Britton Trabert

PhD, MS

NIH

Investigator

PLCO (Learn more about this study)

2016-0047

Nov 21, 2019

Association of endogenous estrogens, estrogen metabolites, androgens and androgen metabolites with Ovarian Cancer

Ovarian cancer is the most fatal gynecologic malignancy and the fifth leading cause of cancer death in women in the US. Early detection efforts have yet to yield useful biomarkers, in part due to lack of symptoms at early stages, as most ovarian cancers are diagnosed at advanced stages and have an exceedingly poor 5-year survival of 28%. Since few of the confirmed risk factors (e.g., low parity and lack of oral contraceptive use) are modifiable on a population-basis there are currently no recommendations for primary prevention. Therefore, it is essential to identify new areas of research that have the potential to improve our understanding of the etiology of ovarian carcinogenesis that may lead to public health recommendations for prevention.

There is strong in vitro and in vivo evidence, as well as some epidemiologic data, suggesting that estrogens and androgens (and potentially other sex steroids) play a role in ovarian carcinogenesis. However, previous studies did not show consistent associations between circulating hormones and overall ovarian cancer risk. Further, the majority of prior studies have relied on measurement of hormones via radio-immunoassays, which have recognized limitations in terms of sensitivity and specificity. We evaluated estrogens and estrogen metabolites in a nested case-control study from the Women’s Health Initiative Observational Study (WHI-OS) Cohort measured via a highly sensitive and specific liquid chromatography-tandem mass spectrometry (LC/MS-MS) assay developed at the NCI-Frederick lab by analytic chemist Dr. Xia Xu. In this study we found striking heterogeneity of associations between estrogen metabolites and ovarian cancer subtypes (odds ratios > 2.5 for non-serous tumors). We did not find associations with serous cancers, the most common and fatal subtype, and consequently, we did not see strong associations with overall ovarian cancer risk. However, for the first time, we provide evidence suggesting that estrogens and estrogen metabolites in postmenopausal women are associated with non-serous ovarian cancers.

Using a recently developed LC/MS-MS based assay, with demonstrated sensitivity and specificity, 11 androgens and androgen metabolites are currently being measured in the WHI-OS ovarian cancer nested case-control sample set. Importantly, this assay measures all three glucuronide androgen metabolites that combined with the other androgens measured will enable a comprehensive assessment of total androgenic activity and ovarian cancer risk.

To replicate the important results from our nested case-control study of circulating hormones and ovarian cancer risk in the WHI-OS, we propose to measure endogenous estrogens, estrogen metabolites, androgens, and androgen metabolites in pre-diagnostic serum or plasma of postmenopausal women with ovarian cancer and matched postmenopausal controls (women free from ovarian cancer). The low prevalence of ovarian cancer and need to restrict to postmenopausal women not currently taking hormone therapy limits the availability of women with ovarian cancer in an individual cohort. Therefore, to achieve a sample size of 575 cases we are seeking to pool nested case-control sample sets that have pre-diagnostic sera/plasma from cohorts within the Ovarian Cancer Cohort Consortium (OC3), of which PLCO has already contributed questionnaire data.

Aim 1:
• To investigate the association between endogenous estrogen/estrogen metabolite levels and ovarian cancer risk in postmenopausal women.
We hypothesize that increased pre-diagnostic estrogen and estrogen metabolite levels confer an elevated risk of non-serous ovarian cancer in postmenopausal women.

Aim 2:
• To investigate the association between endogenous androgen/androgen metabolite levels and ovarian cancer risk in postmenopausal women.
We hypothesize that increased pre-diagnostic androgen and androgen metabolite levels confer an elevated risk of ovarian cancer in postmenopausal women.