226 mCRC patients after progression to oxaliplatin-based treatment, regardless of biological previous therapies. mOS (13.50 vs 12.06 months) and mPFS (6.90 vs 4.67 months) were increased, which led to aflibercept approval. We do not have yet enough information on aflibercept after anti-EGFR treatment. Our goal was to analyze efficacy and safety data of aflibercept in this specific context.

Methods

Retrospective analysis of clinical, therapeutic, and survival data collected from 120 consecutive RASwt mCRC patients treated from 2012 to 2017 with FOLFIRI-aflibercept after progression to standard chemotherapy + anti-EGFR in 12 Spanish hospitals.

Results

Median age was 60, 62.5% male, 37.5% female. 24% were right-sided tumours and 76% left-sided, with primary tumour resection in 41%. 100% RASwt, 5% BRAFmt. All patients received prior anti-EGFR therapy and 96% had ECOG 0/1. Median of FOLFIRI-Aflibercept cycles was 12, with 33% ORR. mPFS was 6.9 months (95% CI 6.0-7.7). BRAF, ECOG, primary tumour resection and nº of metastatic sites had statistical significance in univariate analysis; and primary tumour resection was also significant in multivariate analysis. mOS was 14.5 months (95% CI 9.7-19.3), with statistical significance in univariate for primary tumour resection, ECOG, and nº of metastatic sites. ECOG and nº of metastatic sites reached significance in multivariate analysis. As for toxicity, only 18.3% needed aflibercept dose reduction. 2nd line treatment was discontinued in 71.8% (mostly due to progression: 51.7%, 6.7% toxicity,1.7% surgery). 37% reached G3-4 toxicity (16.6% hematologic, 7.5% HTN, 5.9% asthenia, 2.5% perforation) 59% received a 3rd line therapy: 23% TAS-102, 18% regorafenib, 9% capecitabine.

Conclusions

RASwt mCRC patients reached similar results to those reported in VELOUR trial. The efficacy of subsequent aflibercept-containing 2nd line was maintained regardless of prior anti-EGFR. The efficacy of subsequent aflibercept-containing 2nd line was maintained regardless of prior anti-EGFR. Our results suggest that FOLFIRI-aflibercept, after 1st line with anti-EGFR, is a good treatment strategy for RASwt mCRC.

Legal entity responsible for the study

Ruth Vera García.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

479P - A phase II study of bevacizumab and irinotecan plus alternate-day S-1 as a second-line therapy for colorectal cancer. The AIRS study

Presentation Number
479P
Lecture Time
12:45 - 12:45
Speakers
  • Michitaka Honda (Fukushima, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The aim of this single-arm phase II clinical trial was to evaluate whether the alternate-day administration of S-1 plus irinotecan would reduce the incidence of severe diarrhea in comparison to consecutive-day S-1 administration (standard IRIS regimen) in second-line treatment in patients with metastatic colorectal cancer.

Methods

Patients with metastatic colorectal cancer after failure with first-line treatment of oxaliplatin and fluoropyrimidine were enrolled. Irinotecan (150 mg/m2) and bevacizumab (5mg/kg) were given intravenously on day 1. Oral S-1 was administered on alternate-days at a dose of 40-60mg twice a day. Cycles were repeated every two weeks. The primary endpoint was the incidence of grade ≥3 diarrhea. Our hypothesis set the 21% as a threshold incidence and 10% as an expected incidence from previous studies with one-sided alpha = 0.05. The secondary endpoints included the relative dose intensity, progression free survival, overall survival and other adverse events.

Results

A total of 51 patients were enrolled. The incidence of grade ≥3 diarrhea was 15.7% (8/51). Other common grade ≥3 adverse events were neutropenia, anemia, thrombocytopenia and fatigue were 13.7% (7/51), 5.9% (3/51), 2.0% (1/51) and 5.9% (3/51), respectively. The relative dose intensities of irinotecan, bevacizumab, and S-1 were 80.0%, 86.8%, and 77.7%, respectively. The median progression free survival and overall survival were 8.4 months (5.8 - 9.8) and 17.1 months (11.8 - 22.3).

Conclusions

The alternate day S-1 administration doesn’t have significant effectiveness to reduce diarrhea in patients who received second line treatment for metastatic colorectal cancer.

Clinical trial identification

UMIN000008947.

Legal entity responsible for the study

Epidemiological and Clinical Research Information Network (ECRIN).

Funding

Taiho Pharmaceutical Co., Ltd.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

480P - The safety and efficacy of FOLFOXIRI plus molecular target therapy as a first-line treatment for metastatic colorectal cancer: A multicentre retrospective study

Presentation Number
480P
Lecture Time
12:45 - 12:45
Speakers
  • Takatsugu Ogata (Kobe, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The TRIBE study showed that FOLFOXIRI plus bevacizumab therapy is an effective treatment for metastatic colorectal cancer (mCRC). This study aimed to determine the safety and effectiveness of FOLFOXIRI therapy as a first-line treatment.

Methods

We retrospectively collected data of patients with mCRC treated with FOLFOXIRI from March 2014 to December 2017 in two centres.

Results

Fifty-five patients were enrolled in this study (median age, 60 years; males 25, females 30). The tumour location was classified as right and left in 15 and 40 patients, respectively. Twenty-nine and twenty-six patients had RAS wild-type disease and mutation-type disease, respectively. Anti-VEGF and anti-EGFR antibodies were used in 38 and 17 patients, respectively. The most common grade 3 or 4 adverse event was neutropenia (51%). Skin toxicities and hypomagnesaemia showed a statistically higher frequency among patients with anti-EGFR antibodies (P < 0.001 and P = 0.039, respectively). The overall response rate (ORR) was 67% (complete response [CR], 7 patients; partial response [PR], 30 patients; not evaluated [NE], 1 patient), and the disease control rate was 96% (stable disease, 16 patients). The median progression free survival (mPFS) was 11.0 (0.43 − 45.3) months and the median overall survival (mOS) was 41.9 (1.00 − 45.3) months. In FOLFOXIRI plus anti-VEGF antibodies, the ORR was 55% (CR, 5 patients; PR 16 patients), and in FOLFOXIRI plus anti-EGFR antibodies, the ORR was 94% (CR, 2 patients; PR, 14 patients; NE, 1 patient) (P = 0.271). With a median follow up of 18.4 months, mPFS and mOS were not significantly different in patients with anti-EGFR antibodies or anti-VEGF antibodies (hazard ratio [HR], 3.12 [0.883 − 11.0]; P = 0.143 and P = 0.063, respectively). Twelve patients had progressive disease (PD) during the induction phase. In these patients, mOS was significantly poorer (13.2 months versus 41.9 months; HR, 23.3 [6.77 − 80.1]; P < 0.001).

Conclusions

FOLFOXIRI plus molecular target therapy showed impressive results for patients with mCRC. The response rate was significantly higher in patients with anti-EGFR antibodies, although skin toxicities and hypomagnesaemia tend to occur in these patients.

Legal entity responsible for the study

Kobe City Medical Center General Hospital.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

481P - Phase II Study of Cetuximab Rechallenge in Patients with RAS Wild-Type metastatic Colorectal Cancer: E-Rechallenge Trial

Presentation Number
481P
Lecture Time
12:45 - 12:45
Speakers
  • Hiroshi Osawa (Tokyo, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Several previous reports indicated that cetuximab (Cmab) rechallenge may be efficacious in patients for whom Cmab was previously effective. On the other hand, some reports did not support this. Considering the plasticity of sensitive clone, we assumed that an anti-EGFR antibody-free interval (aEFI) and efficacy may be correlated. This current study investigates the efficacy and safety of Cmab rechallenge as a salvage chemotherapy.

Methods

The E-Rechallenge tiral is a multicenter phase II study in mCRC patients who have become refractory to fluoropyrimidines, L-OHP, CPT-11, Cmab and bevacizumab, and in whom previous treatment with Cmab was effective in any earlier line (achieving CR, PR, or SD that persisted for ≥6 months). The other main eligibility criteria are; RAS wild-type, measurable disease, aEFI ≥16 weeks between the last dose of Cmab during previous treatment and the start of Cmab rechallenge. Protocol treatment is the combination of weekly Cmab with biweekly CPT-11. The primary endpoint is response rate (RR). Secondary endpoints are progression free survival (PFS), overall survival (OS), association between the aEFI and efficacy, and safety. Using a single-stage binominal design, 45 patients were required; a RR of ≥ 20% was considered promising, and a RR of ≤ 5% unacceptable (one-sided α = 2.5%, β = 10%). Additional research of ctDNA was conducted optionally.

Results

Between Dec 2014 and Oct 2017, 33 patients were enrolled. Patients’ characteristics were as follows; mean age 64.4, male/female 84.8%/15.2%, primary location right/left 12.1%/87.9% and the efficacy in previous Cmab, CR/PR/SD ≥6 months 3%/78.8%/18.2%, respectively. The primary endpoint; the rates of PR/SD/PD (95%CI) were PR 15.6% (5.3-32.7%)/SD 40.6% (23.6-57.6%)/ PD 43.8% (26.4-62.3%). Secondary endpoint; median PFS and OS (95%CI) were 88 days (62-113days) and 262 days (195-307days). There were no statistical significant difference of PFS stratified by median aEFI. New signals of adverse events were not identified.

Conclusions

Cmab rechallenge showed some activity in the salvage setting, in patients for whom Cmab was previously effective. The additional research of ctDNA may contribute to identify patients with benefit from Cmab rechallenge.

Clinical trial identification

UMIN 000016439.

Legal entity responsible for the study

Comprehensive Support Project for Oncological Research.

Funding

Merck Serono.

Disclosure

E. Shinozaki, H. Satake: Honoraria: Merck Serono. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

482P - RET rearrangements may arise following anti-EGFR therapy in advanced colorectal cancer

Presentation Number
482P
Lecture Time
12:45 - 12:45
Speakers
  • Thereasa A. Rich (Redwood City, US)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

RET rearrangements (RETr) are uncommon yet emerging oncogenic targets found in RAS/BRAF wild-type colorectal cancers (CRCs), particularly right-sided, MSI-high tumors. We describe the molecular landscape of metastatic CRCs harboring a somatic RETr detected by next generation sequencing (NGS) of cell-free DNA (cfDNA). cfDNA data complement previous descriptions of RETr in tissue, which are limited by small series of patients (pts) and cfDNA also provides a summary of genomic alterations (alts) across multiple metastatic sites in pts typically exposed to one or more lines of therapy.

Methods

Between 2/2015-3/2018, somatic RETr were identified among 4,234 consecutive metastatic CRC pts with tumor DNA detected on a 68-73 gene cfDNA assay (Guardant360®, Redwood City, CA). This validated NGS assay evaluates single nucleotide variants, and select indels, fusions, and copy number gains with high sensitivity and analytic specificity. Relevant clinicopathologic correlates were obtained from clinicians.

Results

Seventeen RETr were detected in 16 pts (0.4%). Functionally significant alts in other cancer genes were found in 88% of samples with a RETr (median 9.5 additional alts, max 23). There was a high co-occurrence of canonical KRAS alts (14 alts in 7/16 pts), 5 of whom also had alts in NRAS (n = 4pts), the EGFR extracellular domain (ECD, n = 4), and/or BRAF V600E (n = 3). For 4 pts with available comprehensive tissue NGS results, the RETr was detected in cfDNA only. Two also had KRAS, NRAS, and EGFR ECD alts, one had an EGFR activating alt, and the fourth had a FGFR3 fusion, all detected only in cfDNA. Prior to cfDNA collection, all 4 had progressed on anti-EGFR therapy after a median of 12mo (range 8-16mo) of treatment. Four additional RETr/KRAS+ pts had either a KRAS alt that was not detected in tissue (n = 2) or co-occurred with an ALK fusion and/or BRAF V600E in pts who had prior anti-EGFR therapy (n = 2).

Conclusions

RETr commonly co-occur with RAS/RAF alts in cfDNA, a novel observation. The alt pattern and clinicopatholgoic history suggest RETr contribute to acquired resistance to anti-EGFR therapy in metastatic CRC. Our data also raise the question of whether driver RETr may be associated with primary resistance to anti-EGFR therapy.

Legal entity responsible for the study

Guardant Health.

Funding

Has not received any funding.

Disclosure

T.A. Rich, V.M. Raymond, Y. Shiotsu, R.B. Lanman: Employee, Stock owner: Guardant Health. Y. Kagawa, Y. Nakamura: Research support: Guardant Health. W. Okamoto: Research support: Guardant Health; Grant funding: MSD. T. Yoshino: Research support: Guardant Health; Grants: MSD KK, Sanofi KK, Sumitomo Dainippon Pharma Co Ltd, Chugai Pharmaceutical Co Ltd, GlaxoSmithKline KK, Nippon Boehringer Ingelheim Co Ltd; Consulting fees: Sanofi KK, Chugai Pharmaceuticals Co Ltd, Eli Lilly Japan, Merck Serono Co Ltd. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

483P - A biomarker study to validate predictors for clinical outcome of cetuximab based chemotherapy in first-line metastatic colorectal cancer (mCRC) patients: JACCRO CC-05/06AR and FIRE-3

Presentation Number
483P
Lecture Time
12:45 - 12:45
Speakers
  • Yu Sunakawa (Kanagawa, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

We conducted a biomarker study to identify significant genes to predict efficacy of cetuximab (cet) based treatment using tumor samples from mCRC patients (pts) enrolled in JACCRO CC-05/06AR (UMIN000010635) and FIRE-3 (NCT00433927), which evaluated 1st-line doublet plus cet therapy. There are no established predictive biomarkers beyond RAS mutations. We reported recently CDX2 gene expression levels as a promising biomarker for cet treatment in KRAS wild-type mCRC pts of the JACCRO trial (ASCO 2016, abst3592). Therefore, we performed the validation study using tumor samples from pts enrolled in the FIRE-3 trial.

Methods

We analyzed tissue samples of 77 pts of the JACCRO trial for discovery set and 250 pts of cet arm in the FIRE-3 trial for validation set. Gene expression levels were measured by HTG EdgeSeq Oncology Biomarker Panel, which is comprised of probes targeting 2560 genes implicated in numbers of pathways, using next generation sequencing for quantitative analysis of targeted RNAs. Univariate Cox regression analysis was conducted for all genes that passed QC filtering.

Results

Seventy-one pts (male/female, 39/32; median age, 63 yrs) and 102 pts (male/female, 75/27; median age, 63 yrs) were successful for gene expression analysis in the JACCRO and FIRE-3 set, respectively. The Cox regression analysis identified 24 genes for overall survival (OS) and 8 genes for progression-free survival (PFS), which all were significant (p < 0.005) in the JACCRO set. Among those genes, LYZ and RNF43 genes were found to be significantly associated with OS (coefficients, 0.21; p = 0.013) and PFS (coefficients, -0.20; p = 0.037), respectively, in the FIRE-3 set. In the JACCRO set, high expression (log2>9.07) of CDX2 predicted a significantly longer PFS (p = 0.002). The same effect was found in the FIRE-3 set when applied the same cutoff value (median PFS 10.9 vs. 6.9 months, HR 0.39, 95%CI 0.22-0.72, p = 0.002).

Conclusions

Our biomarker study validated CDX2 as a novel predictor for clinical outcome of 1st-line cet based chemotherapy in mCRC. These data warrant further exploration of CDX2 as a biomarker or as a potential target for drug development.

Clinical trial identification

UMIN000010635.

Legal entity responsible for the study

Heinz-Josef Lenz.

Funding

JACCRO, the National Cancer Institute (grant number P30CA014089), The Gloria Borges WunderGlo Foundation-The Wunder Project, Dhont Family Foundation, San Pedro Peninsula Cancer Guild, and Daniel Butler Research Fund.

Editorial Acknowledgement

We acknowledge Sachika Koyama and Yasushi Ohtake (JACCRO) for editorial assistance.

Disclosure

Y. Sunakawa: Honoraria for talks: Taiho Pharmaceutical, Chugai Pharma, Yakult Honsha, Takeda, Merck Serono, Bayer Yakuhin, Sanofi. S. Stintzing: Consulting or advisory role, travel expenses, honoraria: Merck KGaA. A. Tsuji: Honoraria: Taiho Pharmaceutical, Merck Serono. T. Denda: Honoraria: Yakult Honsha, Taiho Pharmaceutical. K. Shimada: Corporate-sponsored research fee: Yakult Honsha, Taiho Pharmaceutical. M. Takeuchi: Consulting fees: Hisamitsu Pharmaceutical, Kowa, Shionogi Pharma, Abbvie, Astellas. W. Ichikawa: Consulting fees: Ono Pharmaceutical; Research funding: Takeda, Taiho Pharmaceutical, Eisai, Chugai Pharma, Merck Serono, Shionogi Pharma, Daiichi Sankyo; Honoraria: Merck Serono, Taiho Pharmaceutical, Chugai Pharma, Takeda, Ono Pharmaceutical, Lilly. V. Heinemann: Consulting or advisory role, travel expenses, honoraria, research funding: Merck. H-J. Lenz: Consulting or advisory role, travel expenses, honoraria, Merck Serono. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

484P - Retrospective RAS Analysis of the EPIC Trial: Cetuximab Plus Irinotecan vs Irinotecan in Patients (pts) With Second-Line Metastatic Colorectal Cancer (mCRC)

Presentation Number
484P
Lecture Time
12:45 - 12:45
Speakers
  • Alberto Sobrero (Genova, IT)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The multicenter, open-label, randomized, phase 3 EPIC study (EMR 062202-025) investigated the addition of cetuximab to irinotecan vs irinotecan in pts with EGFR-expressing mCRC who had previously progressed on first-line fluoropyrimidine- and oxaliplatin-based chemotherapy. The primary endpoint was overall survival (OS). We present the extended RAS analysis (KRAS/NRAS exons 2, 3, and 4) for the EPIC study population.

Methods

1298 RAS-unselected pts were enrolled from May 2003 to February 2006. Existing DNA samples were reanalyzed using BEAMing (beads, emulsion, amplification, magnetics) technology. RAS wild-type (wt) status was defined as having all alleles be analyzable and a sum of RAS mutations of ≤ 5%. Baseline characteristics, efficacy, safety, and post-study therapy were assessed. 10.3% had no RAS data available.

Results

Among the 452 (231 in the cetuximab + irinotecan arm and 221 in the irinotecan arm) pts with RAS wt mCRC, baseline characteristics were comparable to those of the unselected population. 67.5% had 1 prior line of therapy. In the cetuximab + irinotecan vs irinotecan arms, median progression-free survival (PFS) was 5.4 vs 2.6 months (HR, 0.57 [95% CI, 0.46-0.69]; P < .0001), median OS was 12.3 vs 12.0 months (HR, 0.91 [95% CI, 0.71-1.17; P = .4645]), and overall response rate (ORR) was 29.4% vs 5.0% (OR, 8.12 [95% CI, 4.04-17.40]; P < .0001), respectively. 76.4% and 61.8% of pts in the cetuximab + irinotecan vs irinotecan arms, respectively, experienced a grade ≥ 3 adverse event. 47.1% of pts in the irinotecan arm received cetuximab in a subsequent line of therapy vs 11.3% in the cetuximab + irinotecan arm.

Conclusions

This retrospective analysis confirms that cetuximab-based therapy is suitable as a standard, second-line treatment for pts with RAS wt mCRC. Specifically, the addition of cetuximab to irinotecan significantly improved PFS and ORR in this population. A large proportion of pts in the irinotecan arm crossed over to receive post-study cetuximab, potentially masking any OS benefit of the addition of cetuximab to irinotecan in this study. Benefits appear clinically relevantly higher than for pts with RAS-unselected or KRAS wt mCRC.

Clinical trial identification

EMR 062202-025.

Legal entity responsible for the study

Merck KGaA.

Funding

Merck KGaA.

Editorial Acknowledgement

Medical writing support was provided by ClinicalThinking, and was funded by Merck KGaA, Darmstadt, Germany.

Disclosure

R. Esser: Employee, stock ownership: Merck KGaA. J. Nippgen: Employee: Merck KGaA. H. Burris: Consultancy (Includes expert testimony): Mersana, AstraZeneca, Forma, Janssen, Novartis, Roche/Genentech, TG Therapeutics, Medimmune, Bristol-Myers Squibb; Research funding: Roche/Genentech, Bristol-Myers Squibb, Incyte, Tarveda Therapeutics, Mersana, AstraZeneca, Medimmune, Macrogenics, Novartis, Boehringer Ingelheim, Lilly, Seattle Genetics, Abbvie, Bayer, Celldex, Merck, Celgene, Agios, Jounce Therapeutics, Moderna Therapeutics, CytomX Therapeutics, GlaxoSmithKline, Verastem, Tesaro, Immunocore, Takeda, millennium, BioMed Valley Discoveries, Pfizer, PTC Therapeutics, TG Therapeutics, Loxo, Vertex, eFFECTOR Therapeutics, Janssen, Gilead Sciences, Valent Technologies. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

485P - Withholding Anti-EGFR: ImpacT on Outcome of RAS wild-type metastatic Colorectal Tumors (WAIT OR ACT): a multicentric AGEO study

Presentation Number
485P
Lecture Time
12:45 - 12:45
Speakers
  • Lola-Jade Palmieri (Paris, FR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Two phases III studies (FIRE-3 and CALGB/SWOG80405) suggested higher response rate (RR) for doublet chemotherapy with an anti-EGFR (Epidermal Growth Factor Receptor) compared to an anti-VEGF (Vascular Endothelial Growth Factor), in first line RAS/BRAF wild-type (WT) unresectable metastatic colorectal cancer (mCRC). Unfortunately, in clinical practice the delay to obtain RAS/BRAF status may delay the chemotherapy start. No study has evaluated the impact of a delayed introduction of the anti-EGFR.

