Search

International audience; Fluoropyrimidines (fluorouracil, capecitabine, and other analogs) are highly used anticancer drugs worldwide. However, patients with cancer treated with these drugs might experience severe, life-threatening toxicity because of germline genetic variation in the DPYD gene. This is a genetic predisposition with an established mechanistic basis that links genetic variation in the DPYD gene to an increase in systemic drug exposure, resulting in an increased risk of toxicity. Pharmacology guidelines provide recommendations on avoiding treatment with fluoropyrimidines or reducing their dose in patients carrying DPYD genetic variants conferring an increased risk of toxicity. However, oncology societies in the United States do not recommend systematic testing. Instead, on April 30, 2020, the European Society for Medical Oncology issued a document recommending genetic testing. In this scenario of contradicting information, practicing oncologists struggle with reaching an informed decision on whether genetic testing should be applied before treatment. This is mostly due to uncertainty about the clinical relevance of genetic testing from the perspective of a practicing oncologist. To reach an informed decision, practicing oncologists need access to concise information on the genetic variants to be tested and a practitioner-friendly interpretation of the test results. We believe this information is currently lacking. To our knowledge, for the first time, we provide a single guide for health care professionals to make an evidence-based decision about DPYD testing for patients with cancer. This article provides the essential knowledge base for oncologists to have an informed discussion with their patients about the genetic testing for DPYD. This document assists practitioners in quickly evaluating whether, when, where, and how to order a DPYD genetic test.

RESEARCH OBJECTIVE: Racial disparities in health care experiences and access are well‐documented. Yet, little is known regarding racial variations in the confluence of multiple health care access (HCA) experiences among cancer patients. We identified cancer patient subgroups with similar, co‐occurring HCA experiences, and evaluated racial differences in HCA subgroup membership. STUDY DESIGN: We used data from the University of North Carolina Health Registry/Cancer Survivorship Cohort. Participants completed a baseline questionnaire assessing demographics, health history, health‐related quality of life, and health care experiences. HCA was assessed along five domains (ie, doctor interpersonal manner, doctor communication, financial burden, time spent with doctor, and accessibility/convenience) using the RAND Patient Satisfaction Questionnaire. We used latent profile analysis to identify subgroups of patients with similar HCA experiences. Modified Poisson regressions were estimated to assess racial differences in HCA subgroup membership, adjusting for patient clinical and demographic characteristics. POPULATION STUDIED: Black and white breast, gastrointestinal, genitourinary, and head/neck cancer patients aged 18 or older and enrolled in the University of North Carolina Health Registry/Cancer Survivorship Cohort during 2010 to 2016. PRINCIPAL FINDINGS: Our analysis included 393 black (14.8%) and 2265 white (85.2%) participants. The latent profile analysis resulted in an optimal solution of 5 HCA profiles/subgroups, ranging from Low HCA to High HCA. Members of profile 1 (6.0% of sample) reported “Low” HCA along all HCA domains. Profile 2 (10.8%) consisted of individuals reporting low scores on every HCA domain except “financial burden,” where scores were moderate. Profile 3 (49.9%) members exhibited moderate scores on each HCA domain, while members of profile 4 (11.7%%) reported moderate HCA scores on most HCA domains, with the exception of low scores on “financial burden.” Profile 5 (21.7%) was comprised of patients reporting “High” HCA along every HCA domain. In unadjusted chi‐square comparisons, black patients were more likely to be in the “Low” HCA group (Profile 1) than whites (11.11% vs 5.3%, P

