The Frequency of Specific KRAS Mutations, and Their Impact on Treatment Choice and Survival, in Patients With Metastatic Colorectal Cancer

Abstract

Background Patients with metastatic colorectal cancer (mCRC) and KRAS mutations have a poor prognosis, seemingly dependent on the location of the mutation. This multicenter, retrospective, cohort study assessed the frequency and prognostic value of specific KRAS mutation codon locations in mCRC patients, and survival outcomes in relation to treatment. Materials and Methods Data from mCRC patients treated in 10 Spanish hospitals between January 2011 and December 2015 were analyzed. The main objective was to investigate (1) the impact of KRAS mutation location on overall survival (OS), and (2) the effect of targeted treatment plus metastasectomy and primary tumor location on OS in patients with KRAS mutations. Results The KRAS mutation location was known for 337/2002 patients. Of these, 177 patients received chemotherapy only, 155 received bevacizumab plus chemotherapy, and 5 received anti-epidermal growth factor receptor therapy plus chemotherapy; 94 patients underwent surgery. The most frequent KRAS mutation locations were G12A (33.8%), G12D (21.4%), and G12V (21.4%). Compared with other locations, patients with a G12S mutation had the shortest median OS (10.3 [95% CI, 2.5-18.0] months). OS was longer in patients who underwent surgery versus those who did not, with a trend toward prolonged survival with bevacizumab (median OS 26.7 [95% CI, 21.8-31.7] months) versus chemotherapy alone (median OS 23.2 [95% CI, 19.4-27.0] months). Conclusion These findings confirm that KRAS mutation location may predict survival outcomes in patients with mCRC, and suggest that pre-/post-operative bevacizumab plus metastasectomy provides survival benefits in patients with KRAS mutations.

Efficacy and Safety of Liver Chemoembolization Procedures, Combined with FOLFIRI Chemotherapy, in First-Line Treatment of Metastatic Colorectal Cancer in Patients with Oncogene Mutations

“…In cases of inoperable metastases from colorectal cancer, a breakthrough that has increased the effectiveness of first- and second-line systemic chemotherapy is the inclusion of monoclonal antibodies (anti-EGRF or anti-VEGF) [ 10 , 11 ]. A KRAS (Kirsten rat sarcoma viral oncogene)-activating mutation is a potent mechanism of resistance to EGFR inhibitors and occurs in around 40% of patients with advanced CRC, having a negative impact on overall survival (OS) [ 12 ]. BRAF -mutated metastatic CRCs (mCRCs) are also associated with poorer survival outcomes and higher rates of distant lymph node metastases [ 13 ].…”

Recent Advances in Therapeutic Strategies to Improve Colorectal Cancer Treatment

“…The most frequent KRAS mutations in CRC occur at codon 12 (75%), while activating mutations at codon 13 (23%) and codon 61 (2%) also occur [ 66 ]. In general, activating KRAS mutations in mCRC are associated with accelerated metastatic progression [ 67 ] and relatively poor outcomes with G12S mutations associated with a particularly high mortality rate [ 68 ]. Challenges in targeting KRAS through direct targeting of the GTP binding pocket include the high affinity for its native substrate GTP, which is abundant in cancer cells [ 69 ].…”