Evaluation of Somatic Mutations in Solid Metastatic Pan-Cancer Patients

SIMPLE SUMMARY: Cancer metastasis significantly contributes to cancer-related mortality. Our retrospective cohort study aimed to evaluate the mutational landscape of seven solid metastatic tumors and mutational effects on survival using a single molecular testing panel. Additionally, we assessed the treatments used in advanced cancer. We identified somatic mutations that were mutually exclusive in seven gene pairs. Among them, somatic mutations in APC and CDKN2A showed an opposite effect on overall survival (OS). Longer OS was associated with metastatic cases diagnosed post-2015. Progression-free survival was associated with the use of targeted treatments. Our results highlight complex interactions of mutational landscape with a single molecular test, time of metastatic diagnosis, and the impact of targeted therapy usage on survival using a pan-cancer cohort. ABSTRACT: Metastasis continues to be the primary cause of all cancer-related deaths despite the recent advancements in cancer treatments. To evaluate the role of mutations in overall survival (OS) and treatment outcomes, we analyzed 957 metastatic patients with seven major cancer types who had available molecular testing results with a FoundationOne CDx(®) panel. The most prevalent genes with somatic mutations were TP53, KRAS, APC, and LRP1B. In this analysis, these genes had mutation frequencies higher than in publicly available datasets. We identified that the somatic mutations were seven mutually exclusive gene pairs and an additional fifty-two co-occurring gene pairs. Mutations in the mutually exclusive gene pair APC and CDKN2A showed an opposite effect on the overall survival. However, patients with CDKN2A mutations showed significantly shorter OS (HR: 1.72, 95% CI: 1.34–2.21, p < 0.001) after adjusting for cancer type, age at diagnosis, and sex. Five-year post metastatic diagnosis survival analysis showed a significant improvement in OS (median survival 28 and 43 months in pre-2015 and post-2015 metastatic diagnosis, respectively, p = 0.00021) based on the year of metastatic diagnosis. Although the use of targeted therapies after metastatic diagnosis prolonged OS, the benefit was not statistically significant. However, longer five-year progression-free survival (PFS) was significantly associated with targeted therapy use (median 10.9 months (CI: 9.7–11.9 months) compared to 9.1 months (CI: 8.1–10.1 months) for non-targeted therapy, respectively, p = 0.0029). Our results provide a clinically relevant overview of the complex molecular landscape and survival mechanisms in metastatic solid cancers.