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Supplementary Table 1 - PDF file 57K, Supplementary Table 1. Details of platinum sensitivity and best response to olaparib and post-PARPi chemotherapy of the six patients whose tumor samples were analyzed by massively parallel sequencing. (NE: not evaluable)

Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated.Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing.Results: Data were collected from 89 patients who received a median of 3 (range 1–11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13–21] and 34 weeks (95% CI, 26–42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15–29) and OS of 45 weeks (95% CI, 15–75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0–0.375)].Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. Clin Cancer Res; 19(19); 5485–93. ©2013 AACR.

Background The return of research results (RoR) remains a complex and well-debated issue. Despite the debate, actual data related to the experience of giving individual results back, and the impact these results may have on clinical care and health outcomes, is sorely lacking. Through the work of the Australian Pancreatic Cancer Genome Initiative (APGI) we: (1) delineate the pathway back to the patient where actionable research data were identified; and (2) report the clinical utilisation of individual results returned. Using this experience, we discuss barriers and opportunities associated with a comprehensive process of RoR in large-scale genomic research that may be useful for others developing their own policies. Methods We performed whole-genome (n = 184) and exome (n = 208) sequencing of matched tumour-normal DNA pairs from 392 patients with sporadic pancreatic cancer (PC) as part of the APGI. We identified pathogenic germline mutations in candidate genes (n = 130) with established predisposition to PC or medium–high penetrance genes with well-defined cancer associated syndromes or phenotypes. Variants from candidate genes were annotated and classified according to international guidelines. Variants were considered actionable if clinical utility was established, with regard to prevention, diagnosis, prognostication and/or therapy. Results A total of 48,904 germline variants were identified, with 2356 unique variants undergoing annotation and in silico classification. Twenty cases were deemed actionable and were returned via previously described RoR framework, representing an actionable finding rate of 5.1%. Overall, 1.78% of our cohort experienced clinical benefit from RoR. Conclusion Returning research results within the context of large-scale genomics research is a labour-intensive, highly variable, complex operation. Results that warrant action are not infrequent, but the prevalence of those who experience a clinical difference as a result of returning individual results is currently low. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0430-4) contains supplementary material, which is available to authorized users.

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.

Purpose: Preclinical data suggest that exposure to PARP inhibitors (PARPi) may compromise benefit to subsequent chemotherapy, particularly platinum-based regimens, in patients with BRCA1/2 mutation carrier ovarian cancer (PBMCOC), possibly through the acquisition of secondary BRCA1/2 mutations. The efficacy of chemotherapy in the PARPi-resistant setting was therefore investigated. Experimental Design: We conducted a retrospective review of PBMCOC who received chemotherapy following disease progression on olaparib, administered at ≥200 mg twice daily for one month or more. Tumor samples were obtained in the post-olaparib setting where feasible and analyzed by massively parallel sequencing. Results: Data were collected from 89 patients who received a median of 3 (range 1–11) lines of pre-olaparib chemotherapy. The overall objective response rate (ORR) to post-olaparib chemotherapy was 36% (24 of 67 patients) by Response Evaluation Criteria in Solid Tumors (RECIST) and 45% (35 of 78) by RECIST and/or Gynecologic Cancer InterGroup (GCIG) CA125 criteria with median progression-free survival (PFS) and overall survival (OS) of 17 weeks [95% confidence interval (CI), 13–21] and 34 weeks (95% CI, 26–42), respectively. For patients receiving platinum-based chemotherapy, ORRs were 40% (19 of 48) and 49% (26/53), respectively, with a median PFS of 22 weeks (95% CI, 15–29) and OS of 45 weeks (95% CI, 15–75). An increased platinum-to-platinum interval was associated with an increased OS and likelihood of response following post-olaparib platinum. No evidence of secondary BRCA1/2 mutation was detected in tumor samples of six PARPi-resistant patients [estimated frequency of such mutations adjusted for sample size: 0.125 (95%-CI: 0–0.375)]. Conclusions: Heavily pretreated PBMCOC who are PARPi-resistant retain the potential to respond to subsequent chemotherapy, including platinum-based agents. These data support the further development of PARPi in PBMCOC. Clin Cancer Res; 19(19); 5485–93. ©2013 AACR.

5022 Background: Emerging clinical data point to the clinical utility of PARPi in BDOC. However, the impact of PARPi exposure on the prospects of response to further CT remains unclear. In our previous single centre study, we provided the first clinical data relating to the use of post-PARPi CT (JCO 2010: 28(15S), A5041). Our aim here was to re-examine this issue in a larger multi-institutional population. Methods: We included pts with advanced BDOC who received CT, having progressed on ≥200 mg bd olaparib. Pt, tumor and treatment characteristics and clinical outcomes were documented. Relationships between post-PARPi CT overall survival (OS) and other variables were explored using Cox regression. Results: We collected data on 75 pts (median age 51 y [range 31-77], BRCA1:BRCA2 54:21, mean 3 previous lines of CT [95% CI 2.5-3.4], pre-PARPi platinum (Plt) resistance rate 49% and olaparib RECIST-response rate [RR] 39% [95% CI 28-50]). Following olaparib, most pts received Plt alone or in combination with taxane (Tx) or liposomal doxorubicin (PLD). Weekly Plt was used in 36% of all Plt-treated pts, mainly in combination with weekly Tx. Overall RECIST and CA125 (GCIG) RRs were 38% and 48%, respectively; these responses occurred independently of PARPi response or pre-PARPi Plt sensitivity (all p>.1). The median progression free survival and OS of RECIST responders were 7.9 m (95% CI 5.8-10.9) and 10.5 m (95% CI 1.4-19.6), respectively. In all pts, the median OS from the start of post-PARPi CT was 7.9 m (95% CI 5.7-10.1) while that from diagnosis was 64.9 m (95% CI 52.9-76.9). Factors associated with improved OS on post-PARPi CT in the MVA included best olaparib response of non-disease progression (p=.003, HR 0.28), optimal initial debulking (p=.01, HR 0.36) and pre-PARPi Plt sensitivity (p=.05, HR 0.46). Conclusions: These data indicate potential for meaningful responses to CT in BDOC pts with PARPi resistance. Analysis to identify molecular predictors of response is ongoing. [Table: see text]

Case 1: Serous tubal cancer detected on PAP smear A 60 year old woman with a history of breast cancer was referred after malignant cells were found on PAP smear. Abdominal exam, cervical visualisation, transvaginal ultrasound and CT of the abdomen and pelvis were all normal. Endocervical and endometrial curettings demonstrated serous carcinoma cells consistent with tubal / ovarian origin. CA125 was slightly elevated at 53 (Upper Limit of Normal 35). At laparatomy uterus, fallopian tubes and ovaries appeared normal. She had a hysterectomy, bilateral salpingo-oophorectomy, omentectomy, peritoneal biopsies and washings. There was no macroscopic evidence of cancer, but microscopic examination confirmed serous cancer in the fimbrial end of the left fallopian tube(A) with scattered malignant cells in the lumen of both fallopian tubes(B), the omentum(C) and surface of the ovaries(D), surface of uterus and paracolic gutter. Washings were positive. Family history was unremarkable. BRCA mutation screening revealed a BRCA1 mutation. Despite intraperitoneal cisplatin and paclitaxel she relapsed and died 4 years later.