Racial Differences in Survival and Response to Therapy in Patients with Metastatic Colorectal Cancer: A Secondary Analysis of CALGB/SWOG 80405 (Alliance A151931)

Rebecca A Snyder; Jun He; Jennifer Le-Rademacher; Fang-Shu Ou; Andrew B Dodge; Tyler J Zemla; Electra D Paskett; George J Chang; Federico Innocenti; Charles Blanke; Heinz-Josef Lenz; Blase N Polite; Alan P Venook

doi:10.1002/cncr.33649

. Author manuscript; available in PMC: 2022 Oct 15.

Published in final edited form as: Cancer. 2021 Aug 10;127(20):3801–3808. doi: 10.1002/cncr.33649

Racial Differences in Survival and Response to Therapy in Patients with Metastatic Colorectal Cancer: A Secondary Analysis of CALGB/SWOG 80405 (Alliance A151931)

Rebecca A Snyder ¹, Jun He ², Jennifer Le-Rademacher ², Fang-Shu Ou ³, Andrew B Dodge ², Tyler J Zemla ², Electra D Paskett ⁴, George J Chang ⁵, Federico Innocenti ⁶, Charles Blanke ⁷, Heinz-Josef Lenz ⁸, Blase N Polite ^9,^*, Alan P Venook ^10,^*

¹Department of Surgery and Public Health, Brody School of Medicine at East Carolina University. Greenville, North Carolina

²Alliance Statistics and Data Center, Mayo Clinic. Rochester, Minnesota

³Division of Biomedical Statistics and Informatics, Mayo Clinic. Rochester, Minnesota

⁴College of Public Health, The Ohio State University. Columbus, Ohio

⁵Departments of Surgical Oncology and Health Services Research, University of Texas MD Anderson Cancer Center. Houston, Texas

⁶Eshelman School of Pharmacy, University of North Carolina at Chapel Hill. Chapel Hill, North Carolina

⁷Southwest Oncology Group Chair’s Office and Knight Cancer Institute, Oregon Health & Science University. Portland, Oregon

⁸Department of Preventative Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles. Los Angeles, California

⁹University of Chicago Comprehensive Cancer Center. Chicago, Illinois

¹⁰Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco. San Francisco, California

^✉

Corresponding Author: Rebecca A. Snyder, MD, MPH, Assistant Professor of Surgery and Public Health, Brody School of Medicine at East Carolina University, 600 Moye Boulevard, Surgical Oncology Suite 4S-24, Greenville, NC 27834, Phone: 252-744-4110, Fax: 252-744-5777, snyderre19@ecu.edu, Twitter: @RSnyder_MD

Equal contributions by co-senior authors, Drs. Polite and Venook.

Author Contributions: Dr. Rebecca Snyder and Dr. Alan Venook had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Rebecca A. Snyder: Conceptualization, project administration, investigation, methodology, writing- original draft, writing- reviewing and editing. Jun He, PhD: Data curation, methodology, formal analysis, software, visualization, writing- original draft, writing- reviewing and editing Jennifer Le-Rademacher, PhD: Data curation, methodology, formal analysis, writing- reviewing and editing. Fang-Shu Ou, PhD: Methodology, writing- reviewing and editing, supervision, validation. Andrew B. Dodge, MS: Data curation, formal analysis, visualization, writing- reviewing and editing. Tyler J. Zemla, MS: Data curation, formal analysis, visualization, writing- reviewing and editing. Electra D. Paskett, PhD: Methodology, writing- reviewing and editing, supervision. George J. Chang, MD, MS: Methodology, validation, writing- reviewing and editing, supervision. Federico Innocenti, MD, PhD: Validation, writing- reviewing and editing, supervision. Charles Blanke, MD: Validation, writing- reviewing and editing, supervision. Heinz-Josef Lenz, MD: Validatino, writing- reviewing and editing. Blase N. Polite, MD: Conceptualization, methodology, validation, writing- reviewing and editing, supervision. Alan P. Venook, MD: Methodology, validation, writing- reviewing and editing, supervision.

PMCID: PMC8478698 NIHMSID: NIHMS1700072 PMID: 34374082

Abstract

BACKGROUND:

The aim of this study was to evaluate the association between self-identified race and overall survival (OS), progression-free survival (PFS), and response to therapy among patients enrolled in the randomized CALGB/SWOG 80405 trial.

METHODS:

Patients with advanced or metastatic CRC and enrolled in the CALGB/SWOG 80405 trial were identified by race. Based on covariates [treatment arm, KRAS status, gender, age, and body mass index (BMI)], each Black patient was exact matched with a White patient. The association between race and OS and PFS was examined by marginal Cox proportional hazard model for matched pairs. The interaction between KRAS status and race was tested in the model. Association between race and response to therapy, and adverse events was examined by marginal logistic regression model.

RESULTS:

A total of 392 patients were matched and included in the final dataset. No difference in OS (HR: 0.92; 95% CI:0.73-1.16), PFS (HR: 0.97; 95% CI:0.78-1.20), or response to therapy (OR: 1.00; 95% CI:0.65-1.52) was observed between Black and White patients. Patients with KRAS mutant status (HR: 1.31; 95% CI:1.02-1.67), performance score of 1 (Ref: 0; HR: 1.49; 95% CI:1.18-1.88), or ≥ 3 metastatic sites (Ref: 1; HR: 1.67; 95% CI:1.22-2.28) experienced worse OS. Black patients experienced lower rates and risk of ≥ grade 3 fatigue (6.6% vs. 13.3%; OR: 0.46; 95% CI:0.24-0.91) but were equally likely to be treated with a dose reduction (OR: 1.09; 95% CI:0.72-1.65).

