The molecular landscape of pancreatobiliary cancers for novel targeted therapies from real-world genomic profiling
Menée à partir de données génomiques portant sur des échantillons tumoraux issus de 16 913 patients atteints d'un cancer du pancréas et de 3 031 patients atteints d'un cancer des voies biliaires, cette étude identifie des altérations génétiques constituant des cibles thérapeutiques potentielles et évalue leur fréquence en fonction de l'âge des patients, de la présence d'une instabilité des microsatellites et de la charge mutationnelle de la tumeur
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.
Journal of the National Cancer Institute , article en libre accès, 2021