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Topical gel may help decrease breast density
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A clinical trial is underway at University of Southern California to assess whether a topical gel that contains 4-hydroxytamoxifen can effectively reduce breast density.
Dense breasts have been linked to greater levels of estrogen, as well as elevated breast cancer risk.
“To help women with dense breast tissue fight cancer, we need a deeper understanding of the nature of breast density, as well as imaging techniques that can more easily detect tumors in this patient population,” Pulin A. Sheth, MD, assistant professor of clinical radiology and director of breast imaging at Norris Breast Center/Keck School of Medicine at USC, said in a press release. “We are excited to assess a clinical innovation that could potentially fulfill both of those needs through a simple daily topical application.”
HemOnc Today spoke with Sheth about the prevalence of dense breasts among U.S. women, the link between breast density and breast cancer risk, how this gel may reduce breast density, and how the trial will be conducted.
Question: Can you discuss the prevalence of dense breasts among women in the United States, as well as how breast density affects cancer risk?
Answer: Almost half of women in the United States have dense breast tissue. About 10% of women have category D, or very dense breasts. Studies have shown the presence of heterogeneously dense or very dense breasts increases the risk for the development of breast cancer twofold to fourfold compared with age-matched women with fatty or less dense tissue, independent of other risk factors.
Q: How was this gel created?
A: Besins Healthcare has a long history of producing gels. The formulation is not very different from the gel composition used in products like testosterone gel (AndroGel, AbbVie) and estradiol gel (EstroGel, Ascend Therapeutics), both of which are FDA approved and prescribed for male hypogonadism and estrogen replacement therapy. BHR-700 (Besins Healthcare) is a proprietary gel that contains 4-hydroxy tamoxifen (4-OHT) as the active ingredient. This 4-OHT is a metabolite of tamoxifen but, unlike tamoxifen, the gel can be readily absorbed through the skin.
Q: What is the topical gel designed to do and how does it work?
A: 4-OHT has strong affinity for the estrogen receptors in the breast. It binds with these receptors, stopping the cell cycle in breast tissue induced by estradiol. This interference is thought to be linked to preventing cells from proliferating into cancer cells. Unlike the orally administered tamoxifen, which circulates through the entire body, the 4-OHT absorbed from BHR-700 gel stays mostly in the breast tissue after topical application on the breasts. Many of the side effects associated with oral tamoxifen — which is approved for both prevention and treatment of breast cancer — are thought to result from what is called systemic exposure. These side effects include vasomotor symptoms — such as what is seen in menopause — as well as thromboembolic events and endometrial hyperplasia, which seriously limits the usefulness of the drug in prevention.
Q: How is this trial designed?
A: The study uses a double-blind, parallel arm, placebo-controlled design. Eligible patients are randomly assigned to receive two actuations of gel per breast, containing either a total of 8 mg of the active drug or a matching placebo. The analysis will include 330 patients — 220 assigned to the active drug and 110 assigned to placebo — who will be treated for 1 year. Following this, all participants can choose to receive another year of active treatment in an open-label fashion.
There are a number of inclusion/exclusion criteria. In principle, the study is open to healthy women aged 35 to 75 years who have dense breast tissue, are not pregnant and do not want to become pregnant during the study, and who do not have and have never been treated for breast cancer.
Q: What do you intend to assess ?
A: The primary outcome measure is breast density as calculated from a standard digital mammogram. Using special FDA-approved software, a quantitative assessment is made of breast density at the start of the study and after 1 year of treatment. These densities will be compared to calculate the absolute change. In addition, the tolerability and safety of the drug is carefully monitored. Adverse events are recorded and laboratory samples are taken. Finally, blood levels of circulating 4-OHT are measured.
Q: What do you hope to find?
A: We hope to find that there is a statistically significant and clinically meaningful reduction in breast density among patients treated with BHR-700 compared with placebo. It has been shown in studies with tamoxifen that an overall reduction between 4% and 5% is associated with a reduction in the occurrence of breast cancer. As this study focuses on women with dense or very dense breasts, we are hopeful that the effect could be significantly larger.
Q: What is the anticipated timeline for results?
A: Recruitment is ongoing and hopefully will be complete by the end of this year or early 2019. The first results will be available after all patients have been treated for 1 year, so not until early 2020.
Q: What are the potential implications if this approach is proven effective?
A: Potential implications are that a meaningful reduction in breast density is associated with a reduction in the incidence for breast cancer. Although this will need to be established in a longer duration follow-up study, the data will be presented to the FDA for review and it is possible the drug could be conditionally approved for prevention of breast cancer while confirmatory studies are being conducted.
Q: What is known now, or what will be assessed in the trial, regarding safety of this gel and any potential side effects?
A: The gel has already been used in studies of women with dense breasts and women with painfulness of the breasts associated with their menstrual cycles. In all studies, it was very well-tolerated with minimal side effects. The dose used in the current study, however, is higher than that used in previous studies. Thus far, the gel appears to be well tolerated, with few patients discontinuing or reducing the dose level due to side effects. – by Jennifer Southall
For more information:
Pulin A. Sheth, MD, can be reached at Keck School of Medicine of University of Southern California, 1975 Zonal Ave., Los Angeles, CA 90033; email: pulin.sheth@med.usc.edu.
Disclosure: Sheth reports no relevant financial disclosures.