Recruitment with high physiological doses of estradiol preceding chemotherapy: flow cytometric and therapeutic results in women with locally advanced breast cancers--a Southwest Oncology Group study.
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 over-all 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.(ABSTRACT TRUNCATED AT 400 WORDS)
Fabian
C J
CJ
Department of Medicine, University of Kansas Medical Center, Kansas City 66160.
Kimler
B F
BF
McKittrick
R
R
Park
C H
CH
Lin
F
F
Krishnan
L
L
Jewell
W R
WR
Osborne
C K
CK
Martino
S
S
Hutchins
L F
LF
D001943:Breast Neoplasms / Q000097:blood / Q000737:chemistry / Q000401:mortality / Q000473:pathology* / Q000628:therapy; D002