Barbara K. Dunn

Preventive therapy for breast cancer: a consensus statement

In March, 2010, a group of breast cancer experts met to develop a consensus statement on breast cancer prevention, with a focus on medical and therapeutic interventions. We present the conclusions in this Review. First we agreed that the term chemoprevention is inappropriate and suggested that the term preventive therapy better represents this feature of management. Two selective oestrogen-receptor modulators--tamoxifen and raloxifene--are so far the only medical options approved by the US Food and Drug Administration for preventive therapy. Of these tamoxifen has greater efficacy and can be used in premenopausal women, but raloxifene has fewer side-effects. Two newer drugs in this class, lasofoxifene and arzoxifene, also show efficacy and possibly a better overall risk-benefit profile, but need further assessment. Aromatase inhibitors might be more efficacious, and results of prevention trials are eagerly awaited. Newer agents, notably bisphosphonates and metformin, have shown promise in observational studies and need to be assessed in randomised prevention trials. Other agents, such as aspirin, other non-steroidal anti-inflammatory drugs, COX-2 inhibitors, retinoids, rexinoids, and dietary components have limited effects or are in the early phases of investigation. New contralateral tumours in women with breast cancer might be generally useful as a model for prevention, as has been seen for tamoxifen. If valid such a model would facilitate the design of simpler, cheaper, and better-focused trials for assessing new agents.

Metformin and Cancer Risk and Mortality: A Systematic Review and Meta-Analysis taking into account Biases and Confounders

Previous meta-analyses have shown that the antidiabetic agent metformin is associated with reduced cancer incidence and mortality. However, this effect has not been consistently demonstrated in animal models and recent epidemiologic studies. We performed a meta-analysis with a focus on confounders and biases, including body mass index (BMI), study type, and time-related biases. We identified 71 articles published between January 1, 1966, and May 31, 2013, through Pubmed, ISI Web of Science (Science Citation Index Expanded), Embase, and the Cochrane library that were related to metformin and cancer incidence or mortality. Study characteristics and outcomes were abstracted for each study that met inclusion criteria. We included estimates from 47 independent studies and 65,540 cancer cases in patients with diabetes. Overall cancer incidence was reduced by 31% [summary relative risk (SRR), 0.69; 95% confidence interval (CI), 0.52–0.90], although between-study heterogeneity was considerable (I2 = 88%). Cancer mortality was reduced by 34% (SRR, 0.66; 95% CI, 0.54–0.81; I2 = 21%). BMI-adjusted studies and studies without time-related biases also showed significant reduction in cancer incidence (SRR, 0.82; 95% CI, 0.70–0.96 with I2 = 76% and SRR, 0.90; 95% CI, 0.89–0.91 with I2 = 56%, respectively), albeit with lesser magnitude (18% and 10% reduction, respectively). However, studies of cancer mortality and individual organ sites did not consistently show significant reductions across all types of analyses. Although these associations may not be causal, our results show that metformin may reduce cancer incidence and mortality in patients with diabetes However, the reduction seems to be of modest magnitude and not affecting all populations equally. Clinical trials are needed to determine if these observations apply to nondiabetic populations and to specific organ sites. Cancer Prev Res; 7(9); 867–85. ©2014 AACR.

Hypomethylation: One Side of a Larger Picture

Abstract: Hypomethylation signifies one end of a spectrum of DNA methylation states. In most cases hypomethylation refers to a relative state that represents a change from the ‘normal’ methylation level. Hypomethylation, when approached from a topographical perspective, has been used to describe either overall decreases in the methylation status of the entire genome (global hypomethylation) or more localized relative demethylation of specific subsets of the genome, such as the promoter regions of protooncogenes or normally highly methylated repetitive sequences. Global hypomethylation accompanied by gene‐specific hypermethylation is observed in at least two important settings: cancer and aging. Global hypomethylation is generally reflective of decreased methylation in CpGs dispersed throughout repetitive sequences as well as the bodies of genes. Hypomethylation of repetitive and parasitic DNA sequences correlates with a number of adverse outcomes. For example, decreased methylation of repetitive sequences in the satellite DNA of the pericentric region of chromosomes is associated with increased chromosomal rearrangements, a hallmark of cancer. Decreased methylation of proviral sequences can lead to reactivation and increased infectivity. However, hypomethylation in cancer can also affect the CpGs in the promoters of specific genes—namely, protooncogenes—leading to their overexpression and resulting in the functional outcome of increased cell proliferation. Thus, hypomethylation, in a variety of settings in which it represents a deviation from ‘normal,’ appears to correlate with progression to cancer and offers potential mechanisms to explain the carcinogenic process.

