• Increased serum progesterone concentrations were associated with a 16% higher risk for breast cancer in postmenopausal women, according to a case-cohort study of 405 incident breast cancer cases.
• Note that when considering progesterone and estradiol levels together, women who fell into the lowest quintile of circulating estradiol levels actually had a reduced risk for breast cancer with each standard deviation increase in progesterone.

In one prior epidemiologic study, there was a null association between circulating progesterone levels and breast cancer risk among postmenopausal women. However, the study was hampered by methodological limitations, with nearly 30% of samples having undetectable levels of progesterone.

Since natural progesterone is currently being investigated as a safe alternative to progestins in menopausal hormone therapy regimens, it was important to assess a possible association between circulating levels of progesterone and breast cancer risk.

In a recent study in JAMA Network Open, Britton Trabert, PhD, MS, of the National Cancer Institute in Bethesda, Maryland, and colleagues found that increased serum progesterone concentrations were associated with a 16% higher risk for breast cancer in postmenopausal women (hazard ratio [HR] 1.16, 95% CI 1.00-1.35, P=0.048).

This link was even stronger for invasive breast cancers (HR 1.24, 95% CI 1.07-1.43, P=0.004).

However, progesterone levels alone weren’t the only factor at play in this breast cancer risk relationship. Looking at progesterone and estradiol levels together, Trabert’s group found that women who fell into the lowest quintile of circulating estradiol levels — less than 6.30 pg/mL — actually had a reduced risk for breast cancer with each standard deviation increase in progesterone (HR 0.38, 95% CI 0.15-0.95, P=0.04).

And women in any of the other four higher quintiles for estradiol levels — equating to 6.30 pg/mL or higher — saw an 18% higher risk for breast cancer with each standard deviation increase in progesterone levels (HR 1.18, 95% CI 1.04-1.35, P=0.01; P=0.04 for interaction).

Trabert and team used data collected from the Breast and Bone Follow-up to the Fracture Intervention Trial, limiting the sample to women (average age of 67), who weren’t receiving exogenous hormone therapy in the 4 months prior to blood sampling from 1992 to 1993. Using a sensitive liquid chromatography-tandem mass spectrometry assay, the researchers found that the average prediagnostic progesterone concentration was 4.6 ng/dL.

During the 12 years of follow-up, there were 405 incident breast cancer cases (267 invasive breast cancers) diagnosed among the 13,784 women eligible for the case cohort.

The researchers also assessed progesterone metabolite concentrations. As Trabert explained to MedPage Today, this was spurred after previous research suggested that 5α-dihydroprogesterone (5αP) concentrations may have cancer-promoting properties, while 3α-dihydroprogesterone (3αHP) concentrations have cancer-inhibiting properties. However, the team found no overall increased risk for breast cancer with higher levels of 5αP relative to 3αHP (per unit increase in ratio HR 1.00, 95% CI 0.97-1.04, P=0.85), she said.

“Since experimental data support a role of progesterone in the development of breast cancer, we were not surprised to find that higher progesterone levels were associated with increased postmenopausal breast cancer risk,” Trabert said. “However, the lack of differential association with breast cancer risk across the progesterone metabolites that were supported with laboratory data was a little surprising, because previous experimental data supported cancer-promoting properties for 5αP and cancer-inhibiting properties with 3αHP.”

“It is necessary to continue to evaluate the progesterone metabolites further,” she added

Study limitations included the generalizability to other populations, since the women included in the study were white and volunteered to be screened for participation in a clinical trial of medication to reduce fracture risk; in addition, a single blood sample may provide an imprecise average of long-term hormone levels. Also, the researchers did not correct for multiple comparisons, and hormone receptor status for the tumors was largely missing.

Source References: JAMA Network Open 2020; DOI: 10.1001/jamanetworkopen.2020.3645

Editorial: JAMA Network Open 2020; DOI: 10.1001/jamanetworkopen.2020.3608

Study Highlights and Explanation of Findings:

In the first population-based study to evaluate the association between circulating levels of progesterone and postmenopausal breast cancer risk, women with increased serum progesterone concentrations were at higher risk of incident breast cancer.

As previously noted, a prior study showed no association between circulating progesterone levels and breast cancer risk among postmenopausal women. The mean progesterone concentration of 4 ng/dL measured in that study was consistent with the mean concentration of 4.6 ng/dL measured in the present study. However, the decreased sensitivity of the progesterone assay used in the previous study might have limited its ability to find an association, according to the researchers.

In an accompanying commentary, Seema A. Khan, MD, of Northwestern University in Chicago, said that future studies should look at the role of progesterone metabolites and should also be equipped with an analysis of genetic variation in enzyme activity, as this could better solidify if these metabolites could be targeted for future breast cancer therapies.

“Trabert et al. saw no association of these metabolites with risk, except among women in the lowest tertile of 3αHP and the highest tertile of 5αHP, but the hazard ratio in this extreme group was 1.96 (95% CI 1.01-3.81),” Khan wrote. “At first sight, these data do not support the hypothesis that 5αP exposure is associated with breast cancer risk, but serum measurements may not tell the whole story because intramammary concentrations may differ by local enzyme activity, which itself may be associated with genetic variation.”

“One study alone is not sufficient basis for practice changes; however, the findings do open up new avenues for exploration into the hormonal mechanisms that influence breast cancer risk — in particular the important role of progesterone and estrogen,” Trabert concluded.