Hormone Levels Tied to Future Breast Cancer Risk

Circulating progesterone levels may help predict future breast cancer incidence in older women, researchers reported.

During a 12-year follow-up period, postmenopausal women saw a modest 16% higher risk for breast cancer with each standard deviation increase in progesterone levels (hazard 1.16, 95% CI 1.00-1.35, P=0.048), Britton Trabert, PhD, MS, of the National Cancer Institute in Bethesda, Maryland, and colleagues wrote in JAMA Network Open.

This link between higher progesterone levels 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).

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.

In an accompanying commentary, Seema A. Khan, MD, of Northwestern University in Chicago, highlighted this finding as "intriguing."

"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."

Future studies, she said, 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.

The researchers drew upon data from participants in 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.

This method of measurement was a particular strength of the study, Trabert said, noting that the research into understanding the role of endogenous progesterone in breast cancer etiology is "largely unexplored" due to limitations in assay sensitivity, as well as precision of progesterone measurements at low concentrations among postmenopausal women.

"We overcame the issues of assay sensitivity by using a highly sensitive liquid chromatography-tandem mass spectrometry progesterone assay [LC-MS/MS]," she said.

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

"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.

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