Clinical significance of BRAF non-V600E mutations on the therapeutic effects of anti-EGFR monoclonal antibody treatment in patients with pretreated metastatic colorectal cancer: the Biomarker Research for anti-EGFR monoclonal Antibodies by Comprehensive Cancer genomics (BREAC) study.

Abstract

BACKGROUND:

Patients with BRAFV600E-mutated metastatic colorectal cancer (mCRC) have a poorer prognosis as well as resistance to anti-EGFR antibodies. However, it is unclear whether BRAF mutations other than BRAFV600E (BRAFnon-V600E mutations) contribute to anti-EGFR antibody resistance.

METHODS:

This study was composed of exploratory and inference cohorts. Candidate biomarkers identified by whole exome sequencing from super-responders and nonresponders in the exploratory cohort were validated by targeted resequencing for patients who received anti-EGFR antibody in the inference cohort.

RESULTS:

In the exploratory cohort, 31 candidate biomarkers, including KRAS/NRAS/BRAF mutations, were identified. Targeted resequencing of 150 patients in the inference cohort revealed 40 patients with RAS (26.7%), 9 patients with BRAFV600E (6.0%), and 7 patients with BRAFnon-V600E mutations (4.7%), respectively. The response rates in RAS, BRAFV600E, and BRAFnon-V600E were lower than those in RAS/BRAF wild-type (2.5%, 0%, and 0% vs 31.9%). The median PFS in BRAFnon-V600E mutations was 2.4 months, similar to that in RAS or BRAFV600E mutations (2.1 and 1.6 months) but significantly worse than that in wild-type RAS/BRAF (5.9 months).

CONCLUSIONS:

Although BRAFnon-V600E mutations identified were a rare and unestablished molecular subtype, certain BRAFnon-V600E mutations might contribute to a lesser benefit of anti-EGFR monoclonal antibody treatment.

• Authors: Eiji Shinozaki, Takayuki Yoshino, Kentaro Yamazaki, Kei Muro, Kensei Yamaguchi, Tomohiro Nishina, Satoshi Yuki, Kohei Shitara, Hideaki Bando, Sachiyo Mimaki, Chikako Nakai, Koutatsu Matsushima, Yutaka Suzuki, Kiwamu Akagi, Takeharu Yamanaka, Shogo Nomura, Satoshi Fujii, Hiroyasu Esumi, Masaya Sugiyama, Nao Nishida, Masashi Mizokami, Yasuhiro Koh, Yukiko Abe, Atsushi Ohtsu, Katsuya Tsuchihara
• Journal: British journal of cancer (Br J Cancer) Vol. 117 Issue 10 Pg. 1450-1458 (Nov 07 2017) ISSN: 1532-1827 [Electronic] England
• PMID: 28972961 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Biomarkers, Tumor
• Panitumumab
• EGFR protein, human
• ErbB Receptors
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Cetuximab

Topics

• Adult
• Aged
• Antibodies, Monoclonal (therapeutic use)
• Antineoplastic Agents (therapeutic use)
• Biomarkers, Tumor (genetics)
• Cetuximab (therapeutic use)
• Cohort Studies
• Colorectal Neoplasms (drug therapy, genetics, mortality)
• Disease-Free Survival
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (antagonists & inhibitors)
• Female
• Genomics
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Mutation
• Panitumumab
• Proto-Oncogene Proteins B-raf (genetics)