Methods

This retrospective multicentric AGEO (Association Gastro-Entérologues Oncologues) study included mCRC RAS/BRAF WT patients who received a doublet chemotherapy either with an anti-VEGF introduced immediately (control arm) or with an anti-EGFR introduced at cycle 2 or 3 (delayed group) between 2013 and 2016. The primary endpoint was the Progression Free Survival (PFS). The Overall Survival (OS) and the RR were secondary endpoints. Given different characteristics between the two groups, a propensity score was developed.

Results

A total of 262 patients were included: 129 in the control group and 133 in the delayed group. Compared to the delayed group, patients treated in the control group were more likely descendant mCRC (60% vs 44%) and had more metastatic sites (>1 site: 57% vs 40%). In the delayed anti-EGFR group, the time to obtain RAS status was 20.7 days ±18.9. The anti-EGFR was introduced in 70% of cases at C2 and in 30% at C3. Using the propensity score, there was no more difference between the two groups. The median follow-up was 37.9 months. PFS and RR were significantly longer and higher in the delayed anti-EGFR group compared to the control anti-VEGF group (PFS: 13.8 vs 10.8 months, p = 0.03; RR: 67% vs 46%, p = 0.0007). Meantime, no difference was observed concerning OS (30.4 months vs 30.0 months, p = 0.23).

Conclusions

There is no deleterious effect of delayed anti-EGFR introduction at cycle 2 or 3 compared to the immediate introduction of anti-VEGF in patients with RAS/BRAF WT mCRC. Therefore, in current clinical practice, if the response rate is an important goal, it is possible to wait for RAS status and to initially start chemotherapy without targeted therapy.

Legal entity responsible for the study

Lola-Jade Palmieri.

Funding

Has not received any funding.

Disclosure

D. Tougeron: Consulting or advisory role: MSD, BMS, Sanofi, Roche; Speaker’s bureau: Roche, Novartis, Servier; Travel, accomodations, expenses: MSD, BMS, Merck, Amgen. A. Lievre: Consulting or advisory role: Merck, Amgen, Bayer, Ipsen; Speaker’s bureau: Roche, Merck, Ipsen, BMS, Novartis, Servier; Travel, accomodations, expenses: Merck, Novartis, Ipsen, Roche. S. Pernot: Honoraria: Amgen, Sanofi; Travel, accomodations, expenses: Amgen, Merck, Servier, Bayer. O. Bouche: Consulting or advisory role: Roche, Merck, Amgen, Bayer; Speaker’s bureau: Lilly, Pierre Fabre, Novartis, Servier; Travel, accomodations, expenses: Lilly, Roche, Merck. R. Coriat: Amgen, Merck, Roche, Novartis, Ipsen, Keocyt, Bayer, Servier. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

486P - Prospective biomarker study in advanced RAS wild-type colorectal cancer. POSIBA trial.

Presentation Number
486P
Lecture Time
12:45 - 12:45
Speakers
  • Xabier García Albéniz (Boston, US)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

RAS testing is used to select patients sensitive to anti-EGFR therapies in metastatic colorectal cancer (mCRC) but other biomarkers such as BRAF, PIK3CA/PTEN and p-IGF-1R+/MMP7 + (DP phenotype) have not prospectively assessed to predict anti-EGFR resistance.

Methods

We designed a multicenter prospective trial (NCT01276379) to evaluate if the following biomarkers BRAF mutation, PIK3CA mutation/PTEN loss and DP phenotype can improve the prediction of 12-months progression-free survival (PFS) over the use of only clinical variables in patients with RAS WT mCRC treated with standard chemotherapy plus biweekly Cetuximab as first-line therapy. The planned sample size was 170 RAS WT patients to detect a 20% difference in 12-month PFR based on analysis of clinical and selected biomarkers (alpha=.05, beta=.2). The discriminatory capacity of the biomarkers was evaluated using ROC curves.

Results

We included 181 RAS WT patients. The biomarker distribution was: BRAF mutant 20 patients (11%), PIK3CA mutated/PTEN loss 98 patients (58%) and DP 23 patients (12.7%). Median PFS: BRAF WT 11.4 vs BRAF mutant 5.9 months (p = 0.004). PIK3CA/PTEN pathway and DP phenotype did not discriminate PFR (p=NS). Baseline clinical variables with good prognosis in a multivariable model were PS = 0, left sided tumor and resectable liver metastases (i.e. liver only metastases (<3 nodules and <5cm)).

Conclusions

A clinical score discriminates between two groups of patients who benefitted differently from chemotherapy plus cetuximab. The addition of BRAF, PIK3CA/PTEN and DP to the clinical score does not improve the prediction of 12m PFS.

Clinical trial identification

EudraCT: 2010-019236-12.

Legal entity responsible for the study

Grupo Español Multidisciplinar de Cáncer Digestivo.

Funding

Merck.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

487P - Patient selection for targeting integrin with abituzumab in patients with metastatic colorectal cancer (mCRC). A retrospective analysis of the randomized phase I/II Poseidon study.

Presentation Number
487P
Lecture Time
12:45 - 12:45
Speakers
  • Rita Laeufle (Pleasanton, US)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Adding abituzumab (EMD 525797) a humanized monoclonal IgG2 antibody, targeting αν integrin subunit to the control arm (irinotecan+cetuximab) failed to demonstrate a statistically significant PFS benefit in a phase I/II in second line KRAS wild-type (KRAS wt exon-2) mCRC. A pre-planned explorative biomarker analysis suggested that high integrin ανβ6 expression may be negatively prognostic for OS in the control arm and predictive for prolonged OS with abituzumab treatment. {Elez et al Annals of Oncology, Volume 26, Issue 1, 1 January 2015, Pages 132–140}.

Methods

Further retrospective analysis of Poseidon study data were performed (n = 98 patients with high and n = 99 low ανβ6 expression) to correlate the impact of location of tumor (left n = 152 versus right n = 44, and one patient had both right and left colorectal cancer) and integrin ανβ6 expression (low versus high) on overall survival (OS), progression free survival (PFS) and objective response rate (ORR) of abituzumab added to irinotecan+cetuximab.

Results

This retrospective explorative analysis suggest that patients with left sided KRAS wt mCRC and high expression of ανβ6 showed the most benefit for median OS of 25.6 months versus 10.2 months (HR 0.36 [95% CI 0.17; 0.75]; median PFS of 8.6 months versus 4.2 months (HR 0.61 [95% CI 0.31; 1.22]); ORR. 9/20 (45.0%) versus 5/22 (22.7%), when treated with abituzumab 1000 mg + irinotecan+cetuximab versus irinotecan+cetuximab alone. No treatment benefit was observed in right sided mCRC with high expression of ανβ6 and in all mCRC with low expression of ανβ6.

Conclusions

Although the sample size is small, patients with left sided KRAS wt mCRC and high expression of ανβ6 integrin in their tumor seem to benefit most from the addition of abituzumab to irinotecan+cetuximab compared to irinotecan+cetuximab alone. A prospective study in 1L left sided RAS wild-type mCRC with high expression of ανβ6 is planned with the addition of abituzumab 1000mg to SOC.

Clinical trial identification

Explorative, retrospective data analysis of study NCT01008475; first release October 19, 2009.

Legal entity responsible for the study

Merck KGaA and SFJ Pharmaceuticals.

Funding

Merck KGaA and SFJ Pharmaceuticals.

Disclosure

R. Laeufle: Consultant: SFJ Pharmaceuticals. D. Arnold: Consultancy, honoraria: Roche, Merck Serono; Research funding to the Principal Investigator: Roche, Sanofi Aventis. S. Kopetz: Intellectual property rights: Amgen, Array, Bayer, Genentech, Taiho; Ownership interest: MolecularMatch. J. Straub, R. Bruns, G. Massimini: Employee: Merck KGaA. R. Debenedetto: CEO: SFJ Pharmaceuticals. R. Linke: CMO: SFJ Pharmaceuticals. J. Tabernero: Consulting or advisory role: Amgen, Bayer, Boehringer Ingelheim, Celgene, Chugai Pharma, Lilly, Merck Serono, MSD, Novartis, Pfizer, Roche, Sanofi, Symphony Evolution, Taiho Pharmaceutical, Takeda. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

488P - Histopathologic evaluation of patients with liver-limited metastatic colorectal cancer receiving mFOLFOX6 plus bevacizumab or mFOLFOX6 plus cetuximab: The ATOM trial.

Presentation Number
488P
Lecture Time
12:45 - 12:45
Speakers
  • Yasunori Emi (FUKUOKA, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

We previously reported the results of a randomized phase II controlled trial comparing mFOLFOX6 plus bevacizumab (Bmab) with mFOLFOX6 plus cetuximab (Cmab) for KRAS wild-type (wt) colorectal cancer (CRC) with liver-limited metastases that were not optimally resectable. The current study is the first to examine the role of histopathologic response based on the study data of anti-VEGF versus anti-EGFR antibody.

Methods

In the ATOM trial, KRAS wild-type CRC patients with liver-limited metastases were eligible if the number of lesions was more than 5 and/or the size of lesions was more than 5cm in the maximum diameter. The primary endpoint was progression-free survival (PFS). Of 116 eligible patients, patients who underwent liver metastasectomy were evaluated for histopathologic response in this study. Resected liver specimens were assessed by the independent pathological review committee. Preplanned pathological assessments included tumor regression grade (TRG), dangerous halo, and sinusoidal obstruction of resected liver specimens. Patients were categorized into major histopathologic response (MjHR) if they had TRG of 1 (viable tumor cells = 0%) or 2 (< 25%), partial histopathologic response (PHR) if they had TRG of 3 (< 50%), or no histopathologic response (NHR) if they had TRG of 4 (< 75%) or 5 (> 75%).

Results

A total of 59 patients had TRG evaluation based on resected specimens by liver metastasectomy. Of those, 55 (28 in Bmab arm, 27 in Cmab arm) were eligible for analysis. In the Bmab arm, the number of patients with MjHR/PHR/NHR was 12/1/15 (43/4/54%); in the Cmab arm, 13/10/4 (48/37/15%). Median PFS of patients with a MjHR or PHR/NHR was 8.3 or 4.4 months in the Bmab arm and Not Reached or 5.4 months in the Cmab arm. Patients with a MjHR had a longer PFS than those with a PHR/NHR in both the Bmab arm (hazard ratio [HR], 0.50 (95%CI, 0.19-1.28)) and the Cmab arm (HR, 0.17 (95%CI, 0.05-0.58)).

Conclusions

In the TRG assessment, the proportion of MjHR was similar between the two arms. The impact of MjHR on PFS as compared to PHR/NHR was observed in both arms. Further results regarding other assessments will be presented.

Clinical trial identification

NCT01836653.

Legal entity responsible for the study

ATOM study group.

Funding

Chugai Pharmaceutical.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

489P - Verification of guideline conform mCRC treatment with EGFR inhibitors with real-world evidence data from EU5 countries

Presentation Number
489P
Lecture Time
12:45 - 12:45
Speakers
  • Laura Hoyer (Frankfurt am Main, DE)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The EGFR inhibitors cetuximab and panitumumab are indicated for patients suffering from metastatic colorectal cancer (mCRC), which are RAS wildtype. The aim of this analysis is to verify with real-world data whether the drug usage of those EGFR inhibitors reflects clinical guidelines with regards to their genomic profile.

Methods

Anonymized patients-level data collected through a large web-based survey between April 2017 and March 2018 was used. The study reported patient case history information across all cancer types in 5EU (France, Germany, Italy, Spain & UK). Treatment information and biomarker testing information on 5248 mCRC drug treated patients were analyzed.

Results

Evaluating KRAS and NRAS biomarkers status, real-world data analysis showed that 18,9% of mCRC patients were not tested for N-RAS mutation and 11,4% were not tested for K-RAS mutation. 16% of the mCRC population were RAS mutant. However, 3,2% of these patients received cetuximab and panitumumab even though they did not qualify for this treatment, due to their RAS mutation. Among all mCRC patients who were RAS wildtype, 49,4% of them received cetuximab or panitumumab.

Conclusions

This analysis of real-word data showed that biomarkers testing is not carried out in all mCRC patients. Secondly, the use of EGFR inhibitors in the RAS mutant mCRC patient population demonstrates a misalignment with clinical guidelines. Howver, most of patients receiving EGFR inhibitors are RAS wildtype, which implies that the majority of mCRC patients receiving EGFR inhibitors is treated according to medical guidelines regarding their genomic profile.

Legal entity responsible for the study

IQVIA Commercial GmbH & Co. OHG.

Funding

Has not received any funding.

Disclosure

L. Hoyer, N. Schmidt: Employee of IQVIA Commercial GmbH & Co. OHG.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

491P - Impact of delayed addition of anti-EGFR monoclonal antibodies on the outcome of first-line therapy in metastatic colorectal cancer patients: a retrospective registry-based analysis

Presentation Number
491P
Lecture Time
12:45 - 12:45
Speakers
  • Tomas Buchler (Prague, CZ)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The addition of monoclonal antibodies against epidermal growth factor receptor (anti-EGFR Abs) to chemotherapy is commonly delayed in the real-world clinical practice, usually because of delays in obtaining RAS testing results. The aim of this retrospective registry-based analysis was to determine whether the delayed addition of anti-EGFR mAbs up to the fourth cycle of backbone chemotherapy adversely affects outcomes of mCRC patients treated with first-line regimens.

Methods

Clinical data of patients with RAS wild-type mCRC treated with first-line systemic therapy regimens containing anti-EGFR mAbs from a national database were analysed retrospectively. Patients were divided into three groups according to the timing of anti-EGFR mAbs addition to the chemotherapy backbone. Cohort A (n = 401) included patients with anti-EGFR mAbs added to chemotherapy from the first cycle, cohort B (n = 71) patients with anti-EGFR mAbs added to chemotherapy from the second cycle, and cohort C (n = 101) patients who had anti-EGFR mAbs added to chemotherapy from the third or fourth cycle. The chemotherapy backbone regimens consisted of FOLFOX or FOLFIRI regimens.

Results

336 (58.6%) patients received panitumumab and 237 (41.4%) patients received cetuximab. The median progression-free survival (PFS) of the whole cohort was 12.2 months (95% confidence interval [CI] 10.9–13.5), and the median overall survival (OS) was 33.5 months (95% CI 27.6–39.4). Survival results for the cohorts defined by the time of addition of anti-EGFR MoAbs to chemotherapy are shown in the table. In a multivariate test, ECOG performance status and chemotherapy regimen were associated with PFS, whereas the site of primary tumour and chemotherapy regimen were associated with OS.

CohortPFS (95% CI), monthsLog-rank p-valueOS (95% CI), monthsLog-rank p-value
A (n = 401)12.9 (11.5–14.3)30.6 months (25.2–36.1)
B (n = 71)9.7 (9.1–10.3)A vs. B p = 0.185Not reachedA vs. B p = 0.645
C (n = 101)11.5 (9.8–13.2)A vs. C p = 0.82637.9 months (28.6–47.3)A vs. C p = 0.052

Conclusions

Delayed addition of anti-EGFR mAbs up to the fourth cycle of first-line chemotherapy was not associated with inferior survival or response rates.

Legal entity responsible for the study

Tomas Buchler.

Funding

The institute of Biostatistics and Analysis, Faculty of Medicine, Masaryk University, Brno received financial support for the CORECT registry from Bayer, Amgen, Merck, and Roche.

Disclosure

T. Buchler, O. Fiala: Research funding, Travel grants, honoraria: Roche, Merck, Bayer, Servier, BMS, MSD, Sanofi, Amgen. A. Poprach: Honoraria, travel grants: Roche, Amgen. I. Kiss: Speakers’ honoraria: Roche, Merck, Amgen. J. Finek: Lecture honoraria, travel grants: Roche, Merck, Pfizer, Novartis, Amgen. B. Melichar: Research funding, travel grants, Honoraria: Roche, Merck, Bayer, Servier, BMS, MSD, Sanofi, Amgen. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

492P - A multicenter phase II trial to evaluate the efficacy of mFOLFOX6+cetuximab as induction chemotherapy to achieve R0 surgical resection for advanced colorectal liver metastases (NEXTO trial)

Presentation Number
492P
Lecture Time
12:45 - 12:45
Speakers
  • YUJIRO NISHIOKA (Tokyo, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Hepatic resection is known to be the standard treatment for patients with colorectal liver metastasis (CRLM). The recent advancement in chemotherapy has led to the extended surgical indication and better outcome in patients with advanced CRLM. This phase II trial was designed to prospectively evaluate the validity of induction chemotherapy using mFOLFOX with cetuximab for advanced CRLM, which has been reported to provide early tumor shrinkage in CRLM with KRAS wild type.

Methods

Patients having advanced CRLM (tumor number > =5 and/or technically unresectbale) with KRAS wild type were included to this study. The induction of mFOLFOX with cetuximab was followed by the evaluation of surgical indication every 4 cycles (2 months). If all the tumors were regarded as technically resectable, we performed surgical resection after the waiting period of 1 month and postoperative chemotherapy was added until 12 cycles in total. If they were unresctable, we continued the regimen within the upper limit of 12 cycles. The primary endpoint was R0 resection rate. The secondary endpoints included recurrence free survival (RFS), progression free survival (PFS), and overall survival (OS).

Results

Between May 2012 and May 2015, total 50 patients were enrolled to this trial in 14 centers. The induction was not done in 2 patients, who were excluded. The median age of the 48 patients was 62.5 (range: 45 to 79) including 36 men and 12 women. The median tumor number detected by CT before the induction was 12 (1 to 57). R0 and R1 resections were performed in 26 and 5 patients, respectively (R0 resection rate: 54.2%), and there was no mortality. Under the median follow-up of 2.5 years, the 3-year RFS was 14.4%, 3-year PFS was 8.2%, 3-year OS was 60.0%, and median survival time was 3.4year.

Conclusions

For advanced CRLM with KRAS wild type, mFOLFOX with cetuximab induction therapy provided the sufficient R0 resection rate and favorable outcome.

Clinical trial identification

UMIN Clinical Trials Registry; C000007923.

Legal entity responsible for the study

The Institutional Review Board of each participating institutions.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

493P - Initial report of a phase I/II study of S-1 and irinotecan (IRIS) in combination with cetuximab in patients with wild-type RAS metastatic colorectal cancer

Presentation Number
493P
Lecture Time
12:45 - 12:45
Speakers
  • Eiji Oki (FUKUOKA, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Combination therapy with oral fluoropyrimidine and irinotecan with cetuximab has not yet been established as first-line treatment of metastatic colorectal cancer (mCRC). This study was designed to assess the tolerability of different doses of tri-weekly intravenous infusion of irinotecan in combination with S-1 (IRIS) and weekly cetuximab (phase I) and explore the efficacy and safety of the IRIS in combination with cetuximab in patients with mCRC (phase II).

Methods

Main eligibility was RAS (exon 2) wild-type mCRC and without any prior chemotherapy except for adjuvant therapy. S-1 was given orally at a dose of 40 mg/m2 (40-60mg) twice for 2 weeks, followed by a 1-week rest. Irinotecan (150mg/m2) was given on days 1. Cetuximab was administered on days 1 (400 mg/ m2), 8 (250 mg/ m2) and 15 (250 mg/ m2), followed by every week (250 mg/ m2) thereafter. A standard 3 + 3 phase I dose de-escalation design was utilized to decide maximum tolerant dose (MTD) and recommend dose (RD) of irinotecan. Primary endpoint of Phase II part was overall response rate (ORR). We set the expected and threshold RRs at 60% and 40%, respectively. ORR was assessed by central office according to RECIST version 1.1 criteria.

Results

Between December 2014 and September 2017, 58 patients were enrolled. Seven patients were excluded owing to ineligibility. No dose limiting toxicity was observed in phase I part and RD irinotecan was decided at 150mg/m2. In phase II part, the treatment response with confirmation was complete response (CR) in 1, and partial response (PR) in 28, stable disease (SD) in 15, progressive disease (PD) in 6, not evaluated (NE) in 1, final response rate was 56.9% (90 %; CI 44.4 – 68.7 %, p = 0.011). The safety profile revealed the common Grade 3/4 adverse events to be neutropenia (31.4%), appetite loss (27.5%), hypokalemia (11.8%) and diarrhea (11.8%). Grade 3/4 HFS occurred in 9 patients (9.8%).

Conclusions

This study showed the efficacy and safely was comparable to other first line treatment regimens. The results support IRIS/cetuximab is more convenient and provide treatment flexibility in first line treatment with metastatic colorectal cancers.

Clinical trial identification

UMIN000015835.

Legal entity responsible for the study

This work was supported by CReS Kyushu with funding from Merck Serono, Japan, under a research contract.

Funding

Merck Serono.

Disclosure

E. Oki: Honoraria for lecturing: Bayer Yakuhin, Ltd, Japan; Eli Lilly Japan K.K.; Taiho Pharmaceutical Co., Ltd.; Yakult Honsha Co., Ltd.; Merck Serono Co., Ltd.; Takeda Pharmaceutical Co., Ltd.; Johnson & Johnson K.K.; and Chugai Pharmaceutical Co., Ltd. M. Kotaka: Honoraria lecturing: Chugai Pharmaceutical Co., Ltd. H. Baba, Y. Maehara: Lecture fees: Taiho Pharm; Grant research funding: Taiho Pharm, Merck Serono, Yakult Honsha, Japan. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

494P - A multi-institutional randomized phase II study on the timing of Oxaliplatin plus 5-Fluorouracil (FOLFOX) for patients (pts) with operable stage III rectal cancer: The KIR Study.

