Racial Disparities in Colorectal Cancer Survival: Is Elimination of Variation in Care the Cure?

Health disparities are ubiquitous worldwide in diverse health conditions and have been extensively documented across the entire colorectal cancer (CRC) care continuum from risk factors to mortality ( 1 , 2 ). CRC is an excellent disease model for understanding and mitigating disparities. The risk factors and pathogenesis are well described ( 3 , 4 ), and there are also proven prevention, early detection, and treatment options, along with major scientific advances in understanding tumor biology and therapeutic targets ( 3 , 5). Health disparities are correlated highly with socioeconomic status. In the United States, people of African ancestry have the highest CRC mortality rate of any racial or ethnic group and this gap has persisted since the early 1980s ( 1 ). There is convincing evidence that adverse environmental exposures and underuse of health care services are central to this intractable public health problem. Racial disparities in survival have, however, been observed, although attenuated after accounting for receipt of cancer treatment ( 6 ). Such observations could result from unmeasured differences in the quality of care received. However, some studies have reported racial differences in tumor molecular markers ( 7 ), which, if confirmed, have important clinical implications, but the evidence base is limited. In this issue of the Journal, Yoon et al. report that among patients age 50 years and older diagnosed with stage III CRC who were enrolled in a trial, blacks and whites had similar five-year disease-free survival rates ( 8 ). There were no differences in quality of care as measured by the number of lymph nodes examined and cycles of chemotherapy received. All patients had received adjuvant chemotherapy with folinic acid, 5-fluorouracil, and oxaliplatin (FOLFOX) alone or with cetuximab, an inhibitor of the epidermal growth factor receptor (EGFR). This supports the notion that eliminating variations in the quality of care could eliminate disparities in survival in patients diagnosed with CRC. EGFR, a transmembrane tyrosine kinase receptor overexpressed in a high percentage of CRCs, promotes tumor growth through the mitogen-activated protein kinase (MAPK) pathway. K-ras gene mutations, present in about 40% of CRCs, modify the response to anti-EGFR therapy by activating MAPK pathway downstream from EGFR ( 3 , 5 ). B-rafV600E gene mutations may trigger methylation of the promoters of many genes (eg, P16INK4a, hMLH1) or the so called CpG island methylator phenotype (CIMP) of colon cancers ( 9 , 10 ). Consistent with some previous studies ( 2 ), Yoon et al. found that, compared with whites, more blacks had tumors with favorable prognostic features and were similar in mismatch repair (MMR) function, or K-ras or B-rafV600E mutations ( 8 ). These findings do not appear to support a biological explanation for disparities. Yoon et al. also found an Asian-white disparity in patients with N2 tumors that was slightly mediated by B-rafV600E mutation status and also a statistically nonsignificant black-white CRC survival disparity in N1 disease. A surprising finding of the study was, however, the greater than 2.5-fold higher risk of death or tumor recurrence in blacks compared with whites among patients younger than age 50 years. So, how could these differences occur despite similar quality of care and adjustment for prognostic factors? Younger patients are in general healthier and have higher functional status than older patients, characteristics associated with more favorable outcomes. Across all three racial groups in the study, younger age was associated with a higher tumor recurrence rate, suggesting more aggressive or treatment-resistant tumors or treatment intolerance in this patient population that may have disparately affected blacks. Another related question is whether blacks are at higher risk of sporadic CRC at a younger age than whites. In Yoon et al.’s study ( 8 ), a higher percentage of blacks were younger than age 50 years, but this may be a byproduct of study accrual, and the study had relatively small numbers of nonwhite patients. Estimates from clinical trials cannot be interpreted to represent population rates, and prior reports of lower age at diagnosis in blacks may reflect lower life expectancy in the context of a disease in which incidence and mortality peak at older age. Thus, studies in unselected patient populations are necessary. This study is an important contribution to understanding CRC disparities. None of the biological markers of prognosis or treatment effect heterogeneity in the chromosomal ( K-ras and B-rafV600E mutations) and microsatellite (MMR) instability pathways ( 3 ) analyzed appears to substantially explain the observed disparities. Other candidates, such as PI3KCA , a potential therapeutic target that has been found to be in concert with B-rafV600E / K-ras mutations in colon cancer, were not considered in this study ( 11 ). The study also did not account for differences in lifestyle factors or drug metabolism. Thus, the precise molecular mechanisms underlying racial disparities in CRC survival, if any, remain unclear. Race is a social construct and is even less credible as a marker of heritable disease risk with increasing racial admixture in society. But, race is a marker for social, psychological, and environmental factors that are difficult to measure. Racial differences in biological patterns of sporadic CRC could therefore arise from differing downstream molecular effects of gene-environment interactions, but this has not been well studied. Knowledge of the mechanisms for racial disparities in CRC remains incomplete, but the prescription is to eliminate variation in the quality of care received along the entire care continuum. This is even more important in the genomic era to assure that all patients realize the benefits of scientific advances. This includes providing individualized disease risk stratification, increasing clinical trial enrollment in minority populations, providing evidence-based and patient-centered care, and addressing social determinants of health. A multipronged approach involving research, policy, health care delivery transformation, and medical education is necessary to realize the ideal of eliminating health disparities, and CRC is an excellent model for this quest, particularly to identify biomarkers for the disproportionate high risk of tumor recurrence in younger blacks as documented by Yoon et al. ( 8 ). Scientific progress is however hampered by a lack of population-based data on the relation of tumor markers to long-term disease outcomes by race. Routine mutational analysis of CRC will enable precision therapies, but also advance scientific knowledge through comparative studies. The authors have no conflicts of interest to disclose.