The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor–positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease–free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

Abstract Background Although physical activity has been consistently associated with reduced breast cancer mortality, evidence is largely based on data collected at one occasion. We examined how pre- and postdiagnosis physical activity was associated with survival outcomes in high-risk breast cancer patients. Methods Included were 1340 patients enrolled in the Diet, Exercise, Lifestyle and Cancer Prognosis (DELCaP) Study, a prospective study of lifestyle and prognosis ancillary to a SWOG clinical trial (S0221). Activity before diagnosis, during treatment, and at 1- and 2-year intervals after enrollment was collected. Patients were categorized according to the Physical Activity Guidelines for Americans as meeting the minimum guidelines (yes/no) and incrementally as inactive, low active, moderately active (meeting the guidelines), or high active. Results In joint-exposure analyses, patients meeting the guidelines before and 1 year after diagnosis experienced statistically significant reductions in hazards of recurrence (hazard ratio [HR] = 0.59, 95% confidence interval [CI] = 0.42 to 0.82) and mortality (HR = 0.51, 95% CI = 0.34–0.77); associations were stronger at 2-year follow-up for recurrence (HR = 0.45, 95% CI = 0.31 to 0.65) and mortality (HR = 0.32, 95% CI = 0.19 to 0.52). In time-dependent analyses, factoring in activity from all time points, we observed striking associations with mortality for low- (HR = 0.41, 95% CI = 0.24 to 0.68), moderate- (HR = 0.42, 95% CI = 0.23 to 0.76), and high-active patients (HR = 0.31, 95% CI = 0.18 to 0.53). Conclusions Meeting the minimum guidelines for physical activity both before diagnosis and after treatment appears to be associated with statistically significantly reduced hazards of recurrence and mortality among breast cancer patients. When considering activity from all time points, including during treatment, lower volumes of regular activity were associated with similar overall survival advantages as meeting and exceeding the guidelines.

PURPOSE Despite reported widespread use of dietary supplements during cancer treatment, few empirical data with regard to their safety or efficacy exist. Because of concerns that some supplements, particularly antioxidants, could reduce the cytotoxicity of chemotherapy, we conducted a prospective study ancillary to a therapeutic trial to evaluate associations between supplement use and breast cancer outcomes. METHODS Patients with breast cancer randomly assigned to an intergroup metronomic trial of cyclophosphamide, doxorubicin, and paclitaxel were queried on their use of supplements at registration and during treatment (n =1,134). Cox proportional hazards regression adjusting for clinical and lifestyle variables was used. Recurrence and survival were indexed at 6 months after enrollment using a landmark approach. RESULTS There were indications that use of any antioxidant supplement (vitamins A, C, and E; carotenoids; coenzyme Q10) both before and during treatment was associated with an increased hazard of recurrence (adjusted hazard ratio [adjHR], 1.41; 95% CI, 0.98 to 2.04; P = .06) and, to a lesser extent, death (adjHR, 1.40; 95% CI, 0.90 to 2.18; P = .14). Relationships with individual antioxidants were weaker perhaps because of small numbers. For nonantioxidants, vitamin B12 use both before and during chemotherapy was significantly associated with poorer disease-free survival (adjHR, 1.83; 95% CI, 1.15 to 2.92; P < .01) and overall survival (adjHR, 2.04; 95% CI, 1.22 to 3.40; P < .01). Use of iron during chemotherapy was significantly associated with recurrence (adjHR, 1.79; 95% CI, 1.20 to 2.67; P < .01) as was use both before and during treatment (adjHR, 1.91; 95% CI, 0.98 to 3.70; P = .06). Results were similar for overall survival. Multivitamin use was not associated with survival outcomes. CONCLUSION Associations between survival outcomes and use of antioxidant and other dietary supplements both before and during chemotherapy are consistent with recommendations for caution among patients when considering the use of supplements, other than a multivitamin, during chemotherapy.

Cruciferous vegetables contain isothiocyanates, which show potent chemopreventive activity against bladder cancer in both in vitro and in vivo studies. However, previous epidemiologic studies investigating cruciferous vegetable intake and bladder cancer risk have been inconsistent. Cooking can substantially reduce or destroy isothiocyanates, and could account for study inconsistencies. In this hospital-based case-control study involving 275 individuals with incident, primary bladder cancer and 825 individuals without cancer, we examined the usual prediagnostic intake of raw and cooked cruciferous vegetables in relation to bladder cancer risk. Odds ratios (OR) and 95% confidence intervals (CI) were estimated with unconditional logistic regression, adjusting for smoking and other bladder cancer risk factors. We observed a strong and statistically significant inverse association between bladder cancer risk and raw cruciferous vegetable intake (adjusted OR for highest versus lowest category = 0.64; 95% CI, 0.42-0.97), with a significant trend (P = 0.003); there were no significant associations for fruit, total vegetables, or total cruciferous vegetables. The associations observed for total raw crucifers were also observed for individual raw crucifers. The inverse association remained significant among current and heavy smokers with three or more servings per month of raw cruciferous vegetables (adjusted ORs, 0.46 and 0.60; 95% CI, respectively). These data suggest that cruciferous vegetables, when consumed raw, may reduce the risk of bladder cancer, an effect consistent with the role of dietary isothiocyanates as chemopreventive agents against bladder cancer. (Cancer Epidemiol Biomarkers Prev 2008; 17(4):938 -44)

