KRAS A146 Mutations Are Associated With Distinct Clinical Behavior in Patients With Colorectal Liver Metastases

Abstract

PURPOSE Somatic KRAS mutations occur in approximately half of the patients with metastatic colorectal cancer (mCRC). Biologic tumor characteristics differ on the basis of the KRAS mutation variant. KRAS 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 KRAS G12, G13, Q61, K117, or A146. METHODS 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 KRAS mutation status. For the subgroup of patients who carried a KRAS 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. RESULTS Most patients carried a KRAS 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 KRAS A146 mutation versus those with a KRAS 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 KRAS A146 mutation (median TTV 672 cm3 [A146] v 74 cm3 [G12], P = .036). Moreover, KRAS A146 mutation carriers showed inferior overall survival compared with patients with mutations in KRAS G12 (median 10.7 v 26.4 months; hazard ratio = 2.5; P = .003). CONCLUSION Patients with mCRC with a KRAS 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 KRAS mutations in routine clinical care.

Exploring Survival Outcomes in Metastatic Colorectal Cancer Harboring KRAS A146 Mutations: Important Distinction or Simple Distraction?

“…Erve et al 1 report an intriguing new prognostic association of KRAS-A146 mutations in metastatic colorectal cancer in their analysis of a cohort of patients with liver metastases, including 12 with the KRAS-A146 mutation. They reported a marked reduction in overall survival (median 10.7 v 26.4 months; hazard ratio = 2.5; P = .003), which was associated with an increased bulk of disease as measured by circulating tumor DNA and radiologically assessed total tumor volume.…”

Reply to R. Pham et al

“…We thank Pham et al for their letter to the editor, 1 which in several ways, echoes the key messages that we aimed to bring across in our article. 2 Indeed, our observation that KRAS A146 mutations are associated with distinct clinical behavior in patients with colorectal liver metastases is intriguing and warrants further investigation. This concerns both the molecular and biologic mechanisms affected by KRAS A146 mutations and their clinical consequences in patients with colorectal cancer (CRC).…”

“…7 Consequently, the proportion of KRAS A146 mutations identified among KRAS mutants in the TRACC registry is 3.9%, 1 which is only half of 7.8% described in our article and 7.9% described by others for patients with metastatic CRC. 2,8 These data imply that a significant proportion of 50% of patients with a KRAS A146 mutation is missing from the TRACC validation effort. It is unclear whether these missing KRAS A146–mutated patients represent a random subset or a patient subset enriched for individuals with the most advanced disease, which might cause selection bias and complicate validation efforts.…”

“…Therefore, in our opinion, the result presented by Pham et al emphasizes the final conclusion of our article, ie, the importance of testing CRC for all KRAS mutations in routine clinical care. 2…”

Somatic mutations in colorectal cancer: regional experience

“…Среди них ген KRAS принимает участие в сигнальных путях, обеспечивающих регуляцию клеточной пролиферации, дифференцировку и выживание. Соматические мутации KRAS при колоректальном раке встречаются в 35-50% случаев, достигая максимума при метастатическом опухолевом процессе [4][5][6][7].…”