KRAS codon 61, 146 and BRAF mutations predict resistance to cetuximab plus irinotecan in KRAS codon 12 and 13 wild-type metastatic colorectal cancer

Abstract

Background:KRAS codons 12 and 13 mutations predict resistance to anti-EGFR monoclonal antibodies (moAbs) in metastatic colorectal cancer. Also, BRAF V600E mutation has been associated with resistance. Additional KRAS mutations are described in CRC.Methods:We investigated the role of KRAS codons 61 and 146 and BRAF V600E mutations in predicting resistance to cetuximab plus irinotecan in a cohort of KRAS codons 12 and 13 wild-type patients.Results:Among 87 KRAS codons 12 and 13 wild-type patients, KRAS codons 61 and 146 were mutated in 7 and 1 case, respectively. None of mutated patients responded vs 22 of 68 wild type (P=0.096). Eleven patients were not evaluable. KRAS mutations were associated with shorter progression-free survival (PFS, HR: 0.46, P=0.028). None of 13 BRAF-mutated patients responded vs 24 of 74 BRAF wild type (P=0.016). BRAF mutation was associated with a trend towards shorter PFS (HR: 0.59, P=0.073). In the subgroup of BRAF wild-type patients, KRAS codons 61/146 mutations determined a lower response rate (0 vs 37%, P=0.047) and worse PFS (HR: 0.45, P=0.023). Patients bearing KRAS or BRAF mutations had poorer response rate (0 vs 37%, P=0.0005) and PFS (HR: 0.51, P=0.006) compared with KRAS and BRAF wild-type patients.Conclusion:Assessing KRAS codons 61/146 and BRAF V600E mutations might help optimising the selection of the candidate patients to receive anti-EGFR moAbs.

Oncogenic mutations as predictive factors in colorectal cancer

“…A new interesting point concerning KRAS mutations is the description of other mutations than those usually described in codons 12 and 13 of the gene, which might be useful to select non-responder patients to anti-EGFR antibodies (Loupakis et al, 2009b). These mutations, located within KRAS codons 61 and 146, even if they are much less frequent than codons 12 and 13 mutations (present in 8 and 1% of the tumours, respectively), have been shown, in addition to BRAF mutations, to correlate with lack of response to cetuximab (0 vs 37%; P ¼ 0.0005) and to a lower progression-free survival (3.3 vs 5.3 months; P ¼ 0.006) and overall survival (9.7 vs 14.8 months; P ¼ 0.027) in the subgroup of 89 wild-type KRAS patients of the study by (Loupakis et al (2009b), which included a total of 138 irinotecan-resistant colorectal cancers treated with the combination of cetuximab and irinotecan.…”

“…Treatment with sorafenib, a BRAF inhibitor, restored the sensitivity to cetuximab or panitumumab of these three BRAF-mutated colorectal cancer cell lines. Since then, three independent retrospective studies have also shown lack of response to cetuximab and a shorter survival of patients with BRAF-mutated tumour among the subgroup of KRAS wild-type patients (Laurent-Puig et al, 2009;Souglakos et al, 2009;Loupakis et al, 2009b) (Table 2). These findings clearly show that BRAF mutations are an additional tool for the selection of patients who might be resistant to anti-EGFR antibodies and that they should be considered before considering anti-EGFR therapies for mCRC.…”

Prognostic vs predictive molecular biomarkers in colorectal cancer: is KRAS and BRAF wild type status required for anti-EGFR therapy?

“…37 In the CAIRO-2 study, a similar pattern was observed in a large series of mCRC patients treated with chemotherapy and Bevacizumab with or without Cetuximab. It was seen that the BRAF mutation is associated with a worse outcome, both in terms of PFS and of OS, independently of the addition of Cetuximab to the treatment.. 38 To date, therefore, the negative value of mutations of BRAF is only suggested by some reports, 39 while the significant negative prognostic value seems to be now established. 40 …”

Resistance to Anti-EGFR Therapy in Colorectal Cancer: From Heterogeneity to Convergent Evolution

“…Although the role of the canonical exon 2 mutations is considered uncontroversial, the exact properties of the less-frequent mutations have not been fully elucidated. However, data from retrospective studies indicate that RAS mutations occurring beyond KRAS exon 2 could also underlie lack of response to single-agent cetuximab or panitumumab in patients with chemorefractory mCRC (20)(21)(22)(23). Multiple studies have recently shown that mutations in KRAS exons 3 and 4 or NRAS exons 2 to 4 can also predict lack of clinical benefi t to EGFR-targeted antibodies given in combination with fi rst-line chemotherapy (24)(25)(26).…”