Background Multiple claims-based proxy measures of poor function have been developed to address confounding in observational studies of drug effects in older adults. We evaluated agreement between these measures and their associations with treatment receipt and mortality in a cohort of older colon cancer patients. Methods Medicare beneficiaries age 66+ diagnosed with stage II-III colon cancer were identified in the Surveillance, Epidemiology, and End Results-Medicare database (2004-2011). Poor function was operationalized by: (1) summing the total poor function indicators for each model; and (2) estimating predicted probabilities of poor function at diagnosis. Agreement was evaluated using Fleiss' κ and Spearman's correlation. Associations between proxy measures and: (1) laparoscopic versus open surgery; (2) chemotherapy versus none; (3) 5-fluorouracil (5FU)+oxaliplatin (FOLFOX) versus 5FU monotherapy; and (4) 1-year mortality were estimated using log-binomial regression, controlling for age, sex, stage, and comorbidity. Survival estimates were stratified by functional group, age, and comorbidity. Results Among 29,687 eligible colon cancer patients, 67% were 75+ years and 45% had stage III disease. Concordance across the poor function indicator counts was moderate (κ: 0.64) and correlation of predicted probability measures varied (ρ: 0.21-0.74). Worse function was associated with lower chemotherapy and FOLFOX receipt, and higher 1-year mortality. Within age and comorbidity strata, poor function remained associated with mortality. Conclusions While agreement varied across the claims-based proxy measures, each demonstrated anticipated associations with treatment receipt and mortality independent of comorbidity. Claims-based comparative effectiveness studies in older populations should consider applying one of these models to improve confounding control.

Upfront chemoradiation with omission of surgery (CR-only) is increasingly being used to treat rectal cancer. When CR-only is used with curative intent, intense surveillance is recommended. We hypothesized that in practice, few patients treated with CR-only receive intensive post-treatment surveillance.Using Surveillance, Epidemiology, and End Results (SEER)-Medicare, all nonmetastatic rectal cancer patients (≥66 years old) diagnosed from 2004 to 2012, who received upfront chemoradiation, were included. Patients who received CR-only were compared with patients receiving neoadjuvant therapy plus proctectomy. In the 24 months after treatment, markers of surveillance, including carcinoembryonic antigen testing (CEA), endoscopy, and imaging, were compared between groups.A total of 2,482 individuals met the inclusion criteria: 21% (n = 514) had CR-only and 79% had conventional treatment (ie chemoradiation plus proctectomy). Only 2.5% and 3.4% of those in the CR-only and conventional treatment groups, respectively, were in complete compliance with National Comprehensive Cancer Network surveillance guidelines during the first 2 years post-treatment (p0.01). The CR-only group was less likely than the conventional treatment group to receive: CEA (adjusted risk ratio [aRR] 0.57; 95% CI 0.50 to 0.65), endoscopy (aRR 0.76; 95% CI 0.66 to 0.87), and office visits (aRR 0.88; 95% CI 0.84 to 0.92), respectively. However, there were similar rates of cross-sectional imaging between groups (aRR 1.31; 95% CI 0.93 to 1.85).Adherence to guideline-recommended surveillance was poor for all Medicare patients with rectal cancer. Despite recommendations for closer follow-up, patients treated with CR-only were less likely to receive surveillance than those treated with conventional treatment. Efforts should be made to increase adherence to surveillance guidelines for all rectal cancer patients treated with curative intent, but particularly for those with higher risk of recurrence, such as those treated with CR-only.

PURPOSE: In older women, breast cancer and its treatment can have profound impact on their physical, mental, and social health, especially in frail patients. This study evaluated the association between frailty and long-term health-related quality of life (HRQOL) in older women undergoing breast cancer treatment. METHODS: Using the Carolina Senior Registry (CSR), participants with breast cancer were contacted to complete a follow-up HRQOL questionnaire (median 4 years). Baseline Geriatric Assessment (GA) variables were used to calculate the Carolina Frailty Index (CFI) and categorize participants as robust, pre-frail, or frail. Outcomes included HRQOL domains of physical function, social roles, fatigue, depression, anxiety, pain, and sleep disturbance assessed using PROMIS(®) instruments. Regression modeling compared outcomes between frailty groups using adjusted mean differences (AMD). RESULTS: Of 190 eligible patients, 63 completed follow-up HRQOL survey. Mean age was 70 years (range 65–86) and 91% were white. Based on the CFI, 49 (78%) patients were robust, 11 (18%) pre-frail, and 3 (5%) frail. After controlling for age and cancer stage, patients identified as pre-frail/frail reported worse physical function (AMD −9.2, p

