Hepatic resection is currently the only treatment option that can offer, together with perioperative chemotherapy, a chance of long-term survival in patients with colorectal liver metastases (CRLM), resulting in 5-year survival rates of 40% ^[1][2][1,2], and exceeding 50% in selected patients ^[3][4][5][3,4,5]. Several clinico-pathologic factors have been used to assess prognosis following liver resection for CRLM ^[4][6][4,6]. However, it has been showed that these factors, often do not represent the biological heterogeneity of CRLM and are not adequate for predicting long-term outcome.

In the current era of targeted therapies and personalized medicine, molecular biomarkers have been studied as fundamental prognostic predictors that guide the type of chemotherapy and define a better selection of patients for surgery [7]. The KRAS oncogene is currently the most used molecular biomarker in patients with CRLM [8]. This mutation occurs in about 38% of colorectal tumors and in 15–35% of patients with resectable CRLM, involving mainly codons 12 and 13 in more than 95% of cases [9]. A mutation in KRAS is associated with resistance to treatment with epidermal growth factor receptor (EGFR) antibodies, showing a lower response rate to therapy. For this reason, KRAS mutation is associated with lower overall and disease-free survival following liver resection and with higher risk of relapse in the lungs ^[10][11][10,11].

However, it has been showed that resistance to anti-EGFR therapy may also occur among patients without KRAS mutation in colorectal tumors (KRAS wild-type). The discordance of KRAS mutation status between the primary colorectal tumor and the corresponding CRLM may represent a possible explanation for the resistance to monoclonal antibodies targeted therapies.

Generally, metastases have similar mutations to those of the corresponding colorectal primary tumor. For these reasons, in the clinical practice, the KRAS mutation status information is generally obtained from primary colorectal tumor (surgical resection or biopsy). However, if KRAS mutation status of primary tumor may be representative of the corresponding CRLM mutational pattern, is debatable. Indeed, additional mutations may occur, determining the heterogeneity between primary tumor and CRLM. It has been hypothesized that primary tumor and the corresponding CRLM may show a discrepancy in mutational pattern. This event may represent the predominant cause of resistance to therapy. In this situation, it is clear that the only evaluation of KRAS mutation status in primary colorectal tumor may be inadequate to predict response to anti-EGFR therapy of the corresponding CRLM and may provide limited information prior to multimodal treatment. Several studies have been published focusing on the incidence of discordance between primary colorectal tumor and metastases, with controversial results. Some studies reported 100% of concordance ^[12][13][12,13]. On the other hand, several studies have reported different rates of discordance, ranging from 4 to 32% ^{[14][15][16][17][18][19]}[14,15,16,17,18,19]. This heterogeneity of results may be due to the bias of inclusion criteria in several studies, where the KRAS mutation status of primary tumor is compared with a wide variety of metastatic sites.

2. Incidence of KRAS Mutation

Among the 107 patients, 33 (30.8%) had a KRAS mutation in the primary tumor and 36 (33.6%) had a KRAS mutation in the corresponding CRLM (Table 12). The most frequent mutations were found in codon 12. Type of KRAS mutations were not significantly different between primary tumors and CRLM (Table 12).