Which patients need aromatase inhibitors during ovarian stimulation for fertility preservation? er-alpha expression as a surrogate for estrogen responsiveness

Aromatase inhibitors (AI) are recommended for patients with known estrogen receptor (ER) positive cancer (for example, ER+ breast cancer) during ovarian stimulation (OS) for fertility preservation. However, other tumor types may be estrogen responsive and thus benefit from AI therapy during fertility preservation. The objectives of our study were (1) to estimate estrogen responsiveness of various tumor types using The Cancer Genome Atlas (TCGA) to determine ER-alpha (ERa) gene expression, and (2) to investigate molecular subtypes of breast cancer, ER negative by immunohistochemistry, which still express ERa. We hypothesize that ER- breast tumors are heterogenous, and some may still express ERa and benefit from AI during OS. TCGA Pan-Cancer Atlas gene expression data were accessed from UCSC Xena browser; data included >30 primary tumor types from almost 6,000 female patients. Tumors were ranked by average ERa gene expression. A secondary analysis included tumors from only ∼1K females aged 13-44, to represent a population that may undergo fertility preservation with OS. Next, we investigated ERa expression in 459 ER negative (ER-, as determined by immunohistochemistry) breast tumor samples obtained from Molecular Taxonomy of Breast Cancer International Consortium (METABRIC). We computed the average expression of ERa in all molecular subtypes of breast cancer (luminal A, luminal B, Her2 enriched and basal) from the METABRIC cohort. ERa was expressed in nearly all tumor types. ERa expression was highest in breast tumors and lowest in rectal adenocarcinomas in all female patients. The top five tumor types with highest ERa expression included breast, uterine/endometrial, ovarian, cervical, and thyroid tumors. In females aged 13-44, endometrial carcinomas have the highest ERa expression followed by ovarian and breast tumors. ERa expression in breast tumors is very subtype-specific, and some ER- tumors expressed ERa. ERa was relatively highly expressed in ER- luminal breast tumors as compared with basal tumors. Breast, uterine/endometrial, cervical, and thyroid tumors, among others, appear to be estrogen-responsive and may benefit from AI therapy for estrogen blockade during OS for fertility preservation.Even some ER-breast tumors express ERa. Further clinical studies will be necessary to assess the significance of ERa gene expression in determining the benefits of AI during OS.