Background The decision whether to treat older adults with advanced cancer with standard therapy (ST) or reduced therapy (RT) is complicated by heterogeneity in aging. We assessed the potential utility of the chemotherapy toxicity risk score (CTRS) [J Clin Oncol 2011;29:3457–3465] for treatment decisions in older adults. Materials and Methods This was a prospective observational study of patients aged ≥65 years receiving first-line chemotherapy for advanced cancer for which combination chemotherapy is the standard of care. Patients were categorized as high risk (CTRS ≥10), for whom RT (dose-reduced combination or single-agent chemotherapy) is deemed appropriate, or nonhigh risk (CTRS Results Fifty-eight patients (median age, 71 years) were enrolled. Thirty-eight patients received ST (21 had CTRS Conclusion Older patients with cancer with a high CTRS who receive combination chemotherapy have an exceedingly high rate of severe toxicity and hospitalization. Implications for Practice The potential utility of the chemotherapy toxicity risk score (CTRS) in old adults with advanced solid tumors receiving first-line chemotherapy was assessed. Little agreement was found between chemotherapy treatment decisions based on the clinical impression versus what was recommended based on the CTRS. Among patients treated with standard-dose combination chemotherapy, patients with CTRS ≥10 had a very high incidence of grade 3–4 toxicities and hospitalization, which was significantly greater than that of patients with a low CTRS (

Background Our ability to optimize the care of older adults with cancer and comorbid illnesses is insufficient because most clinical trials lack systematic measurement. The primary purpose of this study was to evaluate the association between patient-reported comorbidity and all-cause mortality using various comorbidity scoring algorithms. Materials and Methods The Carolina Senior Registry was linked with the North Carolina Central Cancer Registry to obtain mortality data. Comorbidity was assessed using the patient-reported Older Americans Resources and Services Questionnaire subscale that assesses 13 specific conditions and the degree to which each impairs activities. Multivariable Cox proportional hazard regression models were used to evaluate the association between comorbidities and all-cause mortality. Results The study sample included 539 patients; the median age was 72 years, 72% were female, and 47% had breast cancer. Overall, 92% reported ≥1 comorbid condition, with a mean of 2.7 conditions (range 0–10), with arthritis and hypertension the most common (52% and 50%, respectively). Approximately 60% reported a functional limitation related to comorbidity. After adjusting for time from diagnosis to geriatric assessment, age, cancer type, and stage, the risk of death increased by 5% for each unit increase in comorbidity burden score (adjusted hazard ratio [HR] = 1.05, 95% confidence interval [CI]: 1.01–1.10) and 12% for each comorbid condition impacting function (HR = 1.12, 95% CI: 1.02–1.23). Conclusion Comorbid conditions in older adults with cancer are highly prevalent and associated with all-cause mortality, particularly those conditions that impair function. Routine comorbidity assessment should be included in clinical trials and can be measured via a simple one-page patient-reported questionnaire. Implications for Practice In order to optimize and personalize the care of older adults with cancer, systematic measurement of comorbidities is necessary in both clinical trials and routine practice. Patient-reported comorbid conditions in older adults with cancer are highly prevalent and are associated with increased risk of all-cause mortality, particularly for those conditions that impair function. Comorbidity can be systematically measured via a one-page patient-reported questionnaire and should be incorporated into future clinical trials and considered for use in oncology clinics to aid in assessing older adults with cancer.

