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Browsing Over 2667 Presentations
1512P - Clinicopathologic features and long-term follow-up of metastatic gastrointestinal stromal tumor (GIST) patients (pts) with durable response (≥ 5 years) to frontline imatinib (IM): A case-control study from GEIS (ID 1239)
- C. Serrano
Abstract
Background
IM achieves disease control in most metastatic GIST pts, typically about 18 months. Interestingly, ∼15% GIST pts remain on IM beyond 5 years of continuous treatment. To date, clinicopathologic features predictive of long-term benefit to IM remain largely unknown.
Methods
We analyzed clinical, pathological and molecular characteristics, and long-term outcomes in metastatic GIST pts treated with continuous daily dosing of frontline IM in a cohort of pts benefiting ≥ 5 years, compared with a control group obtained from a national GEIS database.
Results
We found 41 IM long-term responders (IM-LTR) and 71 control cases (CC) with a median time on IM of 90.6 and 18.2 months, respectively. Compared to CC, IM-LTR were younger (59 vs 64 years, p = 0.040), fitter at diagnosis (performance status (PS) 0-1: 100% vs 82.2%, p < 0.001), had fewer metastasis prior to IM initiation (2.6 vs 7.5, p < 0.001), and primary tumors were bigger (10.4 vs 9 cm, p = 0.005) but had lower mitotic count (5.5 vs 15 per 50HPF, p = 0.005). There were no differences in terms of primary tumor location, disease status or metastases location at diagnosis. Mutational profile from IM-LTR (KIT ex 11, 81%; KIT ex 9, 0%; PDGFRA, 8%; wild-type, 11%) did not differ significantly from CC. IM-LTR had significantly better response pattern (complete response 34.1%; partial response 43.9%; stable disease 22%) and overall survival (not reached) over CC (9.2%, 40%, 26.2%; and 63 months, respectively). Only 7 pts (18%) receiving IM ≥ 5 years withdrew IM due to progression (69% CC, p < 0.001). Eight pts (25%) developed ≥ 1 new toxicities after ≥ 5 years on continuous IM; only 1 pt withdrew IM due to toxicity (grade 3 anemia). Univariate analyses show that pts with better PS (p = 0.002), low mitotic count (p = 0.025), low number of metastases (p < 0.001), and better response to IM (p < 0.001) achieve durable benefit from frontline IM.
Conclusions
Clinical and inherently biological tumor characteristics define a subset of GIST pts with increased likelihood to achieve durable benefit from IM. Molecular studies are needed to better identify these pts at treatment initiation.
Legal entity responsible for the study
Spanish Group of Sarcoma Research (GEIS)
Funding
Spanish Group of Sarcoma Research (GEIS)
Disclosure
All authors have declared no conflicts of interest.
252P - Phase II study of gemcitabine, trastuzumab, and pertuzumab for HER2-positive metastatic breast cancer after prior pertuzumab-based therapy (ID 1747)
- N. Iyengar
Abstract
Background
The combination of taxanes with trastuzumab (H) and pertuzumab (P) for first line treatment of HER2-positive metastatic breast cancer (MBC) is associated with improved progression-free (PFS) and overall survival (OS). Treatment per physician’s choice with anti-HER2 therapy after second line therapy is associated with a median PFS of 3 months. While continued use of H in therapeutic combinations after progression on H-based therapy is standard, the efficacy of continuing HP-based treatment after progression on P-based therapy is unknown.
Methods
This is a single arm phase II trial of gemcitabine (G) with HP. Eligible patients (pts) had HER2-positive (IHC 3+ or FISH ≥ 2.0) MBC with prior HP-based treatment and ≤ 3 prior chemotherapies. Pts received G (1200 mg/m2) on days 1 and 8 of a q 3 week (w) cycle, and H (8 mg/kg load
Results
As of 27 April 2017, 45 of 45 pts are enrolled; 39 are evaluable at 3 months and 6 have not had 3-month evaluation. At 3 months, 30/39 (77%) are progression free (1 CR, 8 PR, 21 SD); 9 pts progressed. There are no cardiac or febrile neutropenic events to date. 4 pts required G dose reduction (3 grade 3 neutropenia and 1 grade 3 vomiting) and the study was amended to lower initial G dose to 1000 mg/m2.