CONCLUSION:

No difference in OS, PFS, or response to therapy was observed between Black and White patients in an equal treatment setting of the CALGB/SWOG 80405 randomized controlled trial.

Keywords: Healthcare disparities, colorectal neoplasms, clinical trial, continental population groups

Lay Summary:

Despite improvements in screening and treatment, studies have demonstrated worse outcomes in Black patients with colorectal cancer. The purpose of this study was to determine if there was a difference in cancer-specific outcomes among Black and White patients receiving equivalent treatment on the CALGB/SWOG 80405 randomized clinical trial. In this study, there was no difference in overall survival, progression-free survival, or response to therapy between Black and White patients treated on clinical trial. These findings suggest that access to care and differences in treatment may be responsible for racial disparities in colorectal cancer.

Precis:

In a secondary analysis of the CALGB/SWOG 80405 randomized clinical trial, there was no difference in overall survival, progression-free survival, or response to therapy between matched Black and White patients with advanced or metastatic colorectal cancer. Because racial disparities in metastatic colorectal cancer survival were not observed in a equal treatment setting, differences in access to care and treatment delivery may be responsible for racial disparities observed in epidemiological studies.

INTRODUCTION

Over the past decade in the United States, colorectal cancer (CRC) has become less common, and patients with the disease are living longer and are more likely to be cured. However, these favorable trends are not seen in all racial groups; the incidence of CRC remains approximately 25% higher among Black patients compared to Whites and mortality is as much as 40% higher.^1,2 Although CRC mortality rates are decreasing for both White and Black patients, the decreases are smaller for Black patients within every stage category, particularly for distant-stage disease. From 1985 to 2008, mortality rates declined by 33% in White patients with stage IV CRC compared to only 5% in Black patients, resulting in a widening racial disparity.¹ Because cancer-specific survival remains worse among Black patients with regional or distant stage of disease at diagnosis, it has been suggested that differences in the delivery of care may contribute to disparities in cancer-related outcomes.^1,3–6

Several studies have explored whether racial differences in CRC patient outcomes are seen within the context of a clinical trial, on the premise that the multidisciplinary protocol-driven management of CRC is more uniform across all participating centers in a study in which patients have obviously had access to similar care. A secondary analysis of 1244 patients enrolled in an early stage colon cancer Southwest Oncology Group (SWOG) 5-FU adjuvant trial found no difference in overall survival (OS) by race.⁷ However, an analysis of 3305 patients with stage III colon cancer enrolled in the North Central Cancer Treatment Group (NCCTG) N0147 adjuvant 5-FU, oxaliplatin, and leucovorin (FOLFOX) chemotherapy trial found a worse disease-free survival (DFS) and shorter time to progression (TTP) in Black patients, but only in the subgroup of patients younger than 50 years of age.⁸ Similarly, a secondary analysis of over 14,000 patients enrolled in 12 randomized controlled trials within the Adjuvant Colon Cancer ENdpoinTs (ACCENT) database demonstrated poorer recurrence-free survival (HR 1.14, 95% confidence interval (CI) 1.04-1.24) and OS (HR 1.22, 95% CI 1.11-1.34) among Black patients, despite receiving standardized adjuvant treatment.⁹ Data in the metastatic setting are more limited. A subgroup analysis of the 1412 patients enrolled in NCCTG N9741 and receiving standardized systemic chemotherapy found no difference in TTP or OS by race, although response rates to treatment were lower among Black patients and severe adverse events more frequent.¹⁰

The randomized Cancer and Leukemia Group B (CALGB, now part of the Alliance for Clinical Trials in Oncology)/SWOG 80405 (ClinicalTrials.gov identifier NCT00265850) trial was designed to compare the benefit of cetuximab or bevacizumab, added to FOLFOX or FOLFIRI (5-FU, irinotecan, and leucovorin) chemotherapy, in advanced or metastatic CRC.¹¹ This study provides robust clinical data on a contemporary cohort of CRC patients (2005-2012) treated with standardized treatment regimens with long-term oncologic outcome data, as well as secondary outcomes including response to therapy and adverse events. The primary aim of this analysis was to evaluate the association between self-identified race and OS, progression-free survival (PFS), and response to therapy among patients with advanced or metastatic CRC enrolled in the CALGB/SWOG 80405 trial. Secondary objectives were to compare adverse events, dose reductions, providers’ stated goals of therapy at patient enrollment, and resection with curative-intent of metastatic disease by race.

METHODS

Study Population

The study population for the CALGB 80405 trial has been previously described.¹¹ The initial study protocol enrolled patients regardless of KRAS status; however, an interim amendment revised the inclusion criteria to restrict enrollment to patients with known KRAS wildtype tumors due to emerging evidence demonstrating a lack of benefit of cetuximab in patients with KRAS mutation.

