Hallmarks based stratification of locally advanced GBC according to response to first-line chemotherapy in advanced gallbladder cancer (GBC).

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Background: GBC is a heterogenous disease with high mortality rate. While platinum-based chemotherapy remains the SOC in advanced disease; the treatment responses are highly variable, with no tools for predictive or prognostic stratification of patients. We evaluated potential role of variable activation of cancer hallmark mechanisms inside the cancer cell, that drives disease progression, as a useful tool for upfront patient stratification. Methods: We analysed the tumor biology by CGP (TarGT Indiegene, 1212 genes) in 15 locally advanced GBC patients treated with first line cisplatin and gemcitabine. After four cycles chemotherapy, patients were stratified either as responders (R) (complete response, partial response and stable disease) or non-responders (NR) based on radiological response on CECT by RECIST criteria. For each patient, the Tumor somatic Mutations were grouped based on their potential role in different cancer hallmark mechanisms and scored as +3 (highest contribution), +2 (Moderate representation), +1 (minimal representation), 0 (no representation). Results: We observed that the molecular spectrum of responders had limited number of somatic alterations and restricted to 7 out of 10 cancer hallmarks, involving sustained proliferation, angiogenesis, genomic instability, tumor invasion and metastasis, and evasion of growth suppressors and cell death, with most hallmarks exhibiting low-to-moderate enrichment scores (1+ to 3+). Oncogenic plasticity was less aggressive with a cumulative score of <15 in most of the responders. On the other hand, the non-responders who presented with radiological progression had a broad molecular spectrum of mutations enriched in all the 10 cancer hallmarks, that resulted in a significant increase in cumulative cancer hallmark score >16 highlighting peculiar disparities between responder versus non-responders. Hallmark-based stratification score demonstrated 100% correlation with clinical outcome wherein, non-responders exhibited significantly shorter median progression free survival compared to responders (7 vs. 15 months; p=0.03). Conclusions: This is the first retrospective clinical study demonstrating the clinical utility of hallmark based molecular stratification of advanced GBC, showing significant correlation with clinical outcomes with first-line chemotherapy. High representation of tumor mutations in all 10 established cancer hallmarks, indicate clonal heterogeneity, explaining the ineffectiveness of chemotherapy in non-responder population. Further studies on large cohorts are needed to validate this finding and adopt this in prospective clinical trials.