Breast Cancer Prevention: Current Approaches and Future Directions

Table of Contents

Introduction

While breast cancer death rates increased by 0.4% per year in the United States (U.S.) between 1975 and 1989, between 1989 and 2015 they decreased by 39%, averting 322,600 deaths (1). There has not been a similar decrease in breast cancer incidence. The incidence of breast cancer is increasing in the developing world due to increased life expectancy, increased urbanization and the adoption of western lifestyles (2). There is an emerging epidemic of obesity related cancers, including breast cancer, in many parts of the developed and developing world. The incidence of obesity related cancers (other than those of the colon and rectum) increased in the U.S. by 7 percent between 2005 and 2014, while the rates of non-obesity related cancers declined during that time (3). About 631,000 people in the U.S. were diagnosed with a cancer associated with overweight and obesity in 2014 (3).

The prevention of breast cancer depends on targeting factors that increase risk. Many, but not all of these risk factors can be modified. Those that can be modified include diet; exercise; avoidance of certain things such as tobacco, exogenous female hormones, ionizing radiation, and alcohol in excess; pregnancy and nursing. An important question when discussing breast cancer prevention is which individuals to target. In general, greater focus has been placed on strategies to decrease risk among those at the greatest risk of developing breast cancer. For high risk women, two chemoprevention medications have been approved by the U.S. Food and Drug Administration (FDA), and a third recommended by some governing bodies for use. Surgery has also been recommended for certain subsets of women who are genetically at increased breast cancer risk.

Risk factors are inherited, histopathologic or environmental, each of which is important. Strategies to decrease environmental risks generally focus on directly addressing the environmental factor, whereas genetic and histopathologic risks, which cannot so easily be altered directly, are addressed indirectly, such as through altering known drivers to breast cancer, such as estrogen and its receptor through chemoprevention, or by surgical extirpation of the organ(s) at risk. Mammographic breast density (MBD) also influences breast cancer risk. MBD is appears to be influenced by genetics (4), age and body mass index (5).

There are a variety of risk assessment tools available, some of which require information on breast cancer (BRCA) gene mutation status, and others which do not but rather focus on clinical and histopathologic factors which influence risk (6). The Gail breast cancer risk assessment tool (BCRAT) is the tool most commonly used in the U.S. to estimate a woman’s risk of developing breast cancer. This tool was used to determine eligibility in two large U.S. breast cancer prevention trials (the first evaluating tamoxifen, the second tamoxifen vs. raloxifene) (7). It incorporates a variety of clinical and histopathologic factors. Two European breast cancer prevention trials (the first evaluating tamoxifen, the second anastrozole) used the Tyrer-Cuzick risk assessment tool, which incorporates genetic and clinical breast cancer risk factors (7).

Scientists have identified some of the genetic mutations which drive the development of breast cancer, but we know relatively little of genetic alterations which work together, or in concert with environmental alterations, to promote breast cancer development. Some of the proven or potential driver genetic alterations, including BRCA 1 and 2, TP53, PTEN, STK11, CDH1, PALB2, CHECK2, ATM, NBN, and NF1 (8), are included in commercially available risk assessment panels. Genetic counseling can be provided to discuss detection of one or more alterations in a driver mutation, as well as the implications of an identified deleterious mutation and a patient’s options.

Male breast cancer (MBC) accounts for fewer than 1% of all cancers in men and is less than 1% as common as female breast cancer (9). Due to the relative rarity of MBC, far less is known about what causes the disease, and chemoprevention studies have generally excluded men from enrollment. Nonetheless, limited studies have provided evidence for the causes of MBC. A report which pooled data from 11 case-control and 10 cohort studies, including 2,405 men with and 52,013 men without breast cancer, demonstrated that risk factors for MBC include obesity (odds ratio-OR=1.3), diabetes (OR=1.19), Klinefelter syndrome (OR=24.7), and gynecomastia (OR=9.78) (10). Many of these factors lead to elevated levels of circulating estrogen. Family history is also an important risk factor for MBC. Deleterious mutations in BRCA1 and 2 are known to significantly increase the risk of MBC. Lifetime risk of developing MBC is 1–5 % for BRCA1 and 5–10 % for BRCA2 mutation carriers, compared with a risk of 0.1% in the general male population (9).