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KRAS G12C Metastatic Colorectal Cancer: Specific Features of a New Emerging Target Population
Marta Schirripa1, Floriana Nappo2, Chiara Cremolini3
1Department of Oncology, Veneto Institute of Oncology IOV IRCCS, Padua, Italy.
Background:
Kirsten rat sarcoma viral oncogene (KRAS) G12C mutation occurs in about 4% of colorectal cancers (CRCs). Recently, KRAS G12C was identified to be a potential drug target and predictor of response to the novel on AMG510 target treatment. We described the clinicopathologic features and prognosis of KRAS G12C-mutated metastatic CRCs compared to other KRAS mutation.
Patients And Methods:
Clinicopathologic features and outcome data of KRAS-mutated metastatic CRC (mCRC) patients referred to 3 Italian oncology units from January 2010 to December 2018 were collected. A cohort of KRAS-mutant mCRC patients referred to the Department of Medical Oncology at Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (Italy) within the same time frame was included as external validation.
Results:
A total of 839 KRAS-mutated mCRC cases were included in the main patient population. A total of 145 patients (17%) had KRAS G12C mutation. Our analyses showed that patients harboring KRAS G12C mutation were more likely to be men and to present lung and liver metastases, and were less likely to have peritoneal spread. KRAS G12C mutation was associated with shorter overall survival compared to other KRAS mutations (hazard ratio, 1.32; 95% confidence interval, 1.07-1.63; P = .009). Such results were confirmed in the external validation cohort.
Conclusion:
The knowledge of the distinctive traits of KRAS G12C-mutated CRC patients is crucial to future translational research studies, clinical trial design, and proper interpretation of results.
Insights
The Kirsten rat sarcoma viral oncogene (KRAS) G12C mutation in colorectal cancer (CRC) is linked to specific patient traits and poorer survival. Understanding these features is vital for targeted therapies and clinical trial design.
Area of Science:
- Oncology
- Genetics
- Cancer Research
Background:
- The KRAS G12C mutation is present in approximately 4% of colorectal cancers (CRCs).
- KRAS G12C is recognized as a potential therapeutic target and a predictor of response to treatments like AMG510.
- This study investigates the characteristics and outcomes of metastatic CRCs with KRAS G12C mutations compared to other KRAS mutations.
Purpose of the Study:
- To delineate the clinicopathologic features of metastatic colorectal cancer (mCRC) patients with KRAS G12C mutations.
- To compare the prognosis of KRAS G12C-mutated mCRC with that of mCRC harboring other KRAS mutations.
- To provide insights for future research, clinical trials, and interpretation of results concerning KRAS G12C-mutated CRC.
Main Methods:
- Retrospective analysis of clinicopathologic and outcome data from KRAS-mutated mCRC patients across three Italian oncology centers (January 2010 - December 2018).
- Inclusion of an external validation cohort from a single institution (Fondazione IRCCS Istituto Nazionale dei Tumori, Milan) within the same timeframe.
- Statistical comparison of patient demographics, metastatic patterns, and overall survival between KRAS G12C-mutated and other KRAS-mutated mCRC groups.
Main Results:
- A total of 839 KRAS-mutated mCRC cases were analyzed, with 145 (17%) harboring the KRAS G12C mutation.
- Patients with KRAS G12C mutations were more frequently male and presented with lung and liver metastases, while less commonly exhibiting peritoneal spread.
- KRAS G12C mutation was significantly associated with shorter overall survival (HR, 1.32; 95% CI, 1.07-1.63; P = .009), a finding confirmed in the validation cohort.
Conclusions:
- KRAS G12C-mutated CRC exhibits distinct clinicopathologic features and a poorer prognosis compared to other KRAS mutations.
- Identifying these unique characteristics is crucial for advancing translational research in CRC.
- This knowledge will aid in designing more effective clinical trials and accurately interpreting study outcomes for KRAS G12C-mutated CRC.
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