Risk-Reducing Medications for Breast Cancer Are Becoming Safer and More Tolerable

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Risk-reducing medications for breast cancer may be effective for many women, and recently reported and ongoing trials have led to improvements in their tolerability and safety, Seema A. Khan, MD, reported at the 2021 Annual Lynn Sage Breast Cancer Symposium (virtual).1 Dr. Khan is Professor of Surgery and the Bluhm Family Professor of Cancer Research at Northwestern University Feinberg School of Medicine. She is also Co-Leader of the Cancer Prevention Program at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, which sponsored the symposium.

“Dose and frequency modifications and alternative delivery routes are being applied to known effective agents,” Dr. Khan stated. “Broadening the targets of preventive interventions beyond the estrogen receptor is part of these efforts.”

Seema A. Khan, MD

Seema A. Khan, MD

Minimum Effective Dose

“New concepts to reduce breast cancer risk include data in support of a minimum effective dose, rather than a maximal tolerated dose,” Dr. Khan noted. “Prevention does not need the same dose as therapy. This is something that is eminently logical but has not been demonstrated until very recently.”

Several studies have looked at whether low-dose and shorter-duration tamoxifen could be as effective as the standard dose of 20 mg/d for 5 years in reducing the risk for breast cancer but with lower toxicity. In a multicenter randomized, placebo-controlled trial, 500 women (up to age 75) with atypical lesions or estrogen receptor–positive or estrogen receptor–unknown ductal carcinoma in situ were randomly assigned to receive 5 mg of tamoxifen daily vs placebo for 3 years after surgery.2 “The duration of therapy was shortened as well,” Dr. Khan noted. The women had clinical checkups regularly and mammography every year. Median follow-up was 5.1 years.

“There were 14 neoplastic events with tamoxifen and 20 with placebo,” with a hazard ratio of 0.48, the researchers reported. “Patient-reported outcomes did not differ between arms except for a slight increase in the frequency of daily hot flashes with tamoxifen (P = .02).”

The researchers concluded: “Tamoxifen at 5 mg/d for 3 years can halve the recurrence of breast intraepithelial neoplasia with limited toxicity, which provides a new treatment option in these disorders.”

‘A Solution in Evolution’

“An important additional piece of information” subsequently reported, Dr. Khan noted, was “postmenopausal women appear to be the group deriving a benefit from low-dose tamoxifen. The hypothesis was that high estradiol levels in premenopausal women overcome the effects of low-dose tamoxifen, and premenopausal women may need higher doses. This is not very comforting, since postmenopausal women do have other options, and premenopausal women are the ones in need of relief from symptoms to be able to take these drugs,” Dr. Khan said.

“We have to see where this goes, but clearly it is a solution in evolution,” Dr. Khan said. Although the hypothesis for tamoxifen at 5 mg “is compelling,” and the preliminary data were very strong,” the trial was small. It was underpowered to detect significant safety differences. The comparison group was placebo, not full-dose tamoxifen. The data on improved adherence need to the demonstrated in a larger population.”

Mammographic Density

“Another aspect of low-dose tamoxifen that has been explored intensively recently is mammographic breast density,” Dr. Khan stated. These studies go back to 2011, when researchers conducted a case control study of a subgroup of 123 women from the International Breast Cancer Intervention Study who were diagnosed with breast cancer at or after their first follow-up mammogram. Those women who received tamoxifen and experienced a 10% or greater reduction in mammographic breast density had a 63% reduction in breast cancer risk compared with women receiving placebo.3 “This led to the hypothesis that reduction in mammographic density in women on tamoxifen is a robust target endpoint and can be used as an indicator of benefit, and this has been pursued by others,” Dr. Khan.

Studies are also addressing the issue of mammographic screening sensitivity, which “is strongly reduced by the amount of dense tissue in the breast,” Dr. Khan noted. “Sensitivity steadily decreases as the density increases.”

