A comprehensive genomic profiling study involving more than 13,000 patients has shown that targetable G12C mutations in the KRAS oncogene are rare in genitourinary cancers, potentially limiting the role of routine testing and targeted treatment in these malignancies.
KRAS G12C accounts for approximately 12–15% of all KRAS-mutated cancers and most commonly occurs in non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and pancreatic cancer, explain Kelly Crane, MD, from the Department of Urology at SUNY Upstate Medical University in Syracuse, and co-authors in Oncotarget.
The mutation has emerged as an important therapeutic target following the development of inhibitors such as sotorasib, which is approved by the U.S. Food and Drug Administration for KRAS G12C-mutated NSCLC and metastatic colorectal cancer.
However, the prevalence and clinicogenomic characteristics of KRAS G12C alterations in genitourinary malignancies have been less well studied, despite the availability of targeted therapies.
Crane and colleagues therefore used comprehensive genomic profiling to characterize the KRAS G12C mutations across genitourinary cancers and assess their potential as therapeutic targets.
The researchers analyzed tumor specimens from 13,654 patients with genitourinary cancers, including 1453 renal clear cell carcinomas (RCCC), 3879 urothelial bladder carcinomas (UBC), and 8322 prostate acinar adenocarcinomas (PAAC).
Overall, they identified KRAS genomic alterations in 367 (2.7%) specimens, with the KRAS G12C variant detected in 25 (0.2%) of the samples.
Corresponding author K. R. Seetharam Bhat, MBBS, who is affiliated with the Department of Urology at SUNY Upstate Medical University and Upstate Urology at MVHS, told Inside Precision Medicine that this prevalence was lower than the researchers had hoped.
He also noted that it was lower than other targetable mutations used in treatment planning, pointing out that BRCA, which can be targeted with PARP inhibitors, has a prevalence of 10–13% in breast cancer.
Bhat commented: “Even though KRAS G12C is easy to test for, in our cohort we did not find the prevalence to be significant enough to recommend routine testing.”
“If it had been higher we could have considered treatment with sotorasib,” he said, suggesting that it may be offered off label, after discussion with a tumor board, to rare patients who are known to carry the mutation.
Among the individual cancer types, KRAS alterations occurred in seven (<1%) RCCC cases, 202 (5.2%) UBC cases, and 158 (1.9%) PAAC cases. There were no KRAS G12C variants detected RCCC specimens, 24 detected in UBC, accounting for 12% of all KRAS mutations in UBC, and one detected in PAAC.
Further analysis of the samples from patients with UBC, showed showed that the most common co-mutations with KRAS G12C occurred in TP53, CDKN2A, TERT, CDKN2B, and KDM6A.
Furthermore, patients harboring KRAS G12C-positive had significantly lower levels of TERT co-mutations and significantly higher levels of KDM6A alterations compared than those who were KRAS G12C-negative.
Crane and co-authors conclude that, despite the low prevalence, “the growing therapeutic relevance and potential for enrollment in basket-type clinical trials utilizing novel anti-KRAS G12C therapeutic agents warrants additional study of these alterations in genitourinary malignancies. This holds particular significance for bladder and prostatic carcinomas.”
They add that although “these novel therapeutic approaches may not prove beneficial for the majority of patients with [genitourinary] malignancies, they may become integral in managing the subset of patients harboring the KRAS G12C alteration.”
