Background
Colorectal cancer (CRC) is the third most common malignancy worldwide, accounting for approximately 1.9 million new cases and 880,000 deaths in 2018.1 Especially in Western countries, CRC incidence has declined over the past decade, which might be attributable to implementation of colonoscopic screening, use of nonsteroidal anti-inflammatory drugs, and changes in lifestyle and diet.2,3 Concurrently, major advances have been made in CRC treatment, especially regarding the combination of cytotoxic agents and introduction of targeted therapy in metastatic settings.4,5
Genomic instability is of crucial importance for CRC development and progression and includes several mechanisms, one of which is the loss of DNA mismatch repair (MMR) proteins, which results in microsatellite instability–high (MSI-H) tumors.6 Mutation of the KRAS oncogene, which is downstream from the epidermal growth factor receptor (EGFR), is another genomic abnormality in CRC.7
Both MSI-H and KRAS mutation affect CRC treatment strategies: although immune checkpoint inhibitors have been shown to be effective in treatment of advanced solid tumors that are MSI-H,8,9 KRAS mutations have been reported to mediate resistance to anti-EGFR treatment.10,11 MSI and KRAS status therefore impact individualized treatment strategies for patients with CRC, particularly those with advanced or metastatic CRC (mCRC). Although BRAF mutations have also been described in mCRC, therapeutic targeting is challenging, which has been linked to tumoral resistance mechanisms.12
Furthermore, MSI-H and defects in DNA MMR genes are the mutational hallmarks in patients with Lynch syndrome, who have a high propensity for CRC at an early age.13 Lynch syndrome is diagnosed in approximately 20% of patients with MSI-H CRC.14 Given the implications for treatment and familial CRC risk, NCCN recommends MSI and MMR testing in all newly diagnosed CRC cases.15
Besides hereditary factors, there is increasing evidence that MSI and KRAS status are affected by the primary CRC location.16,17 Still, to date, there are scarce US national data on the prevalence of MSI-H and KRAS mutation that account for the primary cancer sidedness. In this study, we evaluated the prevalence of microsatellite and KRAS status in stage IV CRC using a large-scale US national database and assessed their effect on outcomes of patients with CRC.
Materials and Methods
This study received approval from the Yale School of Medicine Institutional Review Board and was HIPAA compliant.
Study Collective
The National Cancer Database (NCDB), jointly sponsored by the American College of Surgeons and the American Cancer Society, contains approximately 34 million records from hospital cancer registries in the United States. It captures approximately 70% of newly diagnosed cancer cases annually in the United States. The NCDB was queried from 2010 to 2016 for patients who had the following diagnoses: pathologically confirmed AJCC stage IV colorectal adenocarcinoma of the cecum (C18.0), ascending colon (C18.2), hepatic flexure of the colon (C18.3), transverse colon (C18.4), splenic flexure of the colon (C18.5), descending colon (C18.6), sigmoid colon (C18.7), rectosigmoid junction (C19.9), and rectum (C20.9). Analyses were limited to cases with information on microsatellite status, KRAS status, and known stage IV disease. We excluded patients aged <18 years and those with overlapping lesions of the colon (C18.8); colon, not specified (C18.9); and gastrointestinal, not specified (C26.0). Patients were also excluded if their microsatellite status was obtained via immunologic testing and reported as “instability, not otherwise specified.” Survival analyses were limited to patients with complete information on microsatellite and KRAS status, follow-up time, and survival status.
Variables
Patient comorbidities were reported using the Charlson-Deyo comorbidity index (CCI) score, stratifying patients into CCI scores of 0, 1, 2, and ≥3. Microsatellite status was assessed via PCR in tumor samples and stratified as MSI-H, MSI-low (MSI-L), and microsatellite stable (MSS). MSI-L and MSS were grouped for all analyses in this study. Patients evaluated for microsatellite status via immunohistochemistry were not considered for our analyses. KRAS status was stratified as KRAS mutation and wild-type. Radiotherapy was classified as local CRC radiotherapy, radiotherapy for CRC metastases, yttrium-90 radioembolization, and no radiotherapy.
