The Effect of Prior Use of Hormone Therapy on Breast Cancer Survival

AbstraCt & Commentary

By Leon Speroff, MD, Editor, Professor of Obstetrics and Gynecology, Oregon Health and Science University, Portland, is Editor for OB/GYN Clinical Alert.

Synopsis: Current users of estrogen-progestin hormone therapy at the time of breast cancer diagnosis have a reduced risk of breast cancer mortality.

Source: Newcomb PA, et al. Prediagnostic use of hormone therapy and mortality after breast cancer. Cancer Epidemiol Biomarkers Prev 2008;17:864-871.

Newcomb and colleagues reported breast cancer mortality in the Collaborative Breast Cancer Study Cohort, a prospective cohort of 12,269 postmenopausal women from Wisconsin, Massachusetts, or New Hampshire. Women were followed for an average of 10.3 years after breast cancer diagnosis. Observed ratio rates for breast cancer after adjusting for BMI, smoking, and history of mammography screening are listed in Table 1, below.

Table 1

Compared with non-users, mortality from breast cancer was lower among current users of estrogen-progestin, and even greater with 5 or more years of use.

Commentary

These are striking data. They support an argument I have been making in recent months, that, in terms of breast cancer, the use of estrogen and progestin may not be more harmful, but more beneficial. This idea is derived from the possibility that hormone therapy affects pre-existing tumors, and that estrogen-progestin produces a beneficial differentiation of the tumor that leads to earlier diagnosis.1

The evidence that favors an effect of hormone therapy on pre-existing tumors is as follows:

  1. Epidemiologic studies find an increased risk within a few years of hormonal exposure.
  2. Breast cancer associated with estrogen-progestin therapy is estrogen-receptor-positive, lower-grade, lower-stage disease with better survival rates.
  3. Epidemiologic studies find an increased risk only in current users; 5 years after discontinuation the risk returns to baseline.
  4. A recent rapid decrease in breast cancer prevalence coincides with a decrease in the use of postmenopausal estrogen-progestin therapy.

Let me summarize the evidence that supports a beneficial impact of progestins on pre-existing tumors:

  1. An increase in estrogen-receptor-positive tumors is seen sooner with estrogen-progestin treatment, and greater risk is observed with continuous, daily estrogen-progestin use.
  2. Genes up-regulated by estrogen are down-regulated by estrogen-progestin therapy.
  3. Genes that are activated by estrogen-progestin are involved in DNA repair and cell cycle regulation.
  4. Progestins decrease breast tissue levels of PR-A, causing a beneficial change in the PR-A:PR-B ratio that is associated with better differentiation and outcome.
  5. A reduction in breast cancer case mortality has been reported with estrogen-progestin use, and not with estrogen alone.

The strength of the above study is the large size of the cohort. Indeed, this is the strongest evidence thus far published that the use of estrogen-progestin is associated with the development of less aggressive breast cancers. Even in studies that adjusted for the prevalence of mammography screening, breast cancers in hormone users are smaller, have fewer positive axillary lymph nodes, and are of lower-grade disease.

It is also important to note that this prospective cohort reports reduced risks from cardiovascular disease in hormone users, statistically significant for both treatments, estrogen-only and combined estrogen-progestin (see Table 2, below).

Table 2

This is consistent with other observational studies, and with the analyses of the Women's Health Initiative that revealed an increase in coronary heart disease only in women 70 years of age and older when they started hormone therapy.

At this point in time it is impossible to answer the question whether the epidemiologic data indicate a small increase in breast cancer risk associated with hormone therapy or whether we are seeing an effect on pre-existing tumors. But I believe the evidence is sufficient to share with patients the important possibility that hormone therapy affects pre-existing tumors, and that this leads to earlier diagnosis with better outcomes.

References

  1. Speroff L. Postmenopausal hormone therapy and the risk of breast cancer: A contrary thought. Menopause 2008;15:393-400.