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Comprehensive Clinical and Molecular Characterization of KRAS G12C-Mutant Colorectal Cancer
Jason T Henry1, Oluwadara Coker1, Saikat Chowdhury2
1Department of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX.
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.
Insights
Metastatic colorectal cancer patients with KRAS p.G12C mutations show poor progression-free survival and worse overall survival. This highlights innate chemotherapy resistance in this KRAS G12C population.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- KRAS p.G12C mutations are present in approximately 3% of metastatic colorectal cancers (mCRC).
- Emerging KRAS p.G12C inhibitors show promise, necessitating characterization of this patient subgroup.
- Limited data exists on the clinical behavior and molecular landscape of KRAS p.G12C-mutated mCRC.
Purpose of the Study:
- To analyze the clinical characteristics, survival outcomes, and molecular features of patients with KRAS p.G12C-mutated mCRC.
- To establish a historical comparator cohort for ongoing and future clinical trials targeting KRAS p.G12C.
Main Methods:
- Retrospective analysis of 187 patients with KRAS p.G12C-mutated colorectal cancer from MD Anderson Cancer Center (2003-2019).
- Comparison of clinical characteristics, overall survival (OS), and progression-free survival (PFS) against KRAS non-G12C patients.
- Assessment of immune signatures, gene expression, methylation, co-occurring mutations, and proteomics in internal and external datasets.
Main Results:
- KRAS p.G12C mutations were identified in 2.9% of 4,632 profiled mCRC patients.
- Median PFS for first-line chemotherapy in de novo metastatic patients was 6.4 months.
- KRAS p.G12C patients exhibited higher basal EGFR activation and worse OS compared to KRAS non-G12C patients.
Conclusions:
- Patients with KRAS p.G12C mCRC experience poor PFS and worse OS, indicating innate chemotherapy resistance.
- This study provides crucial data characterizing the KRAS p.G12C population for future therapeutic strategies.
- Findings serve as a vital historical benchmark for evaluating novel KRAS p.G12C-targeted therapies.
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