A validated prognostic classifier for BRAF-mutated metastatic colorectal cancer: the ‘BRAF BeCool’ study

Abstract

Background: Despite the well-known negative prognostic value of the V600E BRAF mutation in patients with metastatic colorectal cancer (mCRC), its outcome is quite heterogeneous, and the basis for this prognostic heterogeneity should be better defined. Methods: Two large retrospective series of V600E BRAF-mutated mCRC from 22 institutions served as an exploratory and validation set to develop a prognostic score. The model was internally and externally validated. Results: A total of 395 V600E BRAF-mutated mCRCs were included in the exploratory set. Performance status, CA19.9, lactate dehydrogenase, neutrophil/lymphocyte ratio, grading and liver, lung and nodal involvement emerged as independent prognostic factors for overall survival (OS). Two different scoring systems were built: a 'complete' score (0e16) including all significant covariates and a 'simplified' score (0e9), based only on clinicopathological covariates, and excluding laboratory values. Adopting the complete score, proportions of patients with a low (0e4), intermediate (5e8) and high (9e16) score were 44.7%, 42.6% and 12.6%, respectively. The median OS was 29.6, 15.5 (hazard ratio [HR] for intermediate vs low risk: 2.16, 95% confidence interval [CI]: 1.44e3.22, p < .001) and 6.6 months (HR for high vs low risk: 4.72, 95% CI: 2.72e8.20, p < .001). Similar results were observed also after adjusting for the type of first-line treatment and adopting the simplified score. The simplified prognostic score derived from the exploratory set was then applied to the validation set for external confirmation. Conclusions: These scoring systems are based on easy-to-collect data and defined specific subgroups with relevant differences in their life expectancy. These tools could be useful in clinical practice, would allow better stratification of patients in clinical trials and may be adopted for proper adjustments in exploratory translational analyses.

CDX2: A Prognostic Marker in Metastatic Colorectal Cancer Defining a Better BRAF Mutated and a Worse KRAS Mutated Subgroup

“…However, in the clinic, it has been observed that some patients with BRAFmut tumors have a relatively long survival, despite the mutational status. This was recently explored in study of 395 BRAFmut mCRCs, where clinical prognostic markers defined three vastly different prognostic groups (30). Our study may, at least in part, explain this as it demonstrates that CDX2 expression defines a new prognostic subgroup in patients with BRAFmut (53%) with a much better prognosis, comparable to wild-type patients.…”

BRAF Mutation in Colorectal Cancers: From Prognostic Marker to Targetable Mutation

“…Furthermore, Loupakis et al suggested a more practical classification method by using data which were easily available in daily practice, such as performance status (PS) and laboratory data only. Interestingly, they revealed that the prognosis of BRAF-mutated CRCs was clearly divided according to their clinical subtyping [203]. These results indicated that BRAF-mutated CRCs were not one disease but that there was inter-tumor heterogeneity among BRAF-mutated CRCs.…”

The heterogeneous clinical and pathological landscapes of metastatic Braf-mutated colorectal cancer

“…Therefore, since the remarkable prognostic difference between MSS/BRAFmt and MSI/BRAFmt CRCs, even in metastatic settings, molecular subtyping according BRAF mutational status alone is an insufficient prognostic index and the assessment of MMR status should always be performed [15]. In addition, the inclusion of other clinical and laboratory criteria could be useful to better prognostically stratify BRAF mutant patients as recently demonstrated by Loupakis et al [99,100]; items included in this prognostic score are: performance status, CA19.9, LDH, neutrophils/lymphocytes ratio, grading, liver/lung/nodal involvement. Combining these variables authors built both a "complete" prognostic score, and a "simplified" one (excluding laboratory features).…”