Certain KRAS-variant subtypes tied to worse outcomes in intrahepatic bile duct cancer

Reuters Health - 16/11/2021 - In patients with intrahepatic cholangiocarcinoma (ICC) who underwent curative resection, G12 KRAS variants, especially G12V, were associated with worse survival and increased risk of recurrence in a Chinese cohort study.

For the single-center study, published in JAMA Surgery, researchers at Zhongshan Hospital and Fudan University in Shanghai performed whole-exome, targeted, and Sanger sequencing of samples from 1,024 patients (mean age, 59.2; 60.6% male) to identify KRAS variants.

Fourteen subtypes of KRAS somatic variants affecting 127 patients (12.4%) were identified.

G12D was the most frequent allele in the cohort, accounting for 55 of 127 (43.3%) variants. This was followed by G12V (19.7%), G12C (7.1%), and G13D (6.3%).

Compared with patients with wild-type KRAS, patients with variant KRAS were more likely to have high levels of carbohydrate antigen 19-9 (72.4% vs. 60.9%) and gamma-glutamyltransferase (56.7%] vs. 46.8%).

Multivariable analysis showed that G12 KRAS variants, but not non-G12 KRAS variants, were independently associated with worse overall survival (hazard ratio, 1.69) and disease-free survival (HR, 1.47).

Among those with G12 KRAS variants, the G12V KRAS variant was the strongest prognostic determinant for worst overall survival (HR, 3.05) and disease-free survival (HR, 1.79).

The paper's corresponding authors did not respond to requests for comment.

Dr. Neena Vijayvergia, Assistant Chief, Gastrointestinal Medical Oncology at Fox Chase Cancer Center in Philadelphia, told Reuters Health by email, "Interesting to see the rate of KRAS alterations reported by the group was much higher than expected for ICC (3-5 % TCGA data). The association of KRAS G12V mutations with survival is a novel finding, but the numbers are small."

"Since KRAS G12V mutations were associated with lymph node metastases, which in turn is a known strong prognostic variable, the clinical utility of such data is still lagging behind," she said. "But this provides a way forward and is hypothesis-generating to develop future studies."

Dr. Manmeet Ahluwalia, Deputy Director at Miami Cancer Institute, part of Baptist Health South Florida, commented by email, "This study highlights that there are differences in racial or etiological factors in patients from different ethnicities and backgrounds and it is critical that we perform more extensive molecular profiling in minorities, as most of the data in the Cancer Genome Atlas is derived from Caucasian patients."

"As KRAS is now an actionable mutation and is amenable to being targeted with therapies that are designed for the KRAS alterations, pursuit of specific inhibitors of G12DKRAS and G12VKRAS in a precision oncology approach for patients with ICC needs to be explored."

SOURCE: https://bit.ly/3281Rg2 JAMA Surgery, online November 3, 2021.

By Marilynn Larkin



Posted on 16 November 202121 December 2021