Association of KRAS Variants With Outcomes After Curative Resection of Intrahepatic Cholangiocarcinoma

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In a Chinese single-institution cohort study reported in JAMA Surgery, Zhou et al found that the presence of somatic G12 KRAS variants was associated with poorer overall and disease-free survival in patients who had undergone curative resection of intrahepatic cholangiocarcinoma.

Study Details

The study included 1,024 patients who underwent curative resection at Zhongshan Hospital, Fudan University, Shanghai, between January 2009 and December 2016. Patients receiving palliative procedures or prior interventions (eg, transhepatic artery embolization, chemotherapy, or radiotherapy) or with other primary malignancies and inflammatory diseases during follow-up were excluded from the study.

Whole-exome sequencing, targeted sequencing, and Sanger sequencing were performed to identify somatic KRAS variants. The primary outcome measure was the association of KRAS variant subtypes with overall and disease-free survival.

Key Findings

The median follow-up was 53.4 months (interquartile range = 36.8–74.3 months). A total of 14 different subtypes of KRAS variants in 127 patients (12.4%) were identified. The most common alleles were G12D (n = 55, 43.3%), G12V (n = 25, 19.7%), G12C (n = 9, 7.1%), and G13D (n = 8, 6.3%). Compared with patients with wild-type KRAS, those KRAS variants were more likely to have high levels of carbohydrate antigen 19-9 (72.4% vs 60.9%, P = .01) and γ-glutamyl transferase (56.7% vs 46.8%, P = .04).

Among all patients, the presence of KRAS variants vs wild-type KRAS was associated with poorer overall survival (hazard ratio [HR] = 1.70, 95% confidence interval [CI] = 1.36–2.11, P < .001) and disease-free survival (HR = 1.54, 95% CI = 1.25–1.90, P < .001). Among patients with KRAS variants, median overall survival (11.3 vs 29.1 months, P = .009) and disease-free survival (9.3 vs 20.9 months, P = .003) were poorer in those with G12 vs non-G12 variants. Median overall (28.9 months) and disease-free survival (16.2 months) in patients with wild-type KRAS were similar to those in patients with non-G12 variants.

On multivariate analysis, the presence of G12 KRAS variants but not non-G12 variants was associated with poorer overall survival (HR = 1.69, 95% CI = 1.31–2.18, P < .001) and disease-free survival (HR = 1.47, 95% CI = 1.16–1.88, P = .002). Among patients with G12 variants, the G12V KRAS variant was associated with the poorest overall survival (HR = 3.05, 95% CI = 1.94–4.79, P < .001) and disease-free survival (HR = 1.79, 95% CI = 1.13–2.85, P = .01).

The investigators concluded: “In this cohort study, the distribution of KRAS variant subtypes was characterized in a large cohort of patients with [intrahepatic cholangiocarcinoma] from China. The presence of G12 KRAS variants but not non-G12 KRAS variants was associated with worse survival and increased risk of recurrence. Patients with the G12V variant exhibited the worst outcomes in the whole cohort.”

Shao-Lai Zhou, MD, PhD, and Jian Zhou, MD, PhD, of the Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, are the corresponding authors of the JAMA Surgery article.

Disclosure: The study was supported by the National Key R&D Program of China and National Natural Science Foundation of China. For full disclosures of the study authors, visit

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