Anne Ryan

A nutrient approach to prostate cancer prevention: the Selenium and Vitamin E Cancer Prevention Trial (SELECT).

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) randomized 35,533 healthy men, >55 yr old (>50 yr if African American), with normal digital rectal exams and prostate specific antigens <4 ng/ml to 1) 200 μg/day l-selenomethionine, 2) 400 IU/day all-rac-alpha-tocopheryl acetate (vitamin E), 3) both supplements, or 4) placebo for 7 to 12 yr. The hypotheses underlying SELECT, that selenium and vitamin E individually and together decrease prostate cancer incidence, derived from epidemiologic and laboratory evidence and significant secondary endpoints in the Nutritional Prevention of Cancer (selenium) and Alpha-Tocopherol Beta-Carotene (vitamin E) trials. In SELECT, prostate cancer incidence did not differ among the 4 arms: hazard ratios [99% confidence intervals (CIs)] for prostate cancer were 1.13 (99% CI = 0.95–1.35, P = 0.06; n = 473) for vitamin E, 1.04 (99% CI = 0.87–1.24, P = 0.62; n = 432) for selenium, and 1.05 (99% CI = 0.88–1.25, P = 0.52; n = 437) for selenium + vitamin E vs. 1.00 (n = 416) for placebo. Statistically nonsignificant increased risks of prostate cancer with vitamin E alone [relative risk (RR) = 1.13, P = 0.06) and newly diagnosed Type 2 diabetes mellitus with selenium alone (RR = 1.07, P = 0.16) were observed. SELECT data show that neither selenium nor vitamin E, alone or together, in the doses and formulations used, prevented prostate cancer in this heterogeneous population of healthy men.

Profile of Men Randomized to the Prostate Cancer Prevention Trial: Baseline Health-Related Quality of Life, Urinary and Sexual Functioning, and Health Behaviors

PURPOSE To describe men who agreed to be randomized to the Prostate Cancer Prevention Trial (PCPT), a 7-year, double-blind placebo-controlled study of the efficacy of finasteride in preventing prostate cancer. METHODS Comprehensive health-related quality-of-life data are presented for 18,882 randomized PCPT participants. RESULTS PCPT participants are highly educated, middle to upper income, and primarily white (92%). Participants reported healthy lifestyles. The mean American Urological Association Symptom Index score was well below the maximum entry score of less than 19; existing urinary symptoms were generally not bothersome. The scores for two sexual functioning scales could range from 0 to 100, with higher scores reflecting worse sexual functioning. The mean score for the Sexual Problem Scale was 19.2 out of 100, and the mean Sexual Activities Scale was 44.1 out of 100. Scores for seven of the eight Medical Outcomes Study 36-item Short-Form Health Survey scales (higher scores are better) were 10 to 20 points higher than those reported by a general population sample and differed minimally by race but not by age. Previously reported associations between sexual dysfunction and hypertension, diabetes, and depression were also observed. Men who never smoked reported less sexual dysfunction than did those who either had quit or still smoked. CONCLUSION Individuals who are likely to enroll in primary prevention trials have a high socioeconomic status, healthy lifestyle behaviors, and better health than the general population. These data help oncologists design chemoprevention trials with respect to the selection of health-related quality-of-life assessments and recruitment strategies.

Breast cancer prevention trials: large and small trials.

