KRAS G12C Mutations Have a Different Distribution Pattern in Asian Patients Compared with White Patients

Cancer develops through mutations in tumor suppression genes and oncogenes that cause cancer cells to proliferate and to be resistant to cell death.¹ Identifying the mutations that occur during the development of cancer is important, as doing so can determine the appropriate therapies, clinical management, and overall patient prognosis.¹ One oncogene that drives multiple cancer types, including non–small-cell lung cancer (NSCLC), colorectal cancer, and pancreatic ductal adenocarcinoma, is the Kirsten rat sarcoma (KRAS) gene.¹ The KRAS gene regulates cell growth by binding to GTP, a KRAS-activating molecule, converting it to GDP, which inactivates the protein.¹

The KRAS G12 mutation is the predominant KRAS mutation in cancer, representing 89% of these cases.¹ In NSCLC, the KRAS G12C mutation is the most common mutation type.¹ Treatments have been developed that bind to and inhibit the action of the KRAS G12C mutation, but many patients do not respond well to these drugs due to cancer cell resistance caused by molecular, cellular, or genetic processes.¹ Adding to this drug resistance, NSCLC is typically diagnosed at an advanced stage, leading to high patient mortality.² The prevalence of KRAS G12C in all cancer types varies according to patient sex and ethnic group. This variation may influence the outcome of clinical trials. At the European Society for Medical Oncology Congress 2021, Zhang and colleagues presented the results of a study that used next-generation sequencing to determine the prevalence of KRAS G12C mutations in 41,913 Chinese cancer patients. Researchers identified 911 patients with this mutation. Although most of the patients (732) had lung cancer, the study also included 118 patients who had colorectal cancer. The mutation was also found in small numbers of patients with pancreatic cancer, biliary tract cancer, gastric cancer, hepatocellular carcinoma, and brain tumors. They also found the mutation in 2 males with sarcoma, 1 male with melanoma, and in 1 male with renal pelvis carcinoma. The mutation occurred in 3 females with uterine cancer and 1 female patient each with esophageal carcinoma, peritoneal carcinoma, cervical carcinoma, and squamous-cell carcinoma of the sphenoid sinus.

The investigators next compared 32,138 patients from the American Association for Cancer Research (AACR) GENIE registry with these patients. The AACR GENIE registry indicated white female patients had a higher frequency of occurrence of the KRAS G12C gene than in white male patients with NSCLC or colorectal cancer. The results from this study indicated that Chinese male lung cancer patients (4.85%) were more likely to have a KRAS G12C mutation than Chinese female patients (1.19%). For Chinese colorectal patients there was no statistical difference between male and female patients.

KRAS G12C mutations are common in Chinese patients with lung and colorectal cancer but have a different distribution in Asian populations in various cancer types.

Source

Zhang Y, Li X, Liu C, et al. Distribution of KRAS G12C somatic mutations in 41,913 Chinese cancer patients. Ann Oncol. 2021;32(S5):S1220.

References

1. Liu J, Kang R, Tang D. The KRAS-G12C inhibitor: activity and resistance [published online ahead of print September 1, 2021]. Cancer Gene Ther. https://doi.org/10.1038/s41417-021-00383-9.
2. Uras IZ, Moll HP, Casanova E. Targeting KRAS mutant non-small-cell lung cancer: past, present and future. Int J Mol Sci. 2020;21:4325.