Potential for Clinical Management of Pancreatic Cancer Through Whole Exome Profiling of Site-Specific Metastases and Matched Primary Tumors

Considering the lack of molecular background of the metastatic process in pancreatic ductal adenocarcinoma (PDAC) and the fact that the location of the metastasis may carry prognostic information and potential therapeutic opportunities, we aimed to explore genomic profiles of metastases from diverse loci and their value for the patients’ therapeutic management. DNA samples from paired primary and metastatic tissue of 20 patients were microdissected and sequenced using whole exome target enrichment. Somatic genetic variability, copy number variations (CNVs), and mutational signatures were assessed for associations with clinical data of patients. KRAS (78% in primary tumors, 74% in metastases), TP53 (67%-68%), CDKN2A (28%-37%), and SMAD4 (22%-26%) were the most commonly mutated oncodrivers in primary tumors and metastases. Other frequently mutated genes were CCDC187 (50%-58%), MUC5AC (50%-53%), EPPK1 (39%-63%), SYN2 (39%-26%), MUC19 (33%-47%), MUC3A (33%-26%), DNAH12 (28%-37%), ZBED3 (22%-26%), PKHD1L1 (28%-16%), and GTPBP6 (11%-32%). Lung metastases differed from other metastatic sites (liver, stomach, and locoregional) in a higher frequency of nonsense mutations in the MH2 domain of SMAD4, oncodriver comutations, gains on chromosomes 2 and 20, CNV counts, and share of signature SBS5. Somatic alterations of KRAS in metastases (P = .041) and MUC3A in both loci (P = .041 and P = .011, respectively) and CNVs count and size in metastases (P = .024 and P = .011) associated with response to systemic chemotherapy. Patients with mutated KRAS (P = .045), high mutational load (P = .004), and frequent CNVs (P = .004) in metastatic loci had shortened survival after metastasis resection. Interestingly, the personalized treatment targetable alterations, such as microsatellite instability and mismatch repair or homologous recombination deficiencies did not differ between the primary tumors and paired metastases or between the metastases from different secondary sites and had no prognostic value. The results suggest a potential prognostic role of KRAS mutations, mutation load, and CNVs in PDAC patients after metastasectomy and encourage further molecular profiling for personalized treatment of PDAC patients with different metastasis localization.