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.

中文翻译：

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来自现实世界基因组分析的胰胆癌的分子景观，用于新型靶向治疗


背景化疗对胰腺癌（PC）和胆道癌（BTC）的疗效有限，这凸显了对新疗法的需求。最近，针对晚期实体瘤的一些靶向治疗开发了与肿瘤无关的方法，然而，PC 和 BTC 中临床和基因组背景改变的频率尚不清楚。方法 为了评估可药物基因改变的频率并研究新的潜在治疗性靶向基因组改变，在临床护理过程中，对晚期 PC 和 BTC 患者在 Foundation Medicine 进行了全面基因组分析 (CGP) 测试。结果 16,913 名 PC 患者和 3,031 名 BTC 患者可用于分析，基因组改变频率按年龄 (≥40/<40)、微卫星不稳定性 (MSI) 状态、肿瘤突变负荷 (TMB) 状态（高 ≥10/低 %）进行分层3C10 Muts/Mb)，并选择基因组改变。各个队列中都观察到了 BRCA2、BRAF、ERBB2、CDK12、PIK3CA、FGFR2、EGFR 和其他潜在靶标的变化，并且在特定亚群（例如缺乏 KRAS 突变的 PC 患者）中观察到了富集。在 BTC 患者中，TMB 高人群的 ERBB2 扩增率显着较高（23.3% vs. 13.7%）。有趣的是，在患有 ERBB2 扩增肿瘤的 BTC 患者中观察到 CDK12 重排。在<40-y患者中，PC中观察到FGFR2重排（4%）：BTC患者中观察到GATA6扩增（11.1%）和BRAF（2.8%）/FGFR2（5.6%）重排。 结论 我们在 PC 和 BTC 中发现了明显的免疫治疗生物标志物和靶向基因改变频率，在缺乏 KRAS 突变的 PC 样本和儿童/青少年和年轻人 (AYA) 人群中频率显着，这应该鼓励 CGP 检测。