Breast cancer mortality is at its lowest level in 30 years—progress that has largely been fueled by advances in early detection and treatment. In contrast, our approach to cancer prevention has not progressed at nearly the same rate, as illustrated by the steady rates of breast cancer incidence over the same period. BCRF embarked on a bold new initiative in 2019 to apply the principles of precision medicine to prevention research to address this underfunded area of research. With an initial $5 million investment by Blizzard Entertainment, the Precision Prevention Initiative (PPI) challenged the research community to take a new look at prevention research.
“We envision a future where doctors customize a prevention plan based on an individual person’s biology, history, and lifestyle to stop cancer before it starts,” said Dr. Dorraya El-Ashry, BCRF’s chief scientific officer.
“There is an enormous opportunity for multidisciplinary research in breast cancer prevention,” said Dr. Judy Garber, BCRF’s scientific director. “Just as emerging technologies are transforming precision medicine, this new initiative is capitalizing on these new techniques and discoveries to reduce the incidence of breast cancer with all possible speed.”
Learn about the second group of projects we’re funding in our initiative to develop new targeted interventions for breast cancer prevention.
Jack Cuzick, PhD, FRS, CBE, of Queen Mary University of London, is assessing the utility of measuring blood hormone levels to improve breast cancer risk assessment and predict response to preventive treatment.
Tamoxifen and some aromatase inhibitors are known to reduce the risk of breast cancer in high-risk women, but they do not work for all women. Dr. Cuzick’s earlier studies found that postmenopausal women with low levels of circulating estradiol received little benefit from the aromatase inhibitor anastrozole. Both tamoxifen and anastrozole also have side effects that can substantially reduce quality of life for many women. Because most breast cancers are estrogen receptor (ER)–positive and occur in postmenopausal women, there is a huge opportunity to prevent breast cancers by personalizing risk assessment and preventive hormonal treatment for women most likely to benefit from them.
Lifetime exposure to estrogen is a known risk factor for the development of breast cancer, yet circulating estradiol, the most potent form of estrogen, is not routinely measured or integrated into breast cancer risk prediction models. Likewise, the role of estradiol levels in predicting response to preventive therapy with anti-estrogen/hormonal medicines has not been well studied. The aims of Dr. Cuzick’s project are to determine whether measuring blood hormone levels can predict which women are at high risk of breast cancer and which will benefit from risk-reducing anti-estrogen drugs. Dr. Cuzick and his team will measure hormone levels in over 100,000 women at average and high risk of breast cancer and those with ductal carcinoma in situ (DCIS), a non-invasive breast cancer that may progress to invasive breast cancer. These participants were followed long-term and had many breast cancer risk factors measured. The team will determine whether blood hormone levels correlate with the participants’ risk profiles and observed outcomes. Read more about Dr. Cuzick’s other BCRF-supported research here.
Andrea De Censi, MD, of E.O. Ospedali Galliera, is testing various strategies to improvebreast cancer chemoprevention.
Women at high risk of developing breast cancer may benefit from preventive therapy with anti-estrogen/hormonal medicines like tamoxifen and exemestane to decrease the risk of future invasive breast cancer. However, the uptake of this intervention has been low due to concerns over side effects. Dr. De Censi and his team will compare similar dosing schedules for tamoxifen versus exemestane to determine if either can improve the quality of life for patients. Dr. De Censi anticipates that the results of this study will inform new approaches to breast cancer prevention that are better tolerated and have potential for broader uptake and impact. Read more about this project here.
Camila dos Santos, PhD, of Cold Spring Harbor Laboratory, is investigating pregnancy-associated changes in breast tissue and ways to leverage them to reduce the risk of developing breast cancer.
Pregnancy-associated protection from breast cancer persists for a lifetime, implying a permanent shift in the cells that comprise the mammary gland. Dr. dos Santos is leveraging her finding that specific subtypes of immune cells that suppress tumorigenesis are present post-pregnancy and determining if milk-associated probiotics may mediate their anti-tumorigenic function. Her studies may help identify strategies for exploiting pregnancy-induced breast cancer protection. Read more about this project here.
Olivera J. Finn, PhD, of the University of Pittsburgh, is developing vaccines for breast cancer.
Ideally, vaccines for cancer prevention will prepare the immune system to see tumor antigens on a developing tumor and destroy it. Dr. Finn has been testing one such vaccine based on the tumor antigen MUC1 that is expressed on early, precancerous cells. Dr. Finn and her team are now conducting a trial to test the safety and efficacy of a MUC1 vaccine compared to control in women diagnosed with pre-cancerous lesions prior to surgery. Read more about this project here.
Jennifer Ligibel, MD, of Dana-Farber Cancer Institute, is investigating the link between exercise, irisin, and breast cancer development.
Dr. Ligibel has demonstrated that irisin, a substance released by muscle during exercise, slows breast cancer development potentially through immune system activation. Dr. Ligibel’s research aims to integrate evidence connecting exercise, irisin, and breast cancer development to better understand the pathways through which exercise could lower disease risk. Read more about this project here.
Alvaro Monteiro, PhD, of theH. Lee Moffitt Cancer Center, is identifying and stratifying BRCA1 and BRCA2 gene variants that confer intermediate risk of developing breast cancer.
There are gene variants of uncertain clinical significance for which association with risk cannot be assessed with the information available. Carriers of these variants have no actionable information and cannot benefit from established clinical recommendations. Dr. Monteiro will identify gene variants of intermediate risk that can be used as a point of comparison to integrate clinical and functional data for gene variant classification and risk assessment. Read more about this project here.
Seema Khan, MD, of Northwestern University, is testing personalized dosing of tamoxifen to prevent breast cancer.
Tamoxifen is the only preventive drug available to high-risk premenopausal women and can reduce their risk of ER-positive breast cancer risk by half. However, many women decline tamoxifen due to side effects. Dr. Khan will explore personalized dosing of tamoxifen to improve compliance and expand its use in more women at risk for breast cancer. The standard dose of tamoxifen was defined in treatment trials, which are typically designed around “maximal tolerated dose.” In contrast, “minimal effective dose” is an important principle in cancer prevention. Dr. Khan’s PPI study builds on data from previous trials showing that low-dose tamoxifen is also effective for cancer prevention and reduces breast density, increasing the risk reduction benefit in women with dense breasts.
To test the idea of personalized dosing—so that each individual receives the correct dose of preventive tamoxifen—Dr. Khan and her team will use “mammographic dense area reduction” (DAR) as an indicator of tamoxifen response. Two hundred high-risk premenopausal women will take low-dose tamoxifen; if a mammogram six months later does not show enough density reduction, those participants will have the option to increase the dose. If a 12-month mammogram still shows insufficient DAR, they will have the option to increase the dose again. Participants will continue treatment with their optimal dose for a total of 18 months. This trial will provide the first proof-of-concept of personalized dosing for cancer prevention. Read about Dr. Khan’s other BCRF-supported research here.
Darren Mays, PhD, MPH, of The Ohio State University College of Medicine, is creating a counter-marketing intervention to reduce alcohol use in young women and measuring its effects on alcohol use behavior and breast cancer risk beliefs.
Counter marketing designed to offset industry marketing is effective for reducing cancer risk behaviors such as tobacco use. It may also be effective for reducing alcohol use to prevent breast cancer, but it has not yet been studied for this purpose. Dr. Mays is developing an intervention to reach college-age women and testing its efficacy in changing young women’s beliefs about breast cancer risks from alcohol use and their alcohol use behavior. Read more about this project here.
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