Conclusions
The preliminary 3 month-PFS is 77% in evaluable pts (95% CI 62% to 87%). The updated 3 month-PFS results will be presented. Continuation of P beyond progression is associated with apparent clinical benefit. A randomized trial is justified to confirm this clinically important observation.
Clinical trial identification
NCT02252887
Legal entity responsible for the study
Memorial Sloan Kettering Cancer Center
Funding
Genentech/Roche
Disclosure
All authors have declared no conflicts of interest.
58P - Melanoma affects clock gene machinery of several organs in tumor-bearing mice (ID 1460)
- L. De Assis
Abstract
Background
The accumulation of soluble factors in the tumor microenvironment and their release into the bloodstream lead to systemic effects, resulting in cancer-associated syndromes such as cachexia. Another association observed in the latter scenario is chrono-disruption, which has been related with tumor onset and development. In fact, a positive relationship between master clock integrity and healthiness has already been disclosed; however, it is unclear whether the effects of chronodisruption in cancer are locally or systemically exerted. It is known that lung adenocarcinoma reprograms liver metabolism via a pro-inflammatory response without affecting liver clock genes. Our study evaluated whether a non-metastatic skin tumor can affect clock gene machinery of other organs.
Methods
Eight to sixteen-week old C57BL/6J male mice were inoculated subcutaneously with B16-F10 cells (or PBS, control animals), single housed at 22 ± 2 °C, kept under 12/12h light/dark cycle, and received food and water ad libitum. Two weeks after inoculation mice were euthanized 2 hours after lights on (ZT2) or 2 hours after lights off (ZT14). Skin of control animals and samples of non-tumoral adjacent skin, tumor, liver, lung, and brown adipose tissue (BAT) were collected to evaluate the expression of clock genes (
Results
No oscillatory profile of clock genes was detected in skin of control animals, tumor adjacent skin, and tumor itself of inoculated animals;
Conclusions
The presence of a non-metastatic tumor in the skin alters clock machinery in adjacent skin, liver, lungs, and BAT. These data bring new knowledge of how tumor macro-environment affects clock machinery, resulting in a likely chrono-disruption of the organism as a result of a localized tumor in the skin.
Legal entity responsible for the study
University of Sao Paulo (USP) and Sao Paulo Research Foundation (FAPESP)
Funding
Sao Paulo Research Foundation (FAPESP) and National Council of Technological and Scientific Development (CNPq).
Disclosure
All authors have declared no conflicts of interest.
1411P - Genetic counseling, screening and risk reducing practices in patients with BRCA mutations (ID 2467)
- R. Saroufim
Abstract
Background
Worldwide practices of genetic counseling remain variable. We present genetic counseling, mammography and MRI screening & risk-reducing surgeries on patients with BRCA mutations & VUS of our BRCA mutations study (El Saghir et al, Oncologist 2015).
Methods
Chart review & phone calls for collection of information were done on 45 pts out of the 250 pts tested. IRB approval obtained. 14 pts (5.6% of total) with deleterious mutations & 31 pts (12.4% of total) with VUS were included. 7 pts had metastatic breast cancer. 4 pts were not reachable. We present results on 33 pts for whom we collected information about genetic counseling, screening, Contralateral Prophylactic Mastectomy (CPM) & Risk Reducing Salpingo-oophorectomy (RRSO).