Breast cancer in African-American (AA) women occurs at an earlier age than in European-American (EA) women and is more likely to have aggressive features associated with poorer prognosis, such as high-grade and negative estrogen receptor (ER) status. The mechanisms underlying these differences are unknown. To address this, we conducted a case-control study to evaluate risk factors for high-grade ER- disease in both AA and EA women. With the onset of the Health Insurance Portability and Accountability Act of 1996, creative measures were needed to adapt case ascertainment and contact procedures to this new environment of patient privacy. In this paper, we report on our approach to establishing a multicenter study of breast cancer in New York and New Jersey, provide preliminary distributions of demographic and pathologic characteristics among case and control participants by race, and contrast participation rates by approaches to case ascertainment, with discussion of strengths and weaknesses.

Purpose It has long been held that parity reduces risk of breast cancer. However, accumulating evidence indicates that the effects of parity, as well as breast feeding, may vary according to estrogen receptor (ER) status. We evaluated these associations in a case-control study among African-American women New York City and New Jersey. Methods In the Women’s Circle of Health Study (WCHS), including 786 African-American women with breast cancer and 1015 controls, data on reproductive histories were collected from in-person interviews, with tumor characteristics abstracted from pathology reports. We calculated number of live births and months breastfeeding for each child, and examined each in relation to breast cancer by ER status, and for triple negative (TN) breast cancer. Results Although associations were not statistically significant, having children was associated with reduced risk of ER+ breast cancer (odds ratio (OR) 0.82, 95% confidence interval (CI); 0.58–1.16), but increased risk of ER - tumors, with associations most pronounced for TN breast cancer (OR=1.81, 95% CI 0.93–3.51). Breastfeeding gave no additional benefit for ER+ cancer, but reduced the risk of ER− disease associated with parity. Conclusions Accumulating data from a number of studies, as well as our own in African-American women, indicate that the effects of parity and breastfeeding differ by ER status. African-American women are more likely to have children and not to breastfeed, and to have ER - and TN breast cancer; it is possible that breastfeeding in this population could reduce risk of more aggressive breast cancers.

Purpose Our previous work has shown low serum 25-hydroxyvitamin D concentrations in association with aggressive breast cancer subtypes. Vitamin D receptor (VDR) is central for vitamin D-mediated transcription regulation. Few studies have examined breast VDR expression with tumor characteristics or patient survival. Experimental Design VDR expression in breast tumor tissue microarrays was determined by immunohistochemistry in 1,114 female patients as low, moderate and strong expression based on an immunoreactive score, and examined with histopathological tumor characteristics and survival outcomes including progression free survival, breast cancer specific survival, and overall survival. Results A majority (58%) of breast tumors showed moderate or strong VDR expression. VDR expression was inversely related to aggressive tumor characteristics, including large tumor size, hormonal receptor (HR) negativity, and triple-negative subtype (p<0.05). In addition, VDR expression was also inversely related to Ki-67 expression among patients older than 50 years. Nevertheless, VDR expression was not associated with any patient survival outcomes examined. Conclusions In a large patient population, VDR expression is inversely associated with more aggressive breast cancer, but not with breast cancer survival outcomes. The present findings of VDR expression are consistent with our previous results of circulating vitamin D biomarkers, which provide two converging lines of evidence supporting the putative benefits of vitamin D against aggressive breast cancer. Because of the observational nature of our analyses, future studies are warranted to establish the causality of the reported associations.

Background: Intake of cruciferous vegetables, a rich source of dietary isothiocyanates, has been inversely associated with risk of bladder cancer. Due to the potent antiproliferative effects of dietary isothiocyanates on bladder cancer in in vitro and in vivo models, cruciferous vegetable intake may also play a role in survival among patients with bladder cancer.Methods: Using information obtained from the Roswell Park Cancer Institute Tumor Registry, patient medical records, and routinely collected questionnaire data, we examined potential associations between intake of cruciferous vegetables and survival among bladder cancer patients. As cooking can substantially reduce or destroy isothiocyanates, consumption of raw versus cooked cruciferous vegetables was examined separately. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazard models.Results: A total of 239 bladder cancer patients were included in the study. After an average of 8 years of follow-up, 179 deaths occurred, with 101 deaths attributable to bladder cancer. After adjustment for other prognostic factors, a strong and significant inverse association was observed between bladder cancer mortality and broccoli intake, in particular raw broccoli intake (≥1 versus <1 serving per month; HR for overall death, 0.57; 95% CI, 0.39-0.83; HR for disease-specific death, 0.43; 95% CI, 0.25-0.74). There were no significant associations for total vegetables, total fruits, or other individual cruciferous vegetables.Conclusions: Considering the strong preclinical evidence, intake of broccoli may improve bladder cancer survival. Impact: Further prospective investigation is warranted to confirm the potential role of cruciferous vegetables in bladder cancer prognosis. Cancer Epidemiol Biomarkers Prev; 19(7); 1806-11. ©2010 AACR.