Future directions in cancer prevention

Prevention of cancer remains the most promising strategy for reducing both its incidence and the mortality due to this disease. For more than four decades, findings from epidemiology, basic research and clinical trials have informed the development of lifestyle and medical approaches to cancer prevention. These include selective oestrogen receptor modulators and aromatase inhibitors for breast cancer, the 5-α-reductase inhibitors finasteride and dutasteride for prostate cancer, and the development of vaccines for viruses that are associated with specific cancers. Future directions include genetic, proteomic and other molecular approaches for identifying pathways that are associated with cancer initiation and development, as well as refining the search for immunologically modifiable causes of cancer.

Health disparities in breast cancer: biology meets socioeconomic status

Breast cancer is the most common cancer in women worldwide, accounting for just over 1 million new cases annually. Population-based statistics show that globally, when compared to whites, women of African ancestry (AA) tend to have more aggressive breast cancers that present more frequently as estrogen receptor negative (ERneg) tumors. ERneg tumors fail to respond to current established targeted therapies, whether for treatment or prevention. Subsets of the ERneg phenotype include those that are also negative for the progesterone receptor (PR) and HER2; these are called “triple negative” (TN) breast cancers. TN tumors frequently have pathological characteristics resembling “basal-like” breast cancers. Hence, the latter two terms are often used interchangeably; yet, despite extensive overlap, they are not synonymous. The ERneg, TN, and basal-like phenotypic categories are important because they carry worse prognoses than ER-positive (ERpos) tumors, in addition to lacking obvious molecular targets, such as HER2 and the ER, for known therapies. Furthermore, among premenopausal women the three subsets occur more frequently in women of African descent compared to white women with breast cancer. The contribution of these three subtypes of poor-prognosis tumors to the higher breast cancer mortality in black women is the focus of this review. We will attempt to clarify some of the issues, including risk factors, in terms of their contribution to that component of health disparities that involves biological differences in breast cancer between women of AA and white women.

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.

Prevention of Hormone-Related Cancers: Breast Cancer

Carcinogenesis in the breast is a hormonally dependent process. Evidence implicating estrogen as a key breast carcinogen comes from various lines of investigation. Traditional epidemiologic studies demonstrate associations between estrogen exposure, both exogenous and endogenous, and increased breast cancer risk. Ongoing genetic epidemiologic studies also show associations between specific polymorphisms in estrogen-metabolizing genes and risk, albeit inconsistently. The application of these findings to the treatment and, more recently, the prevention of breast cancer has led to the development of agents that either (1) inhibit estrogen action at the estrogen receptor (selective estrogen receptor modulators (SERMs]); or (2) inhibit estrogen-synthesizing enzymes, thereby abrogating synthesis of this hormone (aromatase inhibitors). Large phase III trials have evaluated the ability of such agents to reduce the incidence of breast cancer in women at increased risk of the disease. The National Surgical Adjuvant Breast and Bowel Project (NSABP) P-1: Breast Cancer Prevention Trial (BCPT) demonstrated the superiority of the SERM tamoxifen to placebo in reducing breast cancer risk, leading to the Food and Drug Administration approval of tamoxifen for risk reduction. The implementation of tamoxifen for this indication has not become widespread in clinical practice, however, for a variety of reasons that we discuss. Results from the NSABP Study of Tamoxifen and Raloxifene, which compares the risk-reducing efficacy as well as toxicity of these two SERMs in a similar high-risk population, will be available in the near future. Based on promising data involving reduction of contralateral breast cancer risk in adjuvant studies, several aromatase inhibitors, including letrozole, anastrozole, and exemestane, are being incorporated into trials evaluating their efficacy as preventive agents in women at increased risk.

