Comprehensive Clinical and Molecular Characterization of KRAS^G12C-Mutant Colorectal Cancer

Abstract

PURPOSE KRAS p.G12C mutations occur in approximately 3% of metastatic colorectal cancers (mCRC). Recently, two allosteric inhibitors of KRAS p.G12C have demonstrated activity in early phase clinical trials. There are no robust studies examining the behavior of this newly targetable population. METHODS We queried the MD Anderson Cancer Center data set for patients with colorectal cancer who harbored KRAS p.G12C mutations between January 2003 and September 2019. Patients were analyzed for clinical characteristics, overall survival (OS), and progression-free survival (PFS) and compared against KRAS nonG12C. Next, we analyzed several internal and external data sets to assess immune signatures, gene expression profiles, hypermethylation, co-occurring mutations, and proteomics. RESULTS Among the 4,632 patients with comprehensive molecular profiling, 134 (2.9%) were found to have KRAS p.G12C mutations. An additional 53 patients with single gene sequencing were included in clinical data but excluded from prevalence analysis allowing for 187 total patients. Sixty-five patients had de novo metastatic disease and received a median of two lines of chemotherapy without surgical intervention. For the first three lines of chemotherapy, the median PFS was 6.4 months (n = 65; 95% CI, 5.0 to 7.4 months), 3.9 months (n = 47; 95% CI, 2.9 to 5.9 months), and 3.0 months (n = 21; 95% CI, 2.0 to 3.4 months), respectively. KRAS p.G12C demonstrated higher rates of basal EGFR activation compared with KRAS nonG12C. When compared with an internal cohort of KRAS nonG12C, KRAS p.G12C patients had worse OS. CONCLUSION PFS is poor for patients with KRAS p.G12C metastatic colorectal cancer. OS was worse in KRAS p.G12C compared with KRAS nonG12C patients. Our data highlight the innate resistance to chemotherapy for KRAS p.G12C patients and serve as a historical comparator for future clinical trials.

The Prognostic Effect of KRAS Mutations in Non-Small Cell Lung Carcinoma Revisited: A Norwegian Multicentre Study

“…Another limitation is that we did not perform any additional molecular analyses to explore differences in expression of the main targets of the mutant Ras proteins. In a recent study of patients with KRAS G12C mutated colon cancer, it was shown that comprehensive analyses of gene expression profiles, co-occurring alterations of other genes and protein expression might shed light on the involvement of signalling pathways [ 36 ].…”

KRAS-G12C Mutation in One Real-Life and Three Population-Based Nordic Cohorts of Metastatic Colorectal Cancer

“…The importance of different KRAS mutations on the clinical behavior of metastatic CRC (mCRC) has been explored, and differences have been reported (9). The clinical relevance of KRAS-G12C is unclear (10)(11)(12)(13)(14)(15)(16)(17). The frequency of KRAS-G12C has been reported to be 2%-8% in large databases of molecularly analyzed CRCs (12,14,18,19).…”

“…The frequency of KRAS-G12C has been reported to be 2%-8% in large databases of molecularly analyzed CRCs (12,14,18,19). In hospital-based series, the proportion of KRAS-G12C tumors was 2%-4% of all mCRC tumors (11,15,16,20), whereas greater variability was seen in the proportion of the KRAS-mutated population (6%-17%) (11,13,16,17,(20)(21)(22). Sex-and age-related differences and differences in the metastatic pattern have been reported between different KRAS mutations, with no consistent results (12,13,22).…”

More than FOLFOX and FOLFIRI: The Management of Metastatic Colorectal Cancer in the Era of Precision Oncology

“…65 Interestingly, patients with KRAS G12C-mutated mCRC seem to present poorer clinical outcomes compared with the patients with KRAS non-G12C mutations. 66,67 A recent singleinstitutional study identified 187 patients with KRAS G12C from an original population of 4,685 patients with mCRC. 66 When compared to a cohort of 720 patients with KRAS non-G12C mutations, these 187 patients had shorter OS, excluding patients who had undergone metastasectomy: 21.2 months versus 31.6 months (p=0.003).…”

“…66,67 A recent singleinstitutional study identified 187 patients with KRAS G12C from an original population of 4,685 patients with mCRC. 66 When compared to a cohort of 720 patients with KRAS non-G12C mutations, these 187 patients had shorter OS, excluding patients who had undergone metastasectomy: 21.2 months versus 31.6 months (p=0.003). Another cohort of 839 patients with mCRC also found an inferior OS in G12C population compared with the non-G12C: 25.9 months versus 35.8 months (HR: 1.55; 95% CI: 1.08-2.24; p=0.018), which was confirmed by multivariate analysis (HR: 1.81; 95% CI: 1.20-2.70; p=0.04).…”