Presentation Number
494P
Lecture Time
12:45 - 12:45
Speakers
  • Petr Kavan (Montreal, CA)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Recent randomized studies have shown low compliance to adjuvant chemotherapy in stage III rectal cancer pts who received preoperative combined chemotherapy and external beam radiation (CT/EBRT) with total mesorectal excision (TME surgery). We examined whether giving part of the chemotherapy prior to radiotherapy (delivered by brachytherapy (HDRBT)) and surgery (instead of chemotherapy after RT and surgery, which is the current standard of care) for pts with node positive operable rectal cancer, would result in higher pt compliance to chemotherapy.

Methods

Between 2010-2017, 180 eligible pts were randomly assigned (2:1) to two arms, 6 cycles of FOLFOX prior to radiotherapy and surgery following by 6 cycles of FOLFOX in adjuvant (Arm A, (AA)), or 12 cycles of FOLFOX in adjuvant (Arm B, (AB)). The primary end point was compliance to chemotherapy (pts receiving at least 85% of full-dose CT prescribed at each cycle (x 12 cycles), 1 yr post-diagnosis); secondary end points were disease free survival rate (DFS), pT0N0, local recurrence rate and overall survival (OS), 5 yrs post-surgery.

Results

All pts were randomly assigned to either AA (n = 120; 84 pts were male (M), median age (MA) was 65 years) or AB (n = 60; 35 pts were M, MA was 63.5 years). Compliance on AA was 78% and 51.9% on AB. Levels of G3/G4 toxicity were 30.8% in AA and 28.3% in AB respectively. 174 of 178 pts completed HDRBT as planned (97.7%). In AA, 3 pts progressed locally under CT. 1 pt refused HDRBT after randomization in AB. pT0N0 for AA and AB were 35pts (30.1%) and 15 pts (25%). The 3-year DFS was 80% with AA and 76% with AB (p = 0.6511). The 3-year OS for AA and AB were 94% and 85%, respectively (p = 0.8219).

Conclusions

The safety and improved compliance to neoadjuvant CT is confirmed in this study using HDRBT as a neoadjuvant modality for rectal cancer. There is no statistical difference in pT0N0 rate, local recurrence, and DFS between the two arms in the early result analysis, but favorable oncological outcomes are observed. At the time of this reporting, pelvic nodal recurrence is seldom isolated, asymptomatic and preceded by systemic failure.

Clinical trial identification

NCT01274962.

Legal entity responsible for the study

Jewish General Hospital-McGill.

Funding

Sanofi.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

495P - Tumor Regression Grading After Preoperative Hyperfractionated Radiotherapy/ Chemoradiotherapy for Locally Advanced Rectal Cancers: A Phase III Clinical Study

Presentation Number
495P
Lecture Time
12:45 - 12:45
Speakers
  • ADAM IDASIAK (Gliwice, PL)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

We investigated tumor regression grading (TRG) as a prognostic marker for disease-free survival (DFS) in patients with advanced rectal cancer treated within phase III randomized study. The study was prospective trial of preoperative hyperfractionated radiotherapy (HART) compared with concomitant hyperfractionated radiotherapy with co-administration of chemotherapy based on 5FU (HART-CT) in patients with T2/N+ or T3/any N resectable mid-low primary rectal cancer.

Methods

The 136 patients were randomly assigned to HART (n = 69) and HART-CT (n = 67). The pelvis was irradiated twice a day (28 fractions of 1.5 Gy), with a minimal interfraction interval of 8 hrs to total dose 42 Gy over 18 days (HART) or mentioned scheme with concurrent chemotherapy: 5FU-325mg/m2 (bolus) on days 1-3 and days 16-18 (HART-CT). Surgery was performed 5-6 weeks after HART/HART-CT. The TRG was recorded using 4-point scale: TRG0 (pCR) denoted no cancer cells; TRG1 - cancer cells less than 10% of a tumor mass; TRG2 cancer cells in 10-50% or TRG3 - cancer cells in more than 50% of tumor mass. Multivariable analysis was performed using Cox regression models adjusted for treatment arm, resection status and pathologic stage. Cox proportional hazard model was used in survival analysis.

Results

The crude rate of patients with any serious adverse events during the follow-up was 12% vs. 17% for HART and HART-CT. Anterior resection was performed in 52% vs. 62% for HART and HART-CT respectively (p = 0.06). Of the 136 patients evaluable for pathologic response there were 3(4%) vs. 9(13%), 16(23%) vs. 24(36%), 40(58%) vs. 30(45%), and 10 (15%) vs. 4(6%) patients with TRG 0, 1, 2 and 3, respectively in HART vs. HART-CT, the difference was statistically significant p = 0.002. The actuarial 2-year cumulative loco-regional relapse free survival control rates (LRC) for HART vs. HART-CT were 86% vs. 91% and actuarial DFS control rates were 70% vs. 76%, respectively.

Conclusions

Significant differences in the tumor regression grading (TRG) were found. Both LRC and DFS of rectal cancer patients treated with HART vs. HART-CT had favorable outcomes in those allocated to HART-CT. Also the sphincter preservation rate tended to favor HART-CT.

Clinical trial identification

NCT01814969.

Legal entity responsible for the study

Maria Skłodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, 44-100 Gliwice, Poland.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

496P - Short-Term radiotherapy plus chEmotherapy versus Long-term chemoradiotherapy in Locally Advanced Rectal cancer (STELLAR): a planned interim analysis

Presentation Number
496P
Lecture Time
12:45 - 12:45
Speakers
  • Jing Jin (Beijing, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

At present, distant metastasis remains the main cause of failure for locally advanced rectal cancer (LARC), efficient short-course radiotherapy (SCRT) combined with neoadjuvant chemotherapy is an attempt of optimizing pre-operative treatment.

Methods

We did this randomized, phase III study in multiple centers in China. Patients with middle or lower rectal adenocarcinomas, staged cT3-4 and/or N1-2 by MRI, were randomly assigned to receive 5Gy × 5 and 4 courses of CAPOX (experimental group) or 50 Gy in 25 fractions concurrently with capecitabine (control group). TME in both groups was performed 6-8 weeks later, then two or six courses of CAPOX as postoperative chemotherapy was prescribed in experimental or control group, respectively. The purpose of this interim analysis was focusing on the compararison of primary enrolled 100 patients.

Results

Initially enrolled 100 patients, 51 in experimental group and 49 in control group were analyzed, with MRF+ 27.5% vs. 30.6%, MRI based T3-4 92.2% vs. 98.0%, N1-2 74.5% vs. 77.6%, and EMVI scores3-4 52.9% vs. 65.3% in each group. The completion rates of neoadjuvant treatment were 98.0% vs. 100% (p = 0.325), with incidences of grade III-IV toxicity 17.6% vs. 4.1% (p = 0.076) in each group, respectively. 80 patients completed surgery and 7 patients (all in experimental group) chose “watch-and-wait” policy due to clinical complete remission (cCR) after neoadjuvant treatment. 92.9% and 89.5% of patients in experimental and control group had R0 resection (p = 0.593), while 26.2% and 5.3% of them achieved ypT0N0 (p = 0.011), respectively. The completion rates of adjuvant chemotherapy were 76.2% vs. 65.8% (p = 0.305) in each group, respectively. On the whole, the patients who had received 6 cycles of chemotherapy accounted for 62.7% vs. 49.0% (p = 0.000) in experimental and control group, and there were 76.5% and 49.0% of patients who could complete all planned treatments in each group, respectively.

Conclusions

The interim analysis revealed the acute toxicity and surgical complication were acceptable and comparable in both groups, however, the people in experimental group showed better treatment completion.

Clinical trial identification

NCT02533271.

Legal entity responsible for the study

National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College.

Funding

Collaborative Innovation Center for Cancer Medicine [No. XT2015-03].

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

497P - mFOLFOXIRI versus mFOLFOX6 as neoadjuvant chemotherapy in locally advanced rectal cancer: A Propensity Score Analysis from two prospective trials

Presentation Number
497P
Lecture Time
12:45 - 12:45
Speakers
  • JianWei Zhang (Guangzhou, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Neoadjuvant chemoradiotherapy (CRT) is the standard of treatment for locally advanced rectal cancer, but it delays administration of systemic chemotherapy, leading to high incidence of distant metastases. To enhance systemic chemotherapy and avoid the damage of radiation, full dose of neoadjuvant chemotherapy regimens with mFOLFOXIRI or mFOLFOX6 were both under investigation. Here, we aimed to compare the safety and efficacy of preoperative chemotherapy with mFOLFOXIRI versus mFOLFOX6 in locally advanced rectal cancer.

Methods

Prospectively maintained databases of patients from two clinical trials (NCT01211210 and NCT02217020) underwent preoperative treatment for locally advanced rectal cancer in a single center were included. Those had received mFOLFOXIRI or mFOLFOX6 chemotherapy alone preoperatively was selected for this study, including 90 patients with mFOLFOXIRI and 119 patients with mFOLFOX6. All patients had undergone total mesorectal excision. A comparative analysis was performed after the implementation of propensity score matching on the 2 main cohorts (mFOLFOXIRI and mFOLFOX6).

Results

A total of 209 patients were enrolled in the study. After propensity score matching, 180 patients were selected. 90 patients were comparable in the two groups. Higher pathologic complete response rate was observed in mFOLFOXIRI group than that of mFOLFOX6 group (16.7% vs. 5.6%, p = 0.03), although the tumor downstaging (ypT0-2N0M0) rate was comparable in this two group (41.1% vs. 37.8%, P = 0.76). The anal preservation rate was similar between the two groups (87.8% vs. 89.2%). Higher incidence of grade 3/4neutropenia (42.2% vs. 10%, P < 0.001) was shown in mFOLFOXIRI group than that of mFOLFOX6 group.

Conclusions

Preoperative mFOLFOXIRI chemotherapy showed higher pCR rate than that of mFOLFOX6. The tumor downstaging rate was comparable between the two regimens. But the adverse events were more common in mFOLFOXIRI group. Whether the intensive regimen would improve the survival is unknown. Further follow-up is needed.

Clinical trial identification

NCT01211210 and NCT02217020.

Legal entity responsible for the study

Yanhong Deng.

Funding

Has not received any funding.

Editorial Acknowledgement

none

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

498P - Phase 1/2 study of valproic acid (VPA) and short-course radiotherapy (SCRT) plus capecitabine (CAP) as preoperative treatment in low-moderate risk rectal cancer (V-shoRT-R3).

Presentation Number
498P
Lecture Time
12:45 - 12:45
Speakers
  • Alfredo Budillon (Napoli, IT)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Recurrence with distant metastases is the predominant pattern of failure in locally advanced rectal cancer (LARC), thus the integration of new agents into preoperative fluoropyrimidine-based chemo-radiotherapy represents a clinical challenge to intensify the therapeutic strategy. We have recently reported synergistic antitumor interaction between valproic acid (VPA), an histone-deacetylase inhibitor, capecitabine (CAP) and radiotherapy in colorectal cancer preclinical models.

Methods

We planned two parallel phase-1 studies in low-moderate risk LARC patients (pts) to assess the safety of preoperative short-course radiotherapy (SCRT) (5 Gy/day on days 1 to 5 days) combined with (a) CAP alone (4 increasing dose levels: 500 to 825 mg/m2/bid, on days -1 to 20), or (b) CAP as above plus VPA (orally on days -14 to 21, with an intra-patient titration for a target serum level of 50-100 μg/ml), followed by surgery 8 weeks after the end of SCRT. Within each of the two phase-1 trials, maximum tolerated dose (MTD) was defined as the dose level that produces a dose-limiting toxicity (DLT) occurring within 5 weeks from day 1 of treatment in more than one-third of pts. Correlative studies on pharmacokinetic and pharmacodynamics biomarkers on both tumor and peripheral blood samples as well as FDG-PET were also planned.

Results

From Apr 2013 and Oct 2018, 28 pts were enrolled in the two phase-1 studies. Median age was 61 (range 46-71), 100% were PS 0. No DLT occurred with CAP alone, but a symptomatic angina occurred in a patient at the first dose level of CAP plus VPA. However, no DLT was observed within the further 3 pts enrolled at the same level, nor at the following dose levels. All but one pts underwent R0 resection. TRG1 was obtained in 6 pts, TRG2 in 11 pts, TRG3 in 8 pts and TRG4 in 3 pts.

Conclusions

The addition of CAP to preoperative SCRT +/- VPA is feasible and 825 mg/m2/bid is the recommended dose that will be used in an ongoing phase-2 trial, aimed to explore whether the addition of VPA and/or CAP to preoperative SCRT might increase TRG1 rate in low-moderate risk LARC pts.

Clinical trial identification

NCT01898104.

Legal entity responsible for the study

Istituto Nazionale Tumori Fondazione G. Pascale.

Funding

Italian Ministry of Health, Grant RF-2011-02346914 to AB.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

499P - A classifier of 53BP1, immune score and texture analysis of MRI images can predict pathological response to chemoradiotherapy in locally advanced rectal cancer

Presentation Number
499P
Lecture Time
12:45 - 12:45
Speakers
  • Hong Ma (Wuhan, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Preoperative chemoradiotherapy is the standard care for advanced rectal cancer. Yet, predicting the response remains a challenge. Our previous studies found that 53BP1 protein deletion leaded to chemoradiotherapy resistance.53BP1 deficiency played pivotal role in inducing lymphocyte mature. As the development of functional imaging, texture analysis can predict response to chemoradiotherapy. Our study aims to explore the relationship among 53BP1 protein, immune score, texture analysis and radiation sensitivity, then set a new classifier to predict response in advanced rectal cancer.

Methods

We enrolled 57 advanced rectal cancer patients who received neoadjuvant chemoradiotherapy in Wuhan Union hospital from January 2015 to January 2018. The expression of 53BP1, CD3, CD8, CD45RO was detected by immunohistochemistry. Immune score were calculated, which are based on the combination of two lymphocyte populations (CD3/CD45RO, CD3/CD8 or CD8/CD45RO) both in the center (CT) and the invasive margin (IM) of tumors. T2W MRI images studies obtained in 34 patients before treatments, texture analysis by manually delineating a region of interest. The response rate, anus preservation rate were collected. The relationship among 53BP1 protein, immune score, texture analysis parameters and radiation sensitivity were explored by t-test. A new classifier was set to predict pathological response.

Results

The results indicated that the response rate in 53BP1 deletion group was significantly lower than that in 53BP1 high expression group (25.00% vs.84.44%, P < 0.005). "CD3+CD8" is the most reasonable immune score, the patients of 53BP1 deletion had lower immune score. The response rate in lower immune score group was lower than higher immune score group (54.54% vs.88.57%, P < 0.005). Texture analysis parameters were related with response rate. We set a new classifier to predict response in advanced rectal cancer, we randomly selected 10 patients as training group, others were selected as predict group, the accuracy is 83.33%.

Conclusions

A classifier of 53BP1, immune score and texture analysis of MRI can predict response in advanced rectal cancer.

Legal entity responsible for the study

Union Hospital, Tongji Medical College, Huazhong University of Science and Technology.

Funding

2015CFB659.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

500P - Mismatch repair deficient rectal cancer is resistant to induction combination chemotherapy

Presentation Number
500P
Lecture Time
12:45 - 12:45
Speakers
  • Andrea Cercek (New York, US)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Although most rectal cancers are responsive to combination induction chemotherapy, the sensitivity of mismatch repair deficient (MMR-D) rectal cancers to chemotherapy remains uncertain.

Methods

MMR-D rectal tumor cases were retrospectively reviewed with tabulation of baseline characteristics, treatment modalities and clinical outcomes. Prevalence of germline mutations in the MMR genes, diagnostic of Lynch syndrome (LS), was compared to LS-associated colon cancer patients. We also assessed somatic mutational status for a subset of these patients.

Results

Twenty of the 49 patients received induction chemotherapy with 5FU and oxaliplatin, 15 received standard neoadjuvant chemoradiation, and 14 proceeded directly to surgery. Of the 15 patients treated with induction chemoradiation, 93% (n = 14) experienced radiographic response and tumor downstaging; and none of these patients showed evidence of disease progression. In contrast, of the 18 patients treated with induction chemotherapy alone, only 61% (n = 11) experienced tumor response and 28% (n = 5) of patients demonstrated progressive disease while on therapy. The majority of these cases, 82% (41/50) harbored germline mutations in the MMR genes and the observed prevalence of germline MSH2 and MSH6 mutations was significantly higher in the rectal (n = 41) versus colon (n = 244) cancer patients (rectal vs colon: MSH2: 57% vs 37%; MSH6: 20% vs 11%; p-value <0.0005).

Conclusions

Patients with MMR-D rectal tumors appear to have a high chance of disease progression on induction chemotherapy. As opposed to LS-associated colon cancers, LS-associated rectal cancers are more likely to harbor MSH2 or MSH6 germline mutations. Upfront testing for MMR status and initial treatment with chemoradiation in MMR-D rectal tumors should be undertaken until better therapies are available.

Legal entity responsible for the study

Andrea Cercek.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

501P - Outcomes of Chemoradiotherapy plus Local Excision in Patients with Clinical T1 or T2, N0 Rectal Cancer

Presentation Number
501P
Lecture Time
12:45 - 12:45
Speakers
  • Toshiyuki Suzuki (Isehara, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

NCCN guidelines recommend local excision (LE) as a standard treatment for selected patients with cT1/T2,N0,M0 rectal cancer. However, the rates of local recurrence after LE alone were 12.5% in cT1 disease and 22.1% in cT2 disease and those after total mesorectal excision (TME) were 6.9% and 15.1%, respectively. In pathological T1 disease, adding (chemo)radiotherapy (CRT) to LE decreased the rate of local recurrence to 5%, which was comparable to the rate after TME (4%). In pT2 disease who underwent LE, the local recurrence rate decreased slightly but remained high (14%) even after CRT.

Methods

In our institution, patients with cT1, N0 disease with a tumor diameter of less than 30 mm underwent transanal full thickness LE and additionally receive CRT (40/45Gy plus UFT or S-1). Patients with poorly differentiated adenocarcinoma or mucinous carcinoma should additionally undergo TME. Patients with cT2, N0 disease underwent transanal LE after CRT. Patients whose tumors include poorly differentiated adenocarcinoma or mucinous carcinoma should receive TME.

Results

In accordance with these treatment policy, LE was performed in 65 patients with cT1, N0 disease, 50 of whom additionally received CRT. The median follow-up was 71 months. Local recurrence occurred in 1 patient (2%), and distant metastasis occurred in 3 patients (6%). The 5-year disease-free survival rate (5y DFS) was 86%, and the 5-year overall survival rate (5y OS) was 92%. Patients with pT1 disease who had local nodal recurrence underwent abdominoperineal resection and are still alive with no recurrence. In 53 patients with cT2, N0 disease, LE was performed after CRT. Four patients had pT3 disease and additionally underwent TME. In the other 49 patients, six patients (12%) had local recurrence at the anastomotic site, and 7 (14%) had distant metastasis. The 5y DFS was 70%, and the 5y OS was 87%.

Conclusions

These results suggested that multidisciplinary treatment combining chemoradiotherapy with local excision is a treatment option in some patients with a preoperative diagnosis of clinical T1, N0 or T2, N0 rectal cancer. However, further studies are needed to determine the optimal treatment for patients with clinical T2, N0 rectal cancer.

Legal entity responsible for the study

Sotaro Sadahiro.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

502P - Comparison of Immune Microenvironment between Different Neoadjuvant Radiotherapy Regimens for Rectal Cancer

Presentation Number
502P
Lecture Time
12:45 - 12:45
Speakers
  • Junxin Wu (Fuzhou, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Conventionally neoadjuvant radiotherapy regimens for rectal cancer are long-course radiotherapy in combination with chemotherapy (LCRT) and short-course radiotherapy (SCRT). We aimed to compare the different immune microenvironment in patients between two the different radiotherapy regimens.

Methods

The expression of LAG-3, CD8 and CD3 was detected by immunohistochemistry on specimen of 76 rectal cancer patients following neoadjuvant treatment. The expression of proteins was assessed as the percentage of positive cells (PP). The variation of proteins expression was compared by Mann-Whitney U test analysis.

Results

LCRT was given in 40 (52.6%) patients and the rest 36 (47.4%) patients were SCRT. The median PP of immune cells LAG-3 expression was 15% (range, 0% - 80%) in all patients. The expression of CD8 and CD3 were 10% (range, 0 - 80%) and 30% (range, 0 - 90%), respectively. The LAG-3 expression was high in patients with SCRT compared to LCRT (22.5% vs. 8.0%, P = 0.0440). On the contrary, CD8+ cells were high in LCRT (15% vs. 8%, P = 0.0146). No difference was observed in CD3+ cells.

Conclusions

Tumor microenvironment might be modified by different fractions and dose. Immune cells LAG-3 expression were high with respect to SCRT. The diverse expression pattern of LAG-3 between SCRT and LCRT supporting the different combination strategies of immune checkpoint blockade and neoadjuvant radiotherapy.

Legal entity responsible for the study

Junxin Wu.

Funding

National Clinical Key Specialty Construction Program, The Fujian Province Natural Science Foundation (2017J01260).

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

503P - Prognostic factors of chemo-radiotherapy efficacy in patients with locally-advanced rectal cancer

Presentation Number
503P
Lecture Time
12:45 - 12:45
Speakers
  • Mikhail Fedyanin (Moscow, RU)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

We decided to evaluate preoperative clinical factors associated with progression free survival, overall survival and tumor regression in patients with locally-advanced rectal cancer after chemo-radiotherapy.

Methods

we analyzed prospective database of patients with locally-advancded rectal cancer (cT3-4N0-2M0) who received preoperative chemo-radiotherapy followed by surgery in our center from 2004 to 2013. Multivariate regression analyses was performed to evaluate odds of absent morphological response (Dworak tumo regression rate system 0-2) and hazards of progression and deaths. Statistical analyses was performed with SPSS v.20.

