Most patients with biliary tract cancer (BTC) are diagnosed with advanced disease, relapse rates are high in those undergoing surgery and prognosis remains poor, while the incidence is increasing. Treatment options are limited, and chemotherapy is still the standard of care in both adjuvant and advanced disease setting. In recent years, different subtypes of BTC have been defined depending on the anatomical location and genetic and/or epigenetic aberrations. Especially for intrahepatic cholangiocarcinoma (iCCA) novel therapeutic targets have been identified, including fibroblast growth factor receptor 2 gene fusions and isocitrate dehydrogenase 1 and 2 mutations, with molecularly targeted agents having shown evidence of activity in this subgroup of patients. Additionally, other pathways are being evaluated in both iCCA and other subtypes of BTC, alongside targeting of the immune microenvironment. The growing knowledge of BTC biology and molecular heterogeneity has paved the way for the development of new therapeutic approaches that will completely change the treatment paradigm for this disease in the near future. This review provides an overview of the molecular heterogeneity of BTC and summarizes new targets and emerging therapies in development. We also discuss resistance mechanisms, open issues, and future perspectives in the management of BTC.

Purpose Metastatic breast cancer (mBC) patients with DPYD genetic variants linked to loss of dihydropyrimidine dehydrogenase (DPD) activity are at risk of severe capecitabine-associated toxicities. However, prospective DPYD genotyping has not yet been implemented in routine clinical practice. Following a previous internal review in which two patients underwent lengthy hospitalisations whilst receiving capecitabine, and were subsequently found to be DPD deficient, we initiated routine DPYD genotyping prior to starting capecitabine. This study evaluates the clinical application of routine DPYD screening at a large cancer centre in London. Methods We reviewed medical records for consecutive patients with mBC who underwent DPYD genotyping before commencing capecitabine between December 2014 and December 2017. Patients were tested for four DPYD variants associated with reduced DPD activity. Results Sixty-six patients underwent DPYD testing. Five (8.4%) patients were found to carry DPYD genetic polymorphisms associated with reduced DPD activity; of these, two received dose-reduced capecitabine. Of the 61 patients with DPYD wild-type, 14 (23%) experienced grade 3 toxicities which involved palmar–plantar erythrodysesthesia (65%), and gastrointestinal toxicities (35%); no patient was hospitalised due to toxicity. Conclusions Prospective DPYD genotyping can be successfully implemented in routine clinical practice and can reduce the risk of severe fluoropyrimidine toxicities.

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Hereditary breast cancer accounts for 5%-10% of breast cancer cases. The majority of familial cases have been linked to germline mutations in BRCA1 and BRCA2 genes, though other high penetrance susceptibility genes have also been identified through genomic testing advances. Optimal surgical treatment for these patients, who are of a younger age, has several challenges as it usually involves aggressive therapeutic and risk reducing interventions. At the same time, the therapeutic armamentarium for BRCA1/2 mutation carriers apart from platinum salts, has been enriched with the addition of poly-ADP ribose polymerase (PARP) inhibitors with promising outcomes. In this review we provide a succinct and comprehensive overview of the surgical and systemic treatment options for patients with BRCA1/2 mutation related breast cancer and an update on the most recent systemic treatment advances.

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e11576 Background: Overexpression of human epidermal growth factor receptor 2 (HER2) occurring in about 20% of breast cancers is associated with increased risk of disease recurrence and worse prognosis. Despite the advent of therapies that target HER2, particularly, trastuzumab and lapatinib, that have altered the natural course of HER2-positive advanced breast cancer, tumor progression remains inevitable. New agents are in clinical development, but up to date there are limited data to direct the treatment of patients after lapatinib progression. Methods: We retrospectively searched for HER2-positive advanced breast cancer patients treated at our clinic, who received both trastuzumab-based therapy and lapatinib upon trastuzumab-progression in the metastatic setting. Thirty patients, all female, suffering from HER2-positive advanced breast cancer were identified. HER-2 positivity was assessed by immunohistochemistry (IHC 3+) or chromogenic in situ hybridization (CISH+). Results: Of the 30 patients, 83.3% had invasive ductal carcinoma; 60% had positive hormone receptor status, and 80% grade 3 tumours. Half of the patients received adjuvant trastuzumab. Median age was 57 years, range 37-79 years. 36.6% were switched to lapatinib after a median of three (range 2-6 lines) trastuzumab-based treatment lines. In 8 pts (37.5%) trastuzumab was re-started after lapatinib progression. In 7 of these patients, trastuzumab was combined with chemotherapy. Median progression free survival and overall survival in these patients was 4.75 and 8.87 months respectively. 3 patients received bevacizumab-based therapy upon lapatinib failure. Conclusions: Trastuzumab rechallenge after lapatinib progression may be active in a subgroup of heavily pre-treated patients. Clinical benefit of this strategy has to be balanced especially in limited resource settings with unavailability of novel agents or early phase clinical trials. As of now, there is no uniform accepted standard to define the optimal treatment approach of patients upon lapatinib progression showing the real need for new therapies in this population.

668 Background: TAS-102 is an orally administered combination of the thymidine-based nucleic acid analogue, trifluridine and the thymidine phosphorylase inhibitor, tipiracil hydrochloride. Following the phase III RECOURSE study, it received approval as third line treatment for metastatic colorectal cancer showing significant improvement in overall and progression free survival and an acceptable toxicity profile. Methods: We performed a multicenter retrospective observational study of patients with metastatic colorectal cancer receiving TAS-102 as third line treatment between 2016 and 2018 in Cancer centers across the UK. Results: A total of 143 patients were included (94 men, 49 women). Median age was 68 years (35-82). All patients had received at least 2 lines of fluoropyrimidine-based chemotherapy doublet with oxaliplatin or irinotecan. About 90% of patients had ECOG ≥ 1. Median duration of treatment was 2.9 months (0.5-22.9), with a response rate of 1.6% and stable disease achieved in 24%. Median OS was 7 months (95% CI 5.84-8.15) and median PFS 2.6 months (95% CI 2.2-3.36). A dose reduction was required in 28% of patients, while 8% discontinued treatment due to toxicity. AEs reported included fatigue 81.3% (G3 16.8%), nausea 34.5% (G3 4.5%) and diarrhoea 25.5% (G3 1.8%). Neutropenia was common 50.4%, (≥ G3: 25.4%) with 4.2% cases of neutropenic fever while thrombocytopenia was less frequent 8.7% (≥ G3 1.8%). Conclusions: The OS, PFS and ORR observed in our real-world experience were consistent with the RECOURSE trial, though we noted a lower disease control rate. Overall, TAS-102 was well tolerated and the most prevalent adverse events seen in our patients were in keeping with those reported in the trial. Although severe toxicities were less frequent than the trial, we experienced higher rates of toxicity induced dose reductions and treatment cessations, which could reflect the differences between trial and real world populations. Further validation is warranted.