At the Karolinska Institute in Sweden, an intervention trial called KARISMA “examined the effects of low-dose tamoxifen on mammographic screening sensitivity in premenopausal women,” Dr. Khan reported. The double blind, placebo-controlled, 6-month noninferiority dose determination trial stratified 499 women by breast density categories (BI-RADS [Breast Imaging Reported and Data System] categories A through D, with D being the highest density). The women were then randomly assigned to no tamoxifen or tamoxifen at one of five doses (1, 2.5, 5, 10, or 20 mg).4

“The results of the 2.5-mg tamoxifen arm of the KARISMA trial were used to define expected changes in mammographic density after 6 months’ exposure and to predict changes in mammographic screening sensitivity and detected tumor size,” the researchers wrote. There was a 5% improvement in screening sensitivity of mammography among women in the tamoxifen arm who had breast density C or D, a 2% increase among women with breast density B, and no difference for women in breast density category A. Estimated data based on calculations showed that a “20% or greater relative reduction in mammographic density led to a 24% reduction in the frequency of interval cancers,” Dr. Khan added.

“Tamoxifen does reduce mammographic density in some women,” Dr. Khan summarized. “That reduction may be accompanied by an improvement in sensitivity of mammographic screening and a reduction in the risk of developing breast cancer.”

Fewer False-Positive Results With Tamoxifen

“Another benefit of tamoxifen we don’t mention that much,” Dr. Khan said, “is its ability to lower the frequency of unnecessary benign biopsies or false-positive results.” A review of medical records of 13,203 women with follow-up who participated in the National Surgical Adjuvant Breast and Bowel Project identified those who had histologic diagnoses of adenosis, cyst, duct ectasia, fibrocystic disease, fibroadenoma, fibrosis, hyperplasia, or metaplasia. “Overall, tamoxifen treatment reduced the risk of benign breast disease by 28%,” and women treated with tamoxifen had a 29% reduction in the risk of biopsy, the researchers reported.5

“This is another benefit that women would value and should be mentioned in the discussion of tamoxifen use for risk reduction,” Dr. Khan pointed out.

Aromatase Inhibitors

Worsening quality of life also leads to the discontinuation of the aromatase inhibitor exemestane. “In general, there is about a twofold or greater increased chance of discontinuation of exemestane in women who experience side effects,” Dr. Khan noted.

A trial randomly assigned 180 postmenopausal women with estrogen receptor–positive early-stage breast cancer to receive exemestane at 25 mg daily, weekly, or three times a week. “The idea is that reducing the dosing frequency of exemestane would result in the same reduction in estradiol levels and therefore a reduction in risk, with fewer side effects,” Dr. Khan said. That trial “recently completed accrual and is in the process of data analysis,” she added.

Bazedoxifene Plus Conjugated Equine Estrogen

“The final ongoing development in endocrine risk reduction for breast cancer is the combination therapy of the selective estrogen receptor modulator bazedoxifene and conjugated equine estrogen. This combination is approved in the United States for postmenopausal women with menopausal symptoms and an intact uterus, since it spares the uterus completely,” Dr. Khan noted. “This has been shown in large, randomized trials, with mature data. Preclinical data suggest it should reduce breast cancer risk.”

An ongoing trial at Northwestern University Feinberg School of Medicine involves 160 women with estrogen receptor–positive ductal carcinoma in situ. The women were randomly assigned in a presurgical setting to receive bazedoxifene plus conjugated equine estrogen with surgery after 3 to 5 weeks.

The newest study, being conducted at the University of Kansas Medical Center, Kansas City, “will enroll 120 women at moderately high risk for breast cancer and randomly assign them to either bazedoxifene plus conjugated equine estrogen (active agent) or waitlist control,” Dr. Khan stated. Following biomarker assessment after 6 months, the waitlist control group will be offered the option of active agent.

“These trials are both exciting, and we are looking forward to the results,” Dr. Khan shared. “This should ameliorate concern about quality-of-life side effects in postmenopausal women and offer this group yet another option for endocrine prevention, which should be better tolerated.”

Approaches on the Horizon

New approaches include local delivery (transdermal or intraductal), repurposed agents, and immunoprevention, which Dr. Khan called “the new star on the horizon,” She continued: “The rationale of immunoprevention basically relates to the statement that ‘mechanisms of an immune response are still intact in unaffected individuals,’ a problem that has plagued vaccine trials in people with later- and advanced-stage cancers,” Dr. Khan noted. The development of breast cancer vaccines is “mainly focusing on HER2.”

