Detecting and Tracking Circulating Tumour DNA Copy Number Profiles during First Line Chemotherapy in Oesophagogastric Adenocarcinoma.

DNA somatic copy number aberrations (SCNAs) are key drivers in oesophagogastric adenocarcinoma (OGA). Whether minimally invasive SCNA analysis of circulating tumour (ct)DNA can predict treatment outcomes and reveal how SCNAs evolve during chemotherapy is unknown. We investigated this by low-coverage whole genome sequencing (lcWGS) of ctDNA from 30 patients with advanced OGA prior to first-line chemotherapy and on progression. SCNA profiles were detectable pretreatment in 23/30 (76.7%) patients. The presence of liver metastases, primary tumour in situ, or of oesophageal or junctional tumour location predicted for a high ctDNA fraction. A low ctDNA concentration associated with significantly longer overall survival. Neither chromosomal instability metrics nor ploidy correlated with chemotherapy outcome. Chromosome 2q and 8p gains before treatment were associated with chemotherapy responses. lcWGS identified all amplifications found by prior targeted tumour tissue sequencing in cases with detectable ctDNA as well as finding additional changes. SCNA profiles changed during chemotherapy, indicating that cancer cell populations evolved during treatment; however, no recurrent SCNA changes were acquired at progression. Tracking the evolution of OGA cancer cell populations in ctDNA is feasible during chemotherapy. The observation of genetic evolution warrants investigation in larger series and with higher resolution techniques to reveal potential genetic predictors of response and drivers of chemotherapy resistance. The presence of liver metastasis is a potential biomarker for the selection of patients with high ctDNA content for such studies.

Survival in Advanced Esophagogastric Adenocarcinoma Improves With Use of Multiple Lines of Therapy: Results From an Analysis of More Than 500 Patients.

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 "real-world" 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 second- and 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 first- and 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.

Genomic loss of heterozygosity and survival in the REAL3 trial.

BACKGROUND: Homologous recombination deficiency (HRD) measured using a genomic signature for loss of heterozygosity (LOH) predicts benefit from rucaparib in ovarian cancer. We hypothesized that some oesophagogastric cancers will have high-LOH which would be prognostic in patients treated with platinum chemotherapy. METHODS: Diagnostic biopsy DNA from patients treated in the REAL3 trial was sequenced using the Foundation Medicine T5 next-generation sequencing (NGS) assay. An algorithm quantified the percentage of interrogable genome with LOH. Multidimensional optimization was performed to identify a cut-off dichotomizing the population into LOH-high and low groups associated with differential survival outcomes. RESULTS: Of 158 available samples, 117 were successfully sequenced; LOH was derived for 74 of these. A cut-off of 21% genomic LOH defined an LOH-high subgroup (n=10, 14% of population) who had median overall survival (OS) of 18.3 months (m) versus 11m for the LOH-low group (HR 0.55 95% CI 0.19-0.97, p= 0.10). Progression free survival (PFS) for LOH-high and LOH-low groups was 10.7m and 7.3m (HR 0.61 (95% CI 0.21 - 1.09, p=0.09). Sensitivity analysis censoring operated patients (n=4), demonstrated OS of 18.3m vs. 10.2m (HR 0.43, 95% CI (0.20-0.92), p=0.02; PFS was 10.5m vs. 7.2m (HR 0.55, (95% CI 0.26-1.17), p=0.09 for LOH-high and LOH-low. CONCLUSION: HRD assessment using an algorithmically derived LOH signature on a standard NGS panel identifies oesophagogastric cancer patients with high LOH who have prolonged survival when treated with platinum chemotherapy. Validation work will determine the signature's predictive value in patients treated with a PARP inhibitor and with platinum chemotherapy.

Novel STAT 3 inhibitors for treating gastric cancer.

INTRODUCTION: Advanced gastric cancer has a poor prognosis, with a median survival of approximately 12 months. There is a continued need to explore the use of novel treatments for this disease. STAT3 inhibitors are under evaluation in a number of early phase trials, some showing promise in gastric cancer. AREAS COVERED: This article explores the role of STAT 3 in gastric cancer and highlights some early phase clinical trials on STAT3 inhibition. The STAT3 protein and signalling pathway are discussed. STAT3 in the pathogenesis of gastric cancer is reviewed; pre-clinical data on the role of STAT3 in the development of cancer is presented together with early and emerging data on STAT3 inhibitors under investigation in the clinical setting. In this review, the authors searched PubMed, clinicaltrials.gov and ASCO abstracts on STAT3 inhibitors, focusing on trials recruiting gastric cancer patients. EXPERT OPINION: Activated STAT3 in gastric cancer is correlated with poor survival. It plays a critical role in regulating tumour growth and metastases. STAT3 inhibitors are emerging as an interesting drug in gastric cancer. However, trials utilising these agents remain in their early phase with one agent currently under evaluation in the phase III setting.

PD-1 and PD-L1 blockade in gastrointestinal malignancies.

Immunotherapy represents a major breakthrough in cancer therapy in recent years. Immune-checkpoint blockade using PD-1 and PD-L1 antibodies appears to be one of the most promising immunotherapy approaches. Immunotherapy differs from conventional cancer treatment because of its ability to produce durable responses in some patients. In this review article, we explore the available evidence and summarise current clinical trials for PD-1 and PD-L1 blockade in gastrointestinal malignancies. The challenge now is to develop strategies to increase the efficacy of PD-1 and PD-L1 blockade in gastrointestinal cancer patients, such as combination therapy with chemotherapy, radiotherapy or other immunotherapy, along with validating biomarkers to select patients and personalise treatment.