Research Highlights: Investigating Ways to Reduce and Avoid Side Effects of Medications for Breast Cancer Risk Reduction

There are multiple approved medications to reduce the risk of breast cancer. However, the chances of those medications causing toxic side effects can lead many people to forego preventive interventions. Two recent studies supported by the NCI Division of Cancer Prevention (DCP) are looking at ways to provide breast cancer risk reduction while reducing the chance of adverse side effects.

Reducing Dose Frequency for Preventive Breast Cancer Treatment

Aromatase inhibitors, a type of cancer treatment, have been shown to reduce the risk of breast cancer in women at high risk, as well as to reduce the risk of cancer recurrence after initial treatment. An aromatase inhibitor called exemestane, when used for cancer prevention, has shown a 65% relative risk reduction in the annual incidence of invasive breast cancer, compared to a placebo.

However, the potential for adverse side effects can stop individuals from using this drug as a preventive method, and side effects can lead to discontinuation of the drug when used after initial cancer treatment. Therefore, researchers are trying to determine the minimal effective dose of aromatase inhibitors to reduce the risk of breast cancer while also limiting the potential for toxic side effects.

In a randomized, phase 2 clinical trial, researchers wanted to see if giving standard dose exemestane (25 mg) in two different less frequent dose schedules had similar effects (or were “noninferior”) to once daily. They measured effectiveness by comparing how much the different dosages reduced concentrations of serum estradiol, a form of the hormone estrogen. The findings from the trial were published in JAMA Oncology.

In the trial, 180 postmenopausal women with estrogen-receptor positive breast cancer who were candidates for surgery were divided into three groups and given exemestane either once daily, three times weekly, or once weekly, 4 to 6 weeks before breast surgery. The researchers found that giving trial participants 25 mg of exemestane three times per week was noninferior to giving participants the once-daily dosage. The once-weekly schedule, however, was less effective than the standard dose at reducing serum estradiol. Based on the findings from this trial, a larger, longer trial with funding from the Breast Cancer Research Foundation will compare the three-times-per-week schedule to the daily schedule.

Reference: Serrano D, Gandini S, Thomas P, et al. Efficacy of Alternative Dose Regimens of Exemestane in Postmenopausal Women With Stage 0 to II Estrogen Receptor–Positive Breast Cancer: A Randomized Clinical Trial. JAMA Oncol. 2023;9(5):664–672.

Exploring Alternative Delivery Methods for Ductal Carcinoma In Situ Treatment

Another recent study looked at the treatment tamoxifen citrate for women with ductal carcinoma in situ (DCIS), a condition in which abnormal cells are found in the lining of a breast duct. Because in some cases DCIS may become invasive breast cancer, most women with DCIS receive some sort of treatment for the condition. Oral tamoxifen has been shown to have beneficial effects in women with DCIS, but, as with the other study, concern about toxic effects has led to limited uptake of the treatment.

Researchers in this study wanted to see if giving tamoxifen through a transdermal (topical) gel might be as effective as the oral medication but have fewer side effects, because providing the medication through the skin avoids the systemic exposure that comes with an oral drug. The findings were published in JAMA Surgery.

In a phase 2 randomized trial, 90 women with DCIS received either oral tamoxifen citrate and a gel placebo, or the tamoxifen gel and oral placebo, for 4 to 10 weeks. In this trial, the researchers could not confirm that delivering an active metabolite of tamoxifen through the gel was noninferior to providing it through the oral tamoxifen. However, researchers learned a great deal about how transdermal treatments might be used for breast cancer prevention. They recommend continued studies looking at improved transdermal delivery of higher drug concentrations in an effort to find effective alternative treatments that can reduce toxic side effects.

Reference:  Khan SA, Mi X, Xu Y, et al. Presurgical Oral Tamoxifen vs Transdermal 4-Hydroxytamoxifen in Women With Ductal Carcinoma In Situ: A Randomized Clinical Trial. JAMA Surg. Published online October 23, 2023.