||1R21CA251343-01A1 Interpret this number
||University Of Michigan At Ann Arbor
||Inflammatory Oxylipins and Aromatase Inhibitor Toxicity in Breast Cancer
Treatment with an aromatase inhibitor (AI), which significantly decreases circulating estrogen concentrations, for
5-10 years reduces 10 year breast cancer mortality by about 40%. However, AI-associated musculoskeletal
symptoms (AIMSS) affect up to half of treated patients, cause poor adherence and compliance with therapy, and
can increase breast cancer recurrence and mortality. Few effective management options have been identified.
The etiology of AIMSS remains poorly understood, although it is thought to be due, at least in part, to estrogen
deprivation and inflammation.
The oxylipin lipid mediators, which are derived from omega-3 and omega-6 fatty acids, are pro- or anti-
inflammatory, and have been implicated in inflammation-related pain. In addition, estrogens are known to
influence the metabolism of fatty acids. Preliminary data from an untargeted lipidomics study of AI-treated
patients identified quantitative differences in polyunsaturated fatty acids (PUFA) in patients who did and did not
develop AIMSS. Based on these data, the central hypothesis is oxylipins, which are metabolites of PUFA, may
play a role in the development of AIMSS, through an estrogen deprivation-induced shift in oxylipins to pro-
inflammatory omega-6 fatty acid-derived metabolites. In addition, genetic predisposition to altered activity of the
key enzymes involved in oxylipin metabolism could further influence the risk of developing AIMSS in individual
patients. This hypothesis will be tested by analyzing samples and data from a previously conducted clinical trial
of women starting AI therapy. Plasma samples, germline DNA, and patient-reported outcomes will be used to
investigate the following Specific Aims: (1) to investigate the effect of estrogen deprivation with AI therapy on
oxylipin profiles, (2) to examine associations between change in oxylipins with AI therapy and development of
AIMSS, and (3) to evaluate associations between genetic alterations related to metabolism of oxylipins and
patterns of oxylipin metabolites in AI-treated patients.
Through this mechanistic study we will learn the impact of AI therapy and estrogen deprivation on inflammatory
lipid mediators, namely oxylipins, and their role in the development of AIMSS, and may identify predictors of
development of AIMSS. These important insights into the etiology of AIMSS can potentially lead to mechanism-
based interventions designed to prevent or treat this treatment-emergent toxicity. Preventing the development
of AIMSS can improve quality of life for breast cancer survivors, and could increase compliance with AI therapy
and reduce breast cancer recurrence and mortality.