Results

Chemo-radiotherapy followed by surgery was performed in 457 patients with locally-advanced rectal cancer. The median f.-up was 46 months (2-141), 3-year progression free survival and overall survival were 79% and 91%, respectively. Multivariate regression analyses revealed factors associated with tumor regression rate 0-2 as high level (above normal range) CEA (carcinoembryonic antigen) before chemo-radiotherapy (OR 1.49 95%CI 1.11-2.02, p = 0.008), neutrophils count ≥ 7,000/µl (OR 2.29, 95%CI 1.0-5.2, p=0.05) and cT4 (OR 3.73, 95%CI 2.03-6.86, p < 0.001). Independent negative prognostic factors for progression free survival were perineural invasion (HR 3.1, 95% CI 1.43-6.89, p<0,001), neutrophil/lymphocyte ratio before surgery ≥ 3 (HR 1.8, 95%CI 1.37-2.42, p=0.01) and ypT3-4 or/and N + (HR 1.82, 95%CI 0.45-0.92, p<0.01). For overall survival: ypT3-4 or/and N + (HR 1.9, 95%CI 1.3-2.65, p<0.01), lymphatic vessel invasion (HR 2.4, 95%CI 1.27-4.59, p<0.01) and leucocytes count before surgery ≥11,000/µl (HR 3.1, 95%CI 1.33-7.33, p<0.01).

Conclusions

ypTNM after preoperative chemo-radiotherapy more effective than cTNM predicts progression free and overall survival in patients with localy-advanced rectal cancer.

Legal entity responsible for the study

Mikhail Fedyanin.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

504P - Association of Systemic and Local Inflammation with Prognosis in Rectal Cancer Treated with Neoadjuvant Radiotherapy

Presentation Number
504P
Lecture Time
12:45 - 12:45
Speakers
  • Jinluan Li (Fuzhou, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

To explore the characteristics of cancer-associated systemic and local inflammation and its impact on overall survival (OS) in locally advanced rectal cancer (LARC) treated with neoadjuvant radiotherapy (RT).

Methods

A consecutive cohort of 76 LARC patients underwent neoadjuvant RT were retrospectively analyzed from February 2012 to September 2015. Peripheral neutrophil to lymphocyte ratio (NLR) was calculated at diagnosis, and tumor-infiltrating lymphocyte was examined in postoperative tumor tissue by immunohistochemistry. The association between clinicopathological features and inflammation was explored through chi-square test. The prognostic factors in terms of OS were investigated through uni- and multivariate Cox regression. SPSS 22.0 was used for statistical analyses.

Results

The median follow-up time was 29.0 months (range, 2-59). The 1-, 3- and 5-year OS rates were 93.4% (95%CI 87.91-98.89), 80.0% (95%CI 69.81-90.19) and 68.6% (95%CI 46.06-91.14), respectively. High NLR (≥2.0) and low CD8+ T-cells (<9%) were more common in 76 patients (53.9% and 59.2%, respectively). For patients with high NLR and low CD8+ T-cells, 5-year OS was significantly worse than those with low NLR and high CD8+ T-cells (P = 0.005). Also, NLR ≥ 2.0 was associated with poor tumor regression after neoadjuvant RT (P = 0.039), while no significant association was found between CD8+ T-cells and tumor regression. In addition, NLR was related to lymphovascular invasion (P = 0.031). CD8+ T-cell was related to neural invasion (P = 0.048) and mucinous adenocarcinoma (P = 0.045). Furthermore, NLR (HR 7.71, 95%CI 1.30-45.71, P = 0.025), CD8+ T-cells (HR 0.09, 95%CI 0.01-0.67, P = 0.018) , age (HR 16.1, 95%CI 1.56-167.15, P = 0.020), lymphovascular invasion (HR 7.17, 95%CI 1.12-46.05, P = 0.038) and T stage (HR 0.03, 95%CI 0.00-0.45, P = 0.011) were independent risk factors for prognosis according to multivariate Cox regression.

Conclusions

High NLR and low CD8+ T-cells were significantly associated with dismal survival. Systemic combined with local inflammation might help to predict prognosis of LARC with neoadjuvant RT.

Legal entity responsible for the study

Jun-xin Wu.

Funding

National Clinical Key Specialty Construction Program.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

505P - Early prediction of histopathological response by PET/CT after two weeks of neoadjuvant chemoradiotherapy for rectal cancer: Wishful thinking or reality?

Presentation Number
505P
Lecture Time
12:45 - 12:45
Speakers
  • Yulia Kundel (Petah Tikva, IL)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Neoadjuvant chemoradiotherapy (CRT) is standard in locally advanced rectal cancer (LARC). Current data on the predictive value of early PET/CT, i.e. the correlation between the tumor’s early metabolic response, manifested by the reduction of its 18F-FDG uptake after two weeks of CRT compared with baseline, and histopathological response, are conflicting.

Methods

Patients (pts) with histologically confirmed LARC who were planned to receive standard CRT regimen of 50.4 Gray radiotherapy with concurrent fluoropyrimidine–based chemotherapy followed by radical surgery were eligible for the study. Baseline PET/CT was done within 4 weeks prior to CRT and the investigational scan was done two weeks+/-two days after its initiation. Maximum standardized uptake value (SUV-MAX) and the changes in FDG uptake between the two scans (ΔSUV-MAX) were compared with the histopathological response at surgery. Response was classified by tumor regression grade (TRG) and presence of pathological complete response (pCR).

Results

Twenty pts were included in the study, 65% with clinical stage II and 35% with stage III. Ninety percents of tumors were located at least 5 cm from the anal verge. Pts underwent surgery within a median of 8.6 weeks (4.5-12.8) after the completion of CRT. Six pts (30%) achieved pCR and 7 (35%) had TRG I-II. Absolute SUV-MAX values at both time points did not correlate with pCR (p = 0.099) nor with TRG (p = 0.670). Histopathological response also did not correlate with ΔSUV-MAX: pts who achieved pCR had median ΔSUV-MAX of -45%, while those who did not had median ΔSUV-MAX of -41% (p = 0.617). Similarly, pts with TRG I-II and those with TRG III-IV had the same median ΔSUV-MAX of -42% (p = 0.882). In addition, using ROC analysis we did not find any cutoff of any the PET-CT parameters that will predict pCR or TRG I-II.

Conclusions

In the current study, early PET/CT done after two weeks of neoadjuvant CRT for LARC, failed to predict histopathological response to treatment.

Legal entity responsible for the study

Rabin Medical Center.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

506P - Association between obesity and efficacy of chemoradiotherapy in rectal cancer patients

Presentation Number
506P
Lecture Time
12:45 - 12:45
Speakers
  • CONSUELO Diaz Romero (Ciudad de México, MX)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Obesity is a major public health problem, in Mexico there is a high prevalence of obesity. However, there have been few studies that have reported association between obesity and rectal cancer outcomes in the Mexican population. Many studies have recently revealed the relationship between obesity and cancer. Controversy remains as to whether obesity has a harmful prognostic effect in advanced stage rectal cancer patients. There is a report that obesity was associated with lower pathologic complete response rates in rectal cancer patients after neoadjuvant chemoradiotherapy. In their study, complete response was associated with better disease-free survival. Therefore, we hypothesized that obesity influenced the local treatment outcomes in patients with rectal cancer after surgery and RT.

Methods

A total of 312 eligible patients were retrospectively analyzed; from 1999 to 2014 at National Cancer Institute Mexico, they received chemo-radiotherapy concomitant before surgery for rectal cancer.

The patients were categorized as obese, overweight, normal weight, or underweight based on BMI according to World Health Organization (WHO) criteria. Pathological complete response (pCR) was defined as no invasive cancer in the rectal or lymph tissue. Chi-squared tests were used for detecting the predictors of pCR and determining the relationship between BMI category and pCR rate in the subgroup analysis with respect to other variables.

Results

Median age was 54 years (18-82), 24% of patients were obese, 31% were overweight, and 45% normal or underweight. 22% (n = 68) of patients were pCR. In multivariate analysis, there was statistical trend in pCR between treatment groups: pCR for obese 16/75 patients, overweight 21/97 and normal or underweight was 31/140 patients (p = 0.057). Nevertheless, obese patients compared with normal weight patients (OR = 0.81; 95% CI, 0.69 to 1.33 p = 0.039) were significantly less likely to have a pCR.

Conclusions

These results show an association between obesity and a poor pathological response in rectal cancer patients. This analysis suggests that higher BMI should be considered, and the mechanism of influence of BMI and obesity, on treatment response in patients with rectal cancer.

Legal entity responsible for the study

Diaz Romero Maria del Consuelo.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

507P - Treatment Outcomes of Patients with Localized Anal Squamous Cell Carcinoma and HIV Infection: Systematic Review and Meta-Analysis

Presentation Number
507P
Lecture Time
12:45 - 12:45
Speakers
  • Marcos Camandaroba (Sao Paulo, BR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Definitive chemoradiation (CRT) is the standard treatment for localized squamous cell carcinoma of the anus (SCCA). Because most phase III trials in SCCA have excluded patients with HIV, the evidence on treatment outcomes of these patients is lacking. We performed a systematic review and meta-analysis on the efficacy and toxicity profiles of HIV-positive SCCA patients treated with definitive CRT.

Methods

The systematic search was conducted Embase, Medline, Cochrane Libary, Scopus, Lilacs and Opengrey, from inception until September 2017. Eligible studies were clinical trials, prospective or retrospective cohorts studies. The main outcome variables were 3-year disease-free (DFS) and overall survival (OS) rates and frequency of grade 3 or 4 (G3/4) treatment-related toxicities, according to HIV status. Meta-analyses using pooled risk ratios were performed for binary outcomes from comparative studies from the antiretroviral therapy era with random and fixed effects models.

Results

Out of 3,951 studies, 40 were deemed eligible, with a total of 3,720 patients. One third (N = 1,298; 34%) were HIV-positive and their median pre CRT CD4 count was 347 um/L. HIV-positive patients presented trends for higher risk of G3/4 cutaneous toxicities (Risk Ratio [RR]: 1.56,95% [CI] 0.98-2.48;p0.061; I2= 77%), G3/4 leukopenia (RR: 1.28, 95% [CI] 0.96-1.70; p = 0.088; I2= 0%) and inferior 3-year DFS rate (RR: 1.52, 95% [CI] 0.99-2.33, p = 0.057; I2= 52.19%), and significantly worse 3-year OS rate (RR: 1.64, 95% [CI] 1.27-2.11,p< 0.001; I2= 0%).

Conclusions

Patients with localized SCCA and HIV infection treated with CRT tend to experience higher risk of toxicities and worse DFS and OS rates. Our findings suggest that future trials should be tailored to HIV-positive patients.

Legal entity responsible for the study

Rachel Riechelmann.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

508P - p16 and PD-L1 expression in locoregional squamous cell carcinoma of the anal canal – A single center retrospective analysis in Japan

Presentation Number
508P
Lecture Time
12:45 - 12:45
Speakers
  • Ryo Takahashi (Tokyo, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Squamous cell carcinoma of the anal canal (SCCA) is a rare malignancy especially in Asia. It is widely known that SCCA is linked to prior infection with human papillomavirus (HPV) in western countries. However, it is unclear whether HPV is associated with SCCA in Japan. In addition, expression of PD-L1, potential predictive marker for anti-PD-1 antibody, and its prognostic impact on locoregional SCCA remain to be elucidated. The aim of this study is to examine expression rates and prognostic impact of p16 and PD-L1 in Japanese patients with SCCA.

Methods

34 patients with locoregional SCCA were treated by concurrent CRT at the Cancer Institute Hospital between 2007 and 2017. Among them, 28 patients whose biopsy specimens were available were enrolled. Radiation consisted of 45.0-59.4 Gy. Chemotherapy was given during radiation: 1000mg/m2 daily fluorouracil on day 1-4 and 29-32, and a single dose of mitomycin C 10mg/m2 administered on day 1 and 29. Data on relapse and death were obtained until March 2018. p16 positive was defined as p16 was stained on tumor nuclei. PD-L1 positive was also defined as PD-L1 was overexpressed on tumor membrane with more than 2+ score and the area was more than 5%.

Results

Of 28 patients, the median age was 59 (range 35-82) years. Male to female sex ratio was 1:6. 6 (21.4%) were clinically staged as I, 4 (14.3%) as II, 5 (17.9%) as IIIA, and 13 (46.4%) as IIIB. SCCA remained or recurred in 1 with cStage II, 1 with cStage IIIA and 7 with cStage IIIB. 3-year disease free survival (DFS) was 65.8% (95%CI, 44.3-80.6%), and 3-year overall survival (OS) was 79.2% (95%CI, 53.4-91.7%). Of 28 cases, 27 (96.4%) were positive for p16, and 6 (21.4%) were positive for PD-L1. In univariate analysis for DFS and OS, lymph node metastasis was significantly related to poor outcomes (DFS, p = 0.0289; OS, p < 0.0001). T factor (p < 0.0001) and tumor stage (p = 0.0035) significantly influenced OS. No significantly difference was found in terms of PD-L1 expression (DFS, p = 0.595; OS, p = 0.544).

Conclusions

High expression rate of p16 was observed in Japanese patients with locoregional SCCA. Lymph node metastasis, advanced T factor and tumor stage were negative prognostic factors for CRT, but no prognostic impact of PD-L1 was found.

Legal entity responsible for the study

Ryo Takahashi.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

509P - Factors influencing conversion to resectability and survival after resection of metastases in RAS WT metastatic colorectal cancer (mCRC): a FIRE-3 analysis

Presentation Number
509P
Lecture Time
12:45 - 12:45
Speakers
  • Dominik P. Modest (Munich, DE)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Paired tumor evaluations before randomization and at best response (nadir) of 270 patients with RAS WT tumors treated with first-line therapy with cetuximab (cet) vs. bevacizumab (bev)- in combination with FOLFIRI were reviewed for resectability of metastates. We assessed parameters influencing resectability, conversion to resectability and survival after nadir.

Methods

Baseline information and resectability were correlated with Fisher’s exact tests. Conversion to resectability was defined as unresectable disease before randomization and resectable disease at nadir. Univariate and multivariate logistic models were fitted with resectability at nadir as response variable. A Cox model comparing the survival from nadir was used to measure the influence of treatment, resectability at nadir and resection (time dependent variable). Interaction of resection and treatment arm on survival was tested by likelihood ratio test.

Results

Initial Lung metastases (OR = 0.35 95% CI = (0.19 - 0.63), p = 0.001), BRAF mutation (OR = 0.33 95% CI = (0.12-0.82), p = 0.03) and high alkaline phosphatase (OR = 0.51, 95% CI = (0.31-0.81), p = 0.006) were associated with less chance of conversion to resectability and in case of lung metastases also of being resected if resectability at nadir was observed (OR = 0.33, 95% CI = (0.08-1.04) p = 0.046). Early tumor shrinkage (=ETS: -20% tumor diameter after 6 weeks therapy) and depth of response (DpR) were associated with conversion to resectability (ETS: OR = 1.86, 95% CI = (1.06-3.3), p = 0.034, DpR: OR = 1.02, 95% CI = (1.01-1.03), p < 0.001). Metastatic resection improved post-nadir survival (HR = 0.53, 95% CI = (0.29- 0.97), p = 0.04). This was pronounced in cet-treated patients as compared to bev-treated patients (HR (cet)=0.17, 95% CI = (0.04-0.69), p = 0.01; HR (bev)=0.89, 95% CI = (0.47-1.69), p = 0.73; interaction test p = 0.02).

Conclusions

Conversion to resectability is associated with baseline characteristics like lung metastases and BRAF mutation as well as with early efficacy parameters (ETS, DpR). In FIRE-3, resection of metastases was associated with improved post-nadir survival, this effect originated predominantly from the cetuximab-based study arm.

Clinical trial identification

NCT00433927.

Legal entity responsible for the study

Klinikum der Universität (LMU), Munich, Germany.

Funding

Merck Serono.

Disclosure

D.P. Modest: Grants: Merck KGaA, Pfizer, Visage Imaging, during the conduct of the study; Grants and personal fees: Merck KGaA, Amgen, Roche, Bayer; Grants: Sanofi, outside the submitted work. V. Heinemann: Grants: Merck, Pfizer during the conduct of this study, Grants: Amgen, Roche, Sanofi Sirtex outside the submitted work. G. Folprecht: Honoraries: Roche/Genentech, Bayer, Amgen, Lilly and Servier, Study grant, Honoraries: Merck-Serono, outside the submitted work. T. Denecke: Grants and personal fees: Bayer and B.E Imaging; Personal fees: Toshiba, Novartis, Ipsen and Parexel; Grants, personal fees and non-financial support: Siemens, GE; Grants: Guerbet; Non-financial support: Visage Imaging, outside the submitted work. C. Bruns: Personal fees: Merck, Sirtex, Grant: Celgene, outside the submitted work B. Gebauer: Personal fees: Merck KGaA, Pfizer; Personal fees, Study support: Visage Imaging, during the conduct of the study; Personal fees: Parexel, C.R. Bard, Sirtex Medical, Roche, Merck, Bayer, Icon, Ipsen, Siemens outside the submitted work; Travel support: Cook Medical, 3M, St Jude Medical; Travel and study support: AngioDynamics; Study support: Philips, outside the submitted work U. Neumann: Study grant: Merck during the conduct of the study; Study grant and personal fees: Merck outside the submitted work; Personal fees: Roche, Amgen, Novartis, Chiesi and Astellas during the submitted work. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

510P - Targeted therapies in conversion therapy in mCRC: A systematic review and meta-analysis

Presentation Number
510P
Lecture Time
12:45 - 12:45
Speakers
  • Baocai Xing (Changsha, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Chemotherapy (CT) plays a vital role as conversion treatment for initially unresectable or borderline resectable colorectal cancer (CRC). Targeted therapies are recommended with CT for conversion therapy; however, their role in conversion of initially unresectable tumours has not been elucidated. This meta-analysis evaluated the role of targeted therapies for conversion aimed at R0 resection in KRAS WT mCRC.

Methods

We conducted a literature search for randomized controlled trials (RCTs) in PubMed, Embase and Cochrane library evaluating the role of anti EGFR and anti VEGF as conversion therapies. A comparison was performed for anti-EGFR + CT vs. anti-VEGF + CT (Gp. A) and anti-EGFR + CT vs. CT (Gp. B). R0 resection rate and objective response rate (ORR) were the primary outcomes; with overall survival (OS), progression free survival (PFS) and safety evaluated as the secondary outcomes. Primary outcomes and safety were presented as relative risk (RR) and 95% confidence interval (CI), whereas survival was presented as hazard ratio (HR) and 95%CI.

Results

We identified 8 RCTs from the potential 81 studies. In Gp. A, a fixed effects model was used for analysis; and showed that although non-significant, anti EGFR + CT had better R0 resection rate (RR 1.44, 95% CI 0.91,2.27; p = 0.1156; I2 = 0%) and ORR (RR 1.05, 95% CI 0.88, 1.24; p = 0.6039; I2 = 0%) compared with anti VEGF + CT. OS with anti EGFR + CT was significantly longer than anti VEGF + CT (HR: 0.64; CI 0.47, 0.86; p = 0.0036; I2 = 0%); however, PFS was numerically better in anti EGFR + CT. Compared with CT alone, anti EGFR + CT resulted in significantly higher R0 resection rate (RR 1.85, 95% CI 1.15,2.98; p = 0.0107; I2 = 57.16%) and ORR (RR 1.19, 95% CI 1.11, 1.28; p < 0.0001; I2 = 0%). In Gp. B, only PFS was significantly longer with anti EGFR + CT vs. CT (HR: 0.85; 95% CI 0.74, 0.98; p = 0.0015; I2 = 45.60%), and not OS. Safety evaluation showed anti EGFR + CT with significantly greater adverse events than CT alone (RR: 1.26; 95% CI: 1.18, 1.35; p < 0.0001).

Conclusions

In conclusion, anti EGFR + CT was an effective conversion therapy compared with anti VEGF + CT and CT in patients with initially unresectable mCRC; however, frequency of AEs was more with targeted therapy.

Legal entity responsible for the study

Merck Serono Co. Ltd.

Funding

Merck Serono Co. Ltd.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

511P - Morphologic response to chemotherapy containing bevacizumab in patients with colorectal liver metastases (CLM): a post hoc analysis of the WJOG4407G phase III study

Presentation Number
511P
Lecture Time
12:45 - 12:45
Speakers
  • Ayumu Hosokawa (Miyazaki, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The phase III WJOG4407G study showed non-inferiority of FOLFIRI plus bevacizumab to mFOLFOX6 plus bevacizumab in progression-free survival, as the first-line chemotherapy for patients with metastatic colorectal cancer. The aim of this study was to evaluate the predictive and prognostic value of morphologic response to first-line chemotherapy containing bevacizumab in patients with CLM.

Methods

This study is a post hoc analysis of patients from the WJOG4407G study. Morphologic response was assessed with the comparison of baseline and week 8 contrast-enhanced CT images. Three blinded radiologists evaluated CT images and classified as optimal, incomplete or none response according to the morphologic criteria. RECIST response, early tumor shrinkage (ETS) and depth of response (DpR) were also evaluated. The Cox proportional hazards model was used to investigate the association between radiological variables and progression-free survival (PFS) and overall survival (OS).

Results

Of 395 patients who were eligible for efficacy analysis in the WJOG4407G study, 70 patients had liver-limited disease. Enhanced CT images of 57 of these patients from 22 participating centers were collected. Two patients were excluded from this analysis because their post-chemotherapy metastases were too small. Optimal morphologic response was identified in 19 of 55 patients (34.5%). The median PFS was 10.7 months for patients with optimal response and 10.1 months in those with incomplete/no response (log-rank p = 0.96). The median OS was 26.2 and 35.5 months, respectively (log-rank p = 0.062). According to univariate analysis, morphologic response was not associated with PFS or OS, whereas RECIST response was significantly associated with both PFS and OS, with ETS and DpR being associated with significantly longer PFS.

