December 13, 2019—San Antonio, Texas—The use of estrogen alone as menopausal hormone therapy has been shown to decrease breast cancer incidence and death with persistent results after discontinuation of use. Estrogen plus progestin increased breast cancer incidence with persistent results after discontinuation of use.
This outcome of the long-term follow-up of two large, randomized, placebo-controlled Women’s Health Initiative trials in postmenopausal women was reported at the 2019 San Antonio Breast Cancer Symposium (SABCS), from December 10 – 14.
Rowan T. Chlebowski, MD, PhD, of the Harbor-University of California, Los Angeles Medical Center, explained that treatment with estrogens and progestin led to significantly increased breast cancer incidence in these trials involving 27,347 postmenopausal women.
Dr. Chlebowski explained that these adverse effects were seen even 10 years following discontinuation of treatment. In contrast to numerous findings from observational studies over decades, estrogen alone led to significantly reduced breast cancer incidence and breast cancer-related deaths.
According to Dr. Chlebowski, these benefits were seen 10 years after discontinuing treatment. Although patient characteristics differed between the observational studies and the Women’s Health Initiative randomized trials, the findings regarding estrogen use alone are difficult to reconcile.
Dr. Chlebowski and colleagues updated earlier findings of two randomized Women’s Health Initiative clinical trials on breast cancer incidence and breast cancer mortality in women randomized to estrogen + progestin, estrogen alone, or placebo after more than 19 years of cumulative follow-up.
They enrolled postmenopausal women aged 50 to 79 years with no prior breast cancer in one of two randomized clinical trials at 40 US centers from 1993 to 1998 and followed them through September 2016.
Postmenopausal women with an intact uterus received estrogen + progestin (n = 8506) or placebo (n = 8102) for a median of 5.6 years. Postmenopausal women who had undergone hysterectomy received estrogen alone (n = 5310) or placebo (n = 5429) for a median of 7.2 years.
After 16.1 years of cumulative follow-up, among those who received estrogen alone, 520 incident breast cancers occurred during the post-intervention period.
Compared with women who had received placebo, those who had received estrogen were 27% less likely to have been diagnosed with breast cancer and 44% less likely to die of the disease.
These positive outcomes are in agreement with earlier findings of this trial during the intervention period. After 18.3 years of cumulative follow-up, among those who received estrogen + progestin acetate, 1003 incident breast cancers occurred during the post-intervention period.
Compared with women who had received placebo, those who had received estrogen + progestin were 29% more likely to have been diagnosed with breast cancer. This negative outcome is in agreement with the earlier finding of this trial during the intervention period.
Estrogen + progestin was associated with an increased risk of death from breast cancer in the extended analysis, but the difference did not reach statistical significance.
Dr. Chlebowski explained that millions of women around the world continue to receive hormone therapy with estrogen + progestin (for menopausal women with an intact uterus) or estrogen alone (for menopausal women who underwent hysterectomy).
He also noted that the influence of hormone therapy for menopausal women on breast cancer incidence and mortality remains unsettled after nearly 50 years, with discordant findings from randomized clinical trials and observational studies.
According to Dr. Chlebowski, the Collaborative Group on Hormonal Factors in Breast Cancer published a meta-analysis of 58 observational studies earlier this year, demonstrating that treatment with estrogen + progestin or estrogen alone were associated with significantly increased risk of breast cancer incidence. Additionally, treatment with estrogen + progestin or estrogen alone were associated with significantly increased breast cancer mortality in the Million Women Study.
Key limitations of the study include that breast cancer mortality analyses were not protocol-specified. Death from breast cancer is the most clinically relevant breast cancer outcome, however. In addition, the trials evaluated one dose and schedule of estrogen + progestin or estrogen alone, respectively. Findings may not apply to other preparations, doses, or schedules.
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Rodrigo Arrangoiz MS, MD, FACS, FSSO 