Abstract P3-05-03: Estrogen receptor alpha reactivation for the treatment of anti-estrogen-resistant breast cancer
Authors: Hosford SR , Kaufman PA , Miller TW 
Published: May 2016

Adjuvant anti-estrogen therapies that antagonize ER transcriptional activity have improved outcome in many patients, yet resistance to anti-estrogen therapies is common, resulting in disease recurrence in 1/3 of patients within 15 years of follow-up. However, prior to the introduction of tamoxifen, estrogens were used for treatment of breast cancer with response rates similar to those obtained by anti-estrogens in the advanced setting. Similarly, withdrawal of anti-estrogen therapy has shown anti-tumor effects, indicating that reactivation of ER may elicit therapeutic benefit.

MCF-7 cells with long-term (&gt;1 yr) acquired resistance to the selective ER downregulator fulvestrant (fulv; MCF-7/FR) retain ER expression and harbor ESR1 (ER) gene amplification. Upon withdrawal of fulv, these cells re-engage ER as demonstrated by increased luciferase transcriptional reporter activity and re-expression of proteins encoded by ER-inducible genes. Following fulv withdrawal, MCF-7/FR cells show drastically decreased proliferation and increased apoptosis that are temporally correlated with ER reactivation. Protein levels of the anti-senescence protein FoxM1 decline following ∼12 d of fulv withdrawal, paralleled by increased staining for senescence-associated β-galactosidase. Transcriptomic analyses confirmed that fulv withdrawal progressively induces gene expression patterns indicative of stress and senescence. Similar effects were observed in long-term estrogen-deprived (LTED) MCF-7 cells treated with 17b-estradiol. Prospective studies characterizing the development of acquired anti-estrogen resistance have demonstrated the MCF-7 cells at 9 months of fulv resistance do not respond to fulv withdrawal, contrasting the long-term (&gt;1 yr) MCF-7/FR cells. Additionally, withdrawal of fulv from T47D/FR, ZR75-1/FR, or HCC-1428/FR cells did not induce cell death or re-engage ER activity, confirming that ER reactivation is required for anti-cancer effects. Ongoing studies are characterizing the temporal changes in ER transcriptional activity during 1) development of acquired anti-estrogen resistance, and 2) 17b-estradiol treatment of mice bearing WHIM16 patient-derived xenografts (regress in response to 17b-estradiol) to elucidate the mechanism underlying sensitivity of anti-estrogen resistant cells to ER reactivation.

While estrogen therapies have shown clinical efficacy for decades, biomarkers to identify patients with tumors likely to respond to estrogen remain undefined. We are conducting a Phase II clinical trial [Pre-emptive OsciLLation of ER activitY levels through alternation of estradiol/anti-estrogen therapies prior to disease progression in ER+/HER2- metastatic breast cancer (POLLY); NCT02188745] that will use tumor biopsy tissues to identify baseline and pharmacodynamic biomarkers that predict response to 17b-estradiol therapy.

Citation Format: Hosford SR, Kaufman PA, Miller TW. Estrogen receptor alpha reactivation for the treatment of anti-estrogen-resistant breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-03.