A study evaluating the genetic landscape of candidate primary resistance alterations relevant to KRAS targeting in KRAS G12C–mutant colorectal cancers and pancreatic ductal adenocarcinomas (PDAC) has found that putative resistance alterations are prevalent in these cancers. The finding may explain the limited efficacy of KRAS G12C inhibitor monotherapy and the importance of sequencing KRAS G12C tumors for co-occurring resistance alterations. The study was published by Jazieh et al in Clinical Cancer Research.
Background
Studies have shown that the KRAS G12C mutation is present in approximately 3% of patients with colorectal cancer and between 1% and 2% of patients with advanced pancreatic cancer. Although KRAS G12C inhibitors such as sotorasib and adagrasib have demonstrated some efficacy in patients whose cancers harbor this mutation, many of these cancers are resistant to therapy despite the absence of prior exposure to KRAS-directed therapy.
Study Methodology
Researchers analyzed circulating tumor DNA (ctDNA) data from a total of 14,344 patients with colorectal cancer (13,603 from de-identified national data sets and 741 from the Mayo Clinic) and 5,438 patients with pancreatic ductal adenocarcinoma (5,016 from de-identified national data sets and 422 from the Mayo Clinic). The tumors were tested using next-generation sequencing of ctDNA via Guardant360. The patient cohorts were divided into three groups: KRAS G12C alone (KRAS G12C without a resistance gene); KRAS G12C with resistance (KRAS G12C and at least one candidate resistance gene), and KRAS not detected. Candidate resistance mutations were inferred from the reported literature.
Key Results
The researchers found that among the national (13,603 patients with colorectal cancer and 5,016 patients with pancreatic cancer) and Mayo (741 patients with colorectal cancer and 422 patients with pancreatic cancer) cohorts, resistance alterations were identified in a considerable number of patients with KRAS G12C (46.5% of national colorectal cancer, 16.4% of national pancreatic cancer, 53.8% of Mayo Clinic colorectal cancer, and 36.4% of Mayo pancreatic cancer). The presence of resistance alterations was associated with a trend toward worse overall survival in KRAS G12C–positive colorectal cancer (P = .05).
“Putative resistance alterations are prevalent in PDAC and colorectal cancer and may limit monotherapy efficacy. Identifying these alterations has potential implications in optimal patient selection for targeted therapies and the development of combination therapy strategies to overcome primary resistance,” concluded the study authors.
Translational Relevance
“These other co-occurring mutations associated with poor prognosis may serve as cellular adaptation and primary resistance mechanisms, and may explain the limited efficacy of KRAS G12C inhibitor monotherapy,” said Hao Xie, MD, PhD, a medical oncologist at the Mayo Clinic Comprehensive Cancer Center in Rochester, Minnesota, and principal investigator of this study, in a statement. “Their presence also indicates the higher level of tumor heterogeneity in colorectal and pancreatic cancers and emphasizes the importance of sequencing tumors with the KRAS G12C mutation for co-occurring resistance alterations. KRAS G12C inhibitors are very promising, but they are not a panacea for these types of cancers. Patients and their doctors need to be aware of the current limitations.”
Dr. Xie, a medical oncologist at the Mayo Clinic Comprehensive Cancer Center, is the corresponding author of this study.
Disclosure: Funding for this study was provided by the Mayo Clinic Norma Lee and Morton Funger Clinician Career Development Fund Award in Colon Cancer Research, the Mayo Clinic Center for Clinical and Translational Science and Center for Biomedical Discovery Pilot Awards for Team Science, a Mayo Clinic Clinical and Translational Science Award from the National Center Advancing Translational Sciences, and the Mayo Clinic Department of Oncology FORIT Award. For full disclosures of the study authors, visit aacrjournals.org.
