Longitudinal imaging and sequence analysis of melanoma metastases reveals heterogeneity in vemurafenib response driven by diverse resistance mechanisms.. paired biopsies melanoma

Vemurafenib has improved the quality of life and life expectancy for many patients with BRAF mutant metastatic melanoma. Unfortunately in time the majority of patients become resistant to treatment. We followed ten patients during treatment with vemurafenib, by performing three-dimensional imaging to monitor growth of individual metastatic lesions. Next generation sequencing was performed on sequential biopsies, obtained prior to treatment and upon disease progression in 4 patients to uncover mechanisms of resistance to vemurafenib. Ten patients were followed during treatment with vemurafenib, by performing three-dimensional imaging to monitor growth of individual metastatic lesions. Next generation sequencing was performed on sequential biopsies, obtained prior to treatment and upon disease progression in 4 patients. In all patients, only a subset of metastatic lesions developed resistance to vemurafenib while other lesions remained in regression. In two of four patients with repetitive biopsies from progressive lesions we identified mutations that explained resistance to vemurafenib: one patient had an activating mutation in PIK3CA, and in another patient we detected a secondary, novel BRAFL505H mutation. The functional relevance of this mutation for resistance to vemurafenib was subsequently confirmed in melanoma cells genetically modified to harbor the same mutations. Our results show the feasibility of sequential biopsies of progressive metastases in melanoma patients to detect both known and unexpected resistance mechanisms, which may lead to new personalized treatment strategies.