<i>KRAS</i> A146 Mutations Are Associated With Distinct Clinical Behavior in Patients With Colorectal Liver Metastases.

Abstract

Somatic <i>KRAS</i> mutations occur in approximately half of the patients with metastatic colorectal cancer (mCRC). Biologic tumor characteristics differ on the basis of the <i>KRAS</i> mutation variant. <i>KRAS</i> mutations are known to influence patient prognosis and are used as predictive biomarker for treatment decisions. This study examined clinical features of patients with mCRC with a somatic mutation in <i>KRAS</i> G12, G13, Q61, K117, or A146. A total of 419 patients with colorectal cancer with initially unresectable liver-limited metastases, who participated in a multicenter prospective trial, were evaluated for tumor tissue <i>KRAS</i> mutation status. For the subgroup of patients who carried a <i>KRAS</i> mutation and were treated with bevacizumab and doublet or triplet chemotherapy (N = 156), pretreatment circulating tumor DNA levels were analyzed, and total tumor volume (TTV) was quantified on the pretreatment computed tomography images. Most patients carried a <i>KRAS</i> G12 mutation (N = 112), followed by mutations in G13 (N = 15), A146 (N = 12), Q61 (N = 9), and K117 (N = 5). High plasma circulating tumor DNA levels were observed for patients carrying a <i>KRAS</i> A146 mutation versus those with a <i>KRAS</i> G12 mutation, with median mutant allele frequencies of 48% versus 19%, respectively. Radiologic TTV revealed this difference to be associated with a higher tumor load in patients harboring a <i>KRAS</i> A146 mutation (median TTV 672 cm³ [A146] <i>v</i> 74 cm³ [G12], <i>P</i> = .036). Moreover, <i>KRAS</i> A146 mutation carriers showed inferior overall survival compared with patients with mutations in <i>KRAS</i> G12 (median 10.7 <i>v</i> 26.4 months; hazard ratio = 2.5; <i>P</i> = .003). Patients with mCRC with a <i>KRAS</i> A146 mutation represent a distinct molecular subgroup of patients with higher tumor burden and worse clinical outcomes, who might benefit from more intensive treatments. These results highlight the importance of testing colorectal cancer for all <i>KRAS</i> mutations in routine clinical care.