Breast cancer is the most common cancer among women in the United States, with 192,870 new cases and 40,170 deaths due to this disease estimated to have occurred 2009. An emphasis on prevention has been increasing in view of a persisting high incidence of disease. Seventy percent of breast cancers are estrogen receptor (ER)-positive, and are therefore presumed to be hormone-responsive and potentially treatable or preventable by anti-estrogenic agents. To date, the large, phase III randomized controlled breast cancer prevention trials have tested and are testing only hormonal drugs designed to antagonize the carcinogenic effect of endogenous estrogen; these agents are either selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs). The SERMs, tamoxifen and raloxifene, have been shown in these large trials to reduce the risk of ER-positive breast cancers; prevention trials of AIs are ongoing. Interest is now focusing on developing agents with a broader spectrum of preventive activity, particularly with regard to ER-negative subtypes of breast cancer. A number of phase I and II trials using tissue-derived surrogate endpoint biomarkers (SEBs) as outcomes have been implemented. These smaller trials address prevention not only of ER-negative but also ER-positive breast cancers, since approximately 50% of the latter have been shown to be resistant to the estrogen-targeting drugs used in the large trials. Issues of importance in these smaller trials include choice of agent, selection of appropriate trial participants, trial design, method of access to breast tissue in women without cancer, selection and monitoring of SEBs, and monitoring of drug toxicity.

Seleneium and Vitamin E Cancer Prevention Trial: A Nutrient Approach to Prostate Cancer Prevention

Prostate cancer continues to be both a major health threat, especially among African-American men, and a public health burden. However, growing evidence suggests that selenium and vitamin E may decrease the risk of this disease. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), a phase III randomized, placebo-controlled study, is designed to determine whether selenium and vitamin E, alone or in combination, decrease the risk of prostate cancer in healthy men. SELECT opened to accrual on 25 July 2001 in more than 400 clinical sites across the United States, Puerto Rico, and Canada; the goal was to randomize 32,400 men. Accrual was completed in June 2004, 2 years ahead of schedule, with a total of 35,534 men randomized. Eligibility requirements include age of at least 55 years (African-American men at least 50 years), and no evidence of prostate cancer as determined by a serum PSA level of no more than 4 ng/ml and a digital rectal exam (DRE) not suspicious for prostate cancer. Participants were randomized to receive selenium (200 microg/ day of l-selenomethionine) and/or vitamin E (400 IU/day of all-rac-alpha-tocopheryl acetate) supplementation for a minimum of 7 years (maximum of 12 years). The rationale for choosing these agents was based on preclinical data as well as analyses of secondary endpoints in cancer prevention clinical trials. The primary endpoint of SELECT is occurrence of prostate cancer based on community standards of diagnosis. Several other non-cancer endpoints are also being explored.

Factors Associated with Adherence to an End-of-Study Biopsy: Lessons from the Prostate Cancer Prevention Trial (SWOG-Coordinated Intergroup Study S9217)

Background: The Prostate Cancer Prevention Trial (PCPT) was a 7-year randomized, double-blind, placebo-controlled trial of the efficacy of finasteride for the prevention of prostate cancer with a primary outcome of histologically determined prevalence of prostate cancer at the end of 7 years. Methods: A systematic modeling process using logistic regression identified factors available at year 6 that are associated with end-of-study (EOS) biopsy adherence at year 7, stratified by whether participants were ever prompted for a prostate biopsy by year 6. Final models were evaluated for discrimination. At year 6, 13,590 men were available for analysis. Results: Participants were more likely to have the EOS biopsy if they were adherent to study visit schedules and procedures and/or were in good health (P < 0.01). Participants at larger sites and/or sites that received retention and adherence grants were also more likely to have the EOS biopsy (P < 0.05). Conclusions: Our results show good adherence to study requirements 1 year before the EOS biopsy was associated with greater odds that a participant would comply with the invasive EOS requirement. Impact: Monitoring adherence behaviors may identify participants at risk of nonadherence to more demanding study end points. Such information could help frame adherence intervention strategies in future trials. Cancer Epidemiol Biomarkers Prev; 23(8); 1638–48. ©2014 AACR.

Development of PF-05280014, a potential biosimilar to trastuzumab.

