Lower-dose vs high-dose oral estradiol therapy of hormone receptor-positive, aromatase inhibitor-resistant advanced breast cancer: a phase 2 randomized study.
BACKGROUND
Estrogen deprivation therapy with aromatase inhibitors has been hypothesized to paradoxically sensitize hormone-receptor-positive breast cancer tumor cells to low-dose estradiol therapy.


OBJECTIVE
To determine whether 6 mg of estradiol (daily) is a viable therapy for postmenopausal women with advanced aromatase inhibitor-resistant hormone receptor-positive breast cancer.


METHODS
A phase 2 randomized trial of 6 mg vs 30 mg of oral estradiol used daily (April 2004-February 2008 [enrollment closed]). Eligible patients (66 randomized) had metastatic breast cancer treated with an aromatase inhibitor with progression-free survival (> or = 24 wk) or relapse (after > or = 2 y) of adjuvant aromatase inhibitor use. Patients at high risk of estradiol-related adverse events were excluded. Patients were examined after 1 and 2 weeks for clinical and laboratory toxicities and flare reactions and thereafter every 4 weeks. Tumor radiological assessment occurred every 12 weeks. At least 1 measurable lesion or 4 measurable lesions (bone-only disease) were evaluated for tumor response.


METHODS
Randomization to receive 1 oral 2-mg generic estradiol tablet 3 times daily or five 2-mg tablets 3 times daily.


METHODS
Primary end point: clinical benefit rate (response plus stable disease at 24 weeks).


RESULTS
toxicity, progression-free survival, time to treatment failure, quality of life, and the predictive properties of the metabolic flare reaction detected by positron emission tomography/computed tomography with fluorodeoxyglucose F 18.


RESULTS
The adverse event rate (> or = grade 3) in the 30-mg group (11/32 [34%]; 95% confidence interval [CI], 23%-47%) was higher than in the 6-mg group (4/34 [18%]; 95% CI, 5%-22%; P = .03). Clinical benefit rates were 9 of 32 (28%; 95% CI, 18%-41%) in the 30-mg group and 10 of 34 (29%; 95% CI, 19%-42%) in the 6-mg group. An estradiol-stimulated increase in fluorodeoxyglucose F 18 uptake (> or = 12% prospectively defined) was predictive of response (positive predictive value, 80%; 95% CI, 61%-92%). Seven patients with estradiol-sensitive disease were re-treated with aromatase inhibitors at estradiol progression, among which 2 had partial response and 1 had stable disease, suggesting resensitization to estrogen deprivation.


CONCLUSIONS
In women with advanced breast cancer and acquired resistance to aromatase inhibitors, a daily dose of 6 mg of estradiol provided a similar clinical benefit rate as 30 mg, with fewer serious adverse events. The efficacy of treatment with the lower dose should be further examined in phase 3 clinical trials.


BACKGROUND
clinicaltrials.gov Identifier: NCT00324259.
Ellis
Matthew J
MJ
Department of Medicine, Division of Oncology, Washington University School of Medicine, St Louis, MO 63110, USA. mellis@dom.wustl.edu
Gao
Feng
F
Dehdashti
Farrokh
F
Jeffe
Donna B
DB
Marcom
P Kelly
PK
Carey
Lisa A
LA
Dickler
Maura N
MN
Silverman
Paula
P
Fleming
Gini F
GF
Kommareddy
Aruna
A
Jamalabadi-Majidi
S
S
Crowder
Robert
R
Siegel
Barry A
BA
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D001943:Breast Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism* / Q000401:mortality; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000008:administration & dosage* / Q000627:therapeutic use; D004967:Estrogens / Q000008:administration & dosage* / Q000627:therapeutic use; D005260:Female; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008875:Middle Aged; D049268:Positron-Emission Tomography; D017698:Postmenopause; D011237:Predictive Value of Tests; D011788:Quality of Life; D019275:Radiopharmaceuticals; D011960:Receptors, Estrogen / Q000378:metabolism*; D016019:Survival Analysis
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D015415:Biomarkers; D004967:Estrogens; D019275:Radiopharmaceuticals; D011960:Receptors, Estrogen; D019788:Fluorodeoxyglucose F18; D004958:Estradiol; D007334:Insulin-Like Growth Factor I
Br Med J. 1973 Aug 25;3(5877):446-50
4353621
J Clin Oncol. 2008 Apr 1;26(10):1664-70
18316794
J Clin Oncol. 1997 Mar;15(3):974-86
9060536
JAMA. 2004 Apr 14;291(14):1701-12
15082697
JAMA. 1977 May 9;237(19):2079-8
576887
Br Med J. 1944 Sep 23;2(4368):393-8
20785660
J Natl Cancer Inst. 2001 Nov 21;93(22):1714-23
11717332
Breast Cancer Res Treat. 2001 May;67(2):111-6
11519859
J Clin Oncol. 2001 Jun 1;19(11):2797-803
11387350
N Engl J Med. 1981 Jan 1;304(1):16-21
7001242
J Clin Oncol. 2004 Jul 15;22(14):2942-53
15254062
Breast Cancer Res Treat. 2009 Feb;113(3):509-17
18327670
J Clin Epidemiol. 2004 Sep;57(9):898-910
15504633