Great heterogeneity exists in the ability of adults with cancer to tolerate chemotherapy. Variability in body composition may affect rates of metabolism of cytotoxic agents and contribute to the variable chemotherapy toxicity observed. The objective of this exploratory study was to examine the association of low skeletal muscle, commonly known as sarcopenia, on the pharmacokinetics (PKs) of 5-fluorouracil (5FU) in patients receiving FOLFOX for colorectal cancer. We performed a secondary analysis of a completed multicenter trial that investigated PK-guided 5FU dosing in patients receiving mFOLFOX6 +/− bevacizumab for colorectal cancer. Cycle 1 PK samples were obtained 2–44 h after the start of the 5FU infusion (steady state). No significant differences in first cycle 5FU area-under-the-concentration-time-curve (AUC) were found between sarcopenic and non-sarcopenic patients (17.3 vs. 19.3 AUC, p = 0.43). Patients with grade 3/4 toxicity had a higher dose of 5FU per kg lean body mass (LBM) (105 vs. 93 mg/kg, p = 0.06), most notably for hematological toxicities (110 vs. 94 mg/kg, p = 0.002); however, no correlation between the dose/LBM and 5FU AUC was found. Although our results did not confirm the impact of low skeletal muscle on PKs of 5FU, further research exploring the impact of body composition on chemotherapy PKs and related toxicities is warranted with the potential for alternative dosing strategies in sarcopenic patients to reduce unnecessary toxicities while maintaining efficacy.

Background and Aims.As a first step toward understanding the increasing incidence of colorectal cancer (CRC) in younger (age < 50) populations, we examined demographic, clinicopathologic, and socioeconomic characteristics and treatment receipt in a population-based sample of patients newly diagnosed with stages II and III CRC.Methods.Patients were sampled from the National Cancer Institute’s Patterns of Care studies in 1990/91, 1995, 2000, 2005, and 2010 (n=6,862). Tumor characteristics and treatment data were obtained through medical record review and physician verification. We compared sociodemographic and clinicopathologic characteristics and treatment patterns of younger (age < 50) and older (age 50–69, age ≥ 70) CRC patients.Results.Younger patients were more likely to be black (13%) and Hispanic (15%) than patients aged 50–69 years (11% and 10%, resp.) and ≥70 years (7% each). A larger proportion of young white (41%) and Hispanic (33%) patients had rectal tumors, whereas tumors in the right colon were the most common in young black patients (39%). The majority of younger patients received chemotherapy and radiation therapy, although receipt of microsatellite instability testing was suboptimal (27%).Conclusion.Characteristics of patients diagnosed with young-onset CRC differ considerably by race/ethnicity, with a higher proportion of black and Hispanic patients diagnosed at the age of < 50 years.

Background Optimal administration of transarterial chemoembolization (TACE), the standard approach for intermediate-stage hepatocellular carcinoma (HCC), requires clinical and technical expertise. We sought to evaluate whether TACE retains its effectiveness when administered across a broad range of health care settings. Furthermore, as the use of yttrium(90) (Y(90)) radioembolization has been increasing, we explored the comparative effectiveness of Y(90) as an alternative to TACE. Methods Patients with HCC diagnosed from 2004 through 2009 treated initially with TACE or Y(90) were identified from the SEER-Medicare linkage. Key covariates included prediagnosis α-fetoprotein (AFP) screening, complications of cirrhosis, and tumor extent. Effect of treatment, patient, and health care system factors on overall survival (OS) was evaluated using multivariable Cox proportional hazards. Stratified OS estimates are provided. Propensity score (PS) weighting was used to compare effectiveness of Y(90) with TACE. Results Of 1528 patients who underwent intra-arterial embolization, 577 received concurrent chemotherapy (eg, TACE). Median OS was 21 months (95% CI, 18-23) following TACE and 9 months (95% CI, 1-41) following Y(90). Refined survival estimates stratified by stage, AFP screening, and liver comorbidity are presented. The 90-day mortality rate after TACE was 21% to 25% in patients with extrahepatic spread or vascular invasion. In the PS-weighted analysis, Y(90) was associated with inferior survival, with an adjusted hazard ratio of 1.39 (95% CI, 1.02-1.90). Conclusions The effectiveness of TACE is generalizable to Medicare patients receiving care in a variety of treatment settings. However, early posttreatment mortality is high in patients with advanced disease. We found no evidence of improved outcomes with Y(90) compared with TACE. Survival estimates from this large cohort can be used to provide prognostic information to patients considering palliative TACE.

