Influence of KRAS mutation status in metachronous and synchronous metastatic colorectal adenocarcinoma

Abstract

BACKGROUND Mutations in the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) are present in approximately 30% to 40% of colorectal adenocarcinomas. Wild-type (WT) KRAS mutation status is predictive of tumor response with epidermal growth factor receptor-directed therapies, but the results from studies evaluating the prognostic value of KRAS status in localized disease have been contradictory. The prognostic value of KRAS in metastatic disease, specifically according to whether patients have synchronous or metachronous disease at presentation, is less understood. METHODS One-hundred ten consecutive patients with metastatic colorectal adenocarcinoma underwent testing for KRAS exon 2 mutations by polymerase chain reaction amplification and direct nucleotide sequencing. The clinical characteristics, treatments, and outcomes of these patients were then analyzed retrospectively, stratified according to whether patients presented with synchronous or metachronous metastasis and according to KRAS mutation status (WT or mutated). RESULTS For the entire cohort, the median overall survival from the date of diagnosis of metastatic disease was 34.3 months (95% confidence interval, 28.3–49.4 months) for patients with WT KRAS (n = 70). The median overall survival for patients with mutated KRAS (n = 40) was 40.3 months (95% confidence interval, 27.9–51.1 months; log-rank P = .91). Kaplan-Meier survival analysis indicated that 3-year overall survival and 5-year overall survival were not statistically different. Within the subgroups of patients with synchronous and metachronous metastatic disease, no significant differences were observed in median overall survival, 3-year overall survival, or 5-year overall survival between the WT KRAS and mutated KRAS groups. CONCLUSIONS In this study, KRAS mutation status did not influence overall survival in either synchronous or metachronous metastatic colorectal adenocarcinoma and, as such, had no prognostic role in this disease setting.

Prognostic Implication of KRAS Status after Hepatectomy for Colorectal Liver Metastases Varies According to Primary Colorectal Tumor Location

“…7,10 Others noted a correlation between mt-KRAS and only RFS or OS, while yet other reports have failed to find any association between KRAS status and long-term outcomes. 8,9,[11][12][13] Given the findings of the current study, the discrepant results from previous reports might be related to the lack of accounting for primary tumor location. As such, future studies examining the impact of KRAS status on prognosis after hepatectomy should take into account the primary CRC tumor site and distinguish between RS and LS tumors.…”

“…[11][12][13] Another factor that has been associated with varied prognostic, as well as potentially therapeutic, implications is the anatomic site of primary CRC. Specifically, several studies have noted that right-sided (RS) versus left-sided (LS) CRC differ in incidence, pathogenesis, genetic susceptibility to neoplastic degeneration, and oncologic outcomes.…”

Molecular testing in metastatic colorectal adenocarcinoma cytology cell pellets

“…3,4 Cetuximab and panitumumab are two EGFR antibodies that have been shown to improve overall survival in mCRC patients. 3,4 Cetuximab and panitumumab are two EGFR antibodies that have been shown to improve overall survival in mCRC patients.…”

“…For patients with activating mutations in the MAPK pathway, identification of either a RAS or RAF mutation determines eligibility for the addition of anti-EGFR therapy to their treatment regimen 3. For patients with activating mutations in the MAPK pathway, identification of either a RAS or RAF mutation determines eligibility for the addition of anti-EGFR therapy to their treatment regimen 3.…”

Oncoselectivity in Oncolytic Viruses against Colorectal Cancer

“…KRAS is activated when bound to GTP, which is (under normal conditions) converted to GDP by the removal of the γ (terminal) phosphate, returning the KRAS GTPase to its inactive state [138]. KRAS mutants can be constitutively active, resulting in continuous signal transduction through its downstream effector components and, ultimately, cellular survival, growth and proliferation uncoupled from EGFR activation [138]- [140].…”