Abstract 604: Biomarkers of amino acid metabolism and endometrial cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO)
Authors: Michels Kara A. , Weinstein Stephanie J. , Wentzensen Nicolas , Pfeiffer Ruth M. , Trabert Britton 
Published: August 2019

Background: Incidence and mortality rates for endometrial cancer have steadily increased during the past decade. Beyond the well-known risk factors of obesity and unopposed estrogen menopausal hormone therapy (MHT), our understanding of the molecular etiology of this disease is limited and few biomarkers for risk are identified. To address this data gap, we explored circulating markers of amino acid metabolism and endometrial cancer risk—with specific interest in assessing whether the associations with branch chain amino acids (BCAAs) differed by known endometrial cancer risk factors.

Methods: We used data from a nested case-control study within the screening arm of the PLCO trial (353 endometrial cancer cases, 353 controls, age 55-74 years at enrollment). We measured absolute concentrations of amino acid metabolism markers in pre-diagnostic serum using targeted mass spectrometry assays. Conditional and unconditional logistic regression adjusted for potential confounders (and matching factors in the latter) was used to estimate associations between these circulating markers and endometrial cancer overall, by body mass index (BMI), and by MHT use at baseline. We evaluated heterogeneity across these groups via likelihood ratio tests (p for interaction [p-int]).

Results: In the full population, associations with endometrial cancer were generally masked/not identified, but we noted substantial effect modification by MHT use and BMI. A doubling in endometrial cancer risk was suggested with the highest concentrations of BCAAs, but only among women not using MHT (odds ratio and 95% confidence interval for the highest quintile [Q5] versus lowest [Q1]: leucine 1.87, 0.91–3.83; isoleucine 2.44, 1.17–5.09; and valine 1.86, 0.89–3.87; p-int &lt;0.15 for all). We similarly noted that high levels of leucine (Q5 v. Q1: 3.26, 0.96–11.08, p-int 0.39) and valine (Q5 v. Q1: 6.40, 1.49–27.47, p-int 0.08) were associated with risk among obese women, but not those with normal BMIs. The highest levels of 3-hydroxyisobutyrate, a bioactive valine precursor, doubled risk among non-MHT users (CI 1.09–4.51, p-int &lt;0.05) and quadrupled it among obese women (CI 1.45–14.86, p-int 0.33). High proline levels were associated with 4- to 7-fold increases in risk among non-MHT users (CI 1.68–10.01) and obese women (CI 2.11–26.81), respectively (p-int&lt;0.05 for both).

Conclusions: Our findings suggest that the regulation of BCAA metabolism may be involved in endometrial carcinogenesis, but this influence depends on other risk factors for the disease. Use of MHT overshadowed potential risks with most markers evaluated, and we identified increased risks associated with a variety of markers only among obese women. Amino acids play crucial roles in cellular energy metabolism and our results highlight the importance of finding ways to maintain and improve metabolic health in postmenopausal women.

Citation Format: Kara A. Michels, Stephanie J. Weinstein, Nicolas Wentzensen, Ruth M. Pfeiffer, Britton Trabert. Biomarkers of amino acid metabolism and endometrial cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 604.