Background Colorectal cancer (CRC) risk is partly conferred by common, low-penetrance single nucleotide polymorphisms (SNPs). We hypothesized that these SNPs are associated with outcomes in metastatic CRC. Methods Six candidate SNPs from 8q24, 10p14, 15q13, 18q21 were investigated for their association with response rate (RR), time to progression (TTP) and overall survival (OS) among 524 patients treated on a phase III clinical trial of first-line chemotherapy for metastatic CRC. Results rs10795668 was weakly associated with TTP (p = 0.02), but not RR or OS. No other SNPs carried statistically significant HRs for any of the primary outcomes (RR, TTP or OS). Conclusion Common low-penetrance CRC risk SNPs were not associated with outcomes among patients with metastatic CRC.

Purpose Standard of care treatment for most stage I rectal cancers is total mesorectal excision (TME). Given the morbidity associated with TME, local excision (LE) for early-stage rectal cancer has been explored. This study examines practice patterns and overall survival (OS) for early-stage rectal cancer. Methods All patients in the National Cancer Data Base diagnosed with rectal cancer from 1998 to 2010 were initially included. Use of LE versus proctectomy and use of adjuvant radiation therapy were compared over time. Adjusted Cox proportional hazards models were used to compare OS based on treatment. Results LE was used to treat 46.5% of patients with T1 and 16.8% with T2 tumors. Use of LE increased steadily over time (P < .001). LE was most commonly used for women, black patients, very old patients, those without private health insurance, those with well-differentiated tumors, and those with T1 tumors. Proctectomy was associated with higher rates of tumor-free surgical margins compared with LE (95% v 76%; P < .001). Adjuvant radiation therapy use decreased over time independent of surgical procedure or T stage. For T2N0 disease, patients treated with LE alone had significantly poorer adjusted OS than those treated with proctectomy alone or multimodality therapy. Conclusion Guideline-concordant adoption of LE for treatment of low-risk stage I rectal cancer is increasing. However, use of LE is also increasing for higher-risk rectal cancers that do not meet guideline criteria for LE. Treatment with LE alone is associated with poorer long-term OS. Additional studies are warranted to understand the factors driving increased use of LE.

Purpose Few patients 75 years of age and older participate in clinical trials, thus whether adjuvant chemotherapy for stage III colon cancer (CC) benefits this group is unknown. Methods A total of 5,489 patients ≥ 75 years of age with resected stage III CC, diagnosed between 2004 and 2007, were selected from four data sets containing demographic, stage, treatment, and survival information. These data sets included SEER-Medicare, a linkage between the New York State Cancer Registry (NYSCR) and its Medicare programs, and prospective cohort studies Cancer Care Outcomes Research and Surveillance Consortium (CanCORS) and the National Comprehensive Cancer Network. Data sets were analyzed in parallel using covariate adjusted and propensity score (PS) matched proportional hazards models to evaluate the effect of treatment on survival. PS trimming was used to mitigate the effects of selection bias. Results Use of adjuvant therapy declined with age and comorbidity. Chemotherapy receipt was associated with a survival benefit of comparable magnitude to clinical trials results (SEER-Medicare PS-matched mortality, hazard ratio [HR], 0.60; 95% CI, 0.53 to 0.68). The incremental benefit of oxaliplatin over non–oxaliplatin-containing regimens was also of similar magnitude to clinical trial results (SEER-Medicare, HR, 0.84; 95% CI, 0.69 to 1.04; NYSCR-Medicare, HR, 0.82, 95% CI, 0.51 to 1.33) in two of three examined data sources. However, statistical significance was inconsistent. The beneficial effect of chemotherapy and oxaliplatin did not seem solely attributable to confounding. Conclusion The noninvestigational experience suggests patients with stage III CC ≥ 75 years of age may anticipate a survival benefit from adjuvant chemotherapy. Oxaliplatin offers no more than a small incremental benefit. Use of adjuvant chemotherapy after the age of 75 years merits consideration in discussions that weigh individual risks and preferences.

