BRAF V600E Mutation in First-Line Metastatic Colorectal Cancer: An Analysis of Individual Patient Data From the ARCAD Database

Romain Cohen; Heshan Liu; Jack Fiskum; Richard Adams; Benoist Chibaudel; Timothy S Maughan; Eric Van Cutsem; Alan Venook; Jean-Yves Douillard; Volker Heinemann; Cornelis Ja Punt; Alfredo Falcone; Carsten Bokemeyer; Richard Kaplan; Heinz-Josef Lenz; Miriam Koopman; Takayuki Yoshino; John Zalcberg; Alex Grothey; Aimery de Gramont; Qian Shi; Thierry André

doi:10.1093/jnci/djab042

BRAF V600E Mutation in First-Line Metastatic Colorectal Cancer: An Analysis of Individual Patient Data From the ARCAD Database

J Natl Cancer Inst. 2021 Oct 1;113(10):1386-1395. doi: 10.1093/jnci/djab042.

Authors

Romain Cohen^{1

2}, Heshan Liu¹, Jack Fiskum¹, Richard Adams³, Benoist Chibaudel⁴, Timothy S Maughan⁵, Eric Van Cutsem⁶, Alan Venook⁷, Jean-Yves Douillard⁸, Volker Heinemann⁹, Cornelis Ja Punt¹⁰, Alfredo Falcone¹¹, Carsten Bokemeyer¹², Richard Kaplan¹³, Heinz-Josef Lenz¹⁴, Miriam Koopman¹⁵, Takayuki Yoshino¹⁶, John Zalcberg¹⁷, Alex Grothey¹⁸, Aimery de Gramont⁴, Qian Shi¹, Thierry André²

Affiliations

¹ Department of Health Science Research, Mayo Clinic, Rochester, MN, USA.
² Department of Medical Oncology, Sorbonne University, Saint-Antoine Hospital, Paris, France.
³ Cardiff University and Velindre Cancer Centre, Cardiff, UK.
⁴ Department of Medical Oncology, Franco-British Institute, Levallois-Perret, France.
⁵ Cancer Research UK and the Medical Research Council Oxford Institute for Radiation Oncology, Oxford, UK.
⁶ Digestive Oncology, University Hospitals Gasthuisberg Leuven and University of Leuven, Belgium.
⁷ Department of Medicine, The University of California San Francisco, San Francisco, CA, USA.
⁸ University of Nantes Medical School Nantes, France.
⁹ Department of Medical Oncology and Comprehensive Cancer Center, University of Munich, Munich, Germany.
¹⁰ Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
¹¹ Department of Oncology, University of Pisa, Italy.
¹² Department of Oncology, Haematology and Bone Marrow Transplantation with Section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹³ Medical Research Council Clinical Trials Unit, University College London, London, UK.
¹⁴ Department of Gastrointestinal Oncology, Keck School of Medicine at USC, Los Angeles, CA, USA.
¹⁵ Department of Medical Oncology, University Medical Center Utrecht, University of Utrecht, Utrecht, the Netherlands.
¹⁶ Department of Gastrointestinal Oncology, National Cancer Center Hospital East, Chiba, Japan.
¹⁷ Monash University, Melbourne, Australia.
¹⁸ West Cancer Center, Germantown, TN, USA.

PMID: 33734401
DOI: 10.1093/jnci/djab042

Abstract

Background: First-line therapeutic strategies for patients with BRAFV600E-mutated (BRAFmt) metastatic colorectal cancer (mCRC) mainly rely on subgroup analyses from randomized controlled trials (RCTs). We aimed to assess the prognostic and predictive impact of BRAFmt on the efficacy of targeted therapies with first-line chemotherapy.

Methods: Individual patient data from first-line RCTs with BRAF and KRAS status data in the ARCAD database were pooled. Progression-free survival and overall survival (OS) were assessed using Kaplan-Meier and Cox models. Outcomes were compared between treatment groups that were concurrently randomly assigned whenever possible.

Results: A total of 6391 patients from 10 RCTs were included: 573 BRAFmt (9.0%), 2059 KRASmt (32.2%), and 3759 double wild type (58.8%). BRAFmt mCRC patients experienced statistically significantly poorer OS than those with KRASmt (adjusted hazard ratio [HRadj] = 1.46, 95% confidence interval [CI] = 1.30 to 1.64) and patients with double wild-type tumors (HRadj = 2.14, 95% CI = 1.94 to 2.36). Anti-EGFR agents did not improve progression-free survival or OS of BRAFmt mCRC patients, based on 4 RCTs testing chemotherapy with or without anti-epidermal growth factor receptor (anti-EGFR) (HRadj = 0.96, 95% CI = 0.71 to 1.30; and HRadj = 0.85, 95% CI = 0.66 to 1.14, respectively).

Conclusions: Our data suggest that the addition of anti-EGFR agents to chemotherapy is ineffective as first-line treatment for BRAFmt mCRC patients.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Colonic Neoplasms*
Colorectal Neoplasms* / drug therapy
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / pathology
Humans
Mutation
Proto-Oncogene Proteins B-raf / genetics
Proto-Oncogene Proteins p21(ras) / genetics
Randomized Controlled Trials as Topic
Rectal Neoplasms*
Treatment Outcome

Substances

BRAF protein, human
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins p21(ras)

Abstract

Publication types

MeSH terms

Substances

Grants and funding