Browsing Over 3689 Presentations
The optimal sequence: Does overall survival matter? (ID 265)
- Tony S.K. Mok (Shatin, Hong Kong PRC)
Introduction (ID 6351)
- Nadia Harbeck (Munich, Germany)
64P - The potential of neratinib plus dasatinib in overcoming and preventing neratinib resistance in HER2-positive breast cancer models (ID 3011)
- Neil Conlon (Dublin, Ireland)
Abstract
Background
Neratinib (NER) is an irreversible pan-HER kinase inhibitor with demonstrated clinical activity for HER2-positive and HER2-mutated breast cancers (BC). Mechanisms of resistance to NER are poorly understood. The Src/Abl inhibitor dasatinib (DAS) has shown ability to overcome resistance to HER2-targeted agents such as lapatinib (LAP) and TRAS in vitro. This pre-clinical study investigated the efficacy of DAS in combination with NER to overcome or prevent NER resistance in BC models.
Methods
Anti-proliferative effects of NER, LAP, TRAS, DAS, and NER plus DAS were assessed in five NER-resistant HER2+ BC cell lines (HCC1954-N, HCC1569-N, EFM192A-N, BT474-N, and SKBR3-N) by acid phosphatase assay. IC50values and Combination index (CI) values were calculated to determine synergy (CI < 0.8) using Calcusyn. Neratinib resistance was defined as an IC50value > 150 nM NER. Apoptosis induction was assessed by Caspase 3/7-Glo assay. Reverse phase protein array was used to determine changes in key signalling pathways in HCC1954-N cells. BC cells were treated twice weekly with NER and/or DAS and crystal violet stained when confluent to examine resistance development.
Results
All NER resistant cell lines examined had significantly reduced response to NER (11-83 fold increase in IC50values versus parental cells), as well as LAP and TRAS, compared to their parental cells.The combination of NER and DAS displayed synergy in all five NER resistant cell lines (CI = 0.1-0.6). NER plus DAS caused a strong induction of apoptosis in the HCC1954-N cells (p = 0.015). NER/DAS treatment caused changes in 23 phospho- or total protein levels, including suppression of Akt, MAPK, Src, p38 and AMPK signalling. NER alone (9 phospho- and 1 total proteins) and DAS alone (3 phospho- and 3 total proteins) altered fewer targets. The addition of DAS to NER prevented the emergence of NER resistance in parental HCC1954 and HCC1569 cells.
Conclusions
This study provides pre-clinical rationale for the combination of NER and DAS in NER-resistant HER2+ BC and shows that this combination warrants further investigation.
Legal entity responsible for the study
The authors.
Funding
Puma Biotechnology.
Disclosure
N. Conlon: Research grant/Funding (institution): Puma Biotechnology. J. Crown: Full/Part-time employment: OncoMark; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Research grant/Funding (institution): Eisai; Honoraria (self): Amgen; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Puma Biotechnology; Honoraria (self): Seattle Genetics; Honoraria (self), Advisory/Consultancy, Speaker Bureau/Expert testimony, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Advisory/Consultancy: Vertex; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution), Travel/Accommodation/Expenses: Roche; Honoraria (self), Travel/Accommodation/Expenses: MSD Oncology; Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Abbvie; Honoraria (self), Advisory/Consultancy, Research grant/Funding (institution): Boehringer Ingelheim; Honoraria (self), Speaker Bureau/Expert testimony: Genomic Health. D.M. Collins: Research grant/Funding (institution): Puma Biotechnology; Research grant/Funding (institution): Roche. All other authors have declared no conflicts of interest.
LBA16 - TCR-beta repertoire convergence and evenness are associated with response to immune checkpoint inhibitors (ID 5435)
- Philip Jermann (Basel, Switzerland)
Abstract
Background
Immune checkpoint inhibitors (ICI) significantly improve clinical outcome of advanced non-small cell lung cancer (NSCLC) patients. However, as only a subset of patients responds to treatment, there is an urgent need for predictive biomarkers. Here we investigated the association of TCR-beta (TCRB) clonal expansion and convergence with treatment response. We assessed these features within the tumor microenvironment of treatment naïve patients and compared their predictive value with other biomarkers such as tumor mutational burden (TMB) and PD-L1 status.
