Understanding the Etiology of Gynecologic Cancers: Profile of Tenure-Track Investigator Britton Trabert

October 30, 2018, by Victoria Fisher, M.P.H.

Tenure-track investigator Britton Trabert, Ph.D., M.S., studies the epidemiology of ovarian cancer and the hormonal etiology of gynecologic cancers. As part of her multidisciplinary research program in the Metabolic Epidemiology Branch, Dr. Trabert is leading studies to understand the etiologic heterogeneity of ovarian cancer by histologic type. She employs classic and molecular epidemiologic research approaches to identify strategies for disease prevention or earlier disease detection.

Ovarian Cancer Epidemiology

Ovarian cancer is the most fatal gynecologic malignancy and the fifth leading cause of cancer death among women in the United States. Most ovarian cancers are diagnosed at advanced stages and have an exceedingly poor five-year survival rate of 28%. Researchers have yet to discover predictive biomarkers for early detection, in part because ovarian cancer is rare, making prospective studies challenging to perform.

Until recently, scientists theorized that ovarian cancer arose from 1) microtrauma to the ovarian epithelium (outer layer) resulting from uninterrupted ovulation and 2) exposure to high levels of gonadotropin—a hormone secreted by the pituitary gland that stimulates the ovaries. These hypotheses were based on the observed reduced risk of ovarian cancer with increasing parity (having borne children), oral contraceptive use, and breastfeeding—all of which interrupt ovulation and alter pituitary function.

Emerging data suggest that many high-grade serous carcinomas (bottom inset) emerge from secretory cells (top inset) in the fimbriated end of the fallopian tube and spread to the ovarian surface epithelium where the bulk of the tumor resides. Source: Drapkin R, et al. *F1000 Med Reports* 2011.

Over the last decade, the understanding of the origin of ovarian cancer has changed dramatically. Many high-grade serous tumors—the most common and lethal subtype—have been shown to develop in the fimbria of the fallopian tubes before proliferating on the surface of the ovary.

Dr. Trabert recently examined trends in fallopian tube cancers using the largest source of population-based data for cancer incidence: the North American Association of Central Cancer Registries (NAACCR). She noted dramatic increases in the reporting patterns of primary fallopian tube cancers, which are likely due to a shift in primary cancer designation (from ovarian to fallopian tube), not a true increase in incidence of these malignancies.

“We are experiencing a paradigm shift,” Dr. Trabert said. “There is more pathologic evidence related to the origins of ovarian cancer from the fallopian tubes, which has altered both surgical approaches to treatment and prevention as well as etiologic investigation. We are realizing that ovarian cancer etiology could be quite heterogeneous.”

Dr. Trabert and colleagues suspect that inflammation may be a key player in cancer development in the ovaries and fallopian tubes. Her research focuses on clarifying the role of both systemic and local (tubal) inflammation in ovarian carcinogenesis by histologic subtype.

Circulating markers of inflammation and sexually transmitted infections

Chronic or persistent inflammation in the body is known to be associated with an increased risk of cancer and other diseases. To explore the role of systemic inflammation, Dr. Trabert conducted a nested case-control study within the Prostate, Lung, Colorectal, and Ovarian Cancer (PLCO) Screening Trial to evaluate prediagnostic levels of 46 circulating cytokines and other immune markers and ovarian cancer risk. She found that elevated levels of CRP, IL-8, and TNF-α were associated with a doubling of risk for ovarian cancer—stronger than many established risk factors.

To assess the effect of local, tubal inflammation arising from sexually transmitted infections and pelvic inflammatory disease (PID), Dr. Trabert and colleagues recently completed a study to characterize the association between ovarian cancer risk and prior infection with Chlamydia trachomatis, one of the primary causes of PID worldwide, as well as markers of other infections, using a novel sensitive multiplex serology assay. This work was supported by funding from an NCI Director’s Intramural Innovation Award. Dr. Trabert measured serologic markers of prior infection in two independent studies: a population-based case-control study (the Polish Ovarian Cancer study) and a nested case-control study in PLCO.

“The gold-standard serologic marker for prior chlamydia infection, the plasmid-encoded Pgp3 protein, was consistently associated with increased ovarian cancer risk across the study populations,” Dr. Trabert said. “Our results for markers of other infections were universally null, further supporting the specificity of the chlamydia-ovarian cancer association.”

Dr. Trabert noted that the team’s novel approach to measuring serologic markers of prior infection is an innovative solution to reliance on clinical diagnoses or self-reports of PID, data that are largely unavailable or unreliable in large epidemiologic studies.

Anti-inflammatory medication use

Women who take aspirin daily may reduce their risk of ovarian cancer.

If inflammation increases risk of ovarian cancer, could the use of anti-inflammatory medication have a protective effect? Previous research suggests that the anti-inflammatory properties of aspirin and non-aspirin NSAIDs (non-steroidal anti-inflammatory drugs) may reduce overall cancer risk. However, studies examining the role of these agents in ovarian cancer have been largely inconclusive.

Dr. Trabert led an analysis of pooled data from 12 large epidemiological studies within the Ovarian Cancer Association Consortium (OCAC); she and collaborators found that daily aspirin use was associated with a 20% reduction in ovarian cancer risk [OR (95% CI): 0.80 (0.67-0.96)]. They recently confirmed this association in data from 13 prospective studies within the Ovarian Cancer Cohort Consortium (OC3).

“Our studies suggest that inflammation is potentially modifiable, and that aspirin regimens may reduce the risk of ovarian cancer,” Dr. Trabert said. “We are incrementally building toward aspirin as a viable chemopreventive agent for this malignancy, alongside oral contraceptives.”

