By Kat J. McAlpine

Clinical trial data can often help scientists find answers in their quest to treat cancers. Sometimes, it can also reveal surprising new evidence about the drivers of disease, illuminating a new tactic for preventing cancer in the first place.

Such was the case during the 1990s clinical trials of tamoxifen, a medicine that blocks the effect of estrogen in breast tissue. While studying tamoxifen treatment in people who had been diagnosed with estrogen receptor-positive (ER+) breast cancer in one breast, clinical investigators observed — years later — that trial participants who had taken tamoxifen developed cancer in their other breast at much lower rates than those who had taken a placebo.

"That's when the lightbulb first went on — could medicines that treat cancer also be used for prevention?" says Tari King, MD, FACS, chief of breast surgery at Dana-Farber Brigham Cancer Center. In the early 2000s, as a breast surgery and research fellow at Memorial Sloan Kettering Cancer Center, Dr. King began studying how changes in breast tissue might predict future cancer risk – and how high-risk breast tissue changes might be modified using anti-cancer medicines.

Today, Dr. King and other pioneering physician-scientists at Dana-Farber's Susan F. Smith Center for Women's Cancers are leading research that is pushing the concept of breast cancer prevention into a new era.

 

Preventing Breast Cancer Without Disruptive Side Effects

"We've seen explosive progress in novel [therapeutic] agents, immunology, targeted therapies, and improved outcomes," says Judy Garber, MD, MPH, Susan F. Smith chair and chief of Dana-Farber's Center for Cancer Genetics and Prevention. "Now, we're working to accelerate the movement of those strategies into the prevention setting."

Since the 1990s, Dr. Garber has been studying how prevention strategies can be tailored to a patient's genetic profile and individualized breast cancer risks. "It's challenging, however, because we cannot ask patients to tolerate [the same level of] side effects from medicines for breast cancer prevention that they would [experience] for treatment," she says.

Tamoxifen, for instance, can be used to treat breast cancer in patients with ER+ breast cancer. It prevents activation of estrogen receptors on cancer cells, blocking their continued proliferation and growth. However, estrogen receptors on normal cells are also affected, causing side effects that can include hot flashes, vaginal dryness, and mood changes, and an elevated risk of uterine cancers and blood clots.

"Even though tamoxifen is very effective at reducing breast cancer risk, healthy people don't want to take a medicine that makes them feel like they're going through menopause early, or for the second time," Dr. King says.

There is now evidence that lower doses of tamoxifen can deter ER+ breast cancers with many fewer side effects, which might make the medicine more acceptable as a preventive measure. Dr. King is leading the "RENAISSANCE," an upcoming phase 2 clinical trial that will enroll pre-menopausal participants to examine whether tamoxifen taken in doses as low as 5mg — much lower than the 20mg doses standard for treating breast cancer — is effective in reducing breast density in patients at higher risk for breast cancer without disrupting quality of life. (Reducing breast density is a short-term marker of reduced breast cancer risk.)

Dr. King is also working on a study for post-menopausal patients at increased risk of ER+ breast cancers to assess the tolerability of another type of anti-cancer medicine, aromatase inhibitors, given at lower doses. Before menopause, estrogen is mainly produced by the ovaries. After menopause, estrogen is generated by the conversion of the male hormone testosterone to estrogen, by an enzyme called aromatase. Inhibiting the activity of this enzyme in post-menopausal patients is also an effective strategy for breast cancer treatment and prevention.

But like tamoxifen, aromatase inhibitors often cause menopausal-like side effects. BabyTears, another upcoming trial Dr. King is co-leading, will compare the feasibility and tolerability of using lower ("baby-sized") doses of aromatase inhibitors or tamoxifen in post-menopausal patients at increased risk of developing ER+ breast cancer.

"If the results [of BabyTears] are encouraging, they may lead to a definitive trial that could change the standard of care for reducing the risk of the most frequent kind of breast cancer," Dr. Garber says.

Getting to the Genetic Root of Breast Cancer

For people with BRCA gene mutations that put them at higher risk for breast cancer, Dr. Garber is pursuing other angles to prevent cancerous cells from taking hold. Patients with BRCA1 mutations who develop breast cancer most often develop estrogen receptor-negative breast cancer, so estrogen-activity-targeting medications like tamoxifen and aromatase inhibitors would not be able to reduce the risk of these cancers.

In recent years, medicines that treat bone loss (osteoporosis) in menopausal and post-menopausal people have attracted research interest in the context of breast cancer. Animal studies have shown that certain medicines approved for the treatment of osteoporosis block a molecule called ‘RANK-ligand' which is critical to the development of BRCA1-associated breast cancers.