618 Background: Previous studies have reported that EGFR ligands, amphiregulin (AREG) and epiregulin (EREG), are potential predictive markers for cet and high ERCC1 expression is associated with resistance to platinum-containing chemotherapy. However, there are still few studies to assess predictive values of these expression levels in JPN mCRC pts. The aim of this study was to evaluate the values in JPN mCRC pts treated with cet. Methods: This study enrolled 77 pts with tissue available from 2 prospective clinical trials evaluating combination of cet with oxaliplatin-based chemotherapy as first-line treatment in pts with KRAS wt and EGFR-expressing tumors, modified FOLFOX6 (n=28/57, UMIN000004197) and SOX (n=49/67, UMIN000007022). Total RNA isolated by macro-dissection from tissue was screened by RT-PCR for mRNA expression levels of AREG, EREG, and ERCC1, the cut-off values of which were based on the optimal cut-off value using the maximal chi-square approach on tumor response with adjusted p values. The...

Abstract A23: Cancer outcomes in the diabetes prevention program outcomes study

Numerous observational studies have reported decreased cancer incidence and cancer-related mortality in patients with diabetes receiving standard doses of metformin. A recent meta-analysis of these studies suggested a 31% reduction in overall cancer incidence, summary relative risk (0.69; 95% confidence interval, 0.52-0.90), in subjects taking metformin as compared with other antidiabetic drugs. Separate meta-analyses of studies that adjusted for BMI or time-related bias suggested an attenuation of this signal, but still showed a significant reduction in cancer incidence. However, studies published to date are limited by the observational nature of the data and the randomized controlled trials that have been used to examine metformin9s potential as an anti-cancer agent in patients with diabetes have had insufficient follow-up for cancer endpoints. These data also do not address the cancer risk in non-diabetic populations, in which the cancer preventive potential of metformin is unknown. The Diabetes Prevention Program (DPP) was a national multi-center, randomized, placebo-controlled clinical trial, which enrolled 3234 participants between 1996 and 1999, designed to investigate whether intensive lifestyle modification or treatment with metformin (850mg twice a day) delayed or prevented the onset of type 2 diabetes in a high risk population. The DPP and its follow up study, the Diabetes Prevention Program Outcomes Study (DPPOS), provide a unique opportunity to examine the role of metformin and lifestyle intervention in reducing cancer incidence in an overweight adult population with impaired glucose regulation, before the onset of diabetes. The National Cancer Institute Division of Cancer Prevention, in collaboration with the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and the DPPOS investigators, proposed a study to examine the hypothesis that metformin and/or lifestyle intervention can modify total cancer incidence and/or obesity-related cancer incidence (breast, colorectal, endometrium, pancreas, lower esophagus, gall-bladder, and kidney) in DPP/DPPOS participants. The DPPOS protocol and consent were modified to allow collection of data to support the inclusion of cancer incidence as an endpoint of interest in the study. Participants complete a cancer risk questionnaire that includes family history of cancer, cancer screening activities, and use of aspirin and NSAIDs including dose and frequency. The participants who previously reported a cancer diagnosis, through the SAE reporting process and/or an annual questionnaire, or during a subsequent follow-up visit, are asked to provide physician information to obtain medical records for case adjudication. This protocol will allow for the examination of the effect of metformin and lifestyle intervention on cancer incidence in an initially pre-diabetic population potentially through a median of 20 years of follow-up. Data from this study will compare incidence of total and obesity-related cancers between the original treatment groups; assess cancer (total and obesity-related) incidence by metformin exposure across all treatment groups, using a “met-years” variable, and explore subgroups to investigate effect modification by sex, age group, race/ethnicity, diabetes status, or weight loss at 1 year or mean weight loss since study baseline. Citation Format: Brandy M. Heckman-Stoddard, Jill P. Crandall, Sharon L. Edelstein, Richard F. Hamman, Philip C. Prorok, Anne Ryan, Dana Dabelea, Helen P. Hazuda, Edward Horton, Mary A. Hoskin, Susan Jeffries, William C. Knowler, Kieren J. Mather, Susana M. Shapiro, Farzana L. Walcott, Leslie G. Ford. Cancer outcomes in the diabetes prevention program outcomes study. [abstract]. In: Proceedings of the Thirteenth Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2014 Sep 27-Oct 1; New Orleans, LA. Philadelphia (PA): AACR; Can Prev Res 2015;8(10 Suppl): Abstract nr A23.