Hormonal Etiology of Gynecologic Cancers

As evidenced by associations with menopausal hormone therapy and oral contraceptive use, hormonal factors play an important role in ovarian, endometrial, and breast cancers. However, the underlying carcinogenic mechanisms are not well understood. Surprisingly little is known about the role of endogenous hormones in ovarian and endometrial carcinogenesis, and although the role of circulating estrogens/estrogen metabolites in breast cancer etiology is established, few studies on circulating androgens and/or progesterone are available.

Endogenous hormones and assay development

Dr. Trabert recently led a nested case-control study analysis within the Women’s Health Initiative Observational Study (WHIOS) to evaluate the role of estrogen metabolism in ovarian and endometrial cancers. “The results of the ovarian cancer analyses demonstrated striking histologic subtype heterogeneity in risks, with results supporting a role for estrogen metabolites in the etiology of nonserous tumors, but not serous tumors,” Dr. Trabert said. Endometrial cancer risk was associated with increased concentrations of both parent estrogens and metabolites. Dr. Trabert also has directed several research projects evaluating associations between known cancer risk factors and circulating estrogen metabolites using data from the WHIOS.

Surprisingly little is known about the role of endogenous hormones in ovarian and endometrial carcinogenesis.

There is emerging recognition of the contribution of other hormones, such as androgens and progesterone, in the etiology of gynecologic cancers. To further facilitate her research in this area, Dr. Trabert led a multidisciplinary project to develop two novel hormone assays with colleagues at the Frederick National Laboratory for Cancer Research. These assays measure androgens and androgen metabolites, and progesterone and progesterone metabolites, which are complementary to the estrogen metabolite assay.

“Importantly, these assays target sex steroid hormones and their metabolites that are likely relevant to female cancer etiology. It was necessary to develop these methods since clinical assays are not routinely available or are not sensitive enough to measure levels in postmenopausal women,” she noted.

Eager to utilize the new assays, Dr. Trabert is leading analyses of androgen/androgen metabolites and ovarian and endometrial cancer in the WHIOS and a similar study of breast cancer within the Bone Density and Cancer Risk Follow-up Study of Women in the Fracture Intervention Trial (BFIT).

“These studies will enable the evaluation of female cancer risk in relation to previously unmeasured androgen metabolites and estimate associations independent of the effects of downstream estrogens,” Dr. Trabert said. In addition, she is leading novel investigations relating progesterone/progesterone metabolites to breast, ovarian, endometrial, and colorectal cancer in BFIT.

Exogenous hormones

Dr. Trabert also investigates exogenous hormone-related risk factors in female cancers, including the long-term effects of oral contraceptive use and infertility treatment.

Across many health behaviors, long-term oral contraceptive use lowers risk for ovarian and endometrial cancers.

Gynecologic oncologists generally recommend that women concerned about their ovarian cancer risk should take at least five years of combined (containing estrogen and progestin) oral contraceptives for chemoprevention. However, the magnitude of benefit remains unclear, given the small increases in breast and cervical cancer risk and increased risks of deep vein thrombosis and/or stroke among current or recent oral contraceptive users. Furthermore, scientists are uncertain whether the effects of oral contraceptives on ovarian and endometrial cancer are consistent across population subgroups, such as smokers and obese women.

To address these gaps, Dr. Trabert and postdoctoral fellow Kara Michels, Ph.D., published two important papers on the alterations in cancer risk associated with oral contraceptive use. First, they analyzed data from nearly 200,000 women from the NIH-AARP Diet and Health Study to investigate whether the relationship between oral contraceptive use and risks for ovarian, endometrial, breast, and colorectal cancers change depending on health behaviors in the years leading up to and during menopause (for example, smoking, alcohol use, body mass index, and physical activity).

“We found that long-term oral contraceptive use (10 years or longer) was associated with reduced risk for ovarian cancer regardless of other health behaviors in later life,” Dr. Trabert said.

Extended oral contraceptive use also reduced risks for endometrial cancer. The most striking reduction was among women who were current smokers, obese, or rarely exercised. “This work has the potential to refine the guidance regarding oral contraceptive use and ovarian and endometrial cancer risk,” Dr. Trabert said.

Drs. Trabert and Michels followed this work with a broad examination of oral contraceptive use and risk of many different cancers using the NIH-AARP Diet and Health Study. They identified cancer risk reductions and increases associated with oral contraceptive use, including expected risk reductions that strengthened with duration of use for ovarian and endometrial cancers. Overall, the net effect of oral contraceptive use on all cancer types was lower risk (a 3% decrease).

“Oral contraceptive use did not influence risks for most other cancers evaluated,” Dr. Trabert said. “This was a new look at whether the beneficial, or potentially harmful, effects of oral contraceptives influenced other cancers, which has important public health implications.”

On the other end of reproductive health, the success of fertility treatments has produced a generation of women with novel hormone exposures. Dr. Trabert initiated a retrospective medical record linkage study in Israel to evaluate in vitro fertilization (IVF) and cancer risk. Israel is a unique and opportune location for this study—they have long-term clinical records, the highest rate of fertility treatment in the world, the Ministry of Health subsidizes fertility treatments, and the country uses unique identification numbers that facilitate registry linkages. Dr. Trabert and colleagues have successfully completed a pilot study, and data collection for the full effort is ongoing.

“When complete, these data will comprise the largest assembled cohort of IVF exposed women (~30,000 women) with the longest follow-up to date,” she said. “Ultimately this work will inform surveillance and early detection guidelines in these women.”