The trial enrolled 2334 patients with advanced or metastatic CRC. Each participant signed an IRB-approved, protocol-specific informed consent document in accordance with federal and institutional guidelines. Of these, eight patients withdrew consent for all use of all data. Patient race was self-identified as White, Black, American Indian or Alaska Native, Asian, Native Hawaiian or other Pacific Islander, and unknown. Due to the unbalanced race ratio between Black and White (1:7), 1:1 covariate exact matching was applied to match each Black patient with a White patient. The priority of categorical variables was in order: treatment arm (bevacizumab vs. cetuximab vs. bevacizumab+ cetuximab), KRAS status (mutation vs. wild vs. missing), gender (male vs. female), age (<40 vs. 40-60 vs. ≥60 years), and body mass index [BMI; normal/underweight (< 25) vs. overweight/obese (≥ 25)]. Patients with KRAS missing status were then excluded.

Outcome Measures & Covariates

OS was defined as time from randomization until death from any cause. Patients who were alive at the time of their last follow-up were censored at that time. PFS was defined as time from randomization until first documented progression or death from any cause. Patients who were alive and did not experience progression at their last follow-up were censored at that time. Best response to therapy was defined as the best objective response during the course of treatment per RECIST 1.0. Patients were classified by their best response of partial response or complete response (CR/PR) versus stable disease or progressive disease (SD/PD). Adverse events were recorded under the guidance of CTCAE version 3.0. For each AE, the maximum grade experienced by a patient on treatment was used for analysis. Other covariates included ethnicity (Hispanic or Latino vs. Non-Hispanic vs. not reported), Eastern Clinical Oncology Group performance status (0 vs. 1), synchronous/metachronous tumor (synchronous vs. metachronous), tumor location (left vs. right/transverse), planned protocol chemotherapy (FOLFOX vs. FOLFIRI), prior pelvic radiation therapy (no vs. yes), prior adjuvant chemotherapy (no vs. yes), disease description (locally advanced vs. metastatic), metastatic site at the site of the primary tumor or tumor bed (no vs. yes), number of metastatic sites (1 vs. 2 vs. ≥3) , and provider-reported intent of treatment at the time of randomization (palliative vs. neoadjuvant with the potential for resection of all sites of metastatic disease).

Statistical Analysis

Primary data analysis was performed using the 1:1 covariate exact matched dataset. Baseline characteristics (all categorical) were compared between race groups using the Chi-square test or Fisher’s exact test as appropriate. OS and PFS were summarized by race using the Kaplan-Meier estimator. The marginal Cox proportional hazard model for matched pairs was used to examine the association between race and OS and between race and PFS.¹² Non-proportional hazard (PH) assumption was checked by Kolmogorov-type Supremum test with the significance level of 0.01.¹³ Variables that did not meet the PH assumption were stratified in the marginal COX model. A marginal logistic regression model for matched pairs was used to examine the association between race and response to therapy, defined as odds of complete or partial response (vs. stable or progressive disease).¹⁴ The covariates which were presented in Table 1 were considered in the marginal Cox model and marginal logistic regression model. Backward selection was conducted to identify covariates to include in the final models. Race and KRAS status as the primary factors of interest were included in all steps of model selection, and the interaction between KRAS status and race was tested in both models. Adverse events were summarized by race and were compared using the marginal logistic regression model for matched pairs. The marginal regression models were also used to assess the association between race and dose reduction, neoadjuvant/palliative treatment intention, and surgical resection of metastatic disease for matched pairs. Data quality was ensured by review of data by the Alliance Statistics and Data Center and by the study chairperson following Alliance policies. Data collection and statistical analyses were conducted by the Alliance Statistics and Data Center. Statistical analyses were performed using SAS statistical software (version 9.4M3, SAS Institute, Cary, NC) on a dataset locked on January 18, 2018.

Table 1.

Patient Demographics and Clinical Characteristics (N=392)

	Race

	Black (n=196)		White (n=196)

	N	%	N	%	p-value
Treatment Arm
A: Bevacizumab	82	41.84	82	41.84	^*
B: Cetuximab	82	41.84	82	41.84
C: Bev + Cetux	32	16.33	32	16.33
*KRAS*
Wildtype	135	68.88	135	68.88	^*
Mutant	61	31.12	61	31.12	^*
Gender
Male	103	52.55	103	52.55	^*
Female	93	47.45	93	47.45	^*
Age
18-59.99	123	62.76	123	62.76	^*
≥ 60	73	37.24	73	37.24	^*
BMI
Normal/underweight	60	30.61	58	29.59	^*
Overweight/obese	136	69.39	138	70.41	^*
Ethnicity
Hispanic or Latino	3	1.53	9	4.59	0.11^a
Non-Hispanic	178	90.82	179	91.33
Not reported	1	0.51
Unknown	14	7.14	8	4.08
Performance Score
0	95	48.47	129	65.82	<0.001
1	101	51.53	67	34.18	<0.001
Synchronous/Metachronous
Missing	7	^*	7	^*
Synchronous	151	79.89	158	83.60	0.35
Metachronous	38	20.11	31	16.40	0.35
Tumor Location (sidedness)
Missing	15	^*	14	^*
Left	104	57.46	110	60.44	0.56
Right/Transverse	77	42.54	72	39.56	0.56
Planned Protocol Chemotherapy
FOLFOX	135	68.88	145	73.98	0.26
FOLFIRI	61	31.12	51	26.02	0.26
Prior Pelvic Radiation Therapy
No	183	93.37	186	94.90	0.52
Yes	13	6.63	10	5.10
Prior Adjuvant Chemotherapy
No	174	88.78	176	89.80	0.74
Yes	22	11.22	20	10.20	0.74
Disease Description
Missing	1	^*	1	^*
Locally advanced	6	3.08	2	1.03	0.28^a
Metastatic	189	96.92	193	98.97	0.28^a
Metastatic Site (Primary or tumor bed)
No	147	75.00	140	71.43	0.43
Yes	49	25.00	56	28.57	0.43
Number of Metastatic Sites
Missing	2	^*	1	^*
1	99	51.03	82	42.05	0.21
2	66	34.02	78	40.00
≥ 3	29	14.95	35	17.95
Intent of Treatment
Missing	5	^*	5	^*
Palliative	169	88.48	155	81.15	0.046
Neoadjuvant	22	11.52	36	18.85	0.046

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no p-value provided for the variables that were used for matching, and no percentage listed for missing proportion.