Results
14 pts with deleterious mutations (7 BRCA1 & 7 BRCA2 positive pts) & 19 pts with 20 VUS mutations (4 BRCA1 & 16 BRCA2; 1 pt had both BRCA1 & BRCA2) were examined. Of the 14 pts with BRCA deleterious mutations, 57.14% (8/14 pts) said they received some genetic counseling from their own oncologist and not a specialized genetic counselor. 85.71% (12/14) are undergoing regular screening mammography, 35.71% (5/14) are undergoing regular screening breast MRI. 50% (7/14) underwent CPM & 57.14% (8/14) underwent RRSO. Also, 57.14% (8/14) advised their family members, namely sisters & daughters, to undergo BRCA mutation testing. Of the 19 pts with VUS mutations, only 10.5% (2/19 pts) of the pts said they received some genetic counseling. 78.9% (15/19) are undergoing regular screening mammogram, 31.5% (6/19) are undergoing regular screening MRI breasts. 1 pt underwent CPM & 2 pts RRSO. Also, only 21.0% (4/19) advised their family members to undergo BRCA mutation testing.
Conclusions
The majority of pts with BRCA mutations continue to undergo screening mammography & breast MRI. Only 50% of pts with BRCA deleterious mutations underwent CPM & 60% RRSO, while a few pts with VUS mutations underwent CPM & RRSO. Genetic counseling is mostly done by medical oncologists. Our data supports recommendations to include genetic counseling in the training and Continuing Medical Education CME of Oncologists, and to improve patient education. More importantly, there is an urgent need for more certified professional genetic counselors in Lebanon & worldwide.
Legal entity responsible for the study
Nagi El Saghir
Funding
None
Disclosure
All authors have declared no conflicts of interest.
ESMO Award lecture - Oncology: The importance of teamwork (ID 6011)
- M. Martin Jimenez
Conclusions (ID 755)
- B. Johnson
General Discussion (ID 397)
Cell context, mutation and treatment response across ovarian cancer subtypes (ID 215)
- D. Huntsman
Clinical implications of HRD beyond BRCA (ID 34)
- J. Jonkers
1231P - Role of an intronic polymorphism in the CREB1 gene, involved in melanogenesis, with the risk and the aggressiveness of cutaneous melanoma (ID 4147)
- J. Silva
Abstract
Background
Recently, we observed 12,882 new single nucleotide polymorphisms (SNPs) associated with cutaneous melanoma (CM) risk in 103 patients and 103 controls, using large-scale genotyping with microarrays. CREB1 c.303 + 373G>A, involved in melanogenesis and located in regulatory sequence of mRNA processing (splicing), was selected for further analyses. An in silico analysis showed that referred SNP may alters the binding sites of splicing regulatory proteins, such as SF1 and hnRNP A1. However, the role of this SNP in the risk, aggressiveness and prognosis of CM is unknown. Verify whether the distinct genotypes of CREB1 c.303 + 373G>A influence the CM risk and prognosis, clinicopathological aspects, and CREB1, SF1 and HNRNPA1 mRNA levels.
Methods
Genomic DNA of 262 patients and 280 controls was analyzed by RT-PCR. Patients were treated with conventional procedures. Gene expressions were determined by qPCR using total RNA of 56 controls. Chi-square, logistic regression model, Mann-Whitney and Student’s t tests analyzed the differences between groups. Progression-free survival (PFS) and overall survival (OS) times were calculated using Kaplan-Meier and Cox regression analyses.
Results
CREB1 GA or AA genotypes were more frequent in CM patients than in controls (72.0% vs. 61.1%, P = 0.02). Carriers of the genotypes were under 1.61-fold increased risk of CM (95% CI: 1.07-2.41) than others. An excess of CREB1 AA variant genotype was seen in patients with Breslow’s thickness higher than 1.5mm (28.2% vs. 18.5%, P = 0.04) and high Clark’s level (26.2% vs. 13.3%, P = 0.02). The median of follow-up of CM patients was 76 months; no association of referred SNP and patients’ PFS and OS was observed in this study. Individuals with CREB1 GA or AA genotypes presented higher mRNA expression of CREB1 (0.94 vs. 0.60 arbitrary units (UAs), P = 0.007), SF1 (1.33 vs. 1.05 UAs, P = 0.03) and HNRNPA1 (0.77 vs. 0.57 UAs, P = 0.02) than those with GG wild-type genotype.
Conclusions
Our data suggest, for the first time, that CREB1 c.303 + 373G>A SNP is an important hereditary factor for the risk and aggressiveness of CM, possibly due to variation of the splicing factors.
