KRAS codon 12 mutations linked to worse survival with colorectal liver metastasis

Last Updated: 2015-06-10

By Will Boggs MD

NEW YORK (Reuters Health) - Certain KRAS codon 12 mutations are associated with worse overall survival in people with colorectal liver metastasis (CRLM), according to a retrospective study.

"Our results showed that specifically G12V and G12S confer an unfavorable prognosis while other mutations such as codon 13 ones do not," Dr. Timothy M. Pawlik from The Johns Hopkins University School of Medicine in Baltimore, Maryland, told Reuters Health. "We suspect that different activating KRAS point mutations activate different downstream signaling pathways that in turn confer variable biologic tumor behaviors."

"Till now KRAS mutations in CRLM were viewed as a uniform cohort," he explained. "Our study aimed to discover if specific KRAS mutations impact differently on the long-term survival of patients who underwent resection of CRLM."

Dr. Pawlik's team analyzed data about specific mutations in the KRAS (Kirsten rat sarcoma viral oncogene homolog) gene for 331 patients who underwent curative-intent hepatic resection for CRLM.

They detected KRAS codon 12 mutations in 67 patients (20.2%) and KRAS codon 13 mutations in 24 patients (7.3%). Codon 12 mutations included G12V in 32.8% of cases, G12D in 37.3%, G12S in 10.4%, and G12A in 6.0%.

Median overall survival was shorter in patients with KRAS mutations than in patients with wild-type KRAS (32.4 months vs. 58.5 months, p=0.02), and five-year overall survival rates were lower in patients with codon 12 mutations than in patients with wild-type KRAS (34.4% vs.46.9%, p<0.05).

KRAS codon 12 mutations were independently associated with worse overall survival after controlling for other competing risk factors.

The long-term risk of death was 78% higher with G12V mutations and 3.33 times higher with G12S mutations, compared with wild-type KRAS.

Among the six most common KRAS codon 12 and 13 mutations, none was significantly associated with worse recurrence-free survival, the researchers report in JAMA Surgery, online June 3.

"Our study showed that certain KRAS activating mutations have an impact on long-term survival while others have not," Dr. Pawlik said. "That means we have made a step towards a more refined and precise prognosis of patients with CRLM."

"Identifying those more-homogenous subsets of patients is the first step towards shaping more individualized treatment strategies," Dr. Pawlik said. "However, our results should be further validated before translating to treatment decisions in clinical practice."

Dr. Des Winter from University Hospital, Dublin, Ireland, who wrote an invited commentary on the study, said he believes determination of tumor molecular biology will improve cancer care over the next decade.

"Professor Pawlik's team has shown how," he told Reuters Health by email.

"Despite a greater understanding of molecular biological processes, our therapeutic options in metastatic colorectal cancer remain somewhat limited," he added. "The primacy of solid tumor extirpation remains the keystone of colon and rectal cancer care, but approximately half of patients will have hepatic secondaries. Although never submitted to randomized trial, a criticism often leveled at liver resection, it is hard to argue against the improved survival observed following successful surgery."

Dr. Yeul Hong Kim from Korea University College of Medicine's department of medical oncology in Seoul also called for validation of the new results.

"The prognostic difference of each KRAS mutation needs to be validated with more large scale prospective clinical trials," Dr. Kim told Reuters Health by email. "Since we do not have a therapeutic strategy to overcome the poor outcome developed by specific mutation of KRAS, I would not treat a patient differently. Furthermore, the molecular pathway of KRAS has very complex communications with downstream or upstream genes, including BRAF, MEK, PIK3CA, etc."

Dr. Nancy E. Kemeny from Memorial Sloan-Kettering Cancer Center in New York agreed: "We do not change how we treat KRAS-mutated patients, but we are more careful on follow-up because there is some suggestion that KRAS-mutated patients are more likely to have more recurrence outside of the liver, especially in the lung."

"KRAS mutations should be used in stratification when doing randomized trials after liver resection," she added.

SOURCE: http://bit.ly/1dvYYGP and http://bit.ly/1L18DDw

JAMA Surg 2015.