SAN FRANCISCO – When it comes to KRAS mutational status, liver metastases originating from left-sided colon tumors have different clinical and survival characteristics from those originating from primary rectal tumors. There was no significant difference in survival between bearers of mutated versus wild-type (WT) KRAS in rectal tumor cases, while there was a significant difference in survival from left-sided colon cases, according to a first-time analysis of the effect of KRAS status in this specific population.
The work was presented at the annual clinical congress of the American College of Surgeons by Neda Amini, MD. “The liver metastasis originating from a rectal tumor might have a different biology than from a primary colon tumor, and we should have stratification according to the primary tumor location in clinical trials testing chemotherapy and targeted agents,” said Dr. Amini, who is a surgical resident at Sinai Hospital of Baltimore, during her presentation of the research.
“I thought that was interesting because most of the studies that have been done look at KRAS mutations in colorectal cancers, and [colon and rectal cancers] are two completely different entities,” said session comoderator Valentine Nfonsam, MD, associate professor of surgery at the University of Arizona, Tucson, in an interview. The findings could also impact clinical practice. “If a patient has rectal cancer, if they have a KRAS mutation, whether you treat them with cetuximab or not, the overall survival doesn’t really change. Whereas for colon cancer patients you really want to make that distinction. You want to truly personalize their therapy, because of the difference in survival in a patient with the KRAS mutation in colon cancer” Dr. Nfonsam said.
“It gets to the heart that there might be different biology between colon cancers and rectal cancers. It’s important to understand the differences in the basic biology, which affects the treatment and the surgery,” said the other comoderator, Jonathan Mitchem, MD, in an interview. Dr. Mitchem is an assistant professor at the University of Missouri–Columbia.
KRAS is common in colorectal cancer, occurring in 30% of cases, and multiple trials have shown it is associated with nonresponse to the epidermal growth factor receptor inhibitors cetuximab or panitumumab. All colorectal cancer patients with liver metastases should be screened for KRAS mutations, according to National Comprehensive Cancer Network guidelines.
The researchers conducted a retrospective analysis of 1,304 patients who underwent curative-intent surgery for colorectal liver metastases at nine institutions between 2000 and 2016. The KRAS mutation rate was similar in the primary colon and rectal tumors (34.2% vs. 30.9%; P = .24). The frequency was highest in right-sided colon tumors (39.4%). There was a statistically significant difference in the frequency of KRAS mutation between primary rectal tumors (30.9%), and left-sided colon tumors (21.1%; P = .001).
There were several differences in clinical characteristics between left-sided colon cancers and rectal cancers. Rectal cancer patients were more likely to be male (73.4% vs. 62.4%; P = .001); more likely to be stage T1-T2 (16.6% vs. 10.6%; P = .012); less likely to have serum carcinoembryonic antigen greater than 100 ng/mL (8.4% vs. 14.1%; P = .018); and less likely to have a liver metastasis under 3 cm (36.1% vs. 49.3%).
There were significant differences between KRAS mutant and KRAS wild-type patients with a colon primary tumor, including greater likelihood of lymph node metastasis in WT (65.2% vs. 55.37%; P = .004), greater likelihood of liver metastasis greater than 3 cm in WT (48.8% versus 39.3%; P = .01), greater likelihood of extrahepatic disease in mutant KRAS (16.3% vs. 10.4%; P = .01), greater likelihood of prehepatic resection chemotherapy in WT (65.5% vs. 56.0%; P = .005), greater likelihood of posthepatic resection chemotherapy in mutant KRAS (64.5% vs. 55.5%; P = .01), and greater likelihood of receiving anti–epidermal growth factor therapy in WT (5.7% vs. 0.3%; P less than .001). The only difference seen in patients with rectal primary tumors was the odds of receiving post-hepatic surgery chemotherapy, which was higher among patients with mutated KRAS (70.8% vs. 59.0%; P = .03).
After a median follow-up of 26.4 months, the 1-, 3-, and 5-year overall survival rates were 88.9%, 62.5%, and 44.5%. Among patients with primary colon cancer, there was a statistically significant lower survival curve in patients with a KRAS mutation overall and in those with left-sided colon tumors (log rank P less than .001 for both), but there was no significant survival difference between mutation bearers and wild-type patients with a primary rectal tumor (log rank P = .53). A multivariate analysis showed an 82% risk of death from KRAS mutation in primary colon cancer (hazard ratio, 1.82; P less than .001), but a univariate analysis showed no significant mortality association in rectal primary tumors (hazard ratio, 1.13; P = .46).
The funding source was not disclosed. The authors had no relevant financial disclosures.
SOURCE: Amini N et al. J Am Coll Surg. 2019 Oct;229(4):Suppl 1, S69-70.