Fisher’s exact test; otherwise, Chi-square test

RESULTS

Within the CALGB 80405 total cohort of 2334 patients, there were 278 self-identified Black (12.0%), 1896 White (81.5%), 97 Other, and 55 patients with missing race. From these, 276 Black patients were identified and matched with 276 White patients based on covariates including treatment arm, KRAS status (wildtype, mutant, missing), sex, age, and BMI. Two Black patients were matched with White patients based on covariates treatment arm, KRAS status, gender, and age. Matched pairs (82 Black and 82 White patients) with KRAS status missing were excluded. The final data set included a total of 392 patients (196 Black vs. 196 White patients) (Figure 1). A greater proportion of Black compared to White patients had a performance status of 1 vs. 0 (51.5% vs. 34.2%, p<0.001) and were treated with provider-reported palliative intent rather than neoadjuvant intent (88.5% vs. 81.2%, p=0.046). Patients were well-matched on other clinical variables (Table 1). Because tumor location (sidedness) violated non-proportional hazard (PH) assumption, it was stratified in the marginal Cox model.

Figure 1. — Propensity Matched Cohort Selection.

Primary Outcomes

Median OS was 26.4 months (95% CI: 22.6-29.5) for Black patients and 29.3 months (95% CI: 25.0-31.9) for White patients (Figure 2A). Median PFS was 9.7 months (95% CI: 8.4-11.0) for Black patients and 9.5 months (95% CI: 8.9-10.9) for White patients (Figure 2B). Kaplan-Meier curves of OS by KRAS status were shown in Figures 3A and 3B for KRAS wildtype and KRAS mutant, respectively. Median time of follow-up was 73.3 months (95% CI: 62.9-76.3) for Black and 67.8 months (95% CI: 64.4-77.3) for White patients (Data not shown).

Figure 3. — Overall Survival by Race among *KRAS* status.

By marginal Cox model, there was no association between race and OS (HR: 0.92; 95% CI: 0.73-1.16; p=0.49) or PFS (HR: 0.97; 95% CI: 0.78-1.20; p=0.76) after stratifying for tumor location (Table 2). No interaction between race and KRAS status was observed. Patients with mutant KRAS status had worse OS than patients with wildtype KRAS status (HR: 1.31; 95% CI: 1.02-1.67; p=0.033), but no difference in PFS (HR: 1.16; 95% CI: 0.91-1.47; p=0.23). Patients who were overweight or obese had a lower risk of overall mortality than patients who were underweight or normal weight (HR: 0.77; 95% CI: 0.60-0.98; p=0.036), and patients with performance score of 1 or more than 3 metastatic sites had a higher risk of death than patients with performance score of 0 (HR: 1.49; 95% CI: 1.18-1.88; p<0.001) or only 1 metastatic site (HR: 1.67; 95% CI: 1.22-2.28; p=0.002) (Table 2). Patients with 3 or more metastatic sites had a higher risk of progression than patients with only 1 metastatic site (HR: 1.51; 95% CI: 1.11-2.05; p=0.008) (Table 2).

Table 2.

Marginal Cox Regression Model for Overall Survival and Progression-Free Survival.

	OS model		PFS model

Parameter	Hazard ratio with 95% CI	p-value	Hazard ratio with 95% CI	p-value
Race (Black vs. White)	0.92 (0.73, 1.16)	0.490	0.97 (0.78, 1.20)	0.76
KRAS (mutant vs. wildtype)	1.31 (1.02, 1.67)	0.033	1.16 (0.91, 1.47)	0.23
BMI (overweight/obese vs. underweight/normal)	0.77 (0.60, 0.98)	0.036	-	-
Performance (1 vs. 0)	1.49 (1.18, 1.88)	0.0009	-	-
Number of metastatic sites (2 sites vs. 1 site)	1.15 (0.90, 1.48)	0.275	1.16 (0.92, 1.47)	0.22
Number of metastatic sites (≥ 3 sites vs. 1 site)	1.67 (1.22, 2.28)	0.0015	1.51 (1.11, 2.05)	0.008

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Abbreviation: Body mass index (BMI)

Based on marginal logistic regression model, no difference in response to therapy (CR+PR) by race was observed (OR for Black versus White: 1.00; 95% CI: 0.65-1.52; p=0.96) nor by KRAS status (OR for mutant versus wildtype: 0.77; 95% CI: 0.48-1.22; p=0.26) (Data not shown). However, the odds of having complete or partial response was lower for patients treated with palliative intent compared to patients treated with neoadjuvant intent (OR: 0.44; 95% CI: 0.24-0.83; p=0.012) (Data not shown).