Legal entity responsible for the study
University of Campinas
Funding
Foundation for protection of research in the state of São Paulo (FAPESP)
Disclosure
All authors have declared no conflicts of interest.
907P - Impact of CYP3A4*22 on pazopanib pharmacokinetics in cancer patients (ID 3418)
- S. Koolen
Abstract
Background
Pazopanib is characterized by a large interpatient variability in systemic drug exposure. As pazopanib trough levels (>20.5 mg/L) are correlated with clinical outcome (Suttle et al, BJC 2014) in metastatic renal cell carcinoma (mRCC) patients, it is vital to identify factors that influence pazopanib pharmacokinetics (PK). The objective of the current analysis was to evaluate if single nucleotide polymorphisms (SNPs) in the metabolic pathway of pazopanib (i.e.
Methods
We analyzed 97 patients who participated in 3 pazopanib PK studies. Starting point of the current analysis was a population PK model for pazopanib (Yu et al, Clin Pharmacokinet 2017). Four SNPs located on 3 genes, that were associated with decrease of function were analyzed using real time PCR:
Results
From 3 patients, insufficient DNA was isolated to run a PCR analysis. All SNPs were in Hardy-Weinberg equilibrium. Eleven patients (12%) had a variant allele at
Conclusions
Our analysis shows that
Legal entity responsible for the study
Erasmus MC, Rotterdam, The Netherlands
Funding
None
Disclosure
All authors have declared no conflicts of interest.
338P - Chitosan-capped gold nanoparticles impair radioresistant glioblastoma stem-like cells (ID 1060)
- M. Aldea
Abstract
Background
Glioblastoma is a rapidly lethal cancer with a stringent need for new treatment strategies. In this study, we tested if chitosan-capped gold nanoparticles (Chit-GNPs) may overcome the limitations of drug concentrations by an increased cell internalisation in glioblastoma stem-like cells (GSCs) and if such GNPs could enhance the response to irradiation.
Methods
GSCs lines were isolated from glioblastoma tumor fragments and characterised with stemness and neural markers. Chitosan biopolymer was used as reducing and stabilizing agent to generate Chit-GNPs through an environmentally friendly synthesis procedure. The fabricated Chit-GNPs were characterized by UV-vis-NIR extinction spectroscopy, transmission electron microscopy and zeta potential measurements. GSCs and two normal cell lines were selected for in vitro investigations. The uptake and cytotoxicity of Chit-GNPs were evaluated relatively to that of citrate-capped gold nanospheres (GNPs) of similar size. Cell lines were treated with increasing concentrations of GNPs and Chit-GNPs and then irradiated with hypofractionated radiotherapy (3 consecutive fractions of 1, 2 Gy) and brachytherapy (one single fraction of 1 and 2 Gy). The effect was evaluated through the MTT cell viability test and confirmed with Trypan blue-based counting.
Results
GSCs proved to express stem-cell markers and were highly resistant to radiotherapy. Their cell viability and proliferation were impaired by chit-GNPs with an IC50 of 10ug/mL, while remaining unaffected by simple GNP used in similar concentrations. Chit-GNPs were 15 nm in size, with a positive zeta potential and proved a superior cell internalisation compared to simple GNPs. Normal cell lines remained unaffected by GNPs and Chit-GNPs. Radiotherapy at the tested doses failed to give an additional anti-cancer effect when combined with GNP treatment.
Conclusions
The enhanced internalisation within GSCs and the cytotoxic effect of Chit-GNPs make this compound a suitable backbone for drug delivery in glioblastoma treatment, particularly as it proved a selective toxicity for cancer cells. Surprisingly, Chit-GNPs were highly cytotoxic to glioma cell lines irrespective of irradiation.
Legal entity responsible for the study
Iuliu Hatieganu University of Medicine and Pharmacy
Funding
UEFISCDI - PNII-RU-TE-2014-4-0225 (ENERGY)
Disclosure
All authors have declared no conflicts of interest.