While it has long been recognized that drugs that block the cancer-promoting activity of estrogen reduce the risk of developing new breast cancers, a new supercomputer modeling study led by researchers at Georgetown Lombardi Comprehensive Cancer Center and colleagues showed that these treatments could also reduce the risk of dying from the disease in women who are at high risk.

The finding appeared on December 1, 2022, in the Journal of Clinical Oncology.

“Recent studies have shown that women diagnosed with estrogen receptor (ER) positive tumors continue to experience breast cancer recurrence and death for as long as 30 years after their primary diagnosis,” says Claudine Issacs, M.D., Leader of the Breast Cancer Program, medical director of the Fisher Center for Hereditary Cancer and Clinical Genomics Research at Georgetown Lombardi and one of the study’s two senior authors.

She says this new evidence prompted researchers to re-examine the lifetime benefits and harms of risk-reducing medications developed for the primary prevention of breast cancer to see if the drugs could, over the long run, reduce the rate of death from the disease.

Based on the available data, recommendations for preventing ER-positive breast cancer with tamoxifen or aromatase inhibitors presumed that women at elevated risk who took the drugs reduced their chances of developing the disease. Still, our modeling study found that, over the long run, there could also be a significant impact on mortality” Isaacs says. “Giving an estrogen blocker to a woman in her 30s who is at high risk could potentially forestall death due to breast cancer for 20 years or more, which would be significant.”

Over the past several decades, a number of large, federally-funded randomized clinical trials have shown that risk-reducing antiestrogen medications such as tamoxifen and aromatase inhibitors could decrease the incidence of ER-positive breast cancer by 30 to 50 percent in women who are at high risk of developing the disease. Despite evidence from these trials, the drugs have remained underutilized, perhaps due to the risk, albeit low, of endometrial cancer conferred by the drugs as well as other factors.

"What has been missing from our conversation until now is our ability to say to women that these drugs can not only prevent them from getting breast cancer but they can ultimately prevent them from dying of the disease,” Isaacs says.

Studies have shown that chemoprevention drugs are most effective if taken for five years and not longer. This latest study shows that the impact on mortality could confer a long-term and persistent benefit for a decade or more.

The study used supercomputer models developed by the Cancer Intervention and Surveillance Modeling Network (CISNET), a National Cancer Institute-sponsored consortium, to determine the lifetime benefits and harms of estrogen blockers for women with a five-year risk of developing breast cancer equal to or greater than three percent. The researchers evaluated the effects of estrogen blockers along with annual screening mammograms (and magnetic resonance imaging, or MRI, if necessary) to calculate the risk of invasive breast cancer, breast cancer death, side effects, false positives, and chances of overdiagnosis.

Tamoxifen, and the use of annual mammography (and MRIs, if necessary), reduced the risk of developing new invasive breast cancers by 40% and reduced the risk of breast cancer deaths by 57%.  This translates to 95 fewer invasive breast cancers and 42 fewer breast cancer deaths per 1,000 women compared to women who didn’t get a mammogram, an MRI, or risk-reducing drugs. The scientists noted that the drugs were not without downsides, as tamoxifen could increase the number of new endometrial cancers by up to 11 per 1,000 women.

“The Institute of Medicine [now the National Academy of Medicine] suggests that modeling approaches such as ours are going to provide the most definitive answers about the value of these drugs because, given size and cost considerations, a clinical trial would be impractical, even putting aside the fact that evidence of benefit from a clinical trial would take close to 20 years to accrue,” says Isaacs.

In addition to Isaacs, the other authors from Georgetown include Jinani Jayasekera (now at the National Cancer Institute), Amy Zhao, Suzanne O’Neill, and Marc Schwartz.  Clyde B. Schechter is at the Albert Einstein College of Medicine, Bronx, NY. Allison Kurian is at Stanford University School of Medicine, Stanford, California. Karen Wernli is at the Kaiser Permanente Washington Health Research Institute, Seattle. Kathryn Lowry is at the University of Washington, Seattle Cancer Care Alliance, Seattle. Natasha Stout and Jennifer Yeh are at Harvard Medical School, Boston.

National Cancer Institute supported the study grants K99CA241397, R03CA259896, 5P30CA051008-28, P01CA154292, U54CA163303, National Institute of Health grant PCS-1504-30370 and Agency for Health Research and Quality grant R01 HS018366-01A1.

Claudine Isaacs has received research funding support from Tesaro/GSK, Seattle Genetics, Pfizer, AstraZeneca BMS, Genentech, and Novartis; consultation fees from Genentech, PUMA, Seattle Genetics, AstraZeneca, Novartis, Pfizer, ESAI, Sanofi, ION and Gilead; royalties from Wolters Kluwer (UptoDate) and McGraw Hill (Goodman and Gillman) and is the Medical Director of the non-profit SideOut Foundation. Jinani Jayasekera, Clyde B. Schechter, Kathryn Lowry, Jennifer Yeh, Marc Schwartz, Suzanne O’Neill, Karen Wernli, and Natasha Stout, report no disclosures. Allison Kurian has received research funding for her institution from Myriad Genetics.