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KRAS, MSI Testing Associated With Better Outcomes for Colorectal Cancer Patients, Study Finds

NEW YORK – A retrospective analysis of more than 40,000 patients with colorectal cancer in the US found disparities in the rate of biomarker testing for microsatellite instability (MSI) and KRAS mutations by patients' age, education level, and the location and type of hospital where they received treatment.

In the study published in JAMA Network Open on Friday, researchers analyzed metastatic colorectal cancer patients' biomarker testing and overall survival data from 2010 to 2017 in the National Cancer Database, a hospital-based cancer registry in the US. Across the whole cohort of 41,061 patients, 28.8 percent underwent KRAS testing and 43.7 percent received MSI testing.

While the exact timing of the biomarker testing was not recorded in the National Cancer Database, the database included any KRAS or MSI testing that occurred between patients' date of diagnosis and start of first-line treatment. The researchers noted that KRAS testing was not prevalent before 2010, and in 2018, the National Cancer Database changed the MSI and KRAS test variables and no longer indicates when patients who do not receive these tests.

Over this eight-year period, the researchers found that the proportion of patients who underwent MSI and KRAS testing increased significantly. KRAS testing increased from 32.9 percent to 48.5 percent, and MSI testing jumped from 14.2 percent to 50.5 percent.

The database also included sociodemographic information on patients, such as age, sex, self-reported race and ethnicity, insurance type, median household income, treatment facility type, treatment facility location, distance to facility, geographic location, and educational level in patients' area of residence. With this data, the researchers explored which sociodemographic factors were associated with a lower chance of getting biomarker testing.

For MSI testing, patients who were older, between ages 70 and 79, had the lowest odds of receiving testing among all age groups. Other factors associated with lower testing likelihood included living in an area with low educational attainment, getting treated at a community oncology center, living in a rural location, and living in East South Central US states, which include Kentucky, Tennessee, Mississippi, and Alabama.

Starting in 2018, National Comprehensive Cancer Network (NCCN) guidelines recommended universal MSI testing for all patients with newly diagnosed colorectal cancer to identify patients with MSI-high tumors who are eligible for treatment with several immunotherapies, including Merck's Keytruda (pembrolizumab) and Bristol Myers Squibb's Opdivo (nivolumab) with or without Yervoy (ipilimumab). Before the approval of immunotherapies for MSI-high cancer, the guidelines only recommended MSI and mismatch repair deficiency testing to identify colorectal cancer patients with Lynch syndrome, which confers a high-risk hereditary cancer predisposition.

Factors associated with lower likelihood of KRAS testing were similar to MSI testing. Older patients between ages 70 and 79 were less likely to receive KRAS testing than other age groups, as were those living in an area with the lowest educational attainment, those treated at a community practice, and those residing in the East South Central region. Patients with Medicaid also had a lower chance of getting KRAS testing compared to those with private insurance.

The NCCN first recommended KRAS testing in its guidelines for managing colorectal cancer in 2009, when it suggested that testing should be performed to identify patients with KRAS wild-type cancer for treatment with Eli Lilly's EGFR inhibitor Erbitux (cetuximab) or Amgen's EGFR inhibitor Vectibix (panitumumab). More recently, the NCCN has updated its guidelines to recommend KRAS mutation testing for all patients with metastatic colorectal cancer due to clinical trial data showing KRAS inhibitor activity in KRAS-mutant colorectal cancer.

The analysis did not show a negative association between race or ethnicity and biomarker testing. The researchers theorized that the well-documented racial and ethnic disparities in biomarker testing "may be mediated, at least partially, through socioeconomic, demographic, and clinical variables," and added that race and ethnicity "can serve as a precursor for a cascade of socioeconomic disparities."

After analyzing survival outcomes for patients who received biomarker testing and those who didn't, the researchers found median overall survival was improved for those who underwent MSI and KRAS testing. In the MSI group, those who got biomarker testing had a median overall survival of 23.9 months versus 12.3 months for those who did not get testing. The KRAS-tested group had similar benefits, with patients who got tested living a median of 20.4 months compared to 10.7 months for those who did not.

When adjusted for confounding variables, overall survival improvements seen for KRAS- and MSI-tested patients remained statistically significant, though the researchers noted the survival improvement was "modest" when adjusted for other factors. They concluded that the association between survival and biomarker testing status suggests that testing "acts as a surrogate of overall cancer care, reflecting broader systemic disparities in treatment access and quality."

"Patients without biomarker testing can have a perpetual vulnerability of lack of access to other treatment options," the authors wrote. "In short, disparities in MSI and KRAS testing can compromise optimal mCRC treatment."