Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer

Abstract

Purpose Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. Patients and Methods We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC. Results KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele. Conclusion BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.

Can KRAS and BRAF mutations limit the benefit of liver resection in metastatic colorectal cancer patients? A systematic review and meta-analysis

“…As regards BRAF mutations, even if evaluated in a small subgroup of patients, our findings are consistent with the most part of published studies which have validated BRAF mutations obtained from primary tumour specimens as a strong negative prognostic biomarker in metastatic CRC (Ahn et al, 2014), showing a more aggressive and chemo-refractory behavior compared to wild-type tumours (Tran et al, 2011). However it's interesting to observe that the percentages of BRAF mutations (2-4%) in all the included studies is lower than those reported in the literature (5-10%) (Sridhar et al, 2005;Di Nicolantonio et al, 2008), likely due to the clinical selection of patients included in such studies. Indeed, because of their peculiar metastatic spread, BRAF-mutated tumours are usually detected as an advanced disease, rarely candidate for liver surgery.…”

Molecular pathology of lung cancer: key to personalized medicine

“…215 The results showed that none of the patients who experienced a response displayed BRAF mutations, whereas 11 of 79 (14%) nonresponders carried a BRAF V600E allele. 215 As BRAF mutations are mutually exclusive to EGFR and KRAS mutations, it is likely to be associated with lack of response to EGFR TKIs. 138 …”

“…215 BRAF mutations are found in 1-3% of lung cancers, most of which are adenocarcinomas. 206,212 BRAF mutations are found in a mutually exclusive pattern with KRAS mutations, suggesting that these genetic events activate a set of common downstream effectors of transformation.…”

Immunohistochemistry with a mutation-specific monoclonal antibody as a screening tool for the BRAFV600E mutational status in primary cutaneous malignant melanoma

“…14 In the case of colorectal carcinomas, BRAFV600E mutation positive patients have significantly shorter progression-free survival when compared with patients with tumors with BRAF wild-type and its presence is shown to impair the therapeutic effect of drugs such as cetuximab and panitumumab. 15 The recognition of BRAFV600E mutation and its prognostic value has led to accelerated attempts to utilize it as a target for cancer therapy. Briefly, recent drugs targeted against mutated BRAF (particularly in melanomas) have shown great promise in early clinical trials.…”