BACKGROUND: African Americans in the United States have higher rates of colon cancer mortality than other races. This study examines the use of oxaliplatin, a novel chemotherapeutic agent approved in 2004, among African American and Caucasian American patients with stage III colon cancer to determine whether differential receipt or differential effectiveness of the drug may explain the racial disparity in colon cancer mortality. METHODS: The authors conducted a population-based retrospective cohort study of stage III colon cancer patients aged 65 years and older treated from 2004 through 2006 who initiated chemotherapy within 90 days of surgical resection (N = 1162) using Surveillance, Epidemiology and End Results-Medicare data. Patients receiving oxaliplatin (n = 477) were compared with those receiving 5-fluorouracil without oxaliplatin (n = 685). The authors estimated prevalence ratios and hazard ratios (HRs) using multivariate binomial regression and Cox models to evaluate racial differences in oxaliplatin receipt and survival. RESULTS: African Americans were as likely as Caucasian Americans to receive oxaliplatin (40.5 vs 41.1%; prevalence ratio, 0.90; 95% confidence interval [CI], 0.71-1.13). Oxaliplatin was associated with lower mortality compared with 5-fluorouracil (HR, 0.76; 95% CI, 0.58-1.00). This benefit appeared stronger among African Americans (HR, 0.31; 95% CI, 0.09-1.05) than Caucasian Americans (HR, 0.80; 95% CI, 0.60-1.06). CONCLUSIONS: In Medicare-insured patients receiving chemotherapy, the authors observed no meaningful racial disparities in receipt of oxaliplatin and, among those receiving it, potentially better survival among African Americans. Differential receipt and effectiveness of oxaliplatin-containing regimens does not appear to contribute to the previously documented racial disparities in colon cancer survival. Understanding reasons for potentially enhanced effectiveness among African Americans may inform efforts to resolve racial disparities in colon cancer outcomes. Cancer 2011. © 2011 American Cancer Society.

Standard therapy for stage II/III rectal cancer consists of a fluoropyrimidine and radiation therapy followed by surgery. Preclinical data demonstrated that bortezomib functions as a radiosensitizer in colorectal cancer models. The purpose of this study was to determine the maximum tolerated dose (MTD) of bortezomib in combination with chemotherapy and radiation.Patients with locally advanced rectal adenocarcinomas, as staged by endoscopic ultrasound, were eligible. Bortezomib was administered on days 1, 4, 8, and 11 every 21 days for 2 cycles with 5-fluorouracil at 225 mg/m2/day continuously and 50.4 Gy of radiation. Dose escalation of bortezomib was conducted via a standard 3 + 3 dose escalation design. A subset of patients underwent serial tumor biopsies for correlative studies.Nine patients in 2 dose cohorts were enrolled. Diarrhea was the principal dose-limiting toxicity and occurred at the 1.0-mg/m2 dose level. There was no clear evidence of suppression of nuclear factor-kappaB target gene expression in biopsy samples.The MTD of bortezomib in combination with chemotherapy and radiation may be below a clinically relevant dose, limiting the clinical applicability of this combination. Performing biopsies before and during irradiation for determining gene expression in response to radiation therapy is feasible.

N9741 is a clinical trial in patients with metastatic colorectal cancer that was originally written in 1997 and completed patient accrual in 2004. One thousand seven hundred thirty-one patients were enrolled in the study. During the conduct of the trial, N9741 was repeatedly modified to adapt to toxicity findings, to add evaluation of oxaliplatin to what was originally a trial examining various schedules of irinotecan-based therapy, and to ask evolving questions. The trial led to a new U.S. Food and Drug Administration indication for 5-fluorouracil, leucovorin, and oxaliplatin as indicated for the treatment of previously untreated patients with metastatic colorectal cancer and helped to change the standard of care for the disease in the U.S. and worldwide. The data from the trial have been used to study multiple regimens, pharmacogenetics, and quality of life issues, to correlate plasma protein levels with outcomes, to inform trial methodology, and to perform economic analyses. To date nearly 30 papers and an even larger number of abstracts have been based upon data arising from the study. The history of the trial and the major findings are summarized in this review.