Methods
Total RNA was extracted from NSCLC FFPE pretreatment tissue biopsies of patients receiving ICI therapy (n = 45). TCRB repertoire NGS libraries were prepared with the Oncomine TCRB-SR assay and sequenced on the Ion Torrent instrument. TCR convergence (=frequency of clonotypes identical in amino acid but different in nucleotide space) and clonal evenness (=measurement of the similarity of clone sizes) were evaluated independently using Fisher’s test. TMB values from the same biopsies were assessed from extracted genomic DNA via the Oncomine Tumor Mutation Load Assay. PD-L1 status was determined by immunohistochemical staining.
Results
Durable clinical benefit from ICI therapy was associated with increased TCR convergence (p = 0.12) and decreased clonal evenness (p = 0.01) independently. The TCR-based patient classification was able to identify responders who otherwise had low to intermediate (<9 Mutations per Mb) TMB or negative (<1%) PD-L1 status. Adding TCR evenness to TMB and PD-L1-based stratification allowed for the identification of 82% of responders, compared to 47% for TMB alone and to the identification of 94% of responders, compared to 59% for PD-L1 alone.
Conclusions
Our results show that evaluation of the TCR-beta repertoire in NSCLC specimens is an effective tool to stratify patients according to their response to ICI therapy. In particular, TCR assessment identifies subpopulations of responding patients that would otherwise be misclassified by either TMB or PD-L1 status. Thus, combinatorial use of several biomarkers may yield the highest clinical accuracy for ICI therapy selection.
Legal entity responsible for the study
Philip Jermann.
Funding
Thermo Fisher Scientific.
Disclosure
P. Jermann: Honoraria (self), Research grant / Funding (institution), Travel / Accommodation / Expenses: Thermo Fisher Scientific; Research grant / Funding (institution): BMS. K. Leonards: Research grant / Funding (institution): Thermo Fisher Scientific; Research grant / Funding (institution): Bristol-Myers Squibb. T. Looney: Full / Part-time employment: Thermo Fisher Scientific. I. Alborelli: Research grant / Funding (institution), Travel / Accommodation / Expenses: Thermo Fisher Scientific; Research grant / Funding (institution): Bristol-Myers Squibb. S.I. Rothschild: Honoraria (self), Research grant / Funding (institution): AstraZeneca; Honoraria (self), Research grant / Funding (institution): BMS; Research grant / Funding (institution): Merck Serono; Honoraria (self): MSD; Honoraria (self): Roche; Honoraria (self): Novartis. S. Savic Prince: Honoraria (self), Advisory / Consultancy: MSD; Advisory / Consultancy: AstraZeneca; Honoraria (self): Roche. A. Zippelius: Advisory / Consultancy: BMS; Advisory / Consultancy, Research grant / Funding (institution): Roche; Advisory / Consultancy: MSD; Advisory / Consultancy: NBE Therapeutics; Research grant / Funding (institution): Secarna; Research grant / Funding (institution): Beyondsprings; Research grant / Funding (institution): Crescendo; Research grant / Funding (institution): Hookipa. L. Bubendorf: Honoraria (self), Research grant / Funding (institution): Roche; Honoraria (self), Research grant / Funding (institution): MSD; Honoraria (self): BMS; Honoraria (self): AstraZeneca. All other authors have declared no conflicts of interest.
Challenges in caring for patients with rare cancers, nursing implications and the need for international collaboration (ID 7231)
- Helena C. Ullgren (Stockholm, Sweden)
312P - Genomic profiling of Chinese breast cancer patients (ID 4263)
- Zhonghua Tao (Shanghai, China)
Abstract
Background
The complexity of breast cancer (BC) at the clinical, morphological and molecular level has been well demonstrated. Molecular profiling, which reveals the intrinsic biology among subtypes, has significantly advanced the management of this disease. However, previous studies have provided very limited molecular data on Chinese BC patients.
Methods
We performed capture-based targeted sequencing on plasma samples using a panel consisting of 102 BC related genes, spanning 249 kb of human genome, to interrogate the genomic landscape of 236 female Chinese BC patients and compared our results to the TCGA data set. Only genes covered by the panel and occurring in more than 10% patients from at least one subgroup were compared and contrasted between the two cohorts. The Chinese and the TCGA cohort had a median age of 48 and 58, respectively.
