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TOPLINE:

Among patients with KRAS G12C mutations, candidate primary resistance mutations were detected in many patients with colorectal cancer (CRC) and pancreatic ductal adenocarcinoma (PDAC), which may limit the effectiveness of monotherapy with KRAS G12C inhibitors in this population. 

METHODOLOGY:

• KRAS G12C inhibitors have shown modest efficacy as monotherapy in patients with KRAS G12C–mutant advanced CRC and PDAC. This may be attributed, in part, to alterations present in other genes, such as NRAS, BRAF, MAP2K1, and PIK3CA, as well as other KRAS mutations, which could lead to resistance to KRAS G12C inhibitors.
• The current study evaluated the genetic landscape of potential resistance alterations in patients with KRAS G12C–mutant CRC and PDAC.
• Researchers analyzed data from patients in two cohorts: A national cohort involving 13,603 patients with CRC and 5016 patients with PDAC as well as a Mayo Clinic cohort involving 741 patients with CRC and 422 patients with PDAC. Patients had received next-generation sequencing of circulating tumor DNA via Guardant360.
• Patients in each cohort were divided into three groups: KRAS G12C alone (KRAS G12C without a resistance gene), KRAS G12C with resistance (KRAS G12C plus at least one candidate resistance gene), and KRAS not detected.

TAKEAWAY:

• Among patients with KRAS G12C mutations in the national cohort, candidate resistance alterations were identified in 46.5% of patients with CRC and 16.4% of those with PDAC. In the Mayo Clinic cohort, candidate resistance alterations were identified in 53.8% of patients with KRAS G12C–mutant CRC and 36.4% of those with KRAS G12C–mutant PDAC.
• The most common resistance alterations in patients with CRC included other KRAS alterations, EGFR amplification, PIK3CA and BRAF alterations, as well as MYC amplification. The most common resistance alterations in those with PDAC included KRAS and PIK3CA alterations as well as EGFR and MYC amplification.
• Patients with PDAC KRAS G12C resistance had significantly shorter overall survival (median, 4 months) vs those with KRAS G12C alone (median, 22 months) and with KRAS not detected (median, 25 months).
• Among those with CRC, the presence of KRAS G12C was associated with a trend toward worse overall survival (P = .054). Patients with KRAS not detected had longer median overall survival (48.8 months) than those with KRAS G12C resistance (30 months) and those with KRAS G12C alone (21.9 months).

IN PRACTICE:

Overall, alterations in genes, including KRAS, NRAS, BRAF, and PIK3CA, “may confer primary resistance to targeted therapy used to treat KRAS G12C–mutant colorectal cancer and PDAC,” the authors wrote. “Identifying these alterations has potential clinical implications in terms of selecting patients for KRAS G12C inhibitor, as well as developing strategies for combination therapy to overcome primary resistance.”

SOURCE:

This study, led by Khalid Jazieh, Mayo Clinic in Rochester, Minnesota, was published online on March 3 in Clinical Cancer Research.

LIMITATIONS:

This study was retrospective in nature and limited to liquid biopsies that depend on tumor shed, potentially affecting the findings. The subgroups with available clinical data were small, limiting analyses and generalizability of findings. Treatment information and clinical outcomes were only available for a subset of patients in the Mayo Clinic cohort, particularly affecting the Kaplan-Meier analysis for patients with PDAC.

DISCLOSURES:

This study received support from the Center for Clinical and Translational Science and the Center for Biomedical Discovery pilot awards for team science, Mayo Clinic CTSA grant, and Mayo Clinic Department of Oncology FORIT Award. Few authors reported having several ties with various sources.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.