Secondary Outcomes

Compared to White patients, Black patients had lower rates and lower odds of experiencing ≥ grade 3 fatigue (6.6% vs. 13.3%; OR: 0.46; 95% CI: 0.24-0.91; p=0.025) (Supplemental Table 1; Table 3). There was no difference in rates of ≥ grade 3 hematological toxicity, diarrhea, or neuropathy by race.

Table 3.

Odds of Adverse Event by Race.

Common toxicity	Odds ratio with 95% CI	p-value
Hematology (≥3 vs. <3)	1.33 (0.91, 1.96)	0.14
Diarrhea (≥3 vs. <3)	0.80 (0.40, 1.60)	0.52
Neuropathy (≥3 vs. <3)	1.19 (0.64, 2.21)	0.59
Fatigue (≥3 vs. <3)	0.46 (0.24, 0.91)	0.025

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Note: The reference of race is White.

Black patients were equally likely to be treated with a dose reduction (OR: 1.09; 95% CI: 0.72-1.65; p=0.68) (Data not shown). Although Black race was associated with decreased odds of treatment with neoadjuvant intent at the time of study randomization when compared to their White counterparts (OR: 0.56; 95% CI: 0.32-0.995; p=0.048) (Data not shown), there was no association between race and surgical resection of metastatic disease (OR: 0.97; 95% CI: 0.62-1.51; p=0.90) (Data not shown).

DISCUSSION

In this secondary analysis of data from a phase III randomized clinical trial of patients with advanced or metastatic CRC treated with standardized therapy, no difference in OS or PFS was observed between Black and White patients by propensity matched analysis. Response to therapy also did not appear to differ by self-identified race, although differences in toxicity were observed, with Black patients experiencing less fatigue than White patients. However, there was no difference in frequency of dose reduction by race. At enrollment, treating physicians were asked to characterize the goals of treatment as either part of a curative multidisciplinary plan or palliative care plan. Although Black patients had a similar extent of metastatic disease based on number of metastatic sites, they were less likely to be treated with provider-reported neoadjuvant intent than their White counterparts. However, Black and White patients ultimately underwent curative surgical resection for metastatic disease at similar rates.

In addition to detailed data regarding race and clinical outcomes, data collected from the CALGB/SWOG 80405 trial also includes information regarding KRAS mutational status, allowing analysis of the interaction of KRAS status, race, and prognosis in the context of standardized treatment. A recent pooled analysis of 5 randomized trials in metastatic CRC demonstrated an overall RAS mutation prevalence (including KRAS and NRAS) of 55.9%, most commonly consisting of mutations in codon 12 or 13 of exon 2 of the KRAS gene (42.6%).¹⁵ It is well-established that KRAS mutant tumors do not respond to epidermal growth factor receptor therapy.^16,17 Data regarding the prognostic implication of KRAS mutations is conflicting, but according to several studies, including another analysis of CALGB/SWOG 80405, KRAS mutant tumors appear to have a worse prognosis.^18–20 A similar finding was observed here; patients with KRAS mutant tumors had a lower survival probability than those with KRAS wildtype tumors (p=0.004). KRAS mutations have also been shown to occur more frequently in patients with right-sided, or more proximal cancers, which are independently associated with a worse prognosis when compared to left-sided tumors.^18,21–23

Given the well-established disparities in colorectal cancer mortality, potential racial differences in tumor biology are an area of significant scientific interest. In this study, patients were matched based on KRAS status (wildtype, mutant, or unknown), and no difference in tumor sidedness was observed following propensity matching. There is also emerging evidence in the literature to suggest that rates of specific KRAS mutations differ by race, with a higher proportion of KRAS codon 13 mutations among Black CRC patients.^24,25 Alternatively, another analysis identified similar rates of common (codon 12 or 13) KRAS mutations by race, but higher rates of extended RAS mutations (non-codon 12 or 13) among Black compared to White patients (25% vs. 14%, p=0.02).²⁵ These extended RAS mutations were associated with a shorter median OS.^20,25 In this study, a difference in survival was not observed between Black and White patients with KRAS wildtype or KRAS mutant tumors. In two recent correlative analyses of CALGB/SWOG 80405 investigating the association of tumor mutational burden (TMB) and consensus molecular subtypes (CMS) with prognosis, no difference in TMB or CMS by race was identified, although race was not a primary focus of either study.^20,26 Nevertheless, further investigation of the association between race and colorectal cancer molecular profiles appears warranted.

Finally, several prior studies have investigated differences in response to therapy and toxicity by race. In the adjuvant setting, an analysis of 3380 patients enrolled in a randomized trial of 5-FU-based chemotherapy found lower rates of treatment toxicity, including diarrhea, nausea, vomiting, stomatitis, and overall toxicity, in Black patients compared to their White counterparts.²⁷ A secondary analysis of the North Central Cancer Treatment Group (NCCTG) N9741 randomized controlled trial comparing chemotherapy regimens in the treatment of metastatic CRC demonstrated lower response rates (28% vs. 41%, p=0.008) and lower adverse event rates (34% vs. 48%, p=0.004) in Black compared to White patients.¹⁰ Similarly, a study of over 1800 patients with metastatic colorectal cancer treated with bevacizumab and enrolled in a prospective, observational cohort study found lower response rates in Black patients [37.5% vs. 46.3%, OR 0.67 (95% CI 0.5-0.90)].²⁸ In the present study, no difference in response rates or in the frequency of dose reductions was observed by race. Rates of toxicity were similar, with the exception of lower rates of severe fatigue among Black patients compared to White patients. It has been previously hypothesized that the observed worse survival in Black patients could be the result of diminished sensitivity to the effects of therapy, including toxicity and therapeutic benefits; however, this did not appear to be the case in this propensity matched analysis.

