Reducing Breast Cancer Incidence and Mortality: Rethinking an Approach to Risk Assessment and Prevention

Abstract

A comprehensive approach to breast cancer prevention encompasses individualized risk assessment and implementation of risk-reduction strategies, which include lifestyle modification, preventive endocrine medications, surveillance breast imaging, genetic counseling and testing, and for those with a hereditary breast cancer mutation, consideration of risk-reducing surgery (mastectomy and/or salpingo-oophorectomy). Recent agency guidelines promote preventive endo-crine medications (selective estrogen receptor mod-ulators, and aromatase inhibitors [AIs]) that are shown to reduce development of favorable, hormone receptor-positive cancers but have not affected breast cancer-related mortality. 1 In the article that accompanies this editorial, Chle-bowski et al 2 propose a reexamination of breast cancer risk-reduction strategies incorporating a low-fat diet dietary modification and consideration of use of oral conjugated equine estrogen (CEE) to reduce breast cancer mortality. The authors discuss the results of two large randomized trials, the Women's Health Initiative (WHI) Dietary Modification randomized trial and WHI randomized trial with CEE alone in women with prior hysterectomy, both of which demonstrated a reduction in breast cancer mortality. 3,4 Advances in our understanding of tumor biology and breast cancer prognostic categories demonstrate how more favorable hormone receptor-positive (estrogen receptor [ER]-positive and progesterone receptor [PR]-positive) breast cancers are associated with a lower mortality as compared with less favorable tumor biology, such as ER-positive and PR-negative or triple-negative tumors, which have a poor prognosis. 2 To date, breast cancer prevention trials that evaluated the benefit of tamoxifen and AIs (exemestane and anas-trozole) have not been powered to assess breast cancer mortality and only showed reductions in breast cancer incidence of the favorable, hormone receptor-positive breast cancers. 5 Long-term follow-up of the tamoxifen prevention trials showed a higher breast cancer-related mortality in the tamoxifen group despite a reduction in breast cancer incidence. 6 On the basis of available observational studies, the benefits of dietary modification on breast cancer risk has been unclear. However, results from the well-designed, randomized WHI Dietary Modification (DM) Trial demonstrated that after a 19.6-year follow-up, nutrition matters and that a low-fat dietary lifestyle with an increase in vegetables, fruits, and grains reduces breast cancer mortality among postmenopausal women. 7 There was also a significant reduction in worse-prognosis ER-positive PR-negative breast cancer occurrence in the low-fat dietary intervention arm. Metabolic syndrome is associated with a higher risk of breast cancer. In a subgroup analysis in the WHI DM Trial, there was a lower incidence of metabolic syndrome and lower mortality in the low-fat intervention arm. 7-9 In the WHI randomized trial of CEE versus placebo in postmenopausal women with prior hysterectomy, CEE alone significantly reduced incidence of poor-prognosis (ER-positive, PR-negative) breast cancer. There was also an observed reduction in breast cancer-related mortality (hazard ratio, 0.6; 95% CI, 0.37 to 0.97; P 5 .04). 4 The relationship of meno-pausal hormone therapy (HT) and breast cancer risk is complex and likely depends on many factors including type, dose, and formulation of HT and patient factors including, but not limited to, lifestyle, genomics, and epigenetics. The WHI CEE-alone trial findings refute the notion that all HT increases the risk of breast cancer for all women. In fact, high-dose estrogen had previously been used to treat hormone-dependent breast cancer in menopausal women before introduction of tamoxifen. 10 Further study is needed to determine optimal estrogen formulation, dose, duration , and target population as breast cancer prevention modalities. Meanwhile, clinicians should individualize their treatment plans through shared decision making for symptomatic women in menopause for example, those , 60 years and within 10 years of their final menstrual period, as it relates to HT treatment. 11 Since most patients are likely seen in a busy primary care clinical practice, there is a need for easily accessible , efficient, and accurate personalized risk assessment tools. Currently available computerized risk calculation tools have limitations in their ability to provide population-based risk assessment and, as