Geographic information was provided as broader US state regions to facilitate anonymization, including the following regions: New England (Connecticut, Maine, Massachusetts, New Hampshire, Rhode Island, and Vermont), Middle Atlantic (New Jersey, New York, and Pennsylvania), East North Central (Illinois, Indiana, Michigan, Ohio, and Wisconsin), West North Central (Iowa, Kansas, Minnesota, Missouri, Nebraska, North Dakota, and South Dakota), South Atlantic (Delaware, Florida, Georgia, Maryland, North Carolina, South Carolina, Virginia, District of Columbia, and West Virginia), East South Central (Alabama, Kentucky, Mississippi, and Tennessee), West South Central (Arkansas, Louisiana, Oklahoma, and Texas), Mountain (Arizona, Colorado, Idaho, Montana, Nevada, New Mexico, Utah, and Wyoming), and Pacific (Alaska, California, Hawaii, Oregon, and Washington).
Outcomes
Two primary outcomes of interest were defined a priori: (1) correlation of microsatellite and KRAS status with other CRC factors (cancer site, grade, stage, and metastatic status) and (2) impact of microsatellite and KRAS status on CRC overall survival (OS) and interaction with primary CRC sidedness.
Statistical Analyses
Continuous variables are provided as median with interquartile range and categorical variables as absolute number with percent. Continuous variables were compared using the Wilcoxon rank-sum test and categorical variables using the chi-square test. Logistic regression models were used to assess the likelihood of MSI-H and KRAS mutation in separate analyses. Due to concerns for reverse causation, metastatic status and cancer treatment were not considered.
OS was evaluated using univariate and multivariable Cox proportional hazards models. Variables were considered for inclusion in multivariable models based on univariate significance and were retained in the final multivariable model if P<.05. For multivariable modeling, tumor location was combined into right-sided CRC (CRC of the cecum and ascending and transverse colon) and left-sided CRC (CRC of the descending and sigmoid colon and the rectum). Year of CRC diagnosis was included in the final multivariable model to account for changes in therapy over time. Statistical interaction analyses were planned a priori between microsatellite status, KRAS status, and primary tumor sidedness.
All statistical analyses were performed using R version 3.4.3 (R Foundation for Statistical Computing) and RStudio version 1.1.414 (RStudio, Inc.). An α-level of .05 was chosen for statistical significance. All P values are 2-sided.
Results
Among 73,603 patients with mCRC and data on metastatic status, information on microsatellite status was available for 10,844 (14.7%) and on KRAS status for 25,712 (34.9%); these datasets were used for epidemiologic modeling. For 5,904 patients, information on both microsatellite and KRAS status was available (supplemental eFigure 1 and eTable 1, available with this article at JNCCN.org), which was used to assess OS and interactions between variables. The overall prevalence of MSI-H status and KRAS mutation was 3.1% and 42.4%, respectively. The prevalence of KRAS mutation was 28.9% among patients with MSI-H CRC.
Association of CRC Genomic Abnormalities With Geographic, Sociodemographic, and Cancer Factors
Multivariable logistic regression analyses (supplemental eTables 1 and 2) revealed that the likelihood of KRAS mutation was associated with female sex (odds ratio, 1.10; 95% CI, 1.04–1.15; P<.001) and African American race (odds ratio, 1.58; 95% CI, 1.40–1.72; P<.001). Furthermore, microsatellite and KRAS status independently varied according to US region (Figure 1): MSI-H prevalence was highest in East North Central states (4.1%) and prevalence of KRAS mutation was highest in West South Central states (44.1%). Primary CRC sidedness was another independent predictor of microsatellite and KRAS status (Figure 2, supplemental eTables 3 and 4): the prevalence of MSI-H ranged between 1.6% (rectosigmoid junction) and 5.2% (transverse colon), and between 58.2% (cecum) and 34.7% (sigmoid colon) for KRAS mutation.
US geographic variation in MSI-H and KRAS status among patients with stage IV CRC adenocarcinoma.
Abbreviations: CRC, colorectal cancer; MSI-H, microsatellite instability–high.
Citation: Journal of the National Comprehensive Cancer Network 19, 3; 10.6004/jnccn.2020.7619
US geographic variation in MSI-H and KRAS status among patients with stage IV CRC adenocarcinoma.
Abbreviations: CRC, colorectal cancer; MSI-H, microsatellite instability–high.
Citation: Journal of the National Comprehensive Cancer Network 19, 3; 10.6004/jnccn.2020.7619
US geographic variation in MSI-H and KRAS status among patients with stage IV CRC adenocarcinoma.
