Comprehensive Clinical and Molecular Characterization of KRASG12C-Mutant Colorectal Cancer
| Autor: | Jason Henry, David S. Hong, Saikat Chowdhury, Bryan K. Kee, Oluwadara Coker, Van K. Morris, Nikeshan Jeyakumar, Benny Johnson, Shubham Pant, Christine Megerdichian Parseghian, Jean Nicolas Vauthey, John Paul Shen, David R. Fogelman, Maliha Nusrat, Scott Kopetz, Michael J. Overman, Arvind Dasari, Yujiro Nishioka, Robert A. Wolff, Kanwal Pratap Singh Raghav, Limin Zhu |
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| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Cancer Research Colorectal cancer business.industry Allosteric regulation Mutant medicine.disease medicine.disease_cause 03 medical and health sciences 030104 developmental biology 0302 clinical medicine Text mining Oncology 030220 oncology & carcinogenesis Cancer research medicine KRAS Early phase business neoplasms |
| Zdroj: | JCO Precision Oncology. :613-621 |
| ISSN: | 2473-4284 |
| DOI: | 10.1200/po.20.00256 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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