Abstract

One in eight women will develop breast cancer in the US. For women with moderate (15–۲۰%) to average (12.5%) risk of breast cancer, there are few options available for risk reduction. For high-risk (>20%) women, such as BRCA mutation carriers, primary prevention strategies are limited to evidence-based surgical removal of breasts and/or ovaries and anti-estrogen treatment. Despite their effectiveness in risk reduction, not many high-risk individuals opt for surgical or hormonal interventions due to severe side effects and potentially life-changing outcomes as key deterrents. Thus, better communication about the benefits of existing strategies and the development of new strategies with minimal side effects are needed to offer women adequate risk-reducing interventions. We extensively review and discuss innovative investigational strategies for primary prevention. Most of these investigational strategies are at the pre-clinical stage, but some are already being evaluated in clinical trials and others are expected to lead to first-in-human clinical trials within 5 years. Likely, these strategies would be initially tested in high-risk individuals but may be applicable to lower-risk women, if shown to decrease risk at a similar rate to existing strategies, but with minimal side effects.

Introduction

For women in the US, breast cancer (BC) is the most prevalent cancer and the second-leading cause of cancer-related deaths. Projections for 2023 estimate that 55,720 women will be diagnosed with carcinoma in situ, 297,790 with invasive carcinoma, and 43,170 women will die from BC [1]. With the number of new diagnoses still on the rise, one in eight women will develop BC within their lifetime, but all women are at risk. Therefore, there is a need to develop new strategies for primary prevention with a focus on high-risk (>20%) individuals, but that can also be applied to moderate- (15–۲۰%) and average (12.5%)-risk individuals.

There are well-established risk factors that contribute to the absolute risk of developing BC [2,3]. There are modifiable risk factors such as having a healthy diet, regular exercise, and limiting alcohol consumption [2,4]. Cumulative exposure of breast tissue to estrogen is an important risk factor for BC. This risk can be minimized by various actions such as having their first-born before age 30, limiting the use of hormonal birth control medications, and avoiding hormone replacement therapy. Non-modifiable risk factors that increase cumulative exposure to estrogen include younger age at menarche and older age at natural menopause [2]. There are non-modifiable genetic risk factors that include known mutations in a high-penetrant BC gene such as BRCA1 and BRCA2, cumulative interaction of risk-associated alleles of BC susceptible SNPs, and/or family history with multiple incidences of BC [5]. There are also non-modifiable risk factors related to the personal history of radiation therapy to the chest, and the number of breast biopsies [4].

Conclusions and Future Directions

BC is the leading cause of new cancer cases and is the second leading cause of cancer-related deaths in women. The limited, approved prevention interventions available for high-risk individuals can have severe and long-term side effects that deter many women from making proactive choices. Regrettably, BC prevention is an area of translational research that is currently underfunded by federal agencies [182]. Therefore, emerging and novel approaches for the primary prevention of BC that provide the same or superior protection while minimizing the side effects of current interventions should be pursued and prioritized. These approaches seek to eradicate BC and align well with NIH’s All of US Research Program—a nationwide initiative for precision health interventions that proactively prevent rather than treat disease in high-risk individuals. We provide a comprehensive review of emerging approaches for BC prevention based on non-modifiable risk factors that put women at a higher risk of developing BC. Virtually all of these studies were performed in rodent models of BC, which have some limitations and challenges for direct translation to at-risk individuals. Additional scalability and validation studies in larger animal models will be an important step in bridging the gap between discovery and clinical evaluation. Although currently underutilized, rabbit studies should be considered as an appropriate intermediate model. Evolutionarily, anatomically, and physiologically, rabbit mammary glands are more similar to humans than those of rodent models or other large animals such as cows and sheep [183,184]. Female rabbits have four pairs of mammary glands each containing four ductal trees [177], which can be cannulated for ID injection [177,185,186,187,188,189] using a procedure very similar to ID administration of contrast agents in clinical ductography [190,191] and chemotherapeutic agents in first-in-human clinical research [92,145]. Alternatively, or complementary to validation studies in larger animals, judicious determination based on the scientific rigor and clinical feasibility of these emerging approaches should be applied to prioritize those interventions more likely to have an impact on primary prevention of BC.