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Recruitment with High Physiological Doses of Estradiol Preceding Chemotherapy: Flow Cytometric and Therapeutic Results in Women with Locally Advanced Breast Cancer—A Southwest Oncology Group Study¹

Departments of Medicine [C. J. F., R. M., C. H. P.], Radiation Oncology [B. F. K., L. K.], Pathology [F. L.] and Surgery [W. R. J.], University of Kansas Medical Center, Kansas City, Kansas 66160; Department of Medicine/Oncology, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78284 [C. K. O.]; Division of Medical Oncology, Wayne State University Medical Center, Detroit, Michigan 48201 [S. M.]; Department of Medicine, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205 [L. F. H.]; Department of Medical Oncology/Therapeutic Research, City of Hope National Medical Center, Duarte, California 91010 [L. A. L.]; and Southwest Oncology Group Statistical Center, Seattle, Washington 98104 [S. G.]

One theoretical method of increasing chemotherapeutic efficacy in breast cancer is to temporarily increase the number of tumor cells in cycle through hormonal recruitment prior to initiation of chemotherapy. In an effort to determine when and if this could be reliably accomplished, 50 women with locally advanced and/or metastatic breast cancer with known estrogen receptor (ER) status were entered into a serial breast biopsy study designed to measure increases in S-phase fraction (SPF) and proliferative index (PI; S + G₂ + M) following administration of a high physiological dose of estrogen via estradiol vaginal suppositories prior to chemotherapy. Blood levels of estradiol were maintained in a range (0.5–5 nM) known to increase SPF in vitro. Compliance with suppository administration was monitored by serial blood sampling.

Tumors were sampled at 0, 24, 48, 72, and/or 96 h. Thirty-one ER-positive and 9 ER-negative women had evaluable baseline biopsies and at least 1 subsequent biopsy. An increase was seen for SPF in 20 (69%) and for PI in 23 (79%) of 29 ER-positive patients at 48 h after estrogen initiation (95% confidence intervals, 49–85% for SPF and 60–92% for PI); similar increases were seen at 72 h. Median baseline SPF and PI values in ER-positive patients for whom increases were noted at 48 h were 6.2 and 8.5%, respectively. The median relative increases in these patients were 170 and 100%, respectively, at 48 h. The increases observed at 24 h in 4 (SPF) and 6 (PI) of the 9 ER-negative patients could have occurred by chance alone.

Twenty-five of the 28 locally advanced (T4 and/or N2–3) patients achieved a complete response during combined modality treatment (estradiol-chemotherapy, mastectomy, and radiation). At a minimum follow-up time of 42 months, estimated 5-year progression-free and overall survivals are 30 and 49%, respectively, with a median time to progression of 35 months. Twenty-two women had metastatic disease (19 also had locally advanced disease). Thirteen had a complete or partial response, with a median duration of 12 months. Median progression-free and overall survival times for all metastatic patients are 4 and 17 months, respectively. Estimated 5-year survival for metastatic disease patients is 27%.

A high physiological dose of estrogen administered to patients with locally advanced ER-positive tumors can reliably increase the tumor SPF and PI within 48 h. However, the response to Adriamycin-based chemotherapy would not appear to be dramatically altered in the locally advanced or metastatic disease patients by administration of estrogen immediately prior to chemotherapy. The potential reasons for this include lack of a sufficient increase in proliferative activity by estrogen, suboptimal timing of chemotherapy, and prior existence of chemotherapy resistance in this group of patients.

¹ This study was supported in part by USPHS Grant CA 39004 and Public Health Service Cooperative Agreement Grants CA-12644, CA-37429, CA-14028, CA-37981, CA-22433, CA-46368, and CA-32102 awarded by the National Cancer Institute, Department of Health and Human Services.

² To whom requests for reprints should be addressed, at Southwest Oncology Group (SWOG-8568), Operations Office, 14980 Omicron Drive, San Antonio, TX 78245-3217.

Received 6/ 1/94. Accepted 8/18/94.

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