Recent work has shown that expression of the p16 INK4a tumor suppressor increases with chronological age. Expression is accelerated by gerontogenic behaviors such as tobacco use and physical inactivity, and is also influenced by allelic genotype of a polymorphic single nucleotide polymorphism (SNP) rs10757278 that is physically linked with the p16 INK4a ORF. To understand the relationship between p16 INK4a expression, chronologic age, subject characteristics and host genetics, we sought to develop a mathematical model that links p16 INK4a expression with aging. Using an annotated dataset of 170 healthy adults for whom p16 INK4a expression and subject genotypes were known, we developed two alternative stochastic models that relate p16 INK4a expression to age, smoking, exercise and rs10757278 genotype. Levels of p16 INK4a increased exponentially and then saturated at later chronologic ages. The model, which best fit the data, suggests saturation occurs because of p16 INK4a -dependent attrition of subjects at older chronologic ages, presumably due to death or chronic illness. An important feature of our model is that factors that contribute to death in a non p16 INK4a -dependent manner do not affect our analysis. Interestingly, tobacco-related increases in p16 INK4a expression are predicted to arise from a decrease in the rate of p16 INK4a -dependent death. This analysis is most consistent with the model that p16 INK4a expression monotonically increases with age, and higher expression is associated with increased subject attrition.

Purpose Racial disparities in colorectal cancer (CRC) survival are documented, but there are few data on comparative response to chemotherapy. A subgroup analysis of a multisite National Cancer Institute–sponsored trial (N9741) was performed comparing outcomes of black and white patients with metastatic CRC receiving uniform treatment. Patients and Methods Adverse events (AEs), response rate (RR), time to progression (TTP), overall survival (OS), and dose-intensity were examined as a function of self-reported race in 1,412 patients treated with irinotecan/fluorouracil, fluorouracil/oxaliplatin, or irinotecan/oxaliplatin. Pharmacogenetic analysis was performed on 486 patients with blood available for germline DNA analysis. Results OS was 1.5 months shorter and TTP was 0.6 months shorter in black than white patients (OS: hazard ratio [HR] = 1.13; 95% CI, 0.90 to 1.42; TTP: HR = 0.91, 95% CI, 0.73 to 1.13); neither difference was statistically significant. RR was significantly higher in whites (41%) than blacks (28%; P = .008). Grade 3 or greater AEs were also higher in whites (48%) than blacks (34%; P = .004). These relationships were maintained in multivariate models adjusting for arm, age, sex, and performance status. There was no difference in dose-intensity of delivered therapy. Significant racial differences in prevalence of pharmacogenetic variants were observed, although small sample size precluded investigating the relationship between treatment, race, and genotype. Conclusion OS and TTP are similar in black and white patients treated per protocol with standardized therapy for metastatic CRC. However, RR and AEs vary considerably by race. The marked racial differences in relevant pharmacogenetics, a potential explanation for differing RR and AEs, are worthy of future study.

BackgroundGenome-wide association studies (GWAS) have linked common single nucleotide polymorphisms (SNPs) on chromosome 9p21 near the INK4/ARF (CDKN2A/B) tumor suppressor locus with risk of atherosclerotic diseases and type 2 diabetes mellitus. To explore the mechanism of this association, we investigated whether expression of proximate transcripts (p16(INK4a), p15(INK4b), ARF, ANRIL and MTAP) correlate with genotype of representative 9p21 SNPs.Methodology/principal findingsWe analyzed expression of 9p21 transcripts in purified peripheral blood T-cells (PBTL) from 170 healthy donors. Samples were genotyped for six selected disease-related SNPs spanning the INK4/ARF locus. Correlations among these variables were determined by univariate and multivariate analysis. Significantly reduced expression of all INK4/ARF transcripts (p15(INK4b), p16(INK4a), ARF and ANRIL) was found in PBTL of individuals harboring a common SNP (rs10757278) associated with increased risk of coronary artery disease, stroke and aortic aneurysm. Expression of MTAP was not influenced by rs10757278 genotype. No association of any these transcripts was noted with five other tested 9p21 SNPs.Conclusions/significanceGenotypes of rs10757278 linked to increased risk of atherosclerotic diseases are also associated with decreased expression in PBTL of the INK4/ARF locus, which encodes three related anti-proliferative transcripts of known importance in tumor suppression and aging.