Local transdermal therapy is based on “the rationale for drug delivery through the breast skin. It includes the fact that the mammary gland is a skin appendage with a well-developed internal lymphatic circulation and that drugs applied to the breast can reach higher concentrations in the breast than when they are applied to skin elsewhere.” The anabolic steroid 4-hydroxytestosterone (4-OHT) has been “available since the 1980s, and its transdermal delivery has been the subject of various small phase I and II trials,” Dr. Khan reported.

Data from a study in women with ductal carcinoma in situ showed that “4-OHT penetrates breast skin. It achieves good levels in the breast, but circulating levels are low. The decrease in proliferation of ductal carcinoma in situ cells is equivalent, and circulating effects are small, if any,” Dr. Khan said.

Two trials were subsequently launched. The Northwestern trial randomly assigned women with estrogen receptor–positive ductal carcinoma in situ to receive oral tamoxifen at 20 mg/d plus placebo gel on both breasts vs 4-OHT gel (2 mg/breast/d) plus oral placebo). “We hope to see sufficient robust preliminary data to support a phase II trial of this agent and are looking forward to that possibility,” Dr. Khan said. A trial at MD Anderson Cancer Center is randomly assigning women with dense breasts to receive 4-OHT gel (2 mg/breast/d) vs placebo gel.

Repurposed Agents

Repurposed agents “are very attractive,” Dr. Khan noted, because they “provide not only the risk-reducing value, but also multiple benefits to other organ systems.” Nonsteroidal anti-inflammatory drugs “have been ignored for a while, but they are being revisited because the preclinical data are so compelling,” Dr. Khan said. Sulindac has been shown to decrease breast density in women taking aromatase inhibitors.

“Celecoxib has been out in the wilderness for many years,” Dr. Khan noted, but a recent MD Anderson study tested celecoxib in 49 women. Using fine-needle aspiration before and after 6 months of treatment, researchers “observed some improvement in cytologic atypia, which is in fact correlated with breast cancer risk,” Dr. Khan said. “So, there is some movement on the cyclooxygenase inhibition front again. These drugs are available, some of them also as transdermal agents, and hopefully there will be more forward momentum in this area,” she added.

“Metformin is the darling of the cancer prevention world, not just breast cancer prevention, and is being tested in many different trials in many different settings,” Dr. Khan reported. A phase II trial to evaluate biomarker modulation in overweight women randomly assigned 151 women with features of metabolic syndrome to receive a 12-month intervention with either oral metformin at 850 mg/d or oral placebo. So far, researchers “have found that metformin decreases waist-to-hip ratio, which is correlated with cancer risk, and nondense volume of the breast,” Dr. Khan said. “There is increased interest in breast adiposity and the role of the adipose tissue in the promotion of cancer, which require future study.”

“There are “very strong clinical data that RANK ligand will retard cancer development in BRCA1 carriers. This is now being tested in a large international study, where 3,000 subjects will be enrolled. This is just about to open in the United States. It has been open in Australia and Europe for some time,” Dr. Khan said. “These women should not be planning mastectomy. They will be treated for 5 years. The duration of the study from initiation to the end of follow-up will be 12 years.” 

DISCLOSURE: Dr. Khan reported no conflicts of interest.


1. Khan S: Is breast cancer chemoprevention dead? 2021 Annual Lynn Sage Breast Cancer Symposium. October 1, 2021.

2. DeCensi A, Puntoni M, Guerrieri-Gonzaga A, et al: Randomized placebo controlled trial of low-dose tamoxifen to prevent local and contralateral recurrence in breast intraepithelial neoplasia. J Clin Oncol 37:1629-1637, 2019.

3. Cuzick J, Warwick J, Pinney E, et al: Tamoxifen-induced reduction in mammographic density and breast cancer risk reduction: A nested case-control study. J Natl Cancer Inst 103:744-752, 2011.

4. Eriksson M, Czene K, Conant EF, et al: Use of low-dose tamoxifen to increase mammographic screening sensitivity in premenopausal women. Cancers (Basel) 13:302, 2021.

5. Tan-Chiu E, Wang J, Costantino JP, et al: Effects of tamoxifen on benign breast disease in women at high risk for breast cancer. J Natl Cancer Inst 95:302-307, 2003.

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