Abstract P1-14-02: Reversing endocrine resistance: A pilot study of estradiol followed by exemestane
Authors: Chalasani P , Stopeck A , Clarke K , Livingston RB 
Published: August 2014

Abstract
Introduction: Anti-estrogen therapy is highly effective in treating hormone receptor positive breast cancer in both the adjuvant and metastatic settings. However, endocrine resistance frequently develops and strategies to reverse resistance are a high research priority. Pre-clinical data suggest exposure to physiologic or supra-physiologic doses of estrogen induce tumor regression in tamoxifen resistant tumors. Alternating treatment between estrogens and anti-estrogens has also been effective at delaying the development of endocrine resistance in these models. To further test this strategy, we initiated a pilot study of estradiol (E) for reversing endocrine resistance in patients with estrogen receptor (ER+) metastatic breast cancer (MBC) who had failed prior aromatase inhibitor (AI) therapy.
Methods: Postmenopausal women with ER+ MBC who had failed at least 1 prior endocrine therapy (including an AI), were eligible for the study. Patients were treated with daily E that was titrated up from 2mg to 6mg/day over the first week of treatment to minimize gastrointestinal side effects. Patients who had not progressed after 3 months of E were switched to exemestane (Ex) to determine if short term E exposure would reverse endocrine resistance and re-sensitize tumors to estrogen deprivation (AI) therapy. The primary objective of the study was the feasibility and toxicity associated with short-term E followed by Ex therapy.
Results: 15 patients were screened for enrollment. One patient was ineligible and another patient withdrew from study, leaving a total of 13 patients who were treated with E at 6mg daily. All patients were evaluable for toxicity and response at the end of the 3 month E phase. There were no grade 3 or 4 toxicities observed during the entire study (E and Ex phases). At the end of the E phase, 6 patients (46%) had not progressed (3PR, 3SD) and subsequently were switched to Ex. On Ex, 5 progressed and 1 had SD as their best response. Median PFS for all patients was 4.8 months (0.6 – 9.5 months). After progression on Ex, 4 patients were re-exposed to E and 2 had clinical benefit over 6 and 12 months, respectively.
Conclusion: Alternating estrogen with anti-estrogens was not effective at reversing hormone resistance. However, low dose E treatment had significant clinical activity with minimal toxicity and should be considered as a therapeutic option for hormone refractory MBC (Table 1).
Table 1: Reported Estradiol Clinical StudiesStudyDrug & DoseNResponse DataCBRTTP/PFSToxicity (grade 3 or 4)Re-exposure to AIEllis MJ et alEstradiol, 30mg321PR,8 SD28%12wks/16 wks34%N = 7,2 PR and 1 SD Estradiol, 6mg343 PR,7 SD29%12wks/16 wks18% Howell S et alEstradiol valerate,2mg195 SD26%2.8m (0.5-29.8)/NR4 stopped treatment due to toxicity, grade 4 hypercalcemia, grade 4 hyponatremiaN = 3,1 PR and 1 SDIwase H et alEthinyl estradiol, 3mg189 PR, 1 SD55%10.6 wks (0-60wks)/NRNo grade 3/4N = 4, 1 respondedOur studyEstradiol, 6mg133 PR, 3 SD46%NR/4.8m (0.6-9.5m)No grade 3/4N = 7, 1 had CBRAll studies 11616 PR, 24 SD34% N = Number of patients, TTP- Time to progression, PFS- progression free survival, PR- partial response, SD- Stable disease, CBR- Clinical benefit rate, NR- not reported
Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-14-02.