Introduction: The FLOT regimen is a new standard of care in the perioperative management of resectable esophagogastric adenocarcinoma (OGA). There is some concern that incorporating a taxane within up-front chemotherapy may limit treatment options on relapse and adversely impact survival later in the disease course. We evaluated the treatment of relapsed OGA after perioperative chemotherapy in order to inform treatment decisions and plan rational sequencing for this group of patients as the clinical landscape changes. Methods: We performed a retrospective analysis of all patients with OGA who underwent perioperative chemotherapy and surgery with radical intent at the Royal Marsden Hospital between January 2009 and September 2018. Results: Of 369 cases screened, 167 (45%) relapses were identified. Relapsed patients received neoadjuvant chemotherapy consisting of platinum/fluoropyrimidine/anthracycline triplet in 121 (72%), doublet in 40 (24%), and FLOT in 6 (4%) followed by curative-intent surgery, with 92 (55%) then receiving adjuvant chemotherapy. Upon relapse, 46 (28%) patients had no further treatment and 110 (66%) had systemic treatment, consisting of platinum-based therapy in 79 (72%) and taxane-based therapy in 25 (23%). Use of initial taxane-based therapy was greatest in patients relapsing 0-6 months after surgery (38% of all treatments used), decreasing steadily after this. When compared to patients treated initially upon relapse with non-taxane based therapy, taxane-treated patients had a shorter time to relapse from surgery (31.1 vs 61.9 wks; P = .0012), a significantly higher frequency of signet ring or diffuse histology (56 vs 26%; P = .0048), a higher rate of peritoneal relapse (40 vs 20%; P = .0411) and poorer performance status, as well as trends towards increased proportion of female sex, gastric and poorly differentiated tumours. Median PFS for initial taxane vs non-taxane based treatment on relapse was 11.1 vs 30.0 wks (P < .0001). Second-line therapy was used in 52 patients and conversely was predominantly taxane rather than platinum-based (46 vs 33%), with PFS for taxane vs non-taxane based treatment 16.9 vs 18.4 wks (P = .58). Taxanes were used at some point in the advanced treatment pathway on relapse in 52/110 (47%) patients treated with systemic therapy, and there was no difference in median OS between those treated with a taxane at any point and those not (50.7 vs 62.6 wks; P = .20). For 6 patients who relapsed after perioperative FLOT, 3 were treated with systemic therapy using FOLFIRI (n = 2) and a platinum doublet + trastuzumab (n = 1). Conclusion: In this cohort, systemic treatment on initial relapse after perioperative chemotherapy and surgery consisted predominantly of platinum-based rechallenges. Initial taxane-based therapy in this setting was used in earlier-relapsing patients with a higher frequency of a number of adverse prognostic features, potentially contributing to the poorer outcomes seen. Taxane-based therapies were the most commonly used second-line treatments after relapse and their efficacy was similar to that of non-taxane based therapy in this context. Almost half of relapsed patients treated with systemic therapy had a taxane at some point in their pathway, with no significant effect on OS seen. Further research is required to establish the impact that up-front taxane use within FLOT will have on treatment patterns and survival after relapse.

We report on the treatment and survival of 511 patients with advanced esophagogastric adenocarcinoma treated during a 6-year period at a single center. During the period of analysis, the uptake of sequential lines of treatment in the second line and beyond increased, and such an approach was associated with improved survival outcomes. Background: Although progress has been made in the molecular stratification of esophagogastric adenocarcinoma, the outlook for advanced disease remains poor. The present evaluation of over 500 patients treated at a single European high-volume tertiary center during a 6-year period gives important information on current and developing “realworld” treatment patterns and outcomes. Results: The overall survival for the whole cohort was 11.5 months, with a range of treatments used in first-, second-, and third-line settings. Treatment with sequential lines of therapy was associated with better outcomes, although only 39% and 14% of patients subsequently received treatment in the secondand third-line setting, respectively. Treatment within a therapeutic clinical trial was associated with significantly improved survival. Conclusion: At present, a substantial proportion of patients with advanced esophagogastric adenocarcinoma will not proceed beyond first-line therapy, and for this group refinement of initial systemic therapies are required to improve outcomes. Although a number of established firstand second-line treatment options are now available, the therapeutic landscape of the disease continues to change, most notably in the application of immunotherapy and increasing interest in establishing evidence-based interventions in the third-line setting and beyond. A small but growing proportion of patients will benefit from sequential treatment approaches incorporating multiple lines of therapy, and improved selection of such patients will be a key challenge for clinicians moving forwards. Data such as these provide an overview of current treatment patterns and outcomes which can be used to inform planning of future research effectively within existing treatment frameworks. Clinical Colorectal Cancer, Vol. -, No. -, --a 2018 Elsevier Inc. All rights reserved.

Background: Homologous recombination deficiency can result from deleterious BRCA1/2 mutations or other mechanisms and leads to a common phenotype of genomic LOH. LOH is correlated with platinum response and sensitivity to rucaparib (PARP inhibitor) in ovarian cancer (McNeish ASCO 2015). We hypothesized that genomic LOH would be associated with survival in pts treated with EOC ± P in the REAL3 study. Methods: REAL3 was a randomised, open-label phase 3 trial in pts with treatment naïve, metastatic or locally advanced oesophagogastric cancer (OGC) assessing addition of P to EOC; no survival benefit was associated with EOC-P therapy. Pre-treatment tumour biopsies were selected for high tumour content (>30%). The percentage of interrogable genome with LOH (%LOH) was quantified by assessment of single-nucleotide polymorphisms spanning the whole genome using a next-generation sequencing based assay (Frampton et al., Nat. Biotechnol. 2013). Optimisation of survival benefit as measured by Hazard Ratio (HR), its significance, sensitivity and specificity was used to derive an LOH cut-off separating pts into LOH high and low cohorts which were associated with survival. Results: Eighty six (of a total 553 pts treated) tumours were sequenced (n = 42 EOC, n = 44 EOC-P). LOH was inferred for 54 (63%). Median %LOH for the entire cohort was 12.1%; this was highest for oesophagogastric junction (OGJ) tumours (15.4%), median %LOH for stomach and oesophageal tumours were 11.4% and 11.6% respectively. Pts with LOH ≥21% (n = 9/54, 17%) appeared to have a progression free (HR 0.48 (95% CI 0.21-1.09), p = 0.08) and overall survival (HR 0.43 (95% CI 0.19-0.97), p = 0.04) benefit. The proportion of pts with oesophageal, OGJ and stomach cancers with LOH ≥21% were 16%, 23% and 8% respectively. Conclusions: Genomic LOH was inferred for the majority of sequenced samples. OGJ tumours had the highest median LOH. An LOH high cutoff of ≥21% (17% of the population) was associated with an overall survival benefit for pts treated with platinum chemotherapy. LOH high platinum sensitive pts may benefit from PARP inhibitor therapy; we will investigate this hypothesis using rucaparib in the PLATFORM trial.