There are several limitations to this study. First, this is a secondary analysis of a propensity matched cohort of patients. Although the groups were matched for important variables known to affect survival, several differences remained between the groups, specifically performance status and palliative intention of treatment (vs. neoadjuvant). Second, although a 3-month difference in median OS was observed between Whites and Blacks (29 vs. 26 months, respectively), this did not reach significance. It is possible that this study was underpowered to detect a difference in survival by race, and the negative findings could represent a type II error. Third, KRAS status was missing in 30% (82 pairs/278 pairs) of the initial cohort of Black patients, which limits the cohort size eligible for KRAS analysis. Fourth, although underweight has been previously associated with worse mortality, due to the small number of underweight patients in the study cohort (11 patients: 5 Black and 6 White among 392 patients), underweight and normal weight categories were combined for the purposes of body mass index (BMI) analysis. Therefore, the association of overweight/obesity with lower mortality found in this study should be interpreted with caution.

CONCLUSION

Despite prior evidence that Black patients with CRC experience worse outcomes than White patients, no evidence of survival difference between Black and White patients with advanced or metastatic CRC within the context of this randomized clinical trial in which patients receive standardized treatment. In addition, no difference in best response to therapy was observed by race. In this setting of equal treatment, racial disparities in metastatic CRC survival are no longer present, suggesting that differences in access to care and treatment delivery may be responsible for the racial disparities in survival observed in epidemiologic studies.

Supplementary Material

tableS1

NIHMS1700072-supplement-tableS1.docx^{(22KB, docx)}

Acknowledgements:

The authors would like to acknowledge Eric Wolfe for his contributions to data transfer, figure generation, and analytical interpretation.

Funding Statement:

Research reported in this publication was supported by the National Cancer Institute of the National Institutes of Health under the Award Numbers (UG1CA189823, U10CA180821, U10CA180882 to the Alliance for Clinical Trials in Oncology), UG1CA232760, UG1CA233327, UG1CA233329, UG1CA233331, UG1CA233373, U10CA180888 and UG1CA180830 (SWOG) https://acknowledgments.alliancefound.org. Also supported in part by Bristol-Myers Squibb, Genentech, Myriad, Pfizer, and Sanofi (all CALGB 80405). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Footnotes

Conflict of Interest Statement: The authors have no relevant financial conflicts or disclosures to report. This manuscript has been reviewed and approved by all authors.

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6.Lai Y, Wang C, Civan JM, et al. Effects of Cancer Stage and Treatment Differences on Racial Disparities in Survival From Colon Cancer: A United States Population-Based Study. Gastroenterology. 2016;150(5):1135–1146. [DOI] [PMC free article] [PubMed] [Google Scholar]
7.Albain KS, Unger JM, Crowley JJ, Coltman CA, Jr., Hershman DL. Racial disparities in cancer survival among randomized clinical trials patients of the Southwest Oncology Group. J Natl Cancer Inst. 2009;101(14):984–992. [DOI] [PMC free article] [PubMed] [Google Scholar]
8.Yoon HH, Shi Q, Alberts SR, et al. Racial Differences in BRAF/KRAS Mutation Rates and Survival in Stage III Colon Cancer Patients. J Natl Cancer Inst. 2015;107(10). [DOI] [PMC free article] [PubMed] [Google Scholar]
9.Yothers G, Sargent DJ, Wolmark N, et al. Outcomes among black patients with stage II and III colon cancer receiving chemotherapy: an analysis of ACCENT adjuvant trials. J Natl Cancer Inst. 2011;103(20):1498–1506. [DOI] [PMC free article] [PubMed] [Google Scholar]
10.Sanoff HK, Sargent DJ, Green EM, McLeod HL, Goldberg RM. Racial differences in advanced colorectal cancer outcomes and pharmacogenetics: a subgroup analysis of a large randomized clinical trial. J Clin Oncol. 2009;27(25):4109–4115. [DOI] [PMC free article] [PubMed] [Google Scholar]
11.Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017;317(23):2392–2401. [DOI] [PMC free article] [PubMed] [Google Scholar]
12.Gharibvand L, Liu L. Analysis of Survival Data with Clustered Events. SAS Global Forum 2009 Statistics and Data Analysis. 2009. [Google Scholar]
13.Lin DY, Wei LJ, Ying Z. Checking the Cox Model with Cumulative Sums of Martingale-Based Residuals. Biometrika. 1993;80(3):557–572. [Google Scholar]
14.Stokes M, Davis CS, Koch GG. Categorical Data Analysis Using the SAS System. 2 ed.Cary, NC: SAS Institute Inc.; 2001. [Google Scholar]
15.Peeters M, Kafatos G, Taylor A, et al. Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials. Eur J Cancer. 2015;51(13):1704–1713. [DOI] [PubMed] [Google Scholar]
16.Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–1634. [DOI] [PubMed] [Google Scholar]
17.Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28(3):466–474. [DOI] [PubMed] [Google Scholar]
18.Yoon HH, Tougeron D, Shi Q, et al. KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance). Clin Cancer Res. 2014;20(11):3033–3043. [DOI] [PMC free article] [PubMed] [Google Scholar]
19.Jones RP, Sutton PA, Evans JP, et al. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br J Cancer. 2017;116(7):923–929. [DOI] [PMC free article] [PubMed] [Google Scholar]
20.Innocenti F, Ou F-S, Qu X, et al. Mutational Analysis of Patients With Colorectal Cancer in CALGB/SWOG 80405 Identifies New Roles of Microsatellite Instability and Tumor Mutational Burden for Patient Outcome. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019;37(14):1217–1227. [DOI] [PMC free article] [PubMed] [Google Scholar]
21.Brule SY, Jonker DJ, Karapetis CS, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. 2015;51(11):1405–1414. [DOI] [PubMed] [Google Scholar]
22.Tong JH, Lung RW, Sin FM, et al. Characterization of rare transforming KRAS mutations in sporadic colorectal cancer. Cancer Biol Ther. 2014;15(6):768–776. [DOI] [PMC free article] [PubMed] [Google Scholar]
23.Venook AP, Ou F-S, Lenz H-J, et al. Primary (1°) tumor location as an independent prognostic marker from molecular features for overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB / SWOG 80405 (Alliance). Journal of Clinical Oncology. 2017;35(15_suppl):3503–3503. [Google Scholar]
24.Sylvester BE, Huo D, Khramtsov A, et al. Molecular analysis of colorectal tumors within a diverse patient cohort at a single institution. Clin Cancer Res. 2012;18(2):350–359. [DOI] [PMC free article] [PubMed] [Google Scholar]
25.Sehdev A, Niedzwiecki D, Venook AP, et al. Association of RAS mutations with race in metastatic colorectal cancer: CALGB/SWOG 80405 (ALLIANCE). Journal of Clinical Oncology. 2018;36(4_suppl):638–638. [Google Scholar]
26.Lenz HJ, Ou FS, Venook AP, et al. Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2019;37(22):1876–1885. [DOI] [PMC free article] [PubMed] [Google Scholar]
27.McCollum AD, Catalano PJ, Haller DG, et al. Outcomes and toxicity in african-american and caucasian patients in a randomized adjuvant chemotherapy trial for colon cancer. J Natl Cancer Inst. 2002;94(15):1160–1167. [DOI] [PubMed] [Google Scholar]
28.Polite BN, Sing A, Sargent DJ, et al. Exploring racial differences in outcome and treatment for metastatic colorectal cancer: results from a large prospective observational cohort study (BRiTE). Cancer. 2012;118(4):1083–1090. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

