Identification of clinically actionable mutations and immunotherapy biomarkers in Chinese esophageal squamous cell carcinoma patients.

Abstract

e15576 Background: Esophageal squamous cell carcinoma (ESCC), the major esophageal cancer histological type in East Asia, has limited therapeutic options and is associated with poor prognosis. Here, we identified clinically actionable genomic alteration (GA) for potential targeted and immunotherapy in Chinese ESCC patients by next generation sequencing (NGS). Methods: Clinical data were collected from 150 ESCC patients from March 2011 to December 2018, with a median follow-up of 34 months. NGS-panel sequencing of 466 cancer genes was performed on FFPE tumor and matched blood sample. Tumor mutational burden (TMB) was assessed in all patients by standard NGS algorithms. PD-L1 expression was evaluated in 61 samples by IHC (28-8 Ab). Results: Overall, 75.5% of ESCC patients harbored at least one clinically actionable GAs with the most frequent being CCND1 (40%), CDKN2A (40%), CDKN2B (24%), PIK3CA (14%) and FGFR1 (8%). Most clinically actionable GAs occurred in genes involved with cell cycle (61%) and with PI3K pathway (23%). Clinically actionable GAs also distributed in BRCA2 (5%), ATM (3%), MET amp (3%), KIT (3%), EGFR mut (2%), PDGFRA (2%) and ERBB2 amp (1%). The lowest 25% (TMB-L), median and highest 25% TMB (TMB-H) value was 4.6, 6.9 and 9.2 muts/Mb, respectively. Compared with younger patients, patients ≥50 years had higher TMB ( p= 0.047). Compared with TMB-L ESCCs, frequencies of NOTCH2 (15.9% vs 0%, p= 0.015), PIK3CA (22.7% vs 2.8%, p= 0.019) and KMT2D (25.0% vs 5.6%, p= 0.031) were significantly higher in TMB-H. Notably, amplification in 11q13 region, MDM2/ MDM4 and EGFR, which potentially relates to immunotherapy hyperprogression, accounted for 48% of TMB-H. Eleven patients (18%) showed PD-L1≥1%, in which 7 pts were also TMB-H. Conclusions: In Chinese ESCCs, clinically actionable GAs were detected in most patients, which highlights the promise of molecularly directed therapies. Patients with PD-L1 positive/TMB-H/both, who could potentially benefit from immunotherapy, accounted for 41%. Older age, NOTCH2, PIK3CA and KMT2D mutations correlated with TMB-H.