BRAF Mutations in Advanced Cancers: Clinical Characteristics and Outcomes

BACKGROUND: Oncogenic BRAF mutations have been found in diverse malignancies and activate RAF/MEK/ERK signaling, a critical pathway of tumorigenesis. We examined the clinical characteristics and outcomes of patients with mutant (mut) BRAF advanced cancer referred to phase 1 clinic. METHODS: We reviewed the records of 80 consecutive patients with mutBRAF advanced malignancies and 149 with wild-type (wt) BRAF (matched by tumor type) referred to the Clinical Center for Targeted Therapy and analyzed their outcome. RESULTS: Of 80 patients with mutBRAF advanced cancer, 56 had melanoma, 10 colorectal, 11 papillary thyroid, 2 ovarian and 1 esophageal cancer. Mutations in codon 600 were found in 77 patients (62, V600E; 13, V600K; 1, V600R; 1, unreported). Multivariate analysis showed less soft tissue (Odds ratio (OR) = 0.39, 95%CI: 0.20-0.77, P = 0.007), lung (OR = 0.38, 95%CI: 0.19-0.73, p = 0.004) and retroperitoneal metastases (OR = 0.34, 95%CI: 0.13-0.86, p = 0.024) and more brain metastases (OR = 2.05, 95%CI: 1.02-4.11, P = 0.043) in patients with mutBRAF versus wtBRAF. Comparing to the corresponding wtBRAF, mutBRAF melanoma patients had insignificant trend to longer median survival from diagnosis (131 vs. 78 months, p = 0.14), while mutBRAF colorectal cancer patients had an insignificant trend to shorter median survival from diagnosis (48 vs. 53 months, p = 0.22). In melanoma, V600K mutations in comparison to other BRAF mutations were associated with more frequent brain (75% vs. 36.3%, p = 0.02) and lung metastases (91.6% vs. 47.7%, p = 0.007), and shorter time from diagnosis to metastasis and to death (19 vs. 53 months, p = 0.046 and 78 vs. 322 months, p = 0.024 respectively). Treatment with RAF/MEK targeting agents (Hazard ratio (HR) = 0.16, 95%CI: 0.03-0.89, p = 0.037) and any decrease in tumor size after referral (HR = 0.07, 95%CI: 0.015-0.35, p = 0.001) correlated with longer survival in mutBRAF patients. CONCLUSIONS: BRAF appears to be a druggable mutation that also defines subgroups of patients with phenotypic overlap, albeit with differences that correlate with histology or site of mutation

The tumor burden of metastatic colorectal cancer patients at initial diagnosis, pre- versus post-Covid-19 lockdown

AbstractBackgroundThe COVID-19 pandemic led to a significant reduction in the provision of screening, case identification and hospital referrals to cancer patients. To our knowledge, no study has yet correlated quantitatively the consequences of these limitations for cancer patient management. This study evaluates the implications of such reductions for patients newly diagnosed with metastatic colorectal cancer (mCRC) in both the pre- and post-lockdown periods.MethodsWe examined 80 newly identified mCRC patients from 18 different clinical centers. These cases come from the screening procedure of a clinical trial which is using circulating DNA (cirDNA) analysis to determine their RAS and BRAF status.ResultsThe tumor burden as evaluated by the median total plasma cirDNA concentration showed a statistically higher level in patients diagnosed post-lockdown compared to those diagnosed pre-lockdown (119.2 versus 17.3 ng/mL; p&lt;0.0001). In order to link tumor burden to survival, we compared the survival of these mCRC patients with previous studies in which cirDNA was examined in the same way (median survival, 16.2 months; median follow up, 48.7 months, N=135). Given the poor survival rate of mCRC patients with high cirDNA levels (14.7 vs 20.0 and 8.8 vs 19.3 months median survival when dichotomizing the cohort by the median cirDNA concentration 24.4 and 100 ng/mL, respectively), our study points to the potential deleterious consequences of the COVID-19 pandemic.ConclusionsRecognizing that our exploratory study offers a snapshot of an evolving situation, our observations nonetheless clearly highlight the need to determine actions which would minimize delays in diagnosis during the ongoing and future waves of COVID-19.</jats:sec