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. 2020 Sep 1;26(17):4599-4605.
doi: 10.1158/1078-0432.CCR-20-1024. Epub 2020 Jun 22.

Population-based Screening for BRAF V600E in Metastatic Colorectal Cancer Reveals Increased Prevalence and Poor Prognosis

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Population-based Screening for BRAF V600E in Metastatic Colorectal Cancer Reveals Increased Prevalence and Poor Prognosis

Jenny E Chu et al. Clin Cancer Res. .

Abstract

Purpose: BRAF V600E mutations portend poor prognosis in metastatic colorectal cancer (mCRC); however, the true prevalence and prognosis are unknown, as unwell patients may not undergo BRAF sequencing.

Experimental design: We reviewed a population-based cohort of 1,898 patients with colorectal cancer that underwent reflexive IHC mismatch repair (MMR) and BRAF V600E testing. Outcomes among IHC-detected BRAF V600E mCRC (BRAF IHC) were compared with patients with next-generation sequencing (NGS)-identified BRAF V600E-mutated mCRC from two institutions (BRAF NGS) with patients spanning from 2004 to 2018.

Results: All-stage population prevalence of BRAF V600E was 12.5% (238/1,898) and did not differ between early and metastatic stages (P = 0.094). Prevalence among mCRC was 10.6% (61/575), of whom 51 (83.6%) were referred to oncology and 26 (42.6%) had NGS testing. BRAF IHC had worse median overall survival (mOS) than BRAF NGS [5.5 vs. 20.4 months; HR, 2.90; 95% confidence interval (CI), 1.89-4.45; P < 0.0001], which persisted in multivariate analysis (P < 0.0001). Across a combined NGS and IHC cohort, BRAF V600E tumors with deficient MMR showed worse mOS compared with MMR proficient tumors (8.9 vs. 17.2 months; HR, 1.46; 95% CI, 0.96-2.27; P = 0.043). In this combined cohort, first-line progression-free survival was 5.9 months, with minimal differences between regimens. Within the population-based cohort, attrition between treatment lines was high with only 60.7% receiving first-line chemotherapy and 26.2% receiving second line.

Conclusions: Patients with BRAF V600E-mutated mCRC have a worse prognosis than previously suggested, potentially arising from referral bias for testing. High attrition between lines of therapy suggests efficacious therapies need to be prioritized early for patients to benefit.

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Figures

Figure 1.
Figure 1.
Kaplan-Meier estimation of overall survival of patients with mCRC and BRAFV600E mutations detected by IHC (BRAFIHC) and NGS (BRAFNGS).
Figure 2.
Figure 2.
Kaplan-Meier estimation of overall survival of pooled patients with BRAFV600E mutated mCRC (BRAFNGS and BRAFIHC).
Figure 3.
Figure 3.
Kaplan-Meier estimation of progression free survival of (A) a pooled mCRC cohort with BRAFV600E mutations from BC Cancer and MD Anderson and (B) the same pooled cohort stratified by first-line palliative chemotherapy treatment regimen. (C) Attrition of pooled BC Cancer patients with BRAFV600E mutations (BRAFIHC and BRAFNGS, n=84) across lines of therapy. 1 Footnote: Four patients were on trials evaluating BRAF directed therapy

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