Conclusions

Morphologic response might be neither predictive nor prognostic factor in patients with CLM undergoing chemotherapy containing bevacizumab, whereas RECIST response was significantly associated with both PFS and OS.

Clinical trial identification

UMIN000022171.

Legal entity responsible for the study

West Japan Oncology Group.

Funding

West Japan Oncology Group.

Disclosure

A. Hosokawa: Honoraria: Taiho, Chugai, Takeda, Ono, Novartis, Eisai, Eli Lilly; Research funding: Taiho, Chugai, Ono, Eisai, Yakult. K. Yamazaki: Speakers’ bureau: Chugai, Takeda, Taiho, Yakult, Merck Serono, Eli Lilly, Sanofi, Bayer E. Baba: Speakers’ bureau: Chugai, Eli Lilly; Research funding: Ono, Chugai, Eli Lilly, Takeda, Taiho, Merck Serono. K. Shinozaki: Honoraria: Chugai, Takeda, Mochida, Merck Serono, Taiho, Yakult, Astellas, Novartis, Eisai, Eli Lilly, Shionogi, Kyowa Hakko Kirin, Asahi Kasei, MSD. S. Morita: Honoraria: Chugai Pharma, Daiichi Sankyo. K. Muro: Honoraria: Chugai, Taiho, Bayer, Ono, Eli Lilly, Takeda; Research funding: Ono, MSD, Daiichi Sankyo, Kyowa Hakko Kirin, Gilead Sciences, Shionogi. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

512P - KRAS mutations as a prognostic factor after metastasectomy in colorectal cancer patients

Presentation Number
512P
Lecture Time
12:45 - 12:45
Speakers
  • Marta Domenech Viñolas (Barcelona, ES)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Different clinicopathological factors have been associated with survival after liver metastasis resection in metastatic colorectal cancer (mCRC) patients. However, there is a need to better identify those patients who may benefit from metastasis resection. In this retrospective study we aimed to analyse clinical outcomes according to KRAS mutational status in a prospective collected series of mCRC patients.

Methods

We evaluated mCRC patients with exon 2 KRAS mutational status assessed between 2010 and 2014. Exon 2 KRAS mutational analysis was performed by therascreen® or cobas® assays. We excluded patients (pts) with no clinical data available. Disease-free survival (DFS) and overall survival (OS) were calculated using the Kaplan-Meier method.

Results

KRAS mutational status was assessed in 395 mCRC patients, but clinical data were only available in 348 patients. Median age was 66 years old. Two hundred and twenty-six patients were male (65%) and 210 pts (60%) had synchronous metastases at diagnosis. KRAS mutations were detected in 175 tumours (51%). Liver was the most common site of metastasis (210 pts, 60%), followed by lung (133 pts, 33%), lymph nodes (56 pts, 16%) and peritoneum (44 pts, 11%). Lung metastases at diagnosis were more frequent in KRAS mutant tumours (38% vs 27%, p-value = 0.022). We observed different metastasis spread pattern between pts with KRAS mutant and KRAS wt tumours. Risk of lung metastasis after 50 months of follow-up was higher in KRAS mutant tumours (77% vs 60%, p=.023). Risk of brain metastasis was also higher (18% vs 2%, p=.012). Median OS was 37 months, with no differences observed between KRAS mutant and KRAS wt tumours (34 vs 41 months, p-value = .70). One hundred thirty-nine patients underwent metastases resection (39.9%). In this subgroup of patients, KRAS mutations were associated with worse DFS (13.3 vs 24.5 months, p-value=.024).

Conclusions

KRAS mutations were associated with lung metastasis in CRC patients and different pattern spread. Although KRAS mutations were not a prognostic biomarker in the metastatic setting, patients with KRAS mutant tumours had a shorter DFS after metastasis resection.

Legal entity responsible for the study

Catalan Institute of Oncology.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

513P - Impact of response to preoperative chemotherapy on the outcome of pulmonary metastasectomy for colorectal cancer: Results of a retrospective multicenter study

Presentation Number
513P
Lecture Time
12:45 - 12:45
Speakers
  • Takehiro Okumura (Kawasaki, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The benefit of preoperative chemotherapy (pre-CT) and metastasectomy for pulmonary metastasis (PM) from colorectal cancer (CRC) (PM-CRC) are unclear due to a lack of enough studies. However, there are some patients who receive chemotherapy after PM detection and subsequently undergo metastasectomy in clinical practice. The aim of this study was to investigate the impact of response to pre-CT on the outcome of pulmonary metastasectomy for PM-CRC.

Methods

The subjects were 92 patients, who received pre-CT before metastasectomy for PM-CRC, identified from the 1237 patients whose PM-CRC were curatively resected at 46 institutions in Japan between 2004 and 2008.

Results

Twenty-six (28%) patients initially judged to have inoperable PM underwent chemotherapy leading to conversion to be resectable and subsequently received metastasectomy. The remaining 66 patients initially judged to have operable PM received pre-CT and subsequently underwent metastasectomy. Fifty-six (61%) patients received fluoropyrimidine based regimens combined with oxaliplatin or irinotecan, and most of the remaining 26 received tegafur/uracil. Pre-CT yielded partial response (PR), stable disease (SD) and progressive disease (PD) in 28 (30%), 26 (28%) and 38 (42%) patients, respectively. At metastasectomy, the proportions of patients with extrathoracic lesion, multiple PMs, and abnormal carcinoembryonic antigen level were 34, 58, and 40%, respectively. Wedge resection was the most frequent (62%) surgical procedure. The five-year disease-free (DFS) and overall survival (OS) rate of the all 92 patients were 25.1% (95% CI 16.4-34.7) and 45.4% (33.4-56.7). The five-year DFS rates of the patients with PR/SD and PD during pre-CT were 28.2% (16.5-41.1) and 20.6% (9.2-35.2), and those of OS were 58.1% (40.8-71.9) and 27.5% (12.9-44.3), respectively. By multivariate analysis, independent prognosticators were two or less PMs (HR = 0.56, 95% CI 0.33-0.94; p = 0.029) for DFS, and performance status 0 (0.44, 0.22-0.90; 0.024) and PR/SD during pre-CT (0.33, 0.18-0.61; < 0.001) for OS.

Conclusions

Response to Pre-CT had some impacts on OS after metastasectomy for PM-CRC: better in the patients with PR/SD compared to PD.

Legal entity responsible for the study

Nonprofit Organization Tsukuba Cancer Clinical Trial Group.

Funding

Non-profit organization Tsukuba Cancer Clinical Trial Group.

Disclosure

N. Boku: Honoraria: Ono, BMS, Chugai, Merck Serono, Yakult, Eli Lilly companies. I. Hyodo: Honoraria: Taiho, Chugai, Daiichi-Sankyo, Yakult-Honshya companies. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

514P - Long-term Outcomes with Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Peritoneal Carcinomatosis: 10-Year Experience in a Developing Country

Presentation Number
514P
Lecture Time
12:45 - 12:45
Speakers
  • Fernando Arias (Bogota, CO)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Cytoreductive surgery (CRS) plus hyperthermic intraperitoneal chemotherapy (HIPEC) has emerged as a comprehensive treatment of peritoneal malignancies and it is currently a viable option in the increasing number of specialized centers all around the world.

Methods

A review of 119 CRS/HIPEC patients operated between 2007-2017 in a tertiary referral center of Bogotá, Colombia was performed. Patient characteristics, surgical variables, and postoperative outcomes were prospectively collected and analyzed.

Results

Median age at diagnosis was 51-yo (r, 22-78) and 73% (n = 87) were female. Primary origin of the peritoneal carcinomatosis was the appendix in 64%, advanced ovarian and primary peritoneal carcinomas (PC) in 17%, colorectal cancer (CRC) in 10.1%, peritoneal mesothelioma (PM) in 9%, and others in 1.6%. Prior surgical Peritoneal Cancer Index (PCI) was 19 (r, 2-39) and 25.2% were exposed to preoperative chemotherapy. Complete cytoreduction rate (CCR) was 81.5% (75% appendiceal tumors, 94% OC, 83% CRC, and 100% PM [p = 0.81]). Grade III, IV, and V complications were reported in 10%, 12%, and 4% of patients, respectively. Progression-free survival (PFS) was 38.4 months (95%CI 12.6-64.3) and 5-year PFS was 64%. PFS was positively influenced by appendiceal and mesothelioma histology (p = 0.035) as well as complete cytoreduction (p = 0.0001). At 42-month median follow-up 26 patients have died and the median overall survival (OS) was 108.5 months (95%CI 77.5-139.5). OS of patients with t relapse was 78.6 months (95% CI 36.1-121.1) and NR (p = 0.002), respectively, and only this variable adversely affected the multivariate analysis (RR 3.7, 95% CI 1.4-9.5; p = 0.007).

Conclusions

CRS/HIPEC is an effective treatment for patients with PC providing long-term survival and should be considered as standard of care. Our results, from a specialized center in a developing Latin-American country, are comparable to those from first-world centers, implying the importance of group experience in providing high-quality outcomes. Results showed that patients without relapse at the 5th year follow-up could be considered cured, but should always resume observation.

Legal entity responsible for the study

Fundacion Santa Fe de Bogotá.

Funding

Fundacion Santa Fe de Bogotá.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

515P - Clinical impact of 18F-FDG-PET/CT (PET) in patients (P) with oligometastatic disease (OMD) at a skin and gastrointestinal tumour section.

Presentation Number
515P
Lecture Time
12:45 - 12:45
Speakers
  • Juan Jose Garcia-Mosquera (Badalona, ES)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Is important to avoid aggressive treatments in P with OMD with undetected metastasis. Previous data demonstrated that PET can have a significant clinical impact, especially in colorectal cancer.

Methods

Retrospectively, we review the history of P studied with PET at our unit, from October 2013 to December 2017. We included only P with OMD with a PET done to complete disease extension study in addition to conventional imaging and previously to undergo a potential curative management. Baseline data (age, sex, primary and stage), disease extension and initial strategy before PET were collected. After PET, disease extension, definitive strategy and overall survival (OS) was determined.

Results

Overall, 93 P met the inclusion criteria: 72 (77%) colorectal (CRC), 13 (14%) melanoma, 4 (4%) biliary tract, 2 (2%) oesophageal and 2 (2%) other primaries. The mean age was 64 years (range: 24-83) and 58 (62%) P were male. At debut, 64 (79%) P were non-metastatic, and PET was done at the recurrence. After PET, 47 (51%) P were restaged: 35 (38%) were upstaged and 12 (13%) were downstaged. Final strategy was changed in 43 (46%) P, leading to a non-radical plan in 32 (34%) P. On the radical plan group there was 2 (2.2%) p with no malignant disease after surgery (pulmonary tuberculosis and aspergillosis). Median OS after PET in CRC cohort with changed strategy was significantly lower (28m, CI 95% 23-32) versus cohort without changes (47m, CI 95% 29-65); p-value 0.03.

Conclusions

After PET approximately half of P were restaged, consequently avoiding aggressive strategies in one-third of P. PET seems to be effective in selecting P with poor overall survival outcomes that need a palliative rather than a radical management. PET has relevant advantages compared with conventional imaging in the selection of P with OMD disease who may be eligible for surgery or local techniques.

Legal entity responsible for the study

Catalan Institute of Oncology (ICO Badalona).

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

516P - Simultaneous resection of colorectal primary tumor and liver metastasis after neoadjuvant therapy: A propensity score matching analysis

Presentation Number
516P
Lecture Time
12:45 - 12:45
Speakers
  • Ye Xu (Shanghai, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Considering the surgical safety and presentation of perioperative complications, simultaneous resection of colorectal cancer and liver metastasis after neoadjuvant treatment is not regularly conducted in many centers. Herein, we assessed and compared the surgical safety and incidences of postoperative complications in patients with and without neoadjuvant treatment.

Methods

A total of 257 patients who underwent simultaneous resection were included in this single-center, retrospective study. Comparison of the short-term outcomes was performed after propensity score adjustment.

Results

No postoperative death occurred. After matching, the differences from colorectal cancer and liver metastasis were well-balanced. The median operative time, and blood loss and intraoperative transfusion rates did not differ between Group A (without neoadjuvant treatment) and Group B. The morbidity (Group A vs. Group B, 15.4% vs. 19.2%, p = 0.420), and Clavien-Dindo grade of complications (p = 0.632) were also similar. No difference was found when the complications were divided according to the origin (general, colorectal and hepatic). The length of the hospital stays also did not differ between the groups. Ratios of patients with the elevation of some important blood indices related to liver function did not differ, and there was no increase in the number of patients with delayed adjuvant treatment after surgery in Group B.

Conclusions

Simultaneous resection after neoadjuvant treatment was found to be comparably safe. It did not increase morbidity and influence subsequent adjuvant treatment, and may be a treatment option for patients with synchronous liver metastasis.

Legal entity responsible for the study

Fudan University Shanghai Cancer Center.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

517P - Clinical factors are unable to accurately predict the absence of benefit of surgery in patients operated for resection of colorectal liver metastasis

Presentation Number
517P
Lecture Time
12:45 - 12:45
Speakers
  • Ali Bohlok (Brussels, BE)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

A substantial proportion of patients operated of resection for colorectal liver metastases (CRLM) with curative-intent will rapidly recur after surgery, emphasizing the need to improve the current selection process for surgery. The aim of the study is to analyze clinicopathologic prognostic factors that could better identify patients that wouldn’t benefit of surgery.

Methods

A prospective database including patients operated of hepatectomy for CRLM between 2005 and 2017 was analyzed. Within this population, we selected and compared 2 groups: early relapsers (ER), defined as patients with unresectable recurrence ≤1 year postoperatively considered as having not benefited of surgery and long-term survivors (LTS), defined as patients without recurrence ≥5 years after first hepatectomy. In the entire population and in the 2 subgroups, we analyzed potential predictive factors, using uni- and multivariate analysis.

Results

In total population (N = 357), 5 and 10-year disease-free survival (DFS) and overall survival (OS) are 26 and 21.5% and 44 and 25% respectively. In univariate analysis, Fong’s Clinical Risk Score (CRS) >2, mutated-KRAS, major hepatectomy and positive resection margins are significant poor prognostic factors for DFS and OS. In multivariate analysis only mutated-KRAS remains a significant poor prognostic factor for DFS (HR = 1,5 Ci:1,06-2,12 p = 0,02) and OS (HR = 1,8 Ci:1,19-2,70 p = 0,005). Comparing the 2 subgroups ER-group (77 patients) and LTS-group (64 patients), representing respectively 21 and 18% of entire population the univariate analysis showed significantly more synchronous CRLM, multiple metastases, mutated-KRAS and CRS>2 in the ER group. Of note, 25% of LTS had CRS>2. In multivariate analysis, only multiple metastases remain significantly increased in ER (p = 0.016).

Conclusions

Clinical factors are unable to discriminate preoperatively the patients who will benefit of surgery for CRLM from those in whom surgery will be futile. This strongly underlines the need to identify other markers of tumor biology for better individualization of the therapeutic decision.

Legal entity responsible for the study

Vincent Donckier.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

518P - Hepatic arterial infusion (HAI) of oxaliplatin with capecitabine in first line treatment of patients (pts) with liver limited metastases from colorectal cancer (LLmCRC).

Presentation Number
518P
Lecture Time
12:45 - 12:45
Speakers
  • Benny V. Vittrup (Herlev, DK)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The hepatic artery accounts for the primary blood supply of liver metastases from CRC.

Methods

First-line therapy with up to 12 series of HAI with oxaliplatin 100 mg/m2 day 1 and capecitabine 3500 mg/m2 day 1-7 every second week. When the hepatic arterial anatomy did not permit a permanent catheter pts had intravenous oxaliplatin 130 mg/m2 day 1 every third week combined with capecitabine 2000 mg/m2 day 1-14 (CAPOX). RAS mutations were retrospectively determined by next generation sequencing of KRAS Exon (E) 2, codon (C) 12 and 13, E3C59 and 61, E4C117 and 146 and NRAS E2C12 and 13, E3C59 and 61, E4C117 and 146. Pts had a baseline PET/CT scan and was evaluated by liver surgeons for resectability.

Results

Included were 93 pts, 66 had HAI and 27 CAPOX. The groups were comparable with an equal distribution of RAS wildtype (RAS-W) and mutants (RAS-M) tumours. Follow-up was 95-154 mths. Overall response rate (ORR) with complete (CR) and partial remission (PR) was 89% vs 59% in the HAI vs. CAPOX group (P = 0.0008). Progression-free survival (PFS) was independent of RAS status and treatment. Median overall survival (OS) was 6 mths. longer in the HAI vs CAPOX group (HR 1.62, 95% Confidence Interval (CI) 1.0-2.6, P = 0.05). OS was independent of RAS status in the CAPOX group and equal to OS in the HAI RAS-M group. Pts with RAS-W tumours treated with HAI survived double that of all the other groups (HAI-RAS-W vs HAI-RAS-M: HR 1.88, 95%CI 1.1-3.2, P = 0.023, HAI-RAS-W vs. CAPOX-RAS-W: HR 1.60 95%CI 1.12-2.27, P = 0.009). Toxicity of HAI was comparable to CAPOX with abdominal pain, neuropathy, and hand foot syndrome as the most common adverse events.

HAI-CAPOX
Systemic-CAPOX
AllRAS-WRAS-MAllRAS-WRAS-M
No663135271413
NA22312
CR8 (12%)620
PR51 (77%)252616 (59%)106
SD446 (22%)33
PD1122
mOS 136 (28-44)64 (45-81)29 (24-35)30 (24-35)30 (20-41)22 (16-29)
mPFS 112 (10-15)14 (11-17)11 (8-15)11 (9-13)12 (7-17)10 (8-13)

Mths with 95%CI in brackets. NA=not applicable, SD =stable disease and PD=progressive disease.

Conclusions

ORR and OS was significantly higher when pts with LLmCRC was treated with Capecitabine and HAI with oxaliplatin compared to CAPOX. Survival benefit is limited to pts with RAS-W tumours treated with HAI.

Legal entity responsible for the study

Benny Villars Vittrup.

Funding

The Danish Cancer Society.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

519P - Microsatellite instability is associated with distinct clinical and molecular characteristics in early colon cancer: Analysis of a molecular registry of the AIO colorectal study group - Colopredict Plus

Presentation Number
519P
Lecture Time
12:45 - 12:45
Speakers
  • Anke Reinacher-Schick (Bochum, DE)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

High microsatellite instability (MSI-H) is a prognostic marker in early colon cancer (CC) identified in retrospective analysis of many trials. However, broad validation in real-life cohorts and its association with clinical and molecular markers is lacking.

Methods

In Sep 2013 the molecular registry trial Colopredict Plus was intiatied in 70 German community cancer centers recruiting patients with UICC stage II and III CC. MSI was tested by immunohistochemistry (IHC) of mismatch repair proteins MLH1, MSH2, MSH6 and PMS2. In case of any loss of protein expression fragment length analysis (FLA) was performed, defining MSI high tumors (MSI-H) and MS stable tumors (MSS). Moreover, mutations in known prognostic factors in CC such as RAS, BRAF, PI3K and others were determined by next generation sequencing (NGS).

Results

By April 2018, 2102 patients have been recruited: median age 72 yrs., stage II/III: 1108/994 pts. So far, tissue was analysed in 1342 pts. Of these, 377 pts. were IHC neg with 290 pts. subsequently tested MSI-H upon FLA (21.6%). Median age was 73 yrs. female/male: 677/665 pts., stage II/III: 736/606 pts. Association of MS status with clinical and molecular factors is shown in the table. Upon NGS analysis we found 18.9% BRAF mutations, 41.5% KRAS mutations, 3.2% NRAS mutations and 25.1% PI3K mutations. MSI-H status was significantly associated with BRAF mutation and wildtype status of RAS.

Conclusions

MSI-H was more frequent in this community based registry compared to randomised trials, possibly related to a higher median age in our cohort. MSI-H was associated with female sex, right-sided primary tumor and BRAF mutations representing a heterogeneous subgroup of CC. First survival data will be presented at the meeting. Table: Association of clinical features with MSI-H in patients with CC (MS status determined by FLA).

AllMSI-H (%)MSS (%)
1342290 (21,6)1052 (78,4)
Median age737673
Male67778 (11,5)599 (88,5)
Female665212 (31,9)453 (68,1)
Stage II736181 (24,6)555 (75,4)
Stage III606109 (18)497 (82)
Right Colon793242 (30,5)551 (69,5)
Left Colon53647 (8,8)489 (91,2)

Clinical trial identification

DRKS Registry number: DRKS00004305 Release Date: 09-JAN-2013.

Legal entity responsible for the study

Ruhr-University Bochum, Institute of Pathology; Department of Hematology, Oncology and Palliative Care, St. Josef-Hospital.

Funding

State of North-Rhine Westfalia, Roche Pharma GmbH.