tableS1

NIHMS1700072-supplement-tableS1.docx^{(22KB, docx)}

[R1] 1.Robbins AS, Siegel RL, Jemal A. Racial disparities in stage-specific colorectal cancer mortality rates from 1985 to 2008. J Clin Oncol. 2012;30(4):401–405. [DOI] [PubMed] [Google Scholar]

[R2] 2.Siegel RL, Miller KD, Goding Sauer A, et al. Colorectal cancer statistics, 2020. CA Cancer J Clin. 2020. [DOI] [PubMed] [Google Scholar]

[R3] 3.Siegel RL, Miller KD, Fedewa SA, et al. Colorectal cancer statistics, 2017. CA Cancer J Clin. 2017;67(3):177–193. [DOI] [PubMed] [Google Scholar]

[R4] 4.Demissie K, Oluwole OO, Balasubramanian BA, Osinubi OO, August D, Rhoads GG. Racial differences in the treatment of colorectal cancer: a comparison of surgical and radiation therapy between Whites and Blacks. Ann Epidemiol. 2004;14(3):215–221. [DOI] [PubMed] [Google Scholar]

[R5] 5.Gross CP, Smith BD, Wolf E, Andersen M. Racial disparities in cancer therapy: did the gap narrow between 1992 and 2002? Cancer. 2008;112(4):900–908. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R6] 6.Lai Y, Wang C, Civan JM, et al. Effects of Cancer Stage and Treatment Differences on Racial Disparities in Survival From Colon Cancer: A United States Population-Based Study. Gastroenterology. 2016;150(5):1135–1146. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R7] 7.Albain KS, Unger JM, Crowley JJ, Coltman CA, Jr., Hershman DL. Racial disparities in cancer survival among randomized clinical trials patients of the Southwest Oncology Group. J Natl Cancer Inst. 2009;101(14):984–992. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R8] 8.Yoon HH, Shi Q, Alberts SR, et al. Racial Differences in BRAF/KRAS Mutation Rates and Survival in Stage III Colon Cancer Patients. J Natl Cancer Inst. 2015;107(10). [DOI] [PMC free article] [PubMed] [Google Scholar]

[R9] 9.Yothers G, Sargent DJ, Wolmark N, et al. Outcomes among black patients with stage II and III colon cancer receiving chemotherapy: an analysis of ACCENT adjuvant trials. J Natl Cancer Inst. 2011;103(20):1498–1506. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R10] 10.Sanoff HK, Sargent DJ, Green EM, McLeod HL, Goldberg RM. Racial differences in advanced colorectal cancer outcomes and pharmacogenetics: a subgroup analysis of a large randomized clinical trial. J Clin Oncol. 2009;27(25):4109–4115. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R11] 11.Venook AP, Niedzwiecki D, Lenz HJ, et al. Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA. 2017;317(23):2392–2401. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R12] 12.Gharibvand L, Liu L. Analysis of Survival Data with Clustered Events. SAS Global Forum 2009 Statistics and Data Analysis. 2009. [Google Scholar]