From Adjuvant Therapy to Breast Cancer Prevention: BCPT and STAR

Abstract: The continued widespread prevalence of breast cancer supports placing a high priority on research aimed at its primary prevention, particularly among women who are at increased risk for developing this disease. The suggestion of potential agents for the primary chemoprevention of breast cancer evolved out of the treatment setting. Extensive experience with tamoxifen, a first‐generation selective estrogen receptor modulator (SERM) showing efficacy, first, in the treatment of advanced breast cancer and, subsequently, as adjuvant therapy for early stage disease established the safety of this agent. Cumulative data from multiple adjuvant studies documented the efficacy of tamoxifen in reducing second primary breast cancers in the contralateral breast, supporting its potential as a chemopreventive agent for breast cancer. The safety and second primary data on tamoxifen, together with extensive information on its pharmacokinetics, metabolism, and antitumor effects, as well as its potentially beneficial effects on lipid metabolism and osteoporosis, led the National Surgical Adjuvant Breast and Bowel Project (NSABP) to select tamoxifen for testing in the first prospective randomized phase III trial of the efficacy of a chemopreventive agent for preventing breast cancer in women at increased risk of the disease. Accordingly, in 1992 the NSABP started the Breast Cancer Prevention Trial (P‐1) in which 13,388 women 35 years of age who were at increased risk of breast cancer according to Gail model risk factors [family history, age, and personal history (i.e., age at first birth, age at menarche, previous breast biopsies)] were randomized to tamoxifen 20 mg/day or placebo for 5 years. Through 69 months of follow‐up tamoxifen reduced the risk of invasive breast cancer, primarily estrogen receptor‐positive tumors, by 49% (two‐sided p < 0.00001). Tamoxifen reduced the risk of noninvasive breast cancer by 50% (two‐sided p < 0.002). In addition, tamoxifen reduced fractures of the hip, radius, and spine, but it had no effect on the rate of ischemic heart disease. As previously shown, the rates of endometrial cancer and vascular events increased with tamoxifen. With the P‐1 results establishing tamoxifen as the standard of care for the primary chemoprevention of breast cancer in high‐risk women, concern over the side effects of tamoxifen has prompted a continuing search for an agent that displays a more desirable efficacy/toxicity profile. Raloxifene, a second‐generation SERM approved for the prevention of osteoporosis in postmenopausal women, displays antiestrogenic properties in the breast and possibly the endometrium, and estrogenic effects in the bone and on the lipid profile, suggesting it as a candidate for comparison with the chemopreventive standard, tamoxifen. Raloxifene will be compared to tamoxifen in an equivalency trial, the Study of Tamoxifen and Raloxifene (STAR) NSABP P‐2, which began in July 1999 at almost 500 centers in North America. The plan is to randomize 22,000 postmenopausal women 35 years of age at increased risk of breast cancer by Gail criteria to tamoxifen 20 mg/day or raloxifene 60 mg/day for 5 years. Study endpoints include invasive and noninvasive breast cancer, cardiovascular disease, endometrial cancer, bone fractures, and vascular events.

Selenium and prostate cancer prevention: insights from the selenium and vitamin E cancer prevention trial (SELECT).

The Selenium and Vitamin E Cancer Prevention Trial (SELECT) was conducted to assess the efficacy of selenium and vitamin E alone, and in combination, on the incidence of prostate cancer. This randomized, double-blind, placebo-controlled, 2 × 2 factorial design clinical trial found that neither selenium nor vitamin E reduced the incidence of prostate cancer after seven years and that vitamin E was associated with a 17% increased risk of prostate cancer compared to placebo. The null result was surprising given the strong preclinical and clinical evidence suggesting chemopreventive activity of selenium. Potential explanations for the null findings include the agent formulation and dose, the characteristics of the cohort, and the study design. It is likely that only specific subpopulations may benefit from selenium supplementation; therefore, future studies should consider the baseline selenium status of the participants, age of the cohort, and genotype of specific selenoproteins, among other characteristics, in order to determine the activity of selenium in cancer prevention.

The role of tamoxifen in breast cancer prevention: issues sparked by the NSABP Breast Cancer Prevention Trial (P-1).

Abstract: The Breast Cancer Prevention Trial (P‐1: BCPT) of the National Surgical Adjuvant Breast and Bowel Project (NSABP) randomized 13,388 women, ≥35 years of age, at increased risk for breast cancer [≥1.66% by Gail model criteria or with a history of lobular carcinoma in situ (LCIS)] to 5 years of tamoxifen or placebo. A 49% reduction (P < 0.00001) in invasive breast cancers occurred, 175 with placebo versus 89 with tamoxifen, mainly among estrogen receptor (ER)‐positive tumors (130 with placebo vs. 41 with tamoxifen). The major toxicities of tamoxifen were endometrial cancer (15 with placebo vs. 36 with tamoxifen) and thromboembolic disease, both predominantly in women who were ≥50 years old. Ramifications emerging from the P‐1 results regarding the efficacy and toxicities of preventive tamoxifen include the following: (1) Does tamoxifen induce more virulent breast cancers? (2) Does tamoxifen induce more virulent endometrial cancers? (3) Tamoxifen is especially efficacious in reducing breast cancer risk in LCIS (18 invasive breast cancers with placebo vs. 8 with tamoxifen group) and atypical ductal hyperplasia (AH) (23 invasive breast cancers with placebo vs. 3 with tamoxifen). (4) Does tamoxifen reduce breast cancer risk in women at increased risk due to genetic mutations? (5) How can we prevent tamoxifen‐resistant breast cancers? (6) What do the BCPT results tell us about who should take preventive tamoxifen? In its ongoing effort to lower the incidence of breast cancer, the NSABP is now implementing its second breast cancer prevention trial, the Study of Tamoxifen and Raloxifene (STAR), which is comparing the two agents with regard to efficacy and toxicity.