Background Approximately 90% of pancreatic ductal adenocarcinoma (PDAC) cases are driven by the untargetable non‐G12C KRAS mutations, and only a small subset of patients are eligible for FDA‐approved precision therapies. The practice of precision therapy in pancreatic cancer was limited by the paucity of targetable genetic alterations, especially in the Asian population. Methods To explore therapeutic targets in 499 Chinese PDAC patients, a deep sequencing panel (OncoPanscan™, Genetron health) was used to characterize somatic alterations including point mutations, indels, copy number alterations, gene fusions as well as pathogenic germline variants. Results We performed genomic profiling in 499 Chinese PDAC patients, which revealed somatic driver mutations in KRAS, TP53, CDKN2A, SMAD4, ARID1A, RNF43, and pathogenic germline variants (PGVs) in cancer predisposition genes including BRCA2, PALB2, and ATM. Overall, 20.4% of patients had targetable genomic alterations. About 8.4% of patients carried inactivating germline and somatic variants in BRCA1/2 and PALB2, which were susceptible to platinum and PARP inhibitors therapy. Patients with KRAS wild‐type disease and early‐onset pancreatic cancer (EOPC) harbored actionable mutations including BRAF, EGFR, ERBB2, and MAP2K1/2. Compared to PGV‐negative patients, PGV‐positive patients were younger and more likely to have a family history of cancer. Furthermore, PGVs in PALB2, BRCA2, and ATM were associated with high PDAC risk in the Chinese population. Conclusions Our results demonstrated that a genetic screen of actionable genomic variants could facilitate precision therapy and cancer risk reduction in pancreatic cancer patients of Asian ethnicity.
Background: Ampullary carcinoma (AC) is a rare gastrointestinal cancer with few effective standard treatment options. For patients with unresectable diseases, the response rates for radiotherapy, chemotherapy, and chemoradiotherapy are low. Evaluation of the actionable mutations through genomic profiling will enable patients to enroll in matched clinical trials. Methods: To characterize actionable targets in 27 Chinese AC patients, a 500-gene next-generation sequencing panel was applied to assess the mutational status of their tumor tissues, including SNV, insertions/deletions, CNV and re-arrangements. Also, paired genomic DNA sample was extracted and analyzed by a 93-gene NGS panel to characterize germline variants. Results: Recurrent somatic mutated genes were KRAS (63%), TP53 (59%), APC (26%), SMAD4 (19%), CDKN2A (15%), ELF3 (11%), ERBB2 (11%), ERBB3 (11%) and MAP2K4 (11%). Consistent with previous studies, all mutations in AC driver gene ELF3 (n =3) were inactivating (three indels and one in splicing-site). The median tumor mutation burden (TMB) of our cohort was 1.6 (0-6.1) mutations/Mb and none of our patients had high microsatellite instability (MSI-H). Overall, we observed a wide spectrum of hotspot mutations in cancer driver genes including ERBB3 (n =2), FBXW7 (n =2), U2AF1 (n =2), BRAF (n =1), ERBB2/HER2 (n =1) and PIK3CA (n =1). The HER2 R678Q mutation, located in the transmembrane domain (TMD), activated HER2 signaling by improving the active dimer interface or stabilizing an activating conformation of HER2. Interestingly, both ERBB3 mutations (G284R and D297Y) were located in the extracellular domain (ECD) and their oncogenic activity also depended on the kinase-activity of ERBB2. These three mutations, together with one case of ERBB2 amplification, can be targeted by anti-HER2 antibodies and small-molecule HER2 kinase inhibitors. The BRAF N581I mutation is resistant to BRAF inhibitor vemurafenib but sensitive to MEK inhibitor trametinib. The PIK3CA N1044K mutation is oncogenic but its sensitivity to PIK3CA inhibitor alpelisib is unknown. Additionally, one patient had high level of FGFR2 amplification which may be suitable for the clinical trials of FGFR2 inhibitors pemigatnib and erdafitnib. Furthermore, two patients carried loss-of-function germline mutations in DNA repair genes PALB2 and CHEK2 which may confer synthetic lethality with PARP inhibitors. Taken together, at least eight (29.6%) patients in our cohort had actionable therapeutic targets. Conclusions: Through comprehensive genomic characterization of Chinese AC patients, we identified multiple actionable mutations in multiple signaling pathways. Our findings indicated that molecular profiling can provide clinical benefits to a significant portion of AC patients. Citation Format: Fei Wang, Si Liu, Xiaomo Li, Zhiming Zhao, Tonghui Ma, Hongling Yuan, Rong Liu. Evaluation of somatic and germline mutations in ampullary carcinoma reveals actionable targets in multiple signaling pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2182.
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