[R13] 13.Lin DY, Wei LJ, Ying Z. Checking the Cox Model with Cumulative Sums of Martingale-Based Residuals. Biometrika. 1993;80(3):557–572. [Google Scholar]

[R14] 14.Stokes M, Davis CS, Koch GG. Categorical Data Analysis Using the SAS System. 2 ed.Cary, NC: SAS Institute Inc.; 2001. [Google Scholar]

[R15] 15.Peeters M, Kafatos G, Taylor A, et al. Prevalence of RAS mutations and individual variation patterns among patients with metastatic colorectal cancer: A pooled analysis of randomised controlled trials. Eur J Cancer. 2015;51(13):1704–1713. [DOI] [PubMed] [Google Scholar]

[R16] 16.Amado RG, Wolf M, Peeters M, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26(10):1626–1634. [DOI] [PubMed] [Google Scholar]

[R17] 17.Roth AD, Tejpar S, Delorenzi M, et al. Prognostic role of KRAS and BRAF in stage II and III resected colon cancer: results of the translational study on the PETACC-3, EORTC 40993, SAKK 60-00 trial. J Clin Oncol. 2010;28(3):466–474. [DOI] [PubMed] [Google Scholar]

[R18] 18.Yoon HH, Tougeron D, Shi Q, et al. KRAS codon 12 and 13 mutations in relation to disease-free survival in BRAF-wild-type stage III colon cancers from an adjuvant chemotherapy trial (N0147 alliance). Clin Cancer Res. 2014;20(11):3033–3043. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R19] 19.Jones RP, Sutton PA, Evans JP, et al. Specific mutations in KRAS codon 12 are associated with worse overall survival in patients with advanced and recurrent colorectal cancer. Br J Cancer. 2017;116(7):923–929. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R20] 20.Innocenti F, Ou F-S, Qu X, et al. Mutational Analysis of Patients With Colorectal Cancer in CALGB/SWOG 80405 Identifies New Roles of Microsatellite Instability and Tumor Mutational Burden for Patient Outcome. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2019;37(14):1217–1227. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R21] 21.Brule SY, Jonker DJ, Karapetis CS, et al. Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer. 2015;51(11):1405–1414. [DOI] [PubMed] [Google Scholar]

[R22] 22.Tong JH, Lung RW, Sin FM, et al. Characterization of rare transforming KRAS mutations in sporadic colorectal cancer. Cancer Biol Ther. 2014;15(6):768–776. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R23] 23.Venook AP, Ou F-S, Lenz H-J, et al. Primary (1°) tumor location as an independent prognostic marker from molecular features for overall survival (OS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB / SWOG 80405 (Alliance). Journal of Clinical Oncology. 2017;35(15_suppl):3503–3503. [Google Scholar]

[R24] 24.Sylvester BE, Huo D, Khramtsov A, et al. Molecular analysis of colorectal tumors within a diverse patient cohort at a single institution. Clin Cancer Res. 2012;18(2):350–359. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R25] 25.Sehdev A, Niedzwiecki D, Venook AP, et al. Association of RAS mutations with race in metastatic colorectal cancer: CALGB/SWOG 80405 (ALLIANCE). Journal of Clinical Oncology. 2018;36(4_suppl):638–638. [Google Scholar]

[R26] 26.Lenz HJ, Ou FS, Venook AP, et al. Impact of Consensus Molecular Subtype on Survival in Patients With Metastatic Colorectal Cancer: Results From CALGB/SWOG 80405 (Alliance). J Clin Oncol. 2019;37(22):1876–1885. [DOI] [PMC free article] [PubMed] [Google Scholar]

[R27] 27.McCollum AD, Catalano PJ, Haller DG, et al. Outcomes and toxicity in african-american and caucasian patients in a randomized adjuvant chemotherapy trial for colon cancer. J Natl Cancer Inst. 2002;94(15):1160–1167. [DOI] [PubMed] [Google Scholar]

[R28] 28.Polite BN, Sing A, Sargent DJ, et al. Exploring racial differences in outcome and treatment for metastatic colorectal cancer: results from a large prospective observational cohort study (BRiTE). Cancer. 2012;118(4):1083–1090. [DOI] [PubMed] [Google Scholar]

PERMALINK

Racial Differences in Survival and Response to Therapy in Patients with Metastatic Colorectal Cancer: A Secondary Analysis of CALGB/SWOG 80405 (Alliance A151931)

Rebecca A Snyder, MD, MPH

Jun He, PhD

Jennifer Le-Rademacher, PhD

Fang-Shu Ou, PhD

Andrew B Dodge, MS

Tyler J Zemla, MS

Electra D Paskett, PhD

George J Chang, MD, MS

Federico Innocenti, MD, PhD

Charles Blanke, MD

Heinz-Josef Lenz, MD

Blase N Polite, MD

Alan P Venook, MD.

Abstract

BACKGROUND:

METHODS:

RESULTS:

CONCLUSION:

Lay Summary:

Precis:

INTRODUCTION

METHODS

Study Population

Outcome Measures & Covariates

Statistical Analysis

Table 1.

RESULTS

Figure 1.

Primary Outcomes

Figure 2.

Figure 3.

Table 2.

Secondary Outcomes

Table 3.

DISCUSSION

CONCLUSION

Supplementary Material

Acknowledgements:

Funding Statement:

Footnotes

References

Associated Data

Supplementary Materials

ACTIONS

PERMALINK

RESOURCES

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