Next‐generation sequencing survey of biliary tract cancer reveals the association between tumor somatic variants and chemotherapy resistance

Abstract

Background BTC are uncommon and associated with a dismal prognosis. Gemcitabine and platinum-combinations (GP) form the standard approach for treating advanced BTC. To characterize the spectrum of mutations and to identify potential biomarkers for GP response in BTC, we evaluated the genomic landscape and assessed whether mutations affecting DNA repair were associated with GP resistance. Methods Pretreatment FFPE samples from 183 BTC patients treated with GP were analyzed. Cox regression models were used to determine the association between mutations, progression free survival (PFS) and overall survival (OS). Results Considering genes with an incidence >10%, no individual gene was independently predictive of GP response. In patients with unresectable BTC who received GP as first-line therapy, the joint status of CDKN2A, TP53 and ARID1A were associated with PFS (P=0.0004) and OS (P=<0.0001). Patients with mutations in CDKN2A and TP53 were identified as a poor prognostic cohort with a median PFS and OS of 2.63 and 5.22 months. Patients with mutant ARID1A regardless of single mutational status of TP53 or CDKN2A had similar outcomes. A patient who exhibited mutations in all three genes had a median PFS of 20.37 months and OS not reached. Conclusions In the largest exploratory analysis of this nature in BTC, the presence of three prevalent, mutually exclusive mutations represents distinct patient cohorts. These mutations are prognostic and may represent a predictive biomarker to GP response. Prospective studies validate these findings are needed, including the incorporation of therapies that exploit the genomic instability observed with these mutations in BTC.

Inhibition of ATR Increases the Sensitivity to WEE1 Inhibitor in Biliary Tract Cancer

“…In triple-negative breast cancer, WEE1 inhibition overcame cisplatin resistance by disrupting DNA replication and G2/ M cell cycle checkpoint regulation [20]. A clinical trial also revealed that BTC patients harboring DDR-related gene mutations responded better to cisplatin therapy than those with wild-type cancer [21]. Because cytotoxic chemotherapy is the standard treatment for advanced BTC, targeting DDR signaling pathways is extremely important for improving the efficacy of chemotherapeutic agents against BTC.…”

Germline alterations in patients with biliary tract cancers: A spectrum of significant and previously underappreciated findings

“…The utility of next‐generation sequencing has revealed somatic genetic alterations in biliary cancer that are important prognostic factors and potentially predictive of treatment response and survival . Nearly all patients with biliary tract cancer will have at least 1 oncogenic somatic molecular alteration identified by next‐generation sequencing analysis . The most commonly mutated genes are CDKN2A , TP53 , and KRAS with an estimated incidence of more than 20% of patients with biliary tract tumors.…”

Phase II study of everolimus (RAD001) monotherapy as first-line treatment in advanced biliary tract cancer with biomarker exploration: the RADiChol Study

“…17 Activating KRAS mutations are present in 16-22% of BTCs. [18][19][20] mTOR inhibitors are approved for the treatment of renal cell, neuroendocrine and hormone-positive/HER-2-negative advanced breast cancer. [21][22][23] Recently, the phase II Italian Trials in Medical Oncology (ITMO) trial assessed everolimus activity in patients with chemorefractory advanced BTC, where a favourable toxicity profile and encouraging anti-tumour activity was reported.…”