A review of data from two Women's Health Initiative clinical trials reveals the varying effects of menopausal hormone therapy on the incidence of breast cancer over time. The results are published in the journal JAMA Oncology.

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The review revealed that use of estrogen plus progestin was associated with a steady increase in breast cancer incidence, while estrogen alone was found to reduce breast cancer risk.

Hormone replacement therapy was once considered the standard treatment for women suffering menopausal symptoms. It involves the use of medications that contain female hormones - commonly estrogen or a combination of estrogen and progestin (a form of progesterone) - to replace those lost following menopause.

But in 2002 came the results of a clinical trial as part of the Women's Health Initiative (WHI), which found a link between use of combined hormone therapy and increased risk of breast cancer - a finding that was supported by another WHI trial a year later.

According to Dr. Rowan T. Chlebowski, of the Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center in Torrance, CA, and colleagues, the results of these trials led to a significant reduction in the use of hormone therapy.

However, the authors point out that while combined hormone therapy was associated with increased breast cancer risk in these trials, the use of estrogen alone was not. In fact, estrogen use was associated with reduced breast cancer incidence and deaths.

"Such results raised questions regarding the short- and long-term postintervention effects of these two regimens on breast cancer," say the authors.

As such, Dr. Chlebowski and colleagues conducted a longer-term review of the two WHI trials with the aim of going a better understanding of how the use of hormone therapy influences the risk of breast cancer.

Hormone therapy with estrogen alone reduced breast cancer risk

One trial involved 16,608 women with an intact uterus who were randomized to receive combined hormone therapy - estrogen plus progestin - or a placebo for an average of 5.6 years.

The other trial involved 10,739 women who had undergone a hysterectomy who were randomly assigned to receive estrogen alone or a placebo for an average of 7.2 years.

The review revealed that use of estrogen plus progestin throughout the entire intervention period was associated with a steady increase in breast cancer incidence.

However, around 2.75 years after combined hormone therapy began - deemed the early postintervention period - the researchers identified a sharp reduction in breast cancer incidence among women whose therapy had been discontinued.

"This likely represents a therapeutic influence of change in hormone environment on preclinical breast cancers similar to that seen with adjuvant aromatase inhibitor or tamoxifen use in early-stage breast cancer," the authors note.

An increased risk of breast cancer remained for years after treatment ceased, however.

In the estrogen-only trial, the researchers identified an overall significant reduction in breast cancer incidence throughout the entire intervention period. This risk was lowest in the early postintervention period, the team found, though they note it increased over time.

"Nonetheless," say the authors, "use of estrogen alone reduced breast cancer risk throughout the cumulative follow-up."

The researchers say the early reduction in breast cancer risk with estrogen therapy alone may reflect a treatment effect on preclinical breast cancers. "Estrogen receptor-positive cancers respond to sudden lowering of estrogen exposure with tumor reduction," they note.

Commenting on their findings, the team says:

"With longer follow-up of the two WHI hormone therapy trials, a complex pattern of changing year-to-year influences on breast cancer was observed.

The ongoing influences on breast cancer after stopping hormone therapy in the WHI trials require recalibration of breast cancer risk and benefit calculation for both regimens, with greater adverse influence for estrogen and progestin use and somewhat greater benefit for use of estrogen alone."

Review offers 'compelling new evidence' of progesterone's role in breast cancer

In an editorial linked to the study, Rama Khoka, PhD, of the Princess Margaret Cancer Center in Toronto, Canada, and colleagues say this latest review of the WHI trials reveals "compelling new evidence" for the significant role progesterone plays in breast cancer, noting that it has "traditionally taken a backseat to estrogen."

"Although the WHI trials relate to the menopausal setting, lessons learned from them continue to provide additional value in appreciating a potential role of progesterone even in premenopausal breast cancer," they add.

"Furthermore, investigation into the cellular and mechanistic underpinnings of progesterone's impact on the normal breast and breast cancer may provide new opportunities for knowledge translation and therapeutic intervention in breast cancer."

In February, Medical News Today reported on a study published in The Lancet suggesting hormone replacement therapy increases the risk of ovarian cancer after only 5 years of use.