Editorial Acknowledgement

Not applicable

Disclosure

A. Reinacher-Schick: Honoria: Amgen, Roche, Pfizer, Sanofi-Aventis, Merck-Serono, Shire, Calgene, Lilly, BMS; Advisory board member: Amgen, Roche, Pfizer, Sanofi-Aventis, Celgene, Lilly, BMS, Merck-Serono; Studies sponsored by: Roche, Sanofi-Aventis, Calgene, Ipsen. H. Juette: Honoria: Roche, MSD, BMS, AstraZeneca, Amgen. S. Noepel-Duennebacke: Advisory board member: Bexalta, BMS; Studies sponsored by: Roche, Sanofi-Aventis, Celgene, Ipsen. D. Arnold: Honoraria: Bayer, Biocompatibles, Lilly, Merck, MSD, Roche, Sanofi, Servier, Sirtex; Advisory board member: Bayer, Lilly, Merck, Roche, Sanofi, Servier, Sirtex, Termuno; Studies sponsored by: Mologen, Roche, Sanofi. C. Teschendorf: Advisory board member: Roche. A. Tannapfel: Honoraria: Amgen, Roche, Pfizer, Merck-Serono, Celgene, BMS; Advisory board member: Amgen, Roche, Pfizer, Sanofi-Aventis, Celgene, BMS, Merck-Serono; Studies sponsored by: Roche, Celgene, Ipsen. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

520P - Prognostic impact of MSI and 18qLOH in stage II colon cancer: A prospective biomarker study in the SACURA trial

Presentation Number
520P
Lecture Time
12:45 - 12:45
Speakers
  • Toshiaki Ishikawa (Tokyo, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The SACURA trial is a phase III study to evaluate the superiority of 1-year adjuvant treatment with oral tegafur-uracil (UFT) to surgery alone in stage II colon cancer, in which survival benefit of 1-year UFT was not demonstrated (Eur J Cancer 96:54-63, 2018). In an additional biomarker study, we studied MSI status and 18qLOH of cancer tissues and evaluated their clinical value in stage II colon cancer patients.

Methods

A total of 1026 samples were collected from patients enrolled in the SACURA trial. MSI was evaluated by 5 markers; BAT25, BAT26, D2S123, D5S346, and D17S250. MSI-high (MSI-H) was defined as the presence of instability in more than 20% of the markers. 18qLOH was evaluated by 3 markers; D18S69, D18S74E, and D18S851. 18qLOH positivity was defined as the presence of LOH in any of the 18q markers. 18q LOH negativity was strictly defined as the presence of at least one informative markers and the absence of LOH.

Results

MSI-H was observed in 74 (7.2%) patients. The 18q LOH was present in 526 patients (51.3%) and LOH negativity was observed in 354 (34.5%). Informative LOH data was not available in 146 patients (14.2%). Relapse free survival (RFS) in MSI-H patients was better than that in non MSI-H (HR: 0.40, 95%CI: 0.17-0.98, p = 0.045). RFS in 18qLOH positive patients was significantly worse than in 18qLOH negative patients (hazard ratio: 1.44, 95%CI: 1.01-2.07, p = 0.047). When the patients were divided into 3 groups using MSI status and 18qLOH, approximately 5% differences of RFS were observed among the subgroups (Table). In the group 1 and 2, 5-year RFS rates were favorable and there were no differences in RFS between the treatment arms. In the group 3, 5-year RFS rate in the UFT group was +3% better than in the surgery-alone group although the difference was not significant.

5yRFS in the subgroups divided by MSI status and 18qLOH
Subgroup divided by MSI status and 18qLOH5yRFS
OverallSurgery- alone groupUFT group
group 1: MSI-H92.9% (N = 74)94.3% (N = 36)91.7% (N = 38)
group 2: non MSI-H and 18qLOH negative87.2% (N = 327)87.5% (N = 153)87.0% (N = 174)
group 3: non MSI-H and 18qLOH positive/non- informative82.5% (N = 625)81.0% (N = 320)84.0% (N = 305)

Conclusions

In stage II colon cancer, adjuvant chemotherapy might be unnecessary for MSI-H or 18qLOH negative patients. MSI status and 18qLOH might be useful biomarkers in stage II colon cancers.

Clinical trial identification

NCT00392899.

Legal entity responsible for the study

Sacura Study Group.

Funding

The Foundation for Biomedical Research and Innovation, Translational Research Informatics Center (TRI), under the funding contract with Taiho Pharmaceutical Co. Ltd.

Editorial Acknowledgement

This study was supported by the Foundation for Biomedical Research and Innovation, Translational Research Informatics Center (TRI), under the funding contract with Taiho Pharmaceutical Co. Ltd., Japan.

We are grateful to all the patients and the co-investigators for their cooperation in the SACURA trial.

The authors also thank the following collaborators for their contributions to this trial: Kenichi KONO, Satoshi NAKAGAWA, Yasuyo KUSUNOKI, Fumie KINOSHITA, and Naoko KASHIWAGI in data management, Tasuku INAJI, Hayami TSUMURA, Akinori OGASAWARA, Yuri UEDA and Syuichiro SUGIMOTO as the project office staff, Satomi SAKABAYASHI, Yoshihiro MATSUBARA and Tatsuo KAGIMURA as the statistical staff, and Prof. Masanori FUKUSHIMA as a director of the Translational Research Informatics Center.

Disclosure

T. Ishikawa: Honoraria: Chugai Pharma, Merck Serono, Takeda, Sanofi, Taiho Pharmaceutical; Research funding: Taiho Pharmaceutical. M. Ishiguro: Honoraria: Chugai Pharma, Merck Serono, Takeda, Sanofi, Taiho Pharmaceutical; Advisory role: Taiho Pharmaceutical; Research funding: Yakult, Taiho Pharmaceutical. H. Ueno: Honoraria: Chugai Pharma, Yakult, Eazai, Taiho Pharmaceutical. H. Uetake: Honoraria: Chugai Pharma, Merck Serono, Takeda, Taiho Pharmaceutical; Advisory role: Sanofi; Research funding: Taiho Pharmaceutical. N. Tomita: Research funding: Chugai Pharma, Taiho Pharmaceutical. Y. Shimada: Honoraria: Chugai Pharma, Yakult, Takeda, Lilly, Taiho Pharmaceutical; Research funding Merk Serono, Lilly, MSD, Taiho Pharmaceutical. K. Kotake: Honoraria: Chugai Pharma, Bristol-Myers Squibb, Taiho Pharmaceutical. M. Watanabe: Honoraria: Taiho Pharmaceutical: Research funding: Taiho Pharmaceutical: Travel and accommodations: Taiho Pharmaceutical. H. Mochizuki: Honoraria: Becton, Dickinson and Company, Taiho Pharmaceutical; Advisory role: Otsuka Pharmaceutical. K. Sugihara: Honoraria: Chugai Pharma, Lilly, Novertis, Bayer, Taiho Pharmaceutical; Advisory role: Otsuka Pharmaceutical; Research funding: Chugai Pharma, Takeda, Taiho Pharmaceutical. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

521P - miR-31 as a prognostic and predictive marker of disease-free survival (DFS) in resected stage III colon cancer: a retrospective analysis of the PETACC-8 trial.

Presentation Number
521P
Lecture Time
12:45 - 12:45
Speakers
  • Yann Gaston Mathe (Paris, FR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

In RAS wild type metastatic colorectal cancer patients (pts), high tumor expression of microRNA miR-31-3p and miR-31-5p has been associated with poorer benefit of anti-EGFR therapy. miR-31-3p expression has been shown to be predictive of treatment effect in the FIRE-3 trial. The PETACC-8 phase III trial assessed the efficacy of cetux addition to FOLFOX compared to FOLFOX only in pts with resected stage III colon cancer (CC). The primary end point was negative, but a trend towards benefit of cetux on disease free survival (DFS) was observed in pts with RAS/BRAF wild type (WT) tumors. The current study aimed at assessing miR-31-3p and 5p tumor levels as prognostic and predictive biomarkers of adjuvant cetux benefit in these pts.

Methods

miR-31-3p and 5p levels were measured by RT-qPCR from 477 WT pts tumor RNA. The primary objective was to demonstrate a benefit of cetux on DFS for low miR-31-3p expressers. Cox regression model was used for univariate and multivariate analyses. Optimal cut-off values for low and high expressers were determined post hoc.

Results

In the studied population, cetux benefit was significant for DFS (HR = 0.71 [0.50;1.00] p = 0.05) but not for Overall Survival (OS) (HR = 0.79 [0.53;1.18] p = 0.25). Expression of miR-31-3p and miR-31-5p were highly correlated (R > 0.9). Higher miR-31-3p and 5p expression were associated with shorter DFS and OS (p < 0.01). Pts with low miR-31-3p levels (n = 218/435, 50%) had a non-significant benefit from cetux on DFS (HR 0.61 [0.33; 1.11] p = 0.10) and OS (HR = 0.67 [0.33; 1.35] p = 0.26). Pts with low miR-31-5p levels (n = 233/477, 49%) benefited from cetux on DFS (HR = 0.46 [0.25; 0.84] p = 0.01) and OS (HR = 0.50 [0.25; 0.99], p = 0.047) whereas high expressers did not (DFS: HR = 0.87 [0.56; 1.34] ; OS: HR = 1.01 [0.61; 1.67]). miR-31-5p was predictive of treatment effect on DFS at the 10% level (interaction tests: p = 0.09 for DFS and p = 0.103 for OS). Results were still significant after adjustment for clinical covariates.

Conclusions

In pts with resected stage III WT CC, miR-31-3p and 5p were prognostic of DFS and OS. Pts with low miR-31 expression benefited from cetux addition to FOLFOX for adjuvant therapy, and miR-31-5p was predictive of cetux efficacy.

Clinical trial identification

NCT03362684.

Legal entity responsible for the study

IntegraGen SA.

Funding

IntegraGen.

Disclosure

Y. Gaston Mathe: Ex employee: IntegraGen. S. Martin-Lannerée, C. Vazart, K. Fontaine: Employee: IntegraGen. A. Caumont, F. Montestruc: Consultant: IntegraGen. J. Taieb: Honoraria: Lilly, Celgene, Servier, Amgen, Roche, Merck, Sirtex, Sanofi. P. Laurent-Puig: Honoraria: IntegraGen, Merck-Serono, Amgen, Boehringer-Ingelheim, Roche, Lilly, Sanofi. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

522P - Prognostic value of neutrophil-lymphocite ratio in resected high risk colorectal cancer: an analysis of adjuvant TOSCA trial

Presentation Number
522P
Lecture Time
12:45 - 12:45
Speakers
  • Fausto Petrelli (Treviglio, IT)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Prognostic factors in resected colon cancer (CC) guide adjuvant therapy and intensity of follow up. Inflammation parameters as C-reactive protein and neutrophil counts in relation to lymphocyte number (neutrophil/lymphocyte ratio: NLR) have been correlated with poor prognosis in advanced tumors. To confirm the prognostic value of a prechemoterapy NLR in adjuvant setting, we performed a retrospective analysis of high risk stage II and stage III resected CC patients randomized into the TOSCA phase 3 trial comparing 3 or 6 months of adjuvant chemotherapy.

Methods

patients randomized in TOSCA trial with data available for NLR analysis before chemotherapy were included. A recursive partitioning analysis was performed to identify the best cut-off that better discriminates patients in terms of relapse-free survival (RFS). According to this cut-off, RFS and overall survival (OS) hazard ratios (HR) for NLR were calculated and adjusted for age, sex, treatment type (XELOX vs FOLFOX) and duration (3 vs 6 months), grade, stage, performance status (PS), site and CEA level.

Results

Out of 3759 subjects randomized in the TOSCA trial, 1590 were included in the efficacy analysis. Mean NLR was 2.1 (median 1.8; range 0.3-24.0). Among patients analysed, 17.4% relapsed and 12.2% died. The best NLR cut off detect in this analysis population is 2.33. However, only age, PS, stage III and CEA levels were associated with RFS and OS in multivariate analysis, but not NLR>2.33 (RFS: HR = 1.17, 95%CI 0.90-1.51; P = 0.24, OS: HR = 1.16 95%CI 0.84-1.61; P = 0.38). Site was also correlated with poor OS.

Conclusions

Prechemotherapy NLR is not significantly associated with poor prognosis in patients with CC undergoing adjuvant chemotherapy. Resection of primary tumor and the associated reduced inflammatory stimulus may explain the lack of correlation with prognosis of NLR. Baseline evaluation, before surgery, likely represents the better timing to collect this information in cancer patients.

Legal entity responsible for the study

GISCAD.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

523P - Distribution of lymph node metastases can have an impact on survival benefit of oxaliplatin-containing chemotherapy in stage III colon cancer

Presentation Number
523P
Lecture Time
12:45 - 12:45
Speakers
  • Yeesoo Chae (Daegu, KR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

This study investigated the effect of oxaliplatin-containing adjuvant chemotherapy according to the distribution of lymph node (LN) metastases for patients with stage III colon cancer (CC).

Methods

Among 1554 patients with CRC who underwent surgical resection between 2010 and 2014, 254 patients were diagnosed with stage III CC, and adjuvant chemotherapy was administered. Patients were treated with either oxaliplatin-containing chemotherapy or non-oxaliplatin-containing chemotherapy according to each investigator decision. LN distribution was classified on the basis of the Japanese classification of colorectal carcinoma. The patients were grouped into two categories: pericolic LN-positive and extrapericolic LN-positive.

Results

Among the 254 patients enrolled in this study, 175 belonged to the PLN group, whereas the remaining 79 patients to the ELN group. The PLN group was also divided into two groups based on the regimen: 79 patients were included in the non-oxaliplatin-containing chemotherapy group, while 96 in the oxaliplatin-containing chemotherapy group. The characteristics were similar between two groups, except for age and body mass index. During the median follow-up duration of 48.5 months (range 4.7-94.0), 39 (15.4%) patients died and 47 (30.5%) patients experienced recurrence and the estimated DFS and OS at 3 years was 82.8% and 90.1%, respectively. In the univariate analysis, oxaliplatin chemotherapy was not significantly associated with DFS (p = 0.457) and OS (p = 0.147). In the multivariate analysis, the addition of oxaliplatin showed no prognostic significance on DFS (p = 0.073) and OS (p = 0.594).

Conclusions

In conclusion, oxaliplatin-containing adjuvant chemotherapy was not found to have a significant effect on survival for stage III CC patients with only PLN. Accordingly, the current study can provide a novel strategy for subgroups with limited LNs distribution, considering that the state of the LN distribution is a critical factor for therapeutic success.

Legal entity responsible for the study

Jong Gwang Kim.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

524P - Implications of Thymidylate Synthase gene polymorphisms, KRAS and BRAF mutations in the survival of patients with colorectal cancer treated with adjuvant chemotherapy

Presentation Number
524P
Lecture Time
12:45 - 12:45
Speakers
  • Anastasios Ntavatzikos (Athens, GR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Fluoropyrimidine-based adjuvant chemotherapy in colorectal cancer (CRC) is associated with a reduction of recurrence in only 25% of patients (pts) with stage III disease. The aim of this study was to investigate thymidylate synthase (TYMS) gene polymorphisms, KRAS and BRAF as possible factors affecting therapeutic outcome in pts with stage III CRC.

Methods

Formalin-fixed paraffin-embedded tissues of 130 consecutive pts treated with FABC between 2005-2007 were analysed with PCR for the detection of TYMS polymorphisms, mKRAS and mBRAF. Patients were classified into three groups of 5’UTR TYMS polymorphisms according to the predicted expression profile (high, medium and low). Based on the presence or absence of the 3’UTR polymorphism ins/LOH pts were allocated into two groups (high and low risk). Cox regression models examined factors associated with survival outcome.

Results

The 5-year DFS and OS rate was 61.6% and 73.9% respectively. Patients who had tumors with 5’UTR polymorphisms of intermediate TYMS expression profile (2RG/3RG, 2RG/LOH, 3RC/LOH) when compared to those with low (2RG/2RG, 2RG/3RC, 3RC/3RC) or high expression (3RG/3RG, 3RG/LOH, 3RG/3RC) had lower risk for relapse (HR 0.320, p = 0.02 and HR 0.343, p = 0.013 respectively) and death (HR 0.368, p = 0.031 and HR 0.394, p = 0.029 respectively). The 3’UTR polymorphism ins/LOH was independently associated with increased risk for disease recurrence (p = 0.001) and death (p = 0.005). Presence of mBRAF (3.8% pts) was associated with an increased risk of death (HR 4.500, p = 0.022), whereas mKRAS (39% of pts) was not found to correlate with survival.

Conclusions

The group of TYMS polymorphisms 2RG/3RG, 2RG/LOH, 3RC/LOH, the absence of ins/LOH and absence of mBRAF were associated with better prognosis of pts with early stage CRC. Mutated KRAS was not found to affect relapse or risk of death in the adjuvant setting. Further prospective studies investigating the role of TYMS polymorphisms and mBRAF are warranted to identify pts who could benefit from 5FU-based cytotoxic chemotherapy.

Legal entity responsible for the study

Anna Koumarianou.

Funding

National and Kapodistrian University of Athens.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

525P_PR - Profile of individuals who never undergo colorectal cancer screening

Presentation Number
525P_PR
Lecture Time
12:45 - 12:45
Speakers
  • Jérôme Viguier (Boulogne-Billancourt, FR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Colorectal cancer (CRC) screening has been part of a nationally organized program in France since 2009. In 2015, a fecal immunochemical test (FIT) replaced the previously used guaiac test. Nevertheless, the target participation rate has still not been reached. In this context, it is important to have a clear insight into the characteristics of individuals who remain refractory to screening.

Methods

The French nationwide observational survey EDIFICE 6 was conducted online from 26 June to 28 July 2017 on 12 046 individuals (age, 18-69 years). Representativeness was ensured by quota sampling on age, gender, profession, and stratification by geographical area and type of urban district. Multivariate stepwise logistic regression analysis was conducted to identify factors likely to explain non-uptake of CRC screening. The present analysis focused on the 4300 individuals (age, 50-69 years) with no history of cancer.

Results

Of those who were in the target population for CRC screening, 38% (N = 1625) had never taken part in the CRC screening program. Compared to individuals who had undergone at least one screening test in their life time, those who had never been screened were more likely to be younger (58±6 yrs vs 60±6 yrs, P<0.05), current smokers (30% vs 21%, P<0.05) or socially vulnerable (47% vs 36%, P<0.05). In multivariate analysis, items associated with not undergoing screening included belonging to the socio-professional category of skilled manual workers and supervisory or clerical workers (OR=1.83, 95% CI [1.24 – 2.70]), considering that prevention does not provide effective protection from CRC (OR=1.76 [1.48–2.08]), being a current smoker (OR=1.45 [1.25–1.69]) and being socially vulnerable (OR=1.29, [1.13-1.47]). The most frequently cited reasons for not being screened were "I don't feel concerned" (37%), “individual negligence/not a priority” (32%), fear of the examination/results (29%), and a reason related to the physician (i.e., he didn't suggest screening) (23%).

Conclusions

Medical skepticism for CRC prevention efficiency and vulnerability are social indicators of non-participation in a CRC screening program. Likewise, current smoking—which is already acknowledged as a behavioral risk factor for CRC—is also an indicator of non-uptake of CRC screening.

Editorial Acknowledgement

Medical writing assistance was provided by Potentiel d’Action (France)

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

526P - Results of the national organised colorectal cancer screening program with FIT in Paris

Presentation Number
526P
Lecture Time
12:45 - 12:45
Speakers
  • Anna Pellat (Paris, FR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

In France, colorectal cancer (CRC) benefits from a nationwide screening program. The faecal immunochemical test (FIT) is being used since April 2015. The test is recommended in asymptomatic patients followed by a colonoscopy if positive for identification and treatment of colorectal lesions. We investigate the CRC national organised screening program using FIT in Paris.

Methods

We performed a retrospective observational study, collecting data from the screening program in Paris using the ADECA75 database. Rates of participation, numbers of positive FIT, detection rates and positive predictive values (PPV) for advanced adenomas (AA) and/or CRC were determined.

Results

Between 01/01/2016 and 30/06/2017, 620.227 Parisians were eligible and 409.340 were invited to participate to the program. A total of 88.796 participants (23%) performed the test with 3.839 positive tests (4.3%). In the positive test population, 2.706 out of 3.839 individuals (70.5%) performed the required colonoscopy with available reports. Histology reports were only available for 2.401 participants (88,7%). Regarding lesions, 733 (30,5%) and 205 patients (8.5%) had AA and CRC, respectively.

Conclusions

Over 18 months of screening with FIT in Paris, the PPV is in line with expected results while the participation rate is below European recommendations.

Legal entity responsible for the study

Gastroenterology and Digestive Oncology Department, Cochin Hospital, Paris.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

527P - Screening strategy of Lynch syndrome for Chinese colorectal cancer patients with MLH1-immunoloss

Presentation Number
527P
Lecture Time
12:45 - 12:45
Speakers
  • Wenmiao Wang (Beijing, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Inactivation of MLH1 due to promoter hypermethylation strongly suggests a sporadic origin, and nearly half sporadic colorectal cancer patients harbor BRAF mutation, providing exclusion criteria for Lynch syndrome (LS). However, there was little evidence from Chinese population. The aim of this study was to compare the utility of two tests, and explore the possibility of substituting BRAF immunohistochemical staining (IHC) for real-time PCR.

Methods

We reviewed MMR expression status of consecutive patients who had undergone surgery for colorectal cancer between 2012.1.1 and 2014.12.30 in Chinese National Cancer Center. Among 317 patients who were identified as dMMR, 170 patients with MLH1 immunoloss were taken into final analysis. MLH1 methylation status was evaluated by MS-PCR(methylation – specific PCR) ,BRAF mutation was tested by IHC and real-time PCR.

FeatureMLH1 methylated n = 90MLH1 unmethylated n = 80PBRAF mutation n = 24BRAF wild-type n = 146p
Median age62y50y64y54y
Synchronic CRC3(3.3)8(10.0)0.0781(4.2)10(6.8)0.962
FDR or SDR with LS-related tumor17(18.9)14(17.5)0.8153(12.5)28(19.2)0.617
FDR or SDR with CRC12(13.3)32(40)0.000044(30.1)0.002
FDR with CRC9(10.0)27(35.0)0.000036(24.7)0.016
Revised Bethesda guidelines43(47.8)69(86.3)0.0008(33.3)104(71.2)0.000

Results

52.9%patients display MLH1 promoter hypermethylation. As for BRAF status, the mutation rate tested by IHC and real-time PCR was 14.1% and17.1%, respectively, and the concordance rate was 92.1%. BRAF mutation did better on ruling out patients whose relatives had CRC history. Although patients who had unmethylated CRCs had a notably stronger family history of CRC, there were still 13.3% patients in the hypermethylation group having family history of CRC, indicating a likelihood of LS.

Conclusions

The mutation rate of BRAF in Chinese population with MSI CRCs was significantly lower than that in western countries, leading to a decreased specificity. Thus, BRAF mutation alone was not efficient to be a negative predictor of LS. Due to the high specificity of MLH1 methylation test and the high concordance rate of IHC and real-time PCR for BRAF mutation, patients who have MLH1 hypermethylation, BRAF wild-type tested by IHC and family history of CRC should be recommended for germline mutation test additional to those with MLH1 unmethylated CRCs.

Legal entity responsible for the study

National Cancer Center, China.

Funding

Chinese Academy of Medical Science.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

528P - Early detection of colorectal cancer using breath biomarkers: Preliminary study

Presentation Number
528P
Lecture Time
12:45 - 12:45
Speakers
  • Georgia Woodfield (London, GB)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Colorectal cancer (CRC) is the 2nd most common UK cause of cancer death. The bowel cancer screening programme (BCSP) has saved lifes through early cancer diagnosis. However, it only targets those aged 60-74, and leads to many potentially unnecessary colonoscopies. A breath test could be used as a more specific non-invasive screening tool, or to triage/reassure symptomatic patients. Prior studies have shown promising results using exhaled propanal for detecting CRC (96% sensitivity/76% specificity). The Colorectal BReath Analysis (COBRA) study aims to determine the diagnostic accuracy of breath volatile organic compounds for detecting CRC, first by analysing breath of known colorectal cancer patients, then by testing the resultant diagnostic model on a prospective BCSP population, target 2000 patients.

Methods

Clinical data was collected from patients attending for colonoscopies or CRC surgery across 4 London centres July 2017 to May 2018. Exhaled breath (500mls) was collected using the ReCIVA™ breath sampling device, onto thermal desorption tubes. Analysis by gas chromatography mass spectrometry and proton transfer reaction (PTR) mass spectrometry identified and quantified breath compounds.

Results

426 patients were recruited for this preliminary dataset. 80 samples were excluded due to inadequate colonoscopies, instrument faults or inadequate quality measures. This left 346 patients; 20 with known CR adenocarcinoma were sampled pre-operatively, the rest from endoscopy units pre-colonoscopy. All were nil by mouth having had bowel preparation. Colonoscopy results showed: 29 CR adenocarcinoma, 84 normal, 35 benign pathology, 31 IBD, 83, 20 and 57 with low, intermediate and high risk polyps, and 7 with polyposis syndromes. PTR data analysis so far indicates that there are discriminatory breath compounds between pathology groups, but analysis is ongoing to investigate potential confounders.

Conclusions

Further analysis of this preliminary dataset is expected to reveal compounds of interest for colorectal cancer diagnosis. The true diagnostic accuracy of breath testing is expected to be revealed once these compounds are tested on the larger population dataset for COBRA (recruitment ongoing since January 2018).

Legal entity responsible for the study

Imperial College London.

Funding

Imperial College Charity - Rosetrees.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

529P - Survival of stage IV colorectal cancer: interaction of cancer location, microsatellite instability and KRAS mutation.

Presentation Number
529P
Lecture Time
12:45 - 12:45
Speakers
  • Johannes Uhlig (New Haven, US)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The current literature on stage IV colorectal cancer (CRC) indicates a survival advantage for left-sided CRC. Still, the biological basis remains unclear. We assessed the interaction of cancer location with microsatellite instability (MSI) and KRAS mutation to elaborate how key molecular features modify the effect of cancer location on overall survival.

Methods

The 2010-2015 United States National Cancer Database was searched for stage IV colorectal adenocarcinomas. Overall survival (OS) was assessed via Cox models, implementing 2/3-way interaction terms.

Results

A total of 73,685 patients were included, of which n = 11,720/n=25,433 had data on microsatellite and KRAS status. Left-sided CRC was an independent predictor of improved OS (vs. right: HR = 0.75, p < 0.001). Rectal cancer had highest OS (2/5-year OS: 43%/10%) compared to cancers of the rectosigmoid junction (HR = 1.07), sigmoid (HR = 1.12), descending colon (HR = 1.19), transverse colon (HR = 1.41), ascending colon (HR = 1.45) or cecum/appendix (HR = 1.45, p < 0.001 respectively). Patients with stable microsatellites (MSS) had improved OS versus MSI (HR = 0.93, p = 0.027); KRAS wildtype showed superior OS over KRAS mutation (HR = 0.88, p < 0.001). CRC location interacted with microsatellite status and KRAS mutation: the prognostic impact of MSS was more pronounced in rectal cancers versus other locations (interaction p < 0.001); the prognostic impact of KRAS wildtype was larger in rectal cancers (interaction p < 0.001). In a 3-way interaction model, the largest prognostic impact of MSS and KRAS wildtype was noted for rectal cancer (interaction term p < 0.05). The table summarizes 2/4-year OS rates.

Adjusted 2-year and 4-year OS rates by cancer location and mutational status

Location / mutational statusTwo year OSFour year OS
rectal CRC, MSS, KRAS wildtype68%38%
rectal CRC, MSS, KRAS mutation56%29%
rectal CRC, MSI, KRAS wildtype66%39%
rectal CRC, MSI, KRAS mutation43%18%
other CRC, MSS, KRAS wildtype60%31%
other CRC, MSS, KRAS mutation52%24%
other CRC, MSI, KRAS wildtype47%25%
other CRC, MSI, KRAS mutation48%20%

Conclusions

Survival for stage IV CRC shows marked variation depending on location, MSI and KRAS mutation. The prognostic effects of molecular features varies by CRC location, demonstrating largest impact in rectal cancers.

Clinical trial identification

NA

Legal entity responsible for the study

Hyun S. Kim, MD.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

530P - Influence of primary tumour sidedness on survival after upfront primary tumour resection (PTR) in synchronous metastatic colon cancer (mCC)

Presentation Number
530P
Lecture Time
12:45 - 12:45
Speakers
  • Karlijn L. Van Rooijen (Utrecht, NL)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Retrospective data suggest a survival benefit for PTR in synchronous mCC, which is the topic of ongoing prospective trials. Whether outcome after PTR varies by primary tumour sidedness, an important prognostic factor in colorectal cancer (CRC), is currently unknown. We investigated the impact of upfront PTR followed by systemic treatment in synchronous mCC according to sidedness within two randomized phase 3 trials (CAIRO and CAIRO2).

Methods

A total of 408 synchronous mCC patients, with available data on both PTR status and sidedness, were included (CAIRO n = 279; CAIRO2 n = 129, excluding patients treated with both bevacizumab and cetuximab). We used mixed effect Cox regression models to study the association between PTR and overall survival (OS) and to estimate hazard ratios (HR). Models were adjusted for age, treatment arm, WHO performance status (PS), serum lactate dehydrogenase (LDH) and year of enrollment as potential confounders. To analyze whether PTR effect was modified by sidedness, we tested the interaction term of PTR status and sidedness.

Results

A total of 191 patients (46.8%) had right-sided mCC and 217 patients (53.2%) had left-sided mCC. The rate of PTR was comparable in right-sided (69.1%) and left-sided (65.0%) mCC. Patients who underwent PTR had better PS and LDH level compared to patients without PTR. Univariable and multivariable analyses demonstrated significant and comparable (pinteraction >0.05) survival benefits after upfront PTR for both right-sided and left-sided mCC (Table).

HR (95%CI) for OS after PTR versus no PTR
Right-sided mCC (n = 191)Left-sided mCC (n = 217)pinteractionOverall effect (n = 408)
Univariable0.53 (0.38-0.73)0.66 (0.49-0.87)0.310.61 (0.50-0.76)
Multivariable0.60 (0.42-0.84)0.72 (0.53-0.96)0.430.69 (0.55-0.87)

Conclusions

The previously reported better survival after PTR among synchronous mCRC patients included in the CAIRO and CAIRO2 trials was significant for all mCC patients in our analysis, independent of sidedness. Prospective randomized trials on the prognostic effect of PTR in synchronous mCC, i.e. the CAIRO4 trial, remain valid for mCC patients with both right- and left-sided primary tumours.

Clinical trial identification

CAIRO: NCT00312000, published: July 14, 2007 (Lancet) CAIRO2: NCT00208546, published: February 5, 2009 (N Engl J Med).

Legal entity responsible for the study

University Medical Center Utrecht, Utrecht, The Netherlands.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

531P - The Clinical Features and Genomic Landscape of Elevated Microsatellite Alterations at Selected Tetranucleotide Repeats (EMAST) in Patients with Colorectal Cancer

Presentation Number
531P
Lecture Time
12:45 - 12:45
Speakers
  • Ming-Huang Chen (Taipei, TW)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

The form of microsatellite instability (MSI) affecting tetranucleotide repeats known as EMAST (elevated microsatellite alterations at selected tetranucleotide repeats) has emerged as a new potential biomarker in multiple cancers. In colorectal cancer (CRC), the clinical implications and mutation spectrum of EMAST mutations remain inconclusive.

Methods

We evaluated 1,505 CRC cases using five EMAST markers (D20S82, D20S85, D8S321, D9S242 and MYCL1) and the Bethesda panel of MSI markers. Most commonly mutations involved in CRCs were identified by MassArray Assay and DNA repair genes were analyzed by Next-Generation Sequencing (NGS). Clinical characteristics and prognostic relevance were correlated with EMAST. SPSS software (version 16.0) was used to perform all statistical analyses.

Results

Tumors with EMAST-positivity were detected in 159 (10.6%) out of 1,505 CRC cases and associated with unique clinical features including female predominance (p = 0.017), higher prevalence of proximal colon tumors (p < 0.001), early stage tumors (p = 0.002), poorly differentiated tumors (p < 0.001), mucinous histology (p = 0.001), and MSI (p < 0.001) and higher incidence of mutations in PI3KCA (p = 0.003), BRAF (p < 0.001), TGFßR (p < 0.001), PTEN (p = 0.001), and AKT1 (p = 0.04) compared with EMAST-negative tumors. Compared with EMAST-positive alone or MSI-H alone tumors, EMAST-positive MSI-H tumors had higher rates of MSH6, MSH3, PMS2, and EXO1 gene mutation (p < 0.001, p = 0.005, p = 0.001, and p = 0.027) and MLH1, MSH6, and EXO1 gene mutation (p = 0.019, p = 0.005, and p = 0.046), respectively. Finally, EMAST-positivity was a good prognostic indicator in early stage CRC (p = 0.002) but not in late CRC (p = 0.920).

Conclusions

The EMAST defines a unique molecular subtype of CRC.

Legal entity responsible for the study

Taipei Veterans General Hospital.

Funding

Taipei Veterans General Hospital, Ministry of Science and Technology.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

532P - Identification of positively and negatively selected driver gene mutations associated with colorectal cancer with microsatellite instability

Presentation Number
532P
Lecture Time
12:45 - 12:45
Speakers
  • Vincent Jonchere (Paris, FR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Recent studies have shown that cancers arise due to the positive selection of driver somatic events in tumor DNA, with negative selection playing only a minor role. However, these investigations were concerned with alterations at non-repetitive sequences and did not take into account mutations in repetitive sequences that have very high pathophysiological relevance in the tumors displaying Microsatellite Instability (MSI) due to mismatch repair deficiency investigated in the present study.

Methods

We performed whole exome sequencing of 47 MSI CRC and confirmed results in an independent cohort of 53 MSI CRC. We used probabilistic model of mutational events within microsatellites, while adapting preexisting models to analyze non-repetitive DNA sequences. Negatively selected coding alterations in MSI CRC were investigated for their functional and clinical impact in CRC cell lines and in a third cohort of 164 MSI CRC patients.

Results

Both positive and negative selection of somatic mutations in DNA repeats was observed, leading us to identify the expected driver genes associated with the MSI-driven tumorigenic process. Several Coding negatively selected, MSI-related mutational events (n = 5) were demonstrated to have deleterious effects on tumor cells. In the tumors in which deleterious MSI mutations are observed despite the negative selection, they were associated with worse survival in MSI CRC patients (hazard ratio [HR], 3; 95% confidence interval, 1.1-7.9; p = 0.03), suggesting their anticancer impact should be offset by other as yet unknown oncogenic processes that contribute to poor prognosis.

Conclusions

The present results shed new light on the main driver somatic mutations acting in MSI-driven tumorigenesis, suggesting that genomic instability in MSI CRC plays a dual role in achieving tumor cell transformation.

Legal entity responsible for the study

INSERM.

Funding

This work was supported by grants from the ‘Institut National du Cancer’ (INCa, PRTK MICROSPLICOTHER, SIRIC, and HTE CoLi, to AD), the Fondation ARC (to AC) and the Canceropole Ile de France (to AC). AD group has the label ‘La Ligue Contre le Cancer’. This work is part of the Cartes d’Identité des Tumeurs (CIT) research program, funded and developed by the Ligue Nationale Contre le Cancer.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

533P - Distinct Clinico-pathological Features of Hypermutant Colorectal Cancers with POLE Pathogenic Mutations, Lynch Syndrome and Sporadic MSI Analyzed over 1,000 Colorectal Cancer Patients

Presentation Number
533P
Lecture Time
12:45 - 12:45
Speakers
  • Takeshi Nagasaka (Okayama, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

POLE proofreading mutations cause ultrahypermutant-phenotype in colorectal cancer (CRC) but the characters of POLE mutations are still obscure in contrast to Lynch syndrome or sporadic microsatellite instability (MSI). Herein, we examined mutation profiles of POLE in 1,039 CRC Japanese patients, and tried to clarify clinico-pathological features of hypermutant CRC patients with respect to POLE mutations, Lynch syndrome and sporadic MSI.

Methods

We analyzed POLE pathogenic hotspot (exon9, 13 and 14), BRAF codon 600 and KRAS exon 2 mutations by Sanger sequencing. MSI status was confirmed by a multiplex PCR assay. MSI positive cases were confirmed the four mismatch repair (MMR) proteins (MLH1, MSH2, PMS2, and MSH6) expression. Germline mutations were analyzed by Sanger sequencing and a TruSight One Sequencing Panel using a next generation sequencer.

Results

Of 1,039 CRC patients, only four cases showed POLE pathogenic mutations (two P286R, one V411L and one S459F). The four POLE-mutant CRCs showed no MSI. CRC with MMR deficient (=MSI) were observed in 58 cases (5.6%). Of CRCs with MSI, Lynch syndrome was found in 17 cases and the rest of 41 cases were sporadic MSI. Therefore, we divided 1,039 CRCs into the four subsets; POLE-mutant (POLE; n = 4, 0.4%), Lynch syndrome (LS; n = 17, 1.6%), sporadic MSI (MSI; n = 41, 4.0%), and non-hypermutant CRCs (NH; n = 997, 94.0%). Mean age at diagnosis in POLE/LS/MSI/NH was 52.5/55.7/73.6/65.9 years, respectively (P< .0001). Frequency of female in POLE/LS/MSI/NH was 50/23.5/61/41% (P = 0.03). The primary tumor located at the right colon was observed in 100/35/80.5/30% of POLE/LS/MSI/NH (P< .0001). BRAF mutation was observed in 49% of MSI and 4% of NH while KRAS mutation was in 35% of LS and 32% of NH (P< .0001). Interestingly, 100/82/78% of POLE/LS/MSI tumors were diagnosed at the earlier stage, I or II, while 46% of NH (P< .0001). The recurrence free survival rate at 5-years was better in POLE (100%)/LS (86%)/MSI (94%) compared with that in NH (74%).

Conclusions

POLE-mutant CRC was rare, observed in the younger without family history, located at the right colon, and diagnosed at the earlier stage.

Legal entity responsible for the study

The authors.

Funding

The Ministry of Education, Culture, Sports, Science and Technology (MEXT).

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

534P - Patterns of Germline and Somatic Mutations in 16 Mismatch Repair associated genes analyzed with Next Generation Sequencing(NGS) in Colorectal Cancer with EMAST(+) and/or MSI-high

Presentation Number
534P
Lecture Time
12:45 - 12:45
Speakers
  • Shin-Ching Chang (Taipei, TW)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

We assume that besides mismatch repair (MMR) genes, next generation sequencing (NGS) of MMR associated genes could improve detection of driver mutattors and clarify the somatic mutation patterns of subtypes CRC classfied by EMAST and MSI-high.

Methods

Extracted from a 1505 CRC cases database,81 cases with MSI-high and EMAST+,78 cases with EMAST+ and MSS, and 72 cases with MSI-high but EMAST- were identified. The tumor and WBC DNA were applied and got from Biobank of Taipei-Veteran General Hospital afer approval of IRB. The germline and somatic mutations were analyzied with 16- genes NGS (illumina HiSeq2500 system).

Results

Totally 284 pathological germline mutations were identified in 161 patients with MSI-high or EMAST+. The most common gene mutations were EPCAM (17.3%), MSH6 (16.9%), followed by MLH1 (15.2%), and AXIN2(15.2%). Majority of EMAST and MSI resulted from not only MMR dysfunction, but also germline mutations of AXIN2, POLD1 and TGFBR2. After deduction of 284 germline mutations, there were 1,090 somatic mutations in 161 cases with germline mutations, 445 mutations in 70 cases without germline mutations. Tumors with EMAST+ and MSI-high had signifcantly higher mutation number than those of tumors with only EMAST+ or only MSI-high. Besides germline mutations of AXIN2, germline mutations of other genes were similar. With AXIN2 germline mutations, somatic mutation rate was 187.7 ± 97.8 mut/MB significantly higher than those of without germline mutations (137.8± 84.5 mut/MB p = 0.002). Besides five major MMR genes, Eleven Axin2, eight POLE and six TGFbR2 germline mutations resulted in following MSI-high or EMAST (+) genotype without other accompany germline mutation. Clinically, patients with germline mutation had significantly higher frequency of proximal tumor location and early stage disease.

Conclusions

Our result showed that NGS could enhance detection of familial CRC. Somatic mutation burden might be through MSI or EMAST but not only germline mutation genes themselves. Several genes with germline mutations could explain origin of the familiar CRC. AXIN2 gene deserved to do futher experiment to confirm its role in WNT pathway and as a hypermutator.

Legal entity responsible for the study

The Institutional Review Board of Taipei Veterans General Hospital (number 2017-06-004BC).

Funding

Taipei-Veterans General Hospital, Taiwan.

Editorial Acknowledgement

NIL

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

535P - Lower Tumor Mutational Burden (TMB) and Hepatic Metastases May Predict for Lack of Response to PD-1 Blockade in MSI-H Metastatic Colorectal Cancer (MCRC)

Presentation Number
535P
Lecture Time
12:45 - 12:45
Speakers
  • Idoroenyi Amanam (Duarte, US)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

MCRC with microsatellite instability (MSI-H) are associated with cytotoxic lymphocytic infiltration that is counterbalanced by multiple checkpoints. Several prospective clinical trials in chemotherapy-resistant MSI-H MCRC have demonstrated a high rate of disease control and a favorable progression free survival (PFS) with PD-1 inhibitors. However, there is a significant discrepancy in response rates (RR) with pembrolizumab and nivolumab (28% to 52%), likely reflecting patient heterogeneity. We sought to determine the RR to PD-1/PD-L1 targeting in a single center setting.

Methods

All MCRC patients (pts) with MSI-H tumors (by CLIA certified PCR, IHC, or NGS assays) who were treated at City of Hope with PD-1 or PD-L1 inhibitors starting Jan 2016 were identified. RR and PFS were determined by RECIST 1.1. BRAF status, primary tumor location, and metastatic sites were collected on all pts. TMB as determined by FoundationOne® on 0.83-1.1 megabases (Mb) of sequenced DNA was collected, when available.

Results

17 pts with MSI-H tumors were identified (16 treated with pembrolizumab and 1 with darvulumab). Pts characteristics were: males (10, 59%), age (median 53.7 years, range 33-78), BRAF mutant (6, 35%), right sided (11, 65%), and liver-sparing (8, 47%). 7 (41%) had an objective response, 2 (12%) had stable disease. The median PFS was 9.97 months (mo), and the 6 and 12 mo PFS rates were 53% and 35%, respectively. TMB was available for 9 MSI-H cases (range 8 – 73 mutations/Mb): 1 CR (TMB 73), 1 PR (TMB 71), and 1 SD (TMB 31), and 6 PD (TMB: 6, 13, 16, 18, 25, 36). We categorized our patients based on the lowest 10% (TMB < 23.5) and 25% (TMB < 33.06) TMB cut points identified from a large Foundation Medicine database of MSI-H MCRC. All 4/4 patients in the lowest TMB decile and 5/6 in the lowest TMB quartile experienced PD. On univariate analysis, only hepatic metastases (p = 0.01) and low TMB (p = 0.02) were associated with poor PFS.

Conclusions

A substantial percentage of pts with MSI-H tumors will progress with PD-1/PD-L1 inhibitors; these patients appear to be enriched for a low TMB status and hepatic metastases. Additional studies should explore TMB as a predictive marker of response to checkpoint inhibition in MSI-H CRC.

Legal entity responsible for the study

City of Hope.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

536P - Comparison of microsatellite status detections in colorectal carcinoma

Presentation Number
536P
Lecture Time
12:45 - 12:45
Speakers
  • Meili Chen (Nanjing, CN)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

There are two commonly accepted methods for detecting microsatellite status: the one is to detect amplified microsatellite loci by polymerase chain reaction (PCR), and the other is to detect mismatch repair gene (MMR) proteins expression by immunohistochemistry(IHC). The PCR detection is considered to have accuracy in clinic, while the IHC is widely used because of its easier operation and cheaper expense.

Methods

In order to compare IHC with PCR in detecting the microsatellite status in colorectal carcinoma, A total of 569 samples of colorectal carcinoma resection were collected in Department of Pathology, Nanjing Drum Tower Hospital between June 2014 and June 2017, all samples were used IHC and PCR to detect microsatellite status, the consistency of results between the two methods was compared.

Results

We found that 48 cases of microsatellite instability (MSI) were detected by PCR, including 37 cases of microsatellite instability high (MSI-H), 11 cases of microsatellite instability low (MSI-L) and 521 cases of MSS. MSI accounted for 8.44% of all cases, of which the MSI-H accounted for 6.50%.The IHC results of 569 patients showed that 69 cases were deficient mismatch repair (dMMR), 500 cases were proficient mismatch repair (pMMR), dMMR accounted for 12.13% of all cases. The loss expression of PMS2 protein was the most common while the MSH6 was rare. The coincidence rate of the two methods for detecting microsatellite states was 91.92%.

Conclusions

IHC and PCR method had high consistency in microsatellite status. Compared with PCR, IHC method is more economical, convenient for clinical operations. When the 4 repair proteins were without missing detected by IHC, it can be diagnosed as MSS / MSI-L, further PCR was not necessary, and when any repair protein is found to be deficient, PCR detection was needed to determine whether there existed MSI. Our conclusion will save a lot of time and cost for clinical work.

Legal entity responsible for the study

The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University& Clinical Cancer Institute of Nanjing University.

Funding

National Natural Science Foundation of China; Nanjing Medical Science and Technique Development Foundation.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

537P - Assessment of local clinical practice for testing of mismatch repair deficiency in metastatic colorectal cancer: The need for new diagnostic guidelines prior to immunotherapy

Presentation Number
537P
Lecture Time
12:45 - 12:45
Speakers
  • Romain Cohen (Paris, FR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Immune checkpoint inhibitors (ICKi) have been approved for patients with metastatic colorectal cancer (mCRC) displaying MSI/dMMR (microsatellite instability, defective mismatch repair). We aimed to evaluate the accuracy of standard immunohistochemistry and PCR methods for the detection of MSI/dMMR in mCRC in routine clinical practice.

Methods

The study was performed on a multicenter retrospective cohort of mCRCs previously determined as MSI and/or dMMR by local assessment and on a prospective, single center cohort of patients included in ICKi trials based on positive MSI and/or dMMR status previously determined by the originating institutes. We re-assessed dMMR and MSI status in our specialized diagnostic center using immunohistochemistry (antibodies directed against MLH1, MSH2, MSH6 and PMS2), and pentaplex PCR (BAT-25, BAT-26, NR-21, NR-24 and NR-27). The positive predictive value (PPV) of local assessment was the primary objective of the study. Detection rate (i.e. conclusive result) and sensitivity of immunohistochemistry and PCR by central review were evaluated.

Results

Nine false-positives (9.8%) were found in the retrospective cohort (N = 92). These were initially diagnosed as MSI and/or dMMR by the originating institute but were reclassified as MMR proficient /microsatellite stable in our laboratory (PPV=90.2%; 95%CI, 82.2-95.0). The PPV in the prospective cohort (N = 39) was 92.3% (95%CI, 79.0-98.1), with the 3 false-positive patients experiencing progressive disease with ICKi treatment. Amongst the 119 true-positive mCRCs, the detection rate and sensitivity were respectively 100% and 95.8% for immunohistochemistry, while for pentaplex PCR these were 81.5% and 95.9%. Only the combination of immunohistochemistry and pentaplex PCR methods resulted in 100% detection rate and 100% sensitivity.

Conclusions

Local assessment of MSI/dMMR status in mCRC resulted in misdiagnosis of 9.1% of cases as false positive and subsequently incorrect treatment with ICKi. We recommend new guidelines that mandate dual testing of mCRC samples in experienced diagnostic centers using both PCR and immunohistochemistry.

Legal entity responsible for the study

INSERM.

Funding

ARCAD Foundation, Institut National du Cancer, Ligue Contre Le Cancer.

Disclosure

T. André: Consultancy: Bristol-Myers Squibb, Fees: Merck. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

538P - The prognostic role of PD L1 expression according to MSI status in stage III colon cancer after curative resection

Presentation Number
538P
Lecture Time
12:45 - 12:45
Speakers
  • Sang-Hee Cho (Hwasun, KR)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Tumors expressing programmed death ligand 1 (PD-L1) can render immune inactivated via triggering of PD-1 receptor on T cells with various pathways. Based on this mechanism, the blockade PD-1/PD-L1 pathway has been used as a therapeutic target for metastatic CRC. In the present study, we evaluated the prognostic role of PD-L1 expression associated with microsatellite status in surgically resected stage III colon cancer patients.

Methods

PD-L1 expression was performed by immunohistochemistry from 182 stage III colon cancer patients after curative resection. The percentage of PD-L1 positive tumor cells and staining intensity were evaluated and categorized as ‘strong’ or ‘weak’ positive group. Clinical and histopathologic parameters including of MSI status and survival outcomes were analyzed with IDO expression which stands for the suppressive immune environment.

Results

Strong PD-L1 expression was observed in 29% of all patients. Perineural invasion and lymphocyte response were more frequently shown in strong expression of PD-L1 grop. Among resected patients, MSI was shown in 23 patients (12%). Although there was no significant difference between microsatellite status and PD-L1 expression, strong PD-L1 tended to better overall survival in microsatellite stable (MSS) colon cancer (P = 0.056). In contrast, strong PD-L1 expression was significantly correlated with worse DFS (P = 0.001) and OS (P < 0.001) than weak PD-L1 expression group in microsatellite instability (MSI) patients, regardless of adjuvant chemotherapy. Also, the strong IDO expression was tended to be more frequently shown in strong PD-L1 expression (36.4%) group than weak PD-L1 expression (14.3%) group in MSI patients.

Conclusions

The expression of PD-L1 is differently affected on the survival outcomes according to the status of microsatellite. There is no significant relationship between the expression of PD-L1 and prognosis in MSS stage III colon cancer patients. However, in MSI colon cancer which has been well known as a highly immunogenic property, strong PD-L1 expression is significantly associated with poor prognosis on survival outcomes reflecting the immunosuppressive microenvironment in curative resected stage III colon cancer patient.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

539P - Pre-diagnostic anthropometry, sex, and risk of colorectal cancer according to tumor-infiltrating immune cell composition

Presentation Number
539P
Lecture Time
12:45 - 12:45
Speakers
  • Jonna Berntsson (Lund, SE)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Obesity is a well-established risk factor for colorectal cancer (CRC), but whether this risk differs according to CRC subtype defined by the tumor immune microenvironment has been sparsely described. Herein, we examined the relationship between pre-diagnostic anthropometry and CRC risk according to tumor-infiltrating immune cell composition, with particular reference to potential sex differences.

Methods

The density of immune cells expressing PD1, PD-L1 (PD-L1/IC), CD3, CD8, FoxP3, CD20, CD68, CD163, and tumor cells expressing PD-L1 (PD-L1/TC) was assessed by immunohistochemistry in tissue microarrays with tumors from 584 incident CRC cases in the Malmö Diet and Cancer Study (n = 28098). Multivariable Cox regression models, adjusted for age, smoking and alcohol intake, were applied to calculate hazard ratios (HR) for CRC risk according to height, weight, bodyfat %, waist- and hip circumference, waist-hip ratio (WHR), body mass index (BMI), and different immune cell subsets.

Results

Obesity, measured as several anthropometric factors, was significantly associated with PD-L1+/TC low, CD8+ high, FoxP3+ low, CD20+ low, and CD163+ low tumors in both sexes, and with PD1+ low tumors in women. A contrasting risk between sexes was seen for PD-L1/IC+ tumors, in that obesity was significantly associated with risk of PD-L1/IC+ high tumors in women (ptrend for weight = 0.008, ptrend for BMI = 0.039), but with risk of PD-L1/IC+ low tumors in men (ptrend for weight = 0.005, ptrend for bodyfat % = 0.003, ptrend for waist <0.001, ptrend for hip = 0.012, ptrend for BMI = 0.001, ptrend for WHR <0.001). Furthermore, obesity was associated with risk of any CD3+ high or low and any CD68+ high or low tumors in both sexes, and with any PD1+ high or low tumors in men. In age and BMI-adjusted survival analysis, PD1+, CD8+, CD20+, and CD68+ high were favorable prognostic factors only in women, and FoxP3+ high only in men. High PD-L1+ and CD3+ expression was prognostic in both sexes.

Conclusions

Anthropometric factors may influence the immune landscape of colorectal cancer, possibly in a sex-dependent manner. Thus, obesity and sex may be important factors to take into account when stratifying patients for immunotherapy.

Legal entity responsible for the study

Lund University.

Funding

Swedish Cancer Society, Swedish Research Council, the Swedish Government Grant for Clinical Research, the Mrs Berta Kamprad Foundation, Lund University Faculty of Medicine, University Hospital Research Grants.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

540P - Monocyte-to-lymphocyte ratio in metastatic colorectal cancer: prognostic role evaluation and cut-off definition

Presentation Number
540P
Lecture Time
12:45 - 12:45
Speakers
  • Debora Basile (Aviano, IT)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Changes in peripheral blood cells composition may reflect tumor immune microenvironment and its role in cancer growth control. High monocyte-to-lymphocyte ratio (MLR) could be a sign of tumor’s recruitment of suppressive cells, showing a prognostic role in many cancer types. This study aimed to evaluate the prognostic role of MLR in metastatic colorectal cancer (MCRC).

Methods

This retrospective study analyzed a consecutive cohort of 392 patients (pts) with MCRC treated in 2004-2017 at the Oncology Departments of Aviano and Udine (Italy). The prognostic impact of MLR on overall survival (OS) was evaluated with uni and multivariate Cox regression analyses. The best cut-off value to predict survival was defined through ROC analysis.

Results

Before first line therapy, 269 pts (69%) were aged <70, 120 pts (31%) had a right tumor, 150 pts (38%) a left tumor and 117 pts (30%) a rectal one. Of note, 105 pts (27%) received metastasectomy and 142 pts had >1 metastasis. Metastasis were more frequent in liver (40%), lung (20%) and peritoneum (20%) Overall, 57% had a KRAS mutation (m) and 11% had a BRAFm. At median follow-up of 60 months, median OS was 26 months. At univariate analysis, older age (HR 1.61, p < 0.001), nodes (pN2 HR 1.48, p = 0.036; pN3 HR 2.52, p = 0.001), KRASm (HR 1.36, p = 0.020) and MLR (HR 3.32, p < 0.001) were associated with worse OS. Conversely, sidedness (left HR 0.65, p = 0.003; rectum HR 0.73, p = 0.042), metastasectomy (HR 0.36, p < 0.001) and adjuvant chemotherapy (HR 0.66, p = 0.008) were associated with better OS. By multivariate analysis, sidedness and metastasectomy confirmed a better OS, while MLR (HR 3.20, p < 0.001), nodes (pN2 HR 1.89, p = 0.006; pN3 HR 2.25, p = 0.014), and KRASm (HR 1.50, p < 0.001) were associated with worse OS. The adoption of the cut-off value for MLR (i.e. 0.44) predicted worse OS both in univariate (HR 2.23, p < 0.001) and multivariate (HR 2.41; p < 0.001) analyses. Moreover, MLR was associated with number of metastatic sites (p < 0.001), type of sites (p < 0.001), sidedness (p = 0.001) and LDH level (p < 0.001).

Conclusions

High MLR is an independent prognostic factor associated with worse OS and pathological features of MCRC. Further studies are needed to confirm these data.

Legal entity responsible for the study

University of Udine.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

541P - Clinical relevance of circulating tumor DNA using amplicon-based deep sequencing panel in colorectal cancer patients with liver metastasis

Presentation Number
541P
Lecture Time
12:45 - 12:45
Speakers
  • Hiroki Osumi (Tokyo, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Liquid biopsy system using the detection of circulating tumor DNA (ctDNA) is expected to provide the utility as a novel diagnostic tool for cancers.

Methods

We prospectively enrolled a total of 101 metastatic colorectal cancer(mCRC) patients with liver metastasis. We investigated frequency of detectable mutations in cell-free DNA (cfDNA), concordance rate of RAS mutation between tissue and cfDNA, and relationship between the mutant allele frequencies (MAFs) and clinicopathological factors. We further investigated the relationship between time course of ctDNA and chemoresponse. Amplicon-based deep sequencing with molecular barcode (including hotspots of 14 genes) was performed to detect the ctDNA.

Results

Mutation(s) in plasma cfDNA were detected in 87.1% (88/101) of patients. The frequencies of plasma cfDNA mutation at TP53, KRAS, APC, and PIK3CA were 68.3%, 38.6%, 23.7%, and 14.8%, respectively. RAS mutational concordance rate between tissues and cfDNA was 76.2% (77/101). MAFs were significantly associated with CEA (P < 0.0001), CA19-9 (P = 0.006), LDH (P < 0.0001) levels and the number of metastatic organs (P < 0.0001). Patients with liver or lymph node metastasis had significantly higher MAF compared with those without metastases (P < 0.0001, P = 0.008, respectively). The patients with lower MAF at 8 weeks after initiation of chemotherapy showed significantly longer survival than those with higher MAF (>median vs ≤ median, PFS, P = 0.001, OS, P = 0.049). Increase of MAF had been observed earlier than tumor markers before disease progression were confirmed by computed tomography (P = 0.01).

Conclusions

Our results suggested that this cfDNA assay could detect mutations at a high rate of mCRC patients, and could be a useful tool for early detection of chemoresistance as well as a prognostic marker in the clinic.

Clinical trial identification

Legal entity responsible for the study

The Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Institutional Review Board.

Funding

Has not received any funding.

Editorial Acknowledgement

Cancer Precision Medicine Center, JFCR: Ms.Aya Imai, Dr. Hiroshi Ohnishi, Mr. Yuki Sano Clinical Examination Center, JFCR: Ms. Kazumi Kaihara and Dr. Konosuke Nakayama University of Chicago: Dr. Yusuke Nakamura.

Disclosure

All authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

542P - Droplet digital PCR of circulating tumour DNA for the detection of RAS/BRAF mutation in metastatic colorectal cancer

Presentation Number
542P
Lecture Time
12:45 - 12:45
Speakers
  • Eric Van Cutsem (Leuven, BE)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

Circulating tumour DNA (ctDNA) provides a non-invasive approach for gene mutation detection. The aim of this study is to evaluate the concordance of RAS/BRAF mutational status in tumour tissue and plasma in metastatic colorectal cancer (mCRC) patients.

Methods

Plasma samples were collected prospectively from previously untreated mCRC patients (TASCO1 NCT02743221) and analysed centrally by droplet digital PCR (ddPCR) with sensitivity down to 0.2% for KRAS exon 2, 0.5% for NRAS exon 2 and BRAF. Tumour RAS/BRAF status was determined locally from primary or metastatic tumours according to routine practice.

Results

Out of the 153 patients included, 121 had tissue and plasma mutation status available for KRAS exon 2, 129 patients for NRAS exon 2 and 70 patients for BRAF V600E. In these subgroups, the prevalence of KRAS exon 2, NRAS exon 2 and BRAF mutations detected in plasma was 30.6%, 0.8% and 11.4%, respectively vs. 47.1%, 1.6% and 12.9%, respectively in tumours. For KRAS, the concordance was 81.8% with a Kappa coefficient of 0.63. KRAS mutation was detected in tumour tissue and not in plasma for 21 patients (17.4%), potentially explained by low tumour burden or low tumour DNA shedding. KRAS mutation was detected in plasma but not in tumour tissue for just one patient. For NRAS, a concordance of 99.2% (kappa = 0.66) was observed between plasma and tumour tissue. One discordant case (0.8%) was observed for which NRAS was detected only in tissue. This case also presented KRAS mutation both in plasma and tumour tissue excluding an explanation related to tumour DNA shedding. For BRAF, a concordance of 95.7% (kappa = 0.80) was observed between plasma and tumour tissue: BRAF mutation was detected only in plasma in one case (1.4%) and only in tumour tissue in 2 cases (2.9%). One of the two cases displaying BRAF V600E in tumour but not in plasma also had an NRAS mutation in plasma and unknown NRAS status in tumours.

Conclusions

This study showed that RAS/BRAF mutations can be detected in plasma samples from mCRC patients by ddPCR. However, in the context of the study, analysis of the ctDNA did not allow detection of RAS/BRAF mutations in all patients where these mutations were present in the tumour.

Clinical trial identification

TASCO1 NCT02743221.

Legal entity responsible for the study

Servier Oncology.

Funding

Servier.

Disclosure

E. Van Cutsem: Research funding: Amgen, Bayer, Boehringer, Celgene, Ipsen, Lilly, Merck, Merck KgA, Novartis, Roche, Sanofi, Servier. M.P. Saunders: Honoraria: Roche, Merck, Amgen, Servier, Eisai. G. Argiles: Advisor: Hoffman la Roche, BMS, Bayer. C. Borg: Advisory boards: Roche, Servier, Sanofi; Research grant: Roche. P. Pfeiffer: Research funding: Amgen, Celgene, Lilly, Merck KgA, Roche, Taiho, Servier. V. Cattan, G. Desachy, N. Amellal: Employee: Servier. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session

543P - Gene mutation status in circulating tumor DNA (ctDNA) and 1st-line FOLFOXIRI plus bevacizumab (bev) in metastatic colorectal cancer (mCRC) harboring RAS mutation

Presentation Number
543P
Lecture Time
12:45 - 12:45
Speakers
  • Yu Sunakawa (Kanagawa, JP)
Location
Hall A3 - Poster Area Networking Hub, ICM München, Munich, Germany
Date
21.10.2018
Time
12:45 - 13:45

Abstract

Background

We have conducted a phase II trial of 1st-line modified (m)-FOLFOXIRI plus bev for RAS mutant mCRC, which included a biomarker study using liquid biopsies [Oncotarget 2018]. There are few reports on monitoring changes in gene mutation (mt) status in mCRC harboring RAS mt. Therefore, the pre-planned analysis was performed to investigate a number of genes in ctDNA during therapy that might be determinants of therapeutic efficacy.

Methods

Sixty-two patients (pts) with unresectable/measurable tumors received protocol treatment with m-FOLFOXIRI (irinotecan 150 mg/m², oxaliplatin 85 mg/m², levofolinate [LV] 200 mg/m², and fluorouracil 2400 mg/m² repeated biweekly) plus bev. The phase II trial included objective response rate (ORR) for primary endpoint and progression-free survival (PFS), overall survival, early tumor shrinkage, depth of response (DpR), and safety for secondary endpoints. In 53 pts who enrolled in the biomarker study, plasma samples for extraction of ctDNA were collected at 3 points (pre-, 8wks, and progression) and analyzed for specific KRAS and NRAS variants with real-time PCR assays.

Results

Fifty-three pts had the following clinical data: median age of 61yrs, 57% male, 91% PS0, 28% right-sided tumors, ORR of 72%, median DpR of 49%, and median PFS of 10.8 months. RAS mt was detected in pre-treatment plasma in 79% (42/53) of pts. Among pts with mt in ctDNA at pre-treatment, 76% changed to mt-negative 8wks after treatment. ORR and DpR were higher in pts of mt-negative at 8wks compared to pts of mt-positive (81% vs. 50% and 55% vs. 34%, respectively). Median PFS was 11.9 and 8.8 months in pts who were mt-negative and mt-positive, respectively (HR 0.58, 95%CI 0.25-1.33, P = 0.20). Interestingly, in 26 pts who experienced progressive disease (PD) and were evaluable for ctDNA analysis, 52% (11/21) of pts with mt at pre-treatment still had no mt in plasma at PD. Pts of mt-negative at PD had longer survival time from PD compared to pts of mt-positive (9.3 vs. 7.0 months).

Conclusions

Gene mt status in ctDNA during therapy may predict clinical outcome of triplet plus bev treatment in RAS mutant mCRC. Our study suggests that pts with no mt in plasma at PD may have more favorable post-treatment.

Clinical trial identification

UMIN000015152.

Legal entity responsible for the study

Wataru Ichikawa.

Funding

Japan Clinical Cancer Research Organization (JACCRO).

Editorial Acknowledgement

We acknowledge Sachika Koyama and Yasushi Ohtake (JACCRO) for editorial assistance.

Disclosure

Y. Sunakawa: Honoraria for talks: Taiho Pharmaceutical, Chugai Pharma, Yakult Honsha, Takeda, Merck Serono, Bayer Yakuhin, Sanofi. H. Satake: Honoraria: Bayer, Chugai Pharma, Eli Lilly Japan, Merck Serono, Takeda, Taiho Pharmaceutical, Yakult Honsha. M. Nakamura: Honoraria: Chugai Pharma, Taiho Pharmaceutical, Yakult Honsha. M. Takeuchi: Consulting fees: Hisamitsu Pharmaceutical, Kowa, Shionogi Pharma, Abbvie, Astellas. H-J. Lenz: Consulting or advisory role, travel expenses, honoraria: Roche. W. Ichikawa: Consulting fees: Ono Pharmaceutical; Research funding: Takeda, Taiho Pharmaceutical, Eisai, Chugai Pharma, Merck Serono, Shionogi Pharma, Daiichi Sankyo; Honoraria: Merck Serono, Taiho Pharmaceutical, Chugai Pharma, Takeda, Ono Pharmaceutical, Lilly. All other authors have declared no conflicts of interest.

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Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology Poster Display session