Hormone Replacement Therapy (HRT) and Breast Cancer

Synthesis by Cécile Bour, MD, 

December 29, 2020

The debate on the question of the link between HRT and breast cancer is long-standing, dating back to 2002 when an American study suggested an over-risk of cancer in patients on HRT. This first study resulted in great controversy. This WHI (Women Health Initiative) trial is a large randomized American study whose objective is to evaluate the risks and benefits of different dietary and medical strategies that can reduce the incidence of cardiovascular disease, breast cancer, colorectal cancer and fractures in postmenopausal women.

Planned to last more than 8 years, the trial was prematurely stopped in the first half of 2002 after a little more than 5 years, as the risks were deemed to outweigh the benefits, in particular due to the appearance of unfavorable and unexpected cardiovascular effects of HRT.

Indeed, the study confirmed a vertebral and femoral anti-fracture effect, a beneficial effect on the decrease of colon cancer rate, but found an increase in cerebrovascular accidents, myocardial infarction, phlebitis and pulmonary embolism, and breast cancer.

The results were contested in France on the basis that the products used in the study were orally administered and normodosed equine estrogens (whereas in France were used transdermally or orally estradiol), and medroxyprogesterone acetate which was not used in France. Great relief therefore when JAMA[1], in 2017, came back on these first rather frightening results and contested this excess mortality in the WHI study, the French gynecologists then considering HRT globally as a "good thing if the treatment is not standardized but personalized"[2].

However, in medicine, nothing is ever set in stone, and in 2003, another study, an English one[3] conducted from 1996 to 2001 including more than a million menopausal women between 50 and 64 years old, showed an over-risk of breast cancer under HRT, even with treatments commonly used in Europe. The result of the study was that the risk of developing breast cancer as well as the risk of cancer-related death was greater in treated women than in untreated women, and greater in women treated with combined estrogen-progestin therapy than in women receiving estrogen therapy alone. This English study examined many of the treatments used in Europe, both for the types of estrogen-progestin and for their means and routes of administration.

The controversy was such that the systematic prescription of HRT was drastically slowed down in 2004. And it is true that a decrease in the incidence of this cancer was observed around 2004, when HRT was stopped being prescribed on a large scale and for long periods of time. [4]

A 2019 study – an over-risk of cancer confirmed under HRT treatment

This is a review of 58 epidemiological studies on the subject of the association between HRT and breast cancer, mostly observational, involving more than 100,000 women in total. Published in 2019 in The Lancet [5], this review demonstrates an increased risk of breast cancer in women undergoing hormonal treatment for the effects of menopause. While this excess risk decreases well after stopping treatment, it persists for at least ten years.

The study is innovative in that it quantifies the risk for each type of treatment.

For example, a fifty-year-old woman who has been on HRT combining estrogen and progesterone continuously for 5 years has a risk of developing breast cancer within 20 years of starting treatment of 8.3%. The risk would be only 6.3% for women of the same age who have had no treatment.

The risk of developing breast cancer after 20 years would be 7.7% for women who have been treated with estrogen and progesterone but intermittently, and 6.8% for those treated with estrogen alone, according to the researchers.

What should be learned essentially from the study?

  • All hormonal treatments for menopause are associated with increased risk, with the exception of estrogen gels for local application.
  • The risk would also increase with the duration of treatment, the use of HRT for 10 years would result in an excess risk of breast cancer about twice as high as the risk of a 5-year treatment alone.
  • Conversely, using HRT for less than a year would result in a low risk.

Adapt according to the need

Currently the practice aims to individualize prescriptions, carefully considering the risks and benefits of treatment for each woman and taking into account whether or not to use HRT, depending on the woman's climacteric disorders (Climacteric refers to the years of hormonal change experienced by the woman before and after menopause).

The recommendation of the High Authority of Health (HAS-France)

In 2004 the French High Authority for Health (HAS) issued a recommendation[6] that is still in force: HRT should be prescribed for a short period of time. The HAS specifies that there is no need to prescribe additional or specific radiological examinations for women treated with HRT, but the HAS does request that all women treated be systematically included in the screening program. The following is recommended  [7]:

  •  In case of hormone replacement therapy or menopause hormone treatment in progress :

In case of prescription before the age of 50 and in the absence of sufficient data to determine the benefit-risk balance of mammography, no specific radiological monitoring is recommended.
In case of prescription after the age of 50, no specific radiological monitoring is recommended. The woman should be encouraged to participate in the national organized screening program.

Therefore, in the case of prescribing HRT, the prescribing physician cannot, at the risk of legal action, manage the treatment without recommending the systematic screening of his patient for breast cancer[8].

References

[1] https://jamanetwork.com/journals/jama/article-abstract/2653735

[2] https://www.lequotidiendumedecin.fr/actus-medicales/recherche-science/thm-letude-whi-montre-finalement-une-absence-de-surmortalite

[3] https://www.ansm.sante.fr/S-informer/Communiques-Communiques-Points-presse/Traitement-hormonal-substitutif-et-risque-de-cancer-du-sein

[4] Page 6 of the document: " STATUS AND KNOWLEDGE REPORT / GUIDELINE FILES".

FEBRUARY 2015

HORMONE TREATMENTS/MENOPAUSE AND RISKS OF CANCERS

Document written and coordinated by the Prevention Department, Public Health and Care Unit (PSPS)-INCa. "Although this hypothesis needs to be further explored, the decrease in breast cancer incidence has also been described in other countries where the drop in the prescription of THMs (hormonal treatment for menopause) has been spectacular, such as in Canada, Germany, the United States, Belgium and Australia".

[5] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(19)31709-X/fulltext

[6] https://www.has-sante.fr/jcms/c_1754596/fr/traitements-hormonaux-de-la-menopause

[7] https://www.has-sante.fr/jcms/c_1741170/fr/depistage-du-cancer-du-sein-en-france-identification-des-femmes-a-haut-risque-et-modalites-de-depistage#toc_1_2

[8] https://cancer-rose.fr/2020/03/02/depistage-et-paradoxe-lors-de-lusage-de-certains-medicaments/