Abbreviations: CRC, colorectal cancer; MSI-H, microsatellite instability–high.
Citation: Journal of the National Comprehensive Cancer Network 19, 3; 10.6004/jnccn.2020.7619
MSI-H and KRAS mutation prevalence according to primary CRC site.
Abbreviations: CRC, colorectal cancer; MSI-H, microsatellite instability–high.
Citation: Journal of the National Comprehensive Cancer Network 19, 3; 10.6004/jnccn.2020.7619
MSI-H and KRAS mutation prevalence according to primary CRC site.
Abbreviations: CRC, colorectal cancer; MSI-H, microsatellite instability–high.
Citation: Journal of the National Comprehensive Cancer Network 19, 3; 10.6004/jnccn.2020.7619
MSI-H and KRAS mutation prevalence according to primary CRC site.
Abbreviations: CRC, colorectal cancer; MSI-H, microsatellite instability–high.
Citation: Journal of the National Comprehensive Cancer Network 19, 3; 10.6004/jnccn.2020.7619
Exploratory univariate analyses revealed that MSI-H was associated with fewer distant metastases than MSS (ie, 64.4% hepatic metastases in MSI-H vs 75.4% in MSS) (Tables 1 and 2). In contrast, KRAS mutation was associated with higher metastatic probability (ie, 29.8% lung metastases with KRAS mutation vs 20.7% with KRAS wild-type).
Patient and Tumor Characteristics According to Microsatellite Status
Patient and Tumor Characteristics According to KRAS Status
CRC Mutation Status: Impact on OS and Interaction With Tumor Location
For survival analyses, we evaluated a total of 5,904 patients with data on KRAS mutation and microsatellite status and complete information on follow-up. Median follow-up time in this cohort was 44.5 months (interquartile range, 27.1–61.8 months). Univariate analyses revealed that patients with KRAS wild-type had longer OS than those with KRAS mutation (hazard ratio [HR], 0.71; 95% CI, 0.59–0.85; P<.001), and those with MSS had longer OS than those with MSI-H (HR, 0.82; 95% CI, 0.77–0.88; P<.001). Furthermore, CRC sidedness affected patient outcomes, with longer OS for left-sided versus righted-sided CRC (HR, 0.64; 95% CI, 0.60–0.68; P<.001). OS differences are summarized in Figure 3, and corresponding OS rates are summarized in supplemental eTable 4.
Kaplan-Meier plots showing impact on OS of (A) microsatellite status, (B) KRAS status, and (C) primary CRC site.
Abbreviations: CRC, colorectal cancer; MSI, microsatellite instability–high; MSS, microsatellite status–stable; OS, overall survival.
Citation: Journal of the National Comprehensive Cancer Network 19, 3; 10.6004/jnccn.2020.7619
Kaplan-Meier plots showing impact on OS of (A) microsatellite status, (B) KRAS status, and (C) primary CRC site.
Abbreviations: CRC, colorectal cancer; MSI, microsatellite instability–high; MSS, microsatellite status–stable; OS, overall survival.
Citation: Journal of the National Comprehensive Cancer Network 19, 3; 10.6004/jnccn.2020.7619
Kaplan-Meier plots showing impact on OS of (A) microsatellite status, (B) KRAS status, and (C) primary CRC site.
Abbreviations: CRC, colorectal cancer; MSI, microsatellite instability–high; MSS, microsatellite status–stable; OS, overall survival.
Citation: Journal of the National Comprehensive Cancer Network 19, 3; 10.6004/jnccn.2020.7619
After adjustment for patient-, tumor-, and treatment-level variables, microsatellite status, KRAS status, and primary CRC site emerged as independent predictors of OS (Table 3). Longer OS was confirmed for patients with KRAS wild-type versus mutation (multivariable HR, 0.91; 95% CI, 0.85–0.97; P=.004), those with MSS versus MSI-H (multivariable HR, 0.75; 95% CI, 0.62–0.90; P=.003), and those with left-sided versus right-sided CRC (multivariable HR, 0.65; 95% CI, 0.60–0.70; P<.001).
