Evaluation of somatic and germline mutations in Chinese patients with gallbladder carcinoma reveals clinically actionable targets.

Abstract

e16143 Background: Gallbladder cancer (GBC) is an aggressive gastrointestinal cancer and the median survival of GBC patients is less than one year. Given the rarity of this disease, there is no enough evidence to guide the precision therapy for GBC patients. Therefore, it is urgent to identify therapeutic targets in GBC to help physicians to enroll patients in clinical trials. In this study, we aimed to characterize clinically actionable mutations in a large cohort of patients with GBC. Methods: To characterize therapeutic targets in 118 Chinese GBC patients, a deep sequencing panel (OncoPanscan, Genetronhealth) was applied to explore somatic alterations including point mutations, indels, copy number alterations and gene fusions, as well as possible pathogenic germline variants respectively from their tumor tissues and matched genomic DNA sample. Results: Recurrent somatic mutations were identified in TP53 (65%), ERBB2 (18%), ARID2 (13%), ELF3 (13%), CDKN2A (12%), ARID1A (10%), KRAS (10%) and KMT2C (10%). Of the entire cohort, the most frequently mutated genes were in the ErbB pathway including EGFR, ERBB2, ERBB3, and ERBB4. For the patients with ERBB2 genetic aberrations, 67% (14/21) patients had gene amplification and 29% (6/21) patients had the oncogenic S310F/Y (n = 6) mutation which may be eligible for HER2-targeted therapy clinical trial. Importantly, 9% (10/118) patients carried activating PIK3CA mutations including P104L, E110del, E545K/Q/G, E542K, E726K and T1025S which may be targeted by PIK3CA inhibitor alpelisib. Additionally, patients with loss-of-function mutation in NF1 (n = 6), STK11 (n = 5) and PTEN (n = 2) can be respectively targeted with MEK inhibitor and mTOR inhibitor. Furthermore, patients with MET amplification (n = 3) may be eligible for clinical trials of MET inhibitor carbozantinib. There were four patients (3.4%) carried loss-of-function germline mutations in DNA repair genes ( BRCA1, BRCA2 and PALB2) and 19 patients (16%) harbored somatic loss-of-function mutations in BRCA1 (n = 2), BRCA2 (n = 2), ARID1A (n = 12) and ATM (n = 3). These patients may benefit from platinum chemotherapy or targeted therapy with PARP inhibitors. Interestingly, 13% (15/118) patients in our cohort carried ELF3 inactivating mutations which was reported as a potential GBC vaccine candidate. Taken together, at least 54 (46%) patients in our cohort had actionable genetic alterations. Conclusions: Our results indicated that activating mutations in the ErbB and PI3K signaling pathways are the major driving events of GBC. The results of genomic profiling can guide physicians to enroll a significant portion of GBC patients into genomically matched clinical trials.