KRAS Mutation Is Associated with Lung Metastasis in Patients with Curatively Resected Colorectal Cancer

Abstract

Purpose: Oncogene mutations contribute to colorectal cancer development. We searched for differences in oncogene mutation profiles between colorectal cancer metastases from different sites and evaluated these as markers for site of relapse.Experimental Design: One hundred colorectal cancer metastases were screened for mutations in 19 oncogenes, and further 61 metastases and 87 matched primary cancers were analyzed for genes with identified mutations. Mutation prevalence was compared between (a) metastases from liver (n ¼ 65), lung (n ¼ 50), and brain (n ¼ 46), (b) metastases and matched primary cancers, and (c) metastases and an independent cohort of primary cancers (n ¼ 604). Mutations differing between metastasis sites were evaluated as markers for site of relapse in 859 patients from the VICTOR trial.Results: In colorectal cancer metastases, mutations were detected in 4 of 19 oncogenes: BRAF (3.1%), KRAS (48.4%), NRAS (6.2%), and PIK3CA (16.1%). KRAS mutation prevalence was significantly higher in lung (62.0%) and brain (56.5%) than in liver metastases (32.3%; P ¼ 0.003). Mutation status was highly concordant between primary cancer and metastasis from the same individual. Compared with independent primary cancers, KRAS mutations were more common in lung and brain metastases (P < 0.005), but similar in liver metastases. Correspondingly, KRAS mutation was associated with lung relapse (HR ¼ 2.1; 95% CI, 1.2 to 3.5, P ¼ 0.007) but not liver relapse in patients from the VICTOR trial.Conclusions: KRAS mutation seems to be associated with metastasis in specific sites, lung and brain, in colorectal cancer patients. Our data highlight the potential of somatic mutations for informing surveillance strategies.

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

“…Some clinical series have also shown that KRAS mutations are associated with an increased risk of developing lung and liver metastases compared to wild-type population (Vauthey et al, 2013;Kemeny et al, 2014). Others have shown a higher incidence of lung metastases/recurrence than liver metastases/recurrence in KRAS mutated patients (Vauthey et al, 2013;Tie et al, 2011;Kim et al, 2012). Even if KRAS mutations rate in CLM usually corresponds with the mutation status of the primary tumor (Tie et al, 2011;Vakiani et al, 2012), it seems to be different among different metastatic sites, with a higher percentage of mutations in lung and brain metastases, than in liver metastases (Tie et al, 2011;Kim et al, 2012), suggesting specific RAS-related patterns of recurrence, with potential implication in the clinical management of CRC patients, but these trends need to be investigated in larger, prospective studies.…”

“…Others have shown a higher incidence of lung metastases/recurrence than liver metastases/recurrence in KRAS mutated patients (Vauthey et al, 2013;Tie et al, 2011;Kim et al, 2012). Even if KRAS mutations rate in CLM usually corresponds with the mutation status of the primary tumor (Tie et al, 2011;Vakiani et al, 2012), it seems to be different among different metastatic sites, with a higher percentage of mutations in lung and brain metastases, than in liver metastases (Tie et al, 2011;Kim et al, 2012), suggesting specific RAS-related patterns of recurrence, with potential implication in the clinical management of CRC patients, but these trends need to be investigated in larger, prospective studies. 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).…”

Somatic mutation profiles in primary colorectal cancers and matching ovarian metastases: Identification of driver and passenger mutations

“…KRAS mutations in CRC were found to be associated with lung metastases 21. CRCs with a wild type KRAS status showed more frequent liver and distant lymph node metastases 22.…”

Brain metastasis in advanced colorectal cancer: Results from the South Australian metastatic colorectal cancer (SAmCRC) registry

“…Other authors have proposed an opposite theory whereby different molecular features of the cancer explain the pattern of brain metastases. Across the literature, KRAS mutations in mCRC correlate with poor OS and increased incidence of both lung and brain metastases [20][21][22] . In our study, noting the small number in whom the KRAS mutation status was known, 55% of patients with brain metastases presented with KRASmutated cancers compared to 43% of the overall population, in keeping with this hypothesis.…”