Multivariable Cox Proportional Hazards Model Evaluating Overall Survival Based on CRC Mutation Status
Furthermore, a statistical interaction between microsatellite status, KRAS status, and primary CRC site was evident (4-df multivariable interaction test, P=.002). For example, the effect of KRAS wild-type on OS was stronger in left-sided CRC (KRAS wild-type vs mutation: HR, 0.77; 95% CI, 0.71–0.85; P<.001) than in right-sided CRC (KRAS wild-type vs mutation: HR, 1.03; 95% CI, 0.93–1.13; P=.595) (Figure 4).
Kaplan-Meier plots showing differing effects of KRAS status according to microsatellite status and primary (A) left-sided versus (B) right-sided colorectal cancer.
Citation: Journal of the National Comprehensive Cancer Network 19, 3; 10.6004/jnccn.2020.7619
Kaplan-Meier plots showing differing effects of KRAS status according to microsatellite status and primary (A) left-sided versus (B) right-sided colorectal cancer.
Citation: Journal of the National Comprehensive Cancer Network 19, 3; 10.6004/jnccn.2020.7619
Kaplan-Meier plots showing differing effects of KRAS status according to microsatellite status and primary (A) left-sided versus (B) right-sided colorectal cancer.
Citation: Journal of the National Comprehensive Cancer Network 19, 3; 10.6004/jnccn.2020.7619
Discussion
In the large-scale NCDB, the overall rate of MSI-H was 3.1% and that of KRAS mutation was 42.4% in patients with stage IV CRC. MSI rates in our study are comparable to those published for advanced CRC. For example, Fujiyoshi et al18 reported an MSI-H prevalence of 4.1% in 401 patients with stage IV CRC. Furthermore, the KRAS mutation prevalence of 42.4% in our cohort is also similar to that reported elsewhere. For instance, Lowe et al19 reported 35.9% KRAS mutation prevalence in a meta-analysis of patients with metastatic CRC, whereas Kafatos et al20 showed RAS mutations (combined KRAS and NRAS) in 43.6% of patients with metastatic CRC pooled from 12 primary data sources.
In our study, KRAS mutation rates varied with patient demographics, with a higher rate of KRAS mutation seen in female African American individuals, which might contribute to poorer CRC outcomes observed in this population.21 Race- and sex-specific differences in KRAS status differences are supported by earlier literature on stage III CRC and might be attributable to varying neoplasia pathways and enzyme activity.22 Patient age was not associated with MSI-H status in our multivariable analyses, which is counterintuitive, given that 20% of patients with MSI-H CRC are reported to have Lynch syndrome, with disease typically manifesting at a younger age than CRC in other patients.13,14 This discrepancy might be attributable to a low proportion of patients with Lynch syndrome in our cohort and to the anonymization process of the NCDB with suppressed facility location for patients aged <39 years.
Our findings further reveal that CRC genomic abnormalities independently vary with US geography in the NCDB population, with the highest MSI-H prevalence in East North Central states (Illinois, Indiana, Michigan, Ohio, and Wisconsin) and the highest KRAS mutation prevalence in West South Central states (Arkansas, Louisiana, Oklahoma, and Texas). Although this variability could be attributable to the patients’ mutational susceptibility, differences in environmental and socioeconomic factors, dietary behavior, and CRC screening compliance might also contribute. CRC has been described as an environmentally mediated entity. For example, it has been shown that immigrants assume the CRC risk of their new environment within one generation.23 Diets rich in processed and red meat have been linked to a higher CRC risk,24 as have smoking and excessive alcohol consumption.25,26 Still, to date, there are only sparse data on geographic variability of CRC mutations. Turpin et al27 evaluated patients with CRC from northern France and showed spatial heterogeneity that might correlate with environmental factors, such as proximity to major highways and large cities. The association of KRAS mutation with African American race, female sex, and West South Central US state residence further raises the question of whether the geographic differences of KRAS status are affected by racial distribution differences.