In an international trial, Dr. Garber and a colleague in Austria are evaluating whether denosumab, an approved treatment for osteoporosis, can reduce the risk of breast cancer. Trial participants, recruited across 30 sites and representing six countries around the world, will receive an injection of denosumab or a placebo every six months for up to five years.

There are additional genetic strategies that could potentially be leveraged to prevent breast cancer. The genes BRCA1, BRCA2, "[as well as] PALB2, which was first identified by the late David Livingston at Dana-Farber," Dr. Garber says, are well known for the key roles they play in DNA repair. In breast tissue, mutated versions of these genes can disrupt normal DNA repair processes and increase the likelihood of breast cancer. Targeted therapeutic agents called PARP inhibitors can help destroy cancer cells with these BRCA and PALB mutations.

Given daily in pill form, PARP inhibitors have been shown to be relatively safe for treating patients with breast cancer and BRCA or PALB mutations. And in mice, there is evidence PARP inhibitors could reduce the risk of BRCA-associated breast cancers. Now, Dr. Garber is designing a trial to investigate whether PARP inhibitors can be given intermittently — rather than consistently — to eliminate cancerous cells that have started to form.

"This represents a totally new model for breast cancer prevention," Dr. Garber says. If the approach works, she predicts it could delay mastectomies and also have implications for preventing ovarian, prostate, and pancreatic cancers linked to BRCA and PALB mutations.

A Comprehensive Approach to Prevention

At the Breast cancer Personalized Risk assessment, Education and Prevention (B-PREP) program, breast specialists including Drs. King and Garber support patients concerned about their risks for breast cancer due to family history, breast density, or other changes noted on breast biopsies. B-PREP, directed by Dr. King, was founded to help identify and connect patients with elevated breast cancer risks to enhanced screening and innovative clinical trials aimed at preventing cancer.

Whether patients discover that they have high risk factors or generalized risk factors, lifestyle undoubtedly plays a role in many breast cancers.

"We know from decades of research that people who exercise and maintain a healthy weight have a lower risk of breast cancer," says Jennifer Ligibel, MD, co-director of Dana-Farber's Leonard P. Zakim Center for Integrative Therapies and Healthy Living, where many patients in the B-PREP program are referred for more resources. "And there's a lot of data that show that exercise after cancer has a positive impact on treatment and outcomes." So, the pressing question has become: Could exercise and other lifestyle changes be prescribed to prevent breast cancers?

Controlled lab studies in mice have already found that mice fed a calorie-restricted diet develop breast cancers at a lower rate than mice fed a high-fat diet. "It's much more difficult to test the effect of weight loss or other lifestyle factors on breast cancer risk or outcomes in people than it is in mice," Dr. Ligibel says.

Yet, lifestyle change holds promise in preventing and treating breast and other cancers Ligibel designed and launched the Breast Cancer Weight Loss (BWEL) trial, the first phase 3 clinical trial to study if weight loss interventions can prevent breast cancer reoccurrence and death in patients with both obesity and a history of early-stage breast cancers. The trial recruited nearly 3,200 diverse participants from across the U.S. and Canada; half were assigned to a weight loss regimen, while the other half weren't.

Early trial results show the weight loss intervention was successful in helping patients lose nearly five percent of their body weight. The next results from the clinical trial will detail physical activity patterns among participants and look at the effect of weight loss on metabolism and inflammation. Within two years, Dr. Ligibel hopes the BWEL trial will show whether weight loss helped stave off breast cancer reoccurrence and death in participants.

 

Dr. Ligibel is also leading a new clinical trial that explores how exercise could lower the risk of breast cancer. The study is currently enrolling patients who are at increased risk of breast cancer due to the density of their breast tissue. Half of participants will be assigned an exercise routine right after enrolling in the study, while the other half will wait 12 weeks before participating in the exercise program. Dr. Ligibel and collaborators will track and analyze the impact of exercise on changes in breast tissue and blood markers through breast biopsies, blood draws, fitness testing, and questionnaires about physical activity levels and habits.

"Many patients would prefer to avoid medications and to take an active role in cancer prevention," Dr. Ligibel says. "We are hoping to be able to determine which lifestyle strategies work best for which patients, to develop personalized prevention tools to help patients avoid and survive cancer."

Together, Drs. King, Garber, and Ligibel, and other Dana-Farber breast specialists are establishing a new timeline for breast cancer interception — an era when it's possible to eliminate breast cancer before it begins.