A randomized phase 2 trial of low dose (6 mg daily) versus high dose (30 mg daily) estradiol for patients with estrogen receptor positive aromatase inhibitor resistant advanced breast cancer.

Abstract

Abstract Abstract #16 Rationale: It has been postulated that aromatase inhibitor (AI) therapy may sensitize ER+ breast cancer to lower doses of estrogen therapy as second-line endocrine treatment for advanced breast cancer (ABC). We therefore conducted a randomized trial of 30mg generic estradiol daily (10 mg t.i.d.- "recommended" dose) versus 6 mg (2 mg t.i.d - "experimental" dose).
 Materials and Methods: Major eligibility: Postmenopausal ER+ ABC treated with an AI with 24+ wks progression free survival, or relapse after 2+ yrs of adjuvant AI; RECIST measureable non-bone metastases or WHO assessable bone lesions, with elevated tumor markers >2X ULN. Major exclusions: History venous thrombosis, heart disease, uncontrolled hypercalcemia and fulvestant in the last 12 months. FDG PET scans were conducted at baseline and after 24 hours to assess metabolic flare as a predictor of response (pre-defined as a ≥12% increase in FDG uptake).
 Results: Sixty-six patients were enrolled (82% White, 15% Black); mean age 59 years, range 36-84. 34 received 6 mg and 32 received 30 mg. Estradiol levels will be provided at the meeting. There were more patients experiencing grade 3+ SAE on the 30 mg arm versus the 6 mg arm (11 vs. 4; P=0.06) with one venous thrombosis on each arm. There was no difference in total FACT-B QOL scores at one month by treatment arm, QOL decline was associated with more severe estrogen side effects, especially amongst patients on the 30 mg arm (P=0.006). Uterine bleeding was successfully controlled with intermittent progestin therapy. Clinical benefit rates (stable disease at least 24 weeks plus response - intent to treat population) were 25% (CI: 15-37%, 1PR and 7SD out of 32) on the 30 mg arm and 29% (CI: 19-42%, 3PR and 7SD out of 34) on the 6 mg arm. Patients with clinical benefit to estradiol could be retreated with original AI after progression and to date one PR out of three patients with repeat AI therapy noted. There were 44 patients evaluable for the interaction between PET -flare and response. Flare was seen in all responders (3/3), 9 of 13 patients with SD and only 3 of 30 patients with PD (p<0.0001). PPV for PET flare was therefore 12/15 (80%, CI: 61-92%) and NPV 27/31 (87%, CI: 76-94%). 
 Conclusions: The Protocol Review and Monitoring Committee closed the 30 mg arm early after they concluded that the 6 mg arm was as effective as the 30 mg arm with greater safety. We therefore recommend 6 mg as the appropriate dose for the palliative treatment of advanced ER+ breast cancer. FDG PET flare can be used to identify patients who have a high chance of clinical benefit.
 Supported by an AVON NCI Partners in Progress Award: Grant # P30 CA091842-S4. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 16.