Our data further showed that microsatellite and KRAS status varied with the primary tumor side. In tendency, both MSI-H and KRAS mutation were more common in right-sided versus left-sided CRC, whereas specific primary CRC locations showed distinct mutational profiles. These results are supported by Sinicrope et al,16 who described site-specific KRAS mutation and DNA MMR defects in 3,018 patients with stage III disease undergoing adjuvant chemotherapy, reporting higher KRAS mutation and MSI-H rates in right-sided CRC. Yamauchi et al17 described higher MSI-H incidence for CRC of stage I–IV in the proximal colon. Higher rates of KRAS mutation for right-sided stage II and III CRC are also noted in analyses derived from The Cancer Genome Atlas (TCGA).28
The underlying mechanisms of these site-specific mutation rates are not fully understood. Differences in the embryologic origin might contribute, given that the right-sided colon is derived from the midgut and the left-sided colon and rectum are derived from the hindgut.29 Furthermore, there are studies reporting locoregional differences of the microbiome in various colonic locations. For example, a higher incidence of Escherichia coli phylogroup B2 has been described in right-sided versus left-sided CRC.30
Our analyses show that MSI-H status, KRAS mutation, and primary CRC sidedness are independent prognosticators of OS. In general, patients with MSI-H status and KRAS mutation had worse OS than those with MSS status and KRAS wild-type. OS was also shorter in patients with right-sided versus left-sided CRC, which is supported in numerous prior reports.31–33 Moreover, the prognostic effect of KRAS mutation varied with primary cancer location, as the effect size was larger in left-sided versus right-sided CRC. One explanation for site-specific differences is that proximal CRC may have an overall higher mutation rate, potentially associated with worse prognosis, as shown in the PETACC-3 study and TCGA.28,34
In patients with KRAS wild-type CRC, several studies have shown worse outcomes for right-sided versus left-sided cancers.35,36 Sinicrope et al16 conducted an extensive analysis of 3,018 patients with stage III CRC and described results similar to ours, with shorter OS among those with right-sided CRC and KRAS mutation. Furthermore, the RASCAL and RASCAL II studies associated KRAS mutation with earlier recurrence and death, although the smaller PETACC-3 and CALGB 89803 studies in stage II and III CRC showed contradictory results.37–40 Discrepancies in the prognostic value of KRAS in CRC could possibly originate from varying patient populations and treatment regimens. Furthermore, the specific location of KRAS mutations (codon 12 vs 13) seems to have prognostic impact in CRC.41
Although MSI-H has been associated with favorable prognosis in stage II CRC, only few studies have reported on its role in stage IV CRC.42 Price et al43 reported on Australian registry data and showed shorter OS in patients with MSI versus MSS status, although no distinction was made between MSI-H and MSI-L. Jin et al44 described a cohort of 1,268 patients with metastatic CRC from the Mayo Clinic and reported shorter OS in those with MSI-H versus MSS status.
Several mechanisms may contribute to inferior outcomes in patients with MSI-H CRC, including reduced efficacy of fluorouracil-based treatments42,45 and modification of the treatment effectiveness of vascular endothelial growth factor–targeted agents.46 Still, there are some concerns that the coincidence of BRAF status and MSI might confound the prognostic profile of MSI.47
Our study is not devoid of limitations, which are mainly inherent to the use of NCDB as the data source. First, given the stratified coding of the NCDB, no distinction between specific systemic treatment protocols is possible, thereby limiting evaluation of the predictive value of KRAS mutation and microsatellite status. Second, the NCDB does not provide additional details on CRC mutations, such as specific codons and microsatellite status, and KRAS status was not available for all patients in the NCDB, raising concerns about patient selection and the generalizability of our results. Third, there have been concerns about the generalizability of the NCDB data to the general population because it might not cover a cohort representative of the US population. Furthermore, the low proportion of patients with data on KRAS and MSI status among all patients with mCRC raises concerns about potential selection bias and variability in institutional policies regarding MSI testing strategies, which might impair the generalizability of our findings to a broader population. Finally, evaluating data up to 2016, our analyses did not cover the recent use of immunotherapy for advanced CRC, with particular benefit for patients with MSI-H status.
Conclusions
In a large-scale US national cohort, we showed that MSI and KRAS status in stage IV CRC vary according to demography, CRC sidedness, and US geography. MSI-H, KRAS mutation, and primary CRC site (right- vs left-sided) independently affect OS with a worsened prognosis and distinct profiles, although recent developments might change outcomes, particularly for patients with MSI-H status. Our results corroborate that generically classifying adenocarcinomas as CRC might not appreciate the observed mutational and site-specific differences. Additional studies are warranted to evaluate whether these differences translate into site-specific treatment effectiveness for primary or metastatic disease.
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