Background:This randomised phase II study evaluated the efficacy and safety of panitumumab added to docetaxel-based chemotherapy in advanced oesophagogastric cancer.Methods:Patients with metastatic or locally recurrent cancer of the oesophagus, oesophagogastric junction or stomach received docetaxel and a fluoropyrimidine with or without panitumumab for 8 cycles or until progression. The primary end point was response rate (RECIST1.1). We planned to enrol 100 patients, with 50% expected response rate for combination therapy.Results:A total of 77 patients were enrolled. A safety alert from the REAL3 trial prompted a review of data that found no evidence of adverse outcomes associated with panitumumab but questionable efficacy, and new enrolment was ceased. Enrolled patients were treated according to protocol. Response rates were 49% (95% CI 34–64%) in the chemotherapy arm and 58% (95% CI 42–72%) in the combination arm. Common grade 3 and 4 toxicities included infection, anorexia, vomiting, diarrhoea and fatigue. At 23.7 months of median follow-up, median progression-free survival was 6.9 months vs 6.0 months and median overall survival was 11.7 months vs 10.0 months in the chemotherapy arm and the combination arm, respectively.Conclusions:Adding panitumumab to docetaxel-based chemotherapy for advanced oesophagogastric cancer did not improve efficacy and increased toxicities.

Australian New Zealand Clinical Trials Registry Number ACTRN12608000588392.

Gastrointestinal stromal tumors (GISTs) are rare malignancies, and historically had a poor prognosis, with little benefit from traditional anticancer therapies. The management of GISTs has undergone a paradigm change in recent years with the detection of activating mutations in the majority of these tumors. This knowledge has led to the development of targeted treatments which have dramatically improved benefit rates and survival. The tyrosine kinase inhibitor, imatinib, has become the standard of care for both those with high-risk resected GIST, and as first-line therapy in metastatic GIST. However, some patients demonstrate innate resistance to imatinib or, for many, resistance develops despite an initial response. Other tyrosine kinase inhibitors with a broader spectrum of action, such as sunitinib and sorafenib, have been investigated and show some benefit after the use of imatinib. Regorafenib, an orally available multitargeted tyrosine kinase inhibitor with antiangiogenic activity, has also demonstrated preclinical evidence of activity against a number of solid tumors and further studies have proven it to be effective in GISTs following failure of standard therapy, with manageable toxicity profile. It has now received licensing approval in a number of countries both for the treatment of GISTs and for colorectal cancer, and further research is ongoing. With a number of potential agents now available to treat this disease, clinicians must now consider questions of timing and sequencing to maximize the benefit from these treatments, and the role that new agents such as regorafenib could play in further advancing changes.

Background Whether patients who are resected for ampullary adenocarcinoma have a survival benefit from adjuvant chemotherapy is currently not known. The aim of this study was to compare propensity score-matched survival between patients with and without adjuvant chemotherapy after resection of ampullary adenocarcinoma. Methods An international multicentre cohort study was conducted, including patients who underwent pancreatoduodenectomy for ampullary adenocarcinoma (2006-2017) in 13 centres in six countries. Propensity scores were used to match patients who received adjuvant chemotherapy to those who did not; both in the entire cohort and in two subgroups (pancreaticobiliary/mixed and intestinal subtype). Survival was assessed using the Kaplan-Meier method and Cox regressions. Results Overall, 1163 patients underwent pancreatoduodenectomy for ampullary adenocarcinoma. After excluding 179 patients, median survival in the resulting 976 patients was 67 months (95 per cent confidence interval 56-78), of which a total of 520 (53 per cent) patients received adjuvant chemotherapy. In a propensity-matched cohort (194 vs 194 patients), median survival was better after adjuvant chemotherapy compared to those without adjuvant chemotherapy (median survival not reached vs 60 months, respectively; p=0.051). In the pancreaticobiliary/mixed subtype a survival benefit was seen; median survival was not reached in patients receiving adjuvant chemotherapy vs 32 months in the group without chemotherapy, p=0.020. The intestinal subtype did not show survival benefit from adjuvant chemotherapy. Conclusions Patients with resected ampullary adenocarcinoma may benefit from gemcitabinebased adjuvant chemotherapy, but this effect may be reserved for those with the pancreaticobiliary and/or mixed subtype.

26Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly 27 to targeted therapies and chemotherapies. In order to define therapeutically 28 targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. 29 In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, 30 and define therapeutic subsets. We tested the same hypothesis for BLBC. 31Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between 32 BRCA1 loss and high cyclin E1 expression, in contrast to HGSOC in which CCNE1 33 amplification drives increased cyclin E1 gene expression. Instead, BRCA1 loss 34 stabilized cyclin E1 during the cell cycle. Using siRNA we showed that BRCA1 loss 35 leads to stabilization of cyclin E1 by reducing phospho-cyclin E1-T62, and 36 conversely the overexpression of BRCA1 increased phospho-T62. Mutation of cyclin 37 E1-T62 to alanine increased cyclin E1 stability. We showed that tumors with high 38 cyclin E1/BRCA1 mutation in the BLBC cohort had decreased phospho-T62, 39 supporting this hypothesis. 40Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in 41 BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these 42 cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized 43 with PARP inhibitors to reduce cell viability in BRCA1 mutated cell lines. Treatment 44 of BLBC patient-derived xenograft models with combination PARP and CDK2 45 inhibition led to tumor regression and increased survival. We conclude that BRCA1 46 status and high cyclin E1 have potential as predictive biomarkers to dictate the 47 therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC. 48 3 instability in cancer cells, and is frequently elevated in BLBC (9). Perplexingly, in 65 high grade serous ovarian cancer (HGSOC) cyclin E1 amplification and BRCA1/2 66 mutation are mutually exclusive, presumably because both aberrations drive 67 genomic instability and together they precipitate lethal genomic damage (10-12). 68We recently described two subsets of HGSOC, one where cyclin E1 gene 69 amplification and BRCA1 mutation were mutually exclusive, and another where high 70 cyclin E1 protein expression was due to post-transcriptional deregulation rather than 71 4 gene amplification, and was often concurrent with BRCA1/2 mutation (12). Cyclin E1 72 protein stability is regulated by a multi-step process of specific phosphorylation and 73 ubiquitination, leading to its cyclic expression and turnover (13). Key regulators in the 74 turnover of cyclin E1, such as the ubiquitin ligase component FBXW7 and the 75 deubiquitinase USP28, are frequently dysregulated in cancer (13-15) leading to 76 altered stability of the cyclin E1 protein. 77In this study, we examined whether BRCA1 loss and cyclin E1 gain occurred 78 concurrently or independently in breast cancer. We also explored the mechanisms 79 underpinning high cyclin E1 expression in BRCA1 mutated breast cancer including 80 gene amplification and p...

A marker-driven approach to patient selection was feasible in advanced biliary tract cancer in an Australian population. The combination of panitumumab, gemcitabine, and cisplatin in KRAS wild-type cancers was generally well tolerated and showed promising clinical efficacy. Further exploration of anti-EGFR therapy in a more selected population is warranted.

ObjectiveAustralia has a publicly funded universal healthcare system which heavily subsidises the cost of most registered anticancer drugs. The use of anticancer drugs that are unfunded, that is, not subsidised by the government, entails substantial out-of-pocket costs for patients. We sought to determine how frequently Australian medical oncologists discuss and prescribe unfunded anticancer drugs, and their attitudes and beliefs about their use.MethodsMembers of the Medical Oncology Group of Australia (MOGA) completed an online survey about their clinical practices over a recent 3-month period. A negative binomial regression model was used to examine the influence of respondent characteristics on the rate of discussions about, and prescription of, unfunded anticancer drugs.ResultsOf the 154 respondents (27% of 575 MOGA members), 92% had discussed and 68% had prescribed at least one unfunded anticancer drug in the last 3 months. Respondents reported discussing unfunded anticancer drugs with an average of 2.5 patients per month (95% CI 2.1 to 2.9), and prescribed them to an average of 0.9 patients per month (95% CI 0.7 to 1.2). The rate of discussing unfunded anticancer drugs was associated with being fully qualified (p=0.01), and being in a metropolitan practice (p=0.009), the rate of prescription was associated only with being in metropolitan practice (p=0.006). The concerns about discussing and prescribing unfunded anticancer drugs rated most important were as follows: ‘potential to cause financial hardship’ and ‘difficulty for patients to evaluate the benefits versus the costs’.ConclusionsAustralian medical oncologists frequently discuss and prescribe unfunded anticancer drugs, and are concerned about their patients having to face difficult decisions and financial hardship. Further research is needed to better understand the factors that affect how oncologists and patients value expensive, unfunded anticancer drugs.

Basal-like breast cancers (BLBC) are aggressive breast cancers that respond poorly to targeted therapies and chemotherapies. In order to define therapeutically targetable subsets of BLBC we examined two markers: cyclin E1 and BRCA1 loss. In high grade serous ovarian cancer (HGSOC) these markers are mutually exclusive, and define therapeutic subsets. We tested the same hypothesis for BLBC. Using a BLBC cohort enriched for BRCA1 loss, we identified convergence between BRCA1 loss and high cyclin E1 protein expression, in contrast to HGSOC in which CCNE1 amplification drives increased cyclin E1. In cell lines, BRCA1 loss was associated with stabilized cyclin E1 during the cell cycle, and BRCA1 siRNA led to increased cyclin E1 in association with reduced phospho-cyclin E1 T62. Mutation of cyclin E1 T62 to alanine increased cyclin E1 stability. We showed that tumors with high cyclin E1/BRCA1 mutation in the BLBC cohort also had decreased phospho-T62, supporting this hypothesis. Since cyclin E1/CDK2 protects cells from DNA damage and cyclin E1 is elevated in BRCA1 mutant cancers, we hypothesized that CDK2 inhibition would sensitize these cancers to PARP inhibition. CDK2 inhibition induced DNA damage and synergized with PARP inhibitors to reduce cell viability in cell lines with homologous recombination deficiency, including BRCA1 mutated cell lines. Treatment of BRCA1 mutant BLBC patient-derived xenograft models with combination PARP and CDK2 inhibition led to tumor regression and increased survival. We conclude that BRCA1 status and high cyclin E1 have potential as predictive biomarkers to dictate the therapeutic use of combination CDK inhibitors/PARP inhibitors in BLBC.