Results
Our cohort consisted of 55% triple negative breast cancer (TNBC), 10% luminal A, 27% luminal B and 8% HER2 positive BC. 53% of patients were post-menopausal. 190 patients had mutations found from this panel, resulting in a positive detection rate of 81%. Of the 46 patients with no mutation detected from this panel, 24 had TNBC. Collectively, we identified 921 mutations spanning 89 genes. First, we compared and contrasted mutation spectrum among the 4 subtypes. TP53mutations were more commonly seen in TNBC patients (p < 0.01), whereas FGF3, FGF4, FGF19and CCND1amplification were more likely to occur in patients with Lumina A or Luminal B BC (p = 0.002). Next, we compared the mutation spectrum of our cohort to TCGA dataset, and for luminal B breast cancer and TNBC, Chinese patients had significantly more PI3KCA mutation found. Furthermore, Chinese luminal A (p < 0.01) and luminal B (p < 0.01) patients had significantly higher TP53mutation frequency and Chinese HER2 positive BC patients (p < 0.01) had significantly lower TP53mutation frequency than TCGA dataset. In addition, we also identified 10 pathogenic or likely pathogenic BRCA1/2 mutations from this cohort, resulting in a prevalence rate of 4.2%.
Conclusions
We identified distinctive genomic patterns associated with Chinese breast cancer patients compared to TCGA data, suggesting the importance of mutation-based stratification according to ethnic status.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
1177PD - Clinical study of personalized neoantigen peptide vaccination in advanced NSCLC patients (ID 2096)
- Xueming Du (Tianjin, China)
Abstract
Background
Neoantigens derived from tumor-associated mutations can elicit T cell-mediated antitumor immunity and facilitate tumor rejection. Here, we assessed the safety and efficacy of personalized neoantigen peptide vaccination (PPV) in advanced NSCLC patients who had failed conventional therapy.
Methods
24 stage III/IV recurrent NSCLC patients were immunized with mixtures of short and long neoantigen peptides based on personalized tumor-associated mutations and predicted HLA peptide binding affinities. Primary study endpoints were feasibility and safety. Secondary endpoints were PPV-induced immune responses, progression-free survival (PFS) and overall survival (OS).
Results
Aside from transient rash, fatigue and/or fever in 3 patients, no treatment-related adverse events were observed. The median PFS and OS of the 24 PPV patients was 6.0 and 8.9 months, respectively. Of the 16 PPV patients bearing EGFR mutations, 7 experienced objective tumor response by RECIST 1.1, including 6 PR and 1 CR. Of the 8 patients expressing wild-type EGFR, 4 showed SD and no PR or CR. Importantly, 9 PPV patients who continued EGFR inhibitor (EGFRi) therapy in spite of prior progression showed extended survival compared to 7 patients who stopped EGFRi prior to initiating PPV (median OS: 13.8 vs. 7.6 months, P = 0.038), though both patient groups experienced similar objective response rates. Immune monitoring demonstrated the immunogenicity of two highly shared EGFR mutations in multiple responding patients. Robust PPV-specific immune responses were observed in 4 responding patients, with ELISPOT and tetramer staining showing incremental increases in peripheral blood neoantigen-specific CD8+ T cell frequencies for up to 3 months during PPV. T-cell receptor (TCR) Vb sequencing also demonstrated significantly increased frequencies of neoantigen-specific CD8+ TCR clones in both peripheral blood and tumor-infiltrating lymphocytes following PPV.
Conclusions
These results suggest that PPV is safe and potentially beneficial for advanced stage EGFR-mutated NSCLC patients. Survival analyses imply that PPV in combination with EGFRi may be a viable treatment option for NSCLC, in spite of prior EGFRi failure.
Clinical trial identification
ChiCTR-INR-16009867.
Legal entity responsible for the study
Tianjin Beichen Hospital.
Funding
Tianjin HengJia Biotechnology Development Co., Ltd.
Disclosure
F. Li: Shareholder / Stockholder / Stock options: Tianjin HengJia Biotechnology Development Co., Ltd. G. Lizee: Advisory / Consultancy: HengJia Neoantigen Biotechnology (Tianjin) Co., Ltd. P. Hwu: Advisory / Consultancy: Dragonfly Therapeutics; Advisory / Consultancy: GlaxoSmithKline; Advisory / Consultancy, Shareholder / Stockholder / Stock options: Immatics; Advisory / Consultancy: Sanofi; Research grant / Funding (institution): Genentech. L. Deng: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. Q. Zou: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. M.A. Stairs: Advisory / Consultancy: HengJia Neoantigen Biotechnology (Tianjin) Co., Ltd. C. Chen: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. C. Huo: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. Y. Wang: Full / Part-time employment: Tianjin HengJia Biotechnology Development Co., Ltd. All other authors have declared no conflicts of interest.
1142P - To compare two oral mucosa contouring methods in predicting acute oral mucocitis in nasopharyngeal carcinoma treated with helical tomotherapy (ID 3356)
- Yuan-Yuan Chen (hangzhou, China)
Abstract
Background
The purpose of this study was to evaluate prediction effect for acute radiation-induced oral mucositis (A-ROM) of two oral mucosa contouring methods in nasopharyngeal carcinoma (NPC) patients treated with helical tomotherapy.
