Activity of EGFR antibody in non-V600 BRAF mutant metastatic colorectal cancer
Authors: Y. Wang, J.C. Jones, B.R. Kipp, A. Grothey
Journal: Annals of Oncology (2018)

V600E BRAF mutation occurs in 8%–10% of metastatic colorectal cancer (mCRC) and is associated with resistance to epidermal growth factor receptor (EGFR) inhibitors and a poor prognosis [1.Pietrantonio F. Petrelli F. Coinu A. et al.Predictive role of BRAF mutations in patients with advanced colorectal cancer receiving cetuximab and panitumumab: a meta-analysis.Eur J Cancer. 2015; 51: 587-594Abstract Full Text Full Text PDF PubMed Scopus (359) Google Scholar, 2.Rowland A. Dias M.M. Wiese M.D. et al.Meta-analysis of BRAF mutation as a predictive biomarker of benefit from anti-EGFR monoclonal antibody therapy for RAS wild-type metastatic colorectal cancer.Br J Cancer. 2015; 112: 1888-1894Crossref PubMed Scopus (231) Google Scholar]. In contrast, non-V600 BRAF mutations occur in ∼2% of mCRC, and correlate with a significantly better survival [3.Jones J.C. Renfro L.A. Al-Shamsi H.O. et al.Non-V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer.JCO. 2017; 35: 2624-2630Crossref PubMed Scopus (191) Google Scholar]. It is unknown whether non-V600 BRAF mutations also induce resistance to EGFR inhibitors. We report a case of non-V600 BRAF mutant mCRC responding remarkably to single-agent panitumumab. A 51-year-old woman was diagnosed with mCRC with a BRAF G469V mutation. Her disease progressed after several lines of therapy including 5-fluorouracil, oxaliplatin, irinotecan, and TAS-102. Considering a non-V600 BRAF mutation may not confer resistance to EGFR inhibitors, we started her on single-agent panitumumab. She had a remarkable response after four cycles, with noticeable shrinkage of lesions in the liver, right adrenal gland, and retroperitoneal nodes and a 90% reduction of CEA (Figure 1). Unfortunately, her disease progressed again after four additional cycles of panitumumab. Molecular testing using cell-free DNA revealed new KRAS G12V and NRAS Q61L mutations in addition to BRAF G469V, which could conceivably explain progression on panitumumab. Three different classes of BRAF mutations have been defined [4.Yao Z. Torres N.M. Tao A. et al.BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition.Cancer Cell. 2015; 28: 370-383Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar, 5.Yao Z. Yaeger R. Rodrik-Outmezguine V.S. et al.Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.Nature. 2017; 548: 234-238Crossref PubMed Scopus (294) Google Scholar]. Class 1 mutations are V600 mutations, which render BRAF constitutively active as a monomer independent of RAS. Class 2 mutations such as K601, G469, and G464 mutations confer intermediate to high BRAF activity which is dimerization-dependent. While homodimerization of these mutants are independent of RAS, their heterodimerization with CRAF still requires RAS [4.Yao Z. Torres N.M. Tao A. et al.BRAF mutants evade ERK-dependent feedback by different mechanisms that determine their sensitivity to pharmacologic inhibition.Cancer Cell. 2015; 28: 370-383Abstract Full Text Full Text PDF PubMed Scopus (292) Google Scholar]. Class 3 mutations such as G466, D594, and G596 mutations significantly decrease BRAF activity. These mutants require RAS and dimerization to maintain their activity [5.Yao Z. Yaeger R. Rodrik-Outmezguine V.S. et al.Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS.Nature. 2017; 548: 234-238Crossref PubMed Scopus (294) Google Scholar]. The extent of dependency on RAS may dictate response of BRAF mutants to EGFR inhibition. Out patients had a class 2 G469V mutation and a good response to EGFR inhibition. One may expect mCRC patients with class 3 BRAF mutations respond even better to EGFR inhibitors. This case has several clinical implications. First of all, it provides the first direct evidence that non-V600 BRAF mutant mCRC can respond to EGFR inhibitors. Cetuximab and panitumumab, either alone or in combination with chemotherapy, should be considered in patients with such mutations. Based on this proof-of-concept finding, clinical trials can be designed to further evaluate the efficacy of EGFR inhibitors in non-V600 BRAF mutant mCRC. Secondly, the overall indolent course of our patient again demonstrates that non-V600 BRAF mutant mCRC is clinically distinct from V600E BRAF mutant mCRC and may not warrant aggressive therapy such as FOLFOXIRI (with or without bevacizumab). Thirdly, the new emergence of KRAS and NRAS mutations in our patient suggests an important role of repeat molecular testing in guiding treatment of mCRC. Acknowledging intratumor heterogeneity and clonal evolution is critical. Lastly and importantly, precision medicine should be taken to the individual level. Different mutations of the same gene may affect the protein function in different ways and understanding the structural and functional changes associated with a specific mutation is crucial in choosing appropriate treatment strategy. None declared.