Abstract and Introduction
Background: Chemotherapies have limited efficacy in pancreatic cancer (PC) and biliary tract cancer (BTC), underscoring the need for new regimens. Recently, tumor-agnostic approaches have been developed for some targeted therapies in advanced solid tumors; however, the frequency of alterations by clinical and genomic background is unclear in PC and BTC.
Methods: To assess the frequencies of druggable gene alterations and investigate new potential therapeutic targetable genomic alterations, advanced PC and BTC patients were tested with comprehensive genomic profiling at Foundation Medicine during the course of clinical care.
Results: A total of 16 913 PC patients and 3031 BTC patients were available for analyses, and frequencies of genomic alterations were stratified by age (≥40 years or <40 years), microsatellite instability status, tumor mutational burden status (high ≥10 or low <10 Muts/Mb), and select genomic alterations. Alterations in BRCA2, BRAF, ERBB2, CDK12, PIK3CA, FGFR2, EGFR, and other potential targets were seen across cohorts, with enrichment observed within particular subsets such as in PC patients lacking a KRAS mutation. In BTC patients, the rate of ERBB2 amplification was statistically significantly higher in the tumor mutational burden–high population (23.3% vs 13.7%). Interestingly, CDK12 rearrangement was observed in BTC patients with ERBB2 amplification tumors. In patients younger than 40 years, FGFR2 rearrangement (4%) was observed in PC: GATA6 amplification (11.1%) and rearrangement of BRAF (2.8%)FGFR2 (5.6%) was observed in BTC patients.
Conclusions: We identified an appreciable frequency of immunotherapy biomarkers and targetable gene alterations in both PC and BTC, with notable frequencies in PC samples lacking KRAS mutations and children or adolescent and young adult populations, that should encourage comprehensive genomic profiling testing.
Recently, cytotoxic anticancer agents have been developed for pancreatobiliary cancers, which have increased the number of options available for first-line treatment. For pancreatic cancer (PC), FOLFIRINOX, gemcitabine plus nab-paclitaxel, and gemcitabine are standard first-line therapies. Nanoliposomal-irinotecan plus 5-fuluorouracil (5-FU) therapy was approved as a second-line treatment option in 2020. For biliary tract cancer (BTC), gemcitabine plus cisplatin therapy and FOLFOX therapy were approved in 2020 as first- and second-line treatment, respectively. Evidence for first-line therapies for both PC and BTC has been established; however, evidence for second- and later-line therapies is scarce, and their efficacy is also limited. It is necessary to develop new regimens for PC and BTC to improve patient outcomes.
In the development of novel targeted therapy, a tumor-agnostic approach for specific gene alterations has been conducted in advanced solid tumors. Improvements in the analytic capacity achieved by the use of next-generation sequencing (NGS) have put cancer gene panel testing into clinical use. NGS-based comprehensive genome profiling (CGP), specifically FoundationOne CDx, has been approved by the Food and Drug Administration in the United States since 2017 and listed for coverage under the national health insurance in Japan since 2019 for patients with advanced solid tumors. Entrectinib and larotrectinib were approved in Japan in 2019 and 2021, respectively, for clinical use for tumors with NTRK1-3 fusion genes and pembrolizumab for microsatellite instability (MSI)-high tumors in 2018. Furthermore, olaparib was approved in 2021 for advanced PC positive for germline BRCA1/2 mutation and pemigatinib for advanced BTC positive for FGFR2 translocations (fusion/rearrangement) in 2021. There are some reports describing advances in genomic analysis methods allowing for the development of treatments targeting gene alterations found in PC and BTC as well.[11,12] Therefore, it would be clinically beneficial to determine how frequently druggable gene alterations are found in daily clinical practice and to investigate further genomic alterations that are potential new therapeutic targets using relevant information obtained from a large-scale database of genomic profiling.
J Natl Cancer Inst. 2022;114(9):1279-1286. © 2022 Oxford University Press