Methods
A total of 151 AJCC 7th stage II-IVB histologically proven NPC patients receiving radical tomotherapy (TOMO) from Zhejiang Cancer Hospital were included. All patients received 0-4 cycles of platinum-based induction chemotherapy±1-3 cycles of concurrent chemotherapy (all patients received at least one chemotherapy). Oral cavity contour (OCC) and mucosa surface contour (MSC) were applied to radiation treatment plans. A-ROM were prospectively assessed weekly according to RTOG scoring criteria. Absolute DVH data was exported from RayStation V3.0 system. T-test, X2 test, binary logistic regression and ROC curve were used to analyses.
Results
Morbidity of ≥ 3 grade A-ROM was 30.4%. In univariate analysis: V10, V15, V45, V55, V60, V65, V70 of OCC and V15, V55, V60, V65, Dmean of MSC were significant related to ≥ 3 grade A-ROM (Vx, percentage volume of organ received more than Gy, all P0.05). In binary logistic regression analysis, gender, smoking were found significantly related to ≥ 3 grade A-ROM by using OCC (male vs. female : OR=0.070, 95%CI=0.019-0.411, P = 0.008 ; smoking vs. non-smoking: OR = 15.250, 95%CI=4.421-61.980, P = 0.001). For MSC, gender, smoking and MSC V55 were independent predictors (male vs. female : OR=0.152, 95%CI=0.037-0.642, P0.001 ; smoking vs. non-smoking: OR = 4.028, 95%CI=2.145-32.079, P = 0.032 ; MSC-V55 : OR=2.665, 95%CI=1.172-3.365, P0.004). The cutoff of MSC-V55 was 10.38%, area under curve was 0.697, with sensitivity and specificity of 0.635 and 0.704, respectively.
Conclusions
We recommend MSC as a more reasonable method for oral mucosa contouring in TOMO treatment plan for nasopharyngeal carcinoma patients.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.
The patient’s perspective (ID 499)
- Roger Wilson (Church Stretton, United Kingdom)
Translating adjuvant melanoma data into clinical practice (ID 6586)
- Georgina V. Long (Wollstonecraft, NSW, Australia)
Presentation by expert (ID 69)
- Ignacio Melero (Pamplona, Spain)
CN15 - Unmet needs in oncology research related to radiological response evaluation: A multi-center survey in three European countries (ID 6062)
- Sophie Nisse Durgeat (Suresnes, France)
Abstract
Background
A standardized evaluation approach in oncology is essential to optimize treatment and management of patients. In particular, a medical software designed to provide standard metrics and reports may help the communication among health care professionals, facilitating the decision process. To this aim, a large survey study was conducted across the United Kingdom (UK), Spain (ES) and Italy (IT) exploring existing unmet needs and questioning the way oncological data is tracked in daily routine practice with the aim of offering some ideas for improvement.
Methods
Physicians were enrolled by an independent Market Research Company according to diiferent inclusion criteria: a) 2-35 years in practice; b) ≥50% of practice time in direct patient care; c) involvement in making treatment decisions ; d) involvement in ordering and reviewing tumour assessment reports; e) to be an investigator or author of an oncology clinical trial in the past 5 years.The study was conducted in November-December, 2018.
Results
A total number of 270 physicians (medical oncologists: n = 180, radio-oncologists: n = 90) participated (UK/100, ES/95, IT/75). The vast majority of physicians use Response Evaluation Criteria in Solid Tumors (RECIST) criteria in their daily practice (86%). Guidelines for response criteria for use in trials testing immunotherapeutics (iRECIST) and modified RECIST (mRECIST) are also used by between third and a quarter of physicians. Of note, almost half of the physicians indicated that there is a low level of data management in oncology and 2 out of 3 agree that this negatively impacts therapeutic decisions. Over a third of ES physicians believe that there is a low level of data management in oncology and a similar proportion in IT and ES report that it is impacting therapeutic decision making.
Conclusions
Only a third of physicians view their current reporting systems as adequate. All participants agree that any reporting system is in need of a common shared template for radiologists and oncologists. Thus, physicians identify a lack of consistency in diagnostic assessments and delays in receiving the reports as key unmet needs in tumor reporting systems –indicating the need for a streamlined system.
Legal entity responsible for the study
The authors.
Funding
Wehealth Digital Medicine.
Disclosure
All authors have declared no conflicts of interest.