The Molecular Landscape of Pancreatobiliary Cancers for Novel Targeted Therapies From Real-World Genomic Profiling

Abstract

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 are unclear in PC and BTC. Methods To assess the frequencies of druggable gene alterations and to investigate new potential therapeutic targetable genomic alterations, advanced PC and BTC patients were tested with comprehensive genomic profiling (CGP) at Foundation Medicine during the course of clinical care. Results 16,913 PC patients and 3,031 BTC patients were available for analyses and frequencies of genomic alterations were stratified by age (≥40/<40), microsatellite instability (MSI) status, tumor mutational burden (TMB) status (high ≥10/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, rate of ERBB2 amplification was significantly higher in TMB-high population (23.3% vs. 13.7%). Interestingly, CDK12 rearrangement was observed in BTC patients with ERBB2 amplification tumors. In patients with <40-y, FGFR2 rearrangement (4%) was observed in PC: GATA6 amplification (11.1%) and rearrangement of BRAF (2.8%)/FGFR2 (5.6%) were observed in BTC patients. Conclusions We identified an appreciable frequency of immunotherapy biomarkers and targetable genes alterations in both PC and BTC, with notable frequencies in PC samples lacking KRAS mutations and children/adolescent and young adult (AYA) populations, that should encourage CGP testing.

Smaller panel, similar results: genomic profiling and molecularly informed therapy in pancreatic cancer

“…In our series we found KRAS mutations in 84% of cases, which is in line with a very recent large molecular analysis of over 16 000 PDAC patients, in which oncogenic KRAS mutations were reported in 85%. 15 These frequencies are slightly lower than what has often been reported previously. For a rational diagnostic step-up approach, initial screening for a small selection of relevant genes, especially KRAS and BRCA1/2 , was implemented in our center.…”

“… 22 However, their frequency is low with 5.0% (8/158) in our and 0.95% (29/3051) and 1.6% in another series. 15 , 23 The higher frequency in our center may have resulted from referred patients as we could offer a study for this specific KRAS mutation. As this is a minor subgroup of pancreatic cancer patients and with modest efficacy, other specific KRAS inhibitors for the largest subgroups in pancreatic cancer, KRAS(G12D) and KRAS(G12V), would have great therapeutic potential and are under development.…”

“…gene fusions of BRAF (4.0%-6.6%), FGFR2 (5.2%-5.3%), ALK (2.6%), RAF1 (2.2%), RET (1.3%) and NRG1 (1.3%). 14 , 15 For two NRG1 fusion-positive pancreatic cancer patients, targeted therapies demonstrated a therapeutic response of ∼5 months until disease progression. 16 While this shows the therapeutic potential of a precision oncology approach in pancreatic cancer, systematic evidence supporting the use of molecular data in this disease is sparse.…”

Oil blotting paper for formalin fixation increases endoscopic ultrasound‐guided tissue acquisition‐collected sample volumes on glass slides

“… 16 , 17 , 18 , 19 In clinical practice, (CGP) tests have been reported to be beneficial for patients with pancreatic cancer. 20 , 21 , 22 , 23 , 24 Notably, in Japan, CGP tests have been covered by Japanese health insurance since June 2019, highlighting the need for obtaining sufficient samples via EUS‐TA.…”

GATA6amplification is associated with improved survival ofTP53-mutated pancreatic cancer

“…Recent studies suggest that the GATA6 gene expression is a marker for a relatively favorable molecular subtype of pancreatic cancer [10] however GATA6 has been traditionally known as a proto-oncogene that is clearly associated with poor prognosis in many cancers like breast, lung, esophageal, ovarian, and other cancers, and appears causative of tumor proliferation, EMT, and metastasis [14][15][16][17][18]. GATA6 copy number variation (CNV) and overexpression are frequent (~11%) in PDAC [19], and GATA6 expression promotes in vitro cell proliferation possibly through WNT/ β-catenin and other signaling pathways [20][21][22].…”