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Comparing opinions on “Association of Circulating Progesterone With Breast Cancer Risk Among Postmenopausal Women”. by Trabert et al.

Is there a relationship between endogenous progesterone and postmenopausal breast cancer risk?

Summary

Trabert and colleagues investigated the influence of circulating endogenous progesterone on the incidence of postmenopausal breast cancer through a prospective case-cohort study based on a bone follow-up to the Fracture Intervention Trial (B-FIT, n=15595). Participants were not receiving exogenous hormone therapy at the time of blood sampling (1992-1993) [1]. Cancer incidence was based on questionnaire responses with subsequent requests from medical record verification and/or cancer registry linkage at clinical sites. One thousand eight hundred eleven cases were excluded from possible selection in the case-cohort study. Of the remaining 13784 eligible participants, 515 were randomly selected for the subcohort within a 10-year age and clinical center strata. After additional exclusions, 405 incident breast cancer cases diagnosed during 12 follow-up years and a subcohort of 495 postmenopausal women were randomly selected within a 10-year age and clinical center strata. Progesterone assays, using a liquid chromatography–tandem mass spectrometry assay were completed in July 2017. Participants’ mean (SD) age at blood draw was 67.2 (6.2) years, and most were non-Hispanic white (384 [94.8%]). Mean (SD) age for women with breast cancer was 73 (6.4) years at diagnosis (range, 56-89). The key findings were that progesterone concentrations displayed a mean (SD) of 4.6 (1.7) ng/dL. Women with higher circulating progesterone levels had a 16% increased risk of postmenopausal breast cancer per SD increase in progesterone (HR, 1.16; 95% CI,1.00-1.35; P=.048). In conclusion, in postmenopausal women, elevated circulating progesterone levels were associated with a 16% increase in the risk of breast cancer.

Commentary

The debate between MHT and breast cancer risk has always been a hot topic. More than 50 observed studies have shown that hormone therapy can increase breast cancer risk. From the Women’s Health Initiative (WHI) study, we found the breast cancer risk mainly depends on the progestogen components [2]. Some large clinical studies, including the E3N study and Finnish study, found that estradiol combined with progesterone or dydrogesterone showed a lower breast cancer incidence than that of other synthetic progestogens within 5-8 years [3,4]. Mohammed and colleagues found progesterone inhibited estrogen-mediated growth and ERα+ breast tumour explants and had increased anti-proliferative effects. At the same time, they found that tamoxifen combination with progesterone had the highest degree of tumour inhibition [5]. Our team has also focused on MHT and breast cancer risk for many years; from in vitro experiments and in vivo animal experiments, we found some synthetic progestogens can promote the proliferation of breast cancer cells or growth of tumour if there is an overexpression of progesterone receptor membrane component 1 (PGRMC1), whereas natural progesterone does not have these effects [6-8]. Many other studies have also found that different progestogens have different effects. In contrast to synthetic progestogens, progesterone in combination with estrogen has not been associated with increased breast cancer risk. This publication [1] could not support previous findings.

Some confounding factors need to be considered in the present study, such as:

(1) In the B-FIT project, the questionnaire was completed by 64% of eligible women; was there a sampling bias?
(2) During a follow-up of 12 years; many other breast cancer factors could have affected the incidence of breast cancer, such as environment and diet, MHT regimens and types

(3) The serum samples of the study were stored at -20 °C for three years, then -70 °C for more than 20 years (27-28 years), therefore the stability of progesterone and its metabolites could have been affected [9].

Also, even without considering the above potential confounders, the HR is only 1.16, indicating this study was underpowered to detect a very weak association.

To summarize, the current paper from the JAMA 2020 is interesting but the authors should be very careful to conclude that in postmenopausal women, higher circulating progesterone levels are associated with increased risk of breast cancer.

Xiangyan Ruan MD, PhD

Department of Gynecological Endocrinology, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Beijing, China.

Are circulating endogenous progesterone levels associated with breast cancer risk in postmenopausal women?

Summary

A recent paper by Trabert and coworkers [1] aimed at shedding some light on this issue by looking at minimal concentrations of progesterone and metabolites with “high-performance liquid chromatography-tandem mass spectrometry” assay, which is much more sensitive than methods used in previous studies.

The Authors, in a case-cohort study nested within the Breast and Bone Follow-up to the Fracture Intervention Trial (FIT) [2], were able to quantify prediagnostic serum levels of progesterone and progesterone metabolites, in particular the cancer-inhibiting 4-pregnenes (e.g., 3α-dihydroprogesterone[3αHP]) and cancer-promoting 5α-pregnanes (e.g., 5α-dihydroprogesterone[5αP]). They found that women with higher circulating progesterone levels were at increased risk for breast cancer with a linear association between levels and risk, except for women in the lowest quintile of estrogen levels. Contrary to expectations, the ratio of 5αP relative to 3αHP was not associated with the risk of breast cancer. The associations between the ratio of 5αP relative to 3αHP, and progesterone relative to estradiol were also null. Age, body mass index or prior oral contraceptive use did not modify progesterone associations with breast cancer and 5αP/3αHP- associations with breast cancer.
CommentaryA previous study in 2014 [3] evaluated the effect of circulating endogenous estrogens and their metabolites on breast cancer risk in the same cohort. As expected, elevated circulating estradiol levels were associated with increased breast cancer risk. The effect of endogenous progesterone, possibly because of the almost undetectable circulating levels in postmenopausal women, is much less clear. In the only previous study of endogenous progesterone and postmenopausal breast cancer risk, published in 2004, there was no association between progesterone levels and breast cancer risk [4]. However, the low sensitivity of the assay available at the time (30% of the samples had undetectable levels of progesterone) may have limited the study’s ability to find an association. Studies reporting increased breast cancer risk with menopausal estrogen plus progestin therapy, do not provide direct evidence as to the potential association between endogenous progesterone and this risk. Indeed, they evaluated the use of exogenous synthetic progestogens [5,6,7], which can have anti-androgenic, pro-androgenic, glucocorticoid, and anti-mineralocorticoid effects [8]. The studies reporting on the use of estrogens plus natural progesterone found a much weaker association. [9-10]. The study by Trabert is the first suggesting a possible association of progesterone levels and breast cancer risk in postmenopausal women, provided that they have at least moderate to high circulating total estradiol levels. Interestingly, in the lowest quintile of circulating estradiol, the breast cancer risk decreased with increasing levels of circulating progesterone, whereas, in the higher quintiles of circulating estradiol, the breast cancer risk increased with increasing levels of circulating progesterone.

Given that the women in the study were not using exogenous hormones since at least four months from the blood draw, this study suggests a differential role of progesterone at physiologic levels, possibly modulated by the level of circulating estradiol.This observation needs to be confirmed but adds to our knowledge on the synergistic activity of estrogens and progesterone, even at very low levels, on breast cells.

The authors conclude: “Further research is also needed to evaluate the role of progesterone metabolites and the interaction between progesterone and estradiol with breast cancer risk.”

Nicoletta Biglia MD, PhD

Associate Professor of Obstetrics and Gynaecology, The University of Torino School of Medicine

Director, Academic Division of Obstetrics and Gynaecology, Mauriziano Umberto I Hospital, Torino, Italy

References

Is there a relationship between endogenous progesterone and postmenopausal breast cancer risk?

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Are circulating endogenous progesterone levels associated with breast cancer risk in postmenopausal women?

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