Using a much lower dose to reduce the incidence of side effects would be a “way forward,” reasoned Swedish researchers. They report that a substantially lower dose of tamoxifen (2.5 mg) may be as effective as the standard dose (20 mg), but reduced by half the incidence of severe vasomotor symptoms, including hot flashes, cold sweats, and night sweats.
The research was published online March 18 in the Journal of Clinical Oncology.
The study involved 1439 women (aged 40-74 years) who were participating in the Swedish mammography screening program and tested tamoxifen at various doses.
“We performed a dose determination study that we hope will initiate follow-up studies that in turn will influence both adjuvant treatment and prevention of breast cancer,” said lead author Per Hall, MD, PhD, head of the Department of Medical Epidemiology and Biostatistics at Karolinska Institutet in Stockholm, Sweden.
The study measured the effects of the different doses (1, 2.5, 5, 10, and 20 mg) on mammographic breast density.
Hall emphasized that breast density was used as a proxy for therapy response. “We do not know how that translates to actual clinical effect,” he told Medscape Medical News. “This is step one.”
Previous studies have also used breast density changes as a proxy endpoint for tamoxifen therapy response, in both in prophylactic and adjuvant settings, the authors note. There is some data to suggest that this does translate to a clinical effect. A recent study showed that tamoxifen at 5 mg/day taken for 3 years reduced the recurrence of breast intraepithelial neoplasia by 50% and contralateral breast cancer by 75%, with a symptom profile similar to placebo (J Clin Oncol. 2019;37:1629-1637).
Lower Density, Fewer Symptoms
In the current study, Hall and colleagues found that the mammographic breast density (mean overall area) was decreased by 9.6% in the 20 mg tamoxifen group, and similar decreases were seen in the 2.5 and 10 mg dose groups, but not in the placebo and 1 mg dose groups.
These changes were driven primarily by changes observed among premenopausal women where the 20 mg mean decrease was 18.5% (P < .001 for interaction with menopausal status) with decreases of 13.4% in the 2.5 mg group, 19.6% in the 5 mg group and 17% in the 10 mg group.
The results were quite different in postmenopausal participants, where those who received the 20 mg dose had a density mean decrease of 4%, which was not substantially different to the placebo, 1, 2.5, and 10 mg treatment arms.
The authors point out that the difference in density decrease between premenopausal and postmenopausal women was not dependent on differences in baseline density.
When reviewing adverse events with the various doses, the team found a large decrease in severe vasomotor symptoms with the lower doses of tamoxifen: these adverse events were reported by 34% of women taking 20 mg, 24.4% on 5 mg, 20.5% on 2.5 mg, 18.5% on 1 mg, and 13.7% of women taking placebo. There were no similar trends seen for gynecologic, sexual, and musculoskeletal symptoms.
Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer, Hall commented.
“We are planning a trial now where women are offered risk assessment when attending mammography screening,” Hall said. “For those at very high risk, low-dose tamoxifen will be offered.”
The study received support from the Kamprad Foundation, Swedish Research Council, Marit and Hans Rausing’s Initiative Against Breast Cancer, Swedish Cancer Society, and Stockholm County Council.
Hall reports several relationships with industry, and also had a pending patent on compositions and methods for prevention of breast cancer with an option to license to Atossa Therapeutics, and has licensed an algorithm for risk prediction based on analyses of mammographic features to iCAD Travel. Several co-authors have also declared relationships with industry.
J Clin Oncol. Published online March 18, 2021. Abstract