TP53 Mutations Are Frequently Concurrent in Patients with BRAF V600E Mutated Solid Tumors and is Associated with Shorter Duration of Response to BRAF Targeted Therapy

Background: Duration of response to BRAF targeted therapy in patients with BRAF V600E mutated solid tumors varies considerably and no predictive biomarkers exist. The purpose of this study was to explore the association between concurrent mutations at baseline and treatment outcome in patients with BRAF V600E mutated advanced solid tumors. Materials and methods: 24 patients with a BRAF V600E mutated advanced solid tumor treated with BRAF targeted therapy were included in this study. The primary tumors were colon (n = 16), lung (n = 3), neuroendocrine carcinoma (n = 2), breast (n = 1), cholangiocarcinoma (n = 1) and melanoma (n = 1). Baseline genomic profiling was done for all patients. Concurrent mutations were analyzed and interpreted using QIAGEN Clinical Insight Interpret software. Only somatic mutations were studied. Variant classification systems were used to guide interpretation of cancer associated mutations; selecting only mutations classified as “Pathogenic” or “Likely Pathogenic” to report. Clinical data were collected from electronic patient records. A nonparametric Pearson’s chi-squared test was used to estimate difference in median duration of therapy. The Kaplan-Meier method was used to estimate overall survival (OS) and the Cox proportional hazards model method was used to estimate hazard ratio and 95% confidence interval (CI). Results: Mutations in the tumor suppressor gene TP53 were the most frequent co-mutation. At baseline, 62.5% (15/24) of the patients had TP53 mutations with 1 patient having 2 concurrent TP53 alterations. All TP53 mutations were predicted to be loss-of-function mutations and included 14 point mutations and 2 mutations consisting of 13 and 16 base pair deletions, respectively. Median duration of BRAF targeted therapy was 32 weeks (range 8–230 weeks) in the entire cohort and therapy continued until progression of disease in all patients. We found concurrent mutation(s) in TP53 to be associated with a median of 12.4 weeks shorter duration of response to BRAF targeted therapy (p = 0.003). Median OS was 78.6 weeks in the group of patients without TP53 mutation (s) at baseline and 57.1 weeks in the group of patients with concurrent TP53 mutation(s), but this difference was not statistically significant (hazard ratio, 1.3; 95% CI, 0.54–3.2; p = 0.6). Conclusions: Mutations in TP53 were frequently detected in patients with BRAF V600E mutated advanced solid tumors. The presence of concurrent TP53 mutations at baseline were associated with shorter duration of response to BRAF targeted therapy but did not significantly correlate to OS outcome. TP53 mutations at baseline may contribute to the overall assessment of the expected clinical response to BRAF targeted therapy in patients with BRAF V600E mutated advanced solid tumors. Conflict of interest: Ownership: Genmab Advisory Board: Bayer, Novartis, Amgen, MSD Corporate-sponsored Research: BMS, GSK, Pfizer, Roche, Puma Biotechnology, MSD, Genmab, Genentech, Bristol-Myers Squibb, Orion, Loxo/Bayer, Loxo/Lilly, Cantargia AB, Symphogen, Alligator Bioscience, Incyte, AstraZeneca, Novartis, Monta Bioscience, Bioinvent, Pierre Fabre