Metastasectomy and BRAF mutation; an analysis of survival outcome in metastatic colorectal cancer

https://doi.org/10.1016/j.currproblcancer.2020.100637Get rights and content

Abstract

Background: Resection of oligometastases improves survival in metastatic colorectal cancer (mCRC). It is unclear whether the benefit is consistent for BRAF V600E mutant (MT) and wild type (WT) mCRC. This retrospective analysis explores the influence of BRAF MT on survival after metastasectomy. Methods: Overall survival (OS) and recurrence-free survival (RFS) for BRAF MT and WT mCRC were evaluated. Survival was also analyzed in the cohort of BRAF MT with or without metastasectomy. Results: Five hundred and thirteen patients who had undergone metastasectomy were identified, 6% were BRAF-MT. Median age 63. Median OS in BRAF MT vs WT: 25.7 vs 48.5 months (hazard ratio [HR] 1.95; 1.18-3.22). However, difference was not significant in a multivariate model. Right primary tumor, intact primary, >1 metastatic site, non-R0 resection, peritoneal metastasis, and synchronous metastasis were independent predictors of worse OS. Among 364 patients with RFS data there was no difference between BRAF MT and WT (16 vs 19 months, p=0.09). In another cohort of 158 BRAF-MT patients, OS was significantly better after metastasectomy compared to “no metastasectomy” (HR 0.34; 0.18-0.65, P= 0.001). Proficient mismatch repair status showed a trend toward worse survival after metastasectomy in BRAF MT (HR 1.71, P = 0.08). Conclusion: OS did not differ after metastasectomy between BRAF MT and WT in a multivariate model. Median OS was >2 years in this study after metastasectomy among BRAFV600E MT patients suggesting a survival benefit of metastasectomy in this group where systemic therapeutic options are limited. Metastasectomy may be considered in carefully selected BRAF-MT patients.

Section snippets

Background

Metastasectomy increases the survival of patients with oligometastatic colorectal cancer. The 5-year survival rate in multiple surgical series after hepatic metastasectomy ranges from 27% to 58%.1,2 Advances in surgical techniques and systemic therapies have improved the outcomes in the last two decades.3 Even those who present with synchronous metastases, may be considered for curative combined resection at the same time or as a two staged procedure in conjunction with perioperative

Methods

This is a retrospective study of two different datasets extracted from two large Australian cancer registries. The South Australian Cancer Registry19 is a state-wide population based registry which captures all incident cases, while the “Treatment of Recurrent and Advanced Colorectal Cancer” (TRACC) registry20 is a federated national database with data collected from participating cancer centers in the Australian Capital Territory, Victoria and Tasmania. The latter includes patients referred to

Results

Out of 7534 patients screened, a total of 513 patients who had undergone metastasectomy were identified. Median age was 63 and 58% were male. Six percent were BRAF MT (see Table 1). Site of primary CRC was strongly correlated with mutational status (P = <0.001), BRAF MT tumors were most prevalent in right side cancers, consistent with the literature. More than 50% of patients received perioperative chemotherapy. Four percent underwent metastasectomy at more than 1 organ site at diagnosis in

Discussion

The presence of BRAF MT in metastatic CRC confers a poor prognosis, with lower responses to combination systemic anticancer therapies including EGFR inhibitors. The TRIBE study utilized a four-drug combination in the first-line setting which showed improved survival in BRAF MT cohort, however, median OS was still only 13 months in BRAF MT cohort.9 A combination of three RAS pathway protein (BRAF, MEK, EGFR) inhibitors were used to treat BRAF MT mCRC patients in BEACON trial. Though survival

Authors’ Contribution

TP, DY, CK, and PG: conceptualization. MS and TP: formal analysis. TP: writing-original draft. All other authors listed have made substantial, direct, and intellectual contribution in data curation, methodology, writing-review, and editing. All authors have viewed the final manuscript and agreed for submission.

Acknowledgment

Roche Products Pty Limited has provided financial assistance for the development, installation, and maintenance of the BioGrid-TRACC registry. The South Australian State Government has provided support for the maintenance of the SA Metastatic Colorectal Cancer Registry.

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    Conflicts of Interest: PG has disclosed honoraria from Amgen and Merck. DY has indicated grants from Ipsen, Novartis, Roche. ML has indicated honoraria from Amgen and Merck. All other authors have indicated no conflicts of interest.

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