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

• Published in: British journal of cancer 2017-11, Vol.117 (10), p.1450-1458
• Main Authors: Shinozaki, Eiji, Yoshino, Takayuki, Yamazaki, Kentaro, Muro, Kei, Yamaguchi, Kensei, Nishina, Tomohiro, Yuki, Satoshi, Shitara, Kohei, Bando, Hideaki, Mimaki, Sachiyo, Nakai, Chikako, Matsushima, Koutatsu, Suzuki, Yutaka, Akagi, Kiwamu, Yamanaka, Takeharu, Nomura, Shogo, Fujii, Satoshi, Esumi, Hiroyasu, Sugiyama, Masaya, Nishida, Nao, Mizokami, Masashi, Koh, Yasuhiro, Abe, Yukiko, Ohtsu, Atsushi, Tsuchihara, Katsuya
• Format: Article
• Language: English
• Subjects: 692/4017; 692/4028/67/1504/1885; Adult; Aged; Antibodies, Monoclonal - therapeutic use; Antineoplastic Agents - therapeutic use; Biomarkers; Biomarkers, Tumor - genetics; Biomedical and Life Sciences; Biomedicine; Breast cancer; Cancer Research; Cetuximab - therapeutic use; Clinical significance; Clinical Study; Cohort Studies; Colorectal cancer; Colorectal carcinoma; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - genetics; Colorectal Neoplasms - mortality; Disease-Free Survival; Drug Resistance; Drug Resistance, Neoplasm - genetics; Epidemiology; Epidermal growth factor receptors; ErbB Receptors - antagonists & inhibitors; Female; Genomics; Humans; Inference; K-Ras protein; Kaplan-Meier Estimate; Male; Metastases; Metastasis; Middle Aged; Molecular Medicine; Monoclonal antibodies; Mutation; Oncology; Panitumumab; Patients; Proto-Oncogene Proteins B-raf - genetics
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2017.308

Background: Patients with BRAF V600E -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 BRAF V600E ( BRAF non-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 BRAF V600E (6.0%), and 7 patients with BRAF non-V600E mutations (4.7%), respectively. The response rates in RAS , BRAF V600E , and BRAF non-V600E were lower than those in RAS / BRAF wild-type (2.5%, 0%, and 0% vs 31.9%). The median PFS in BRAF non-V600E mutations was 2.4 months, similar to that in RAS or BRAF V600E mutations (2.1 and 1.6 months) but significantly worse than that in wild-type RAS / BRAF (5.9 months). Conclusions: Although BRAF non-V600E mutations identified were a rare and unestablished molecular subtype, certain BRAF non-V600E mutations might contribute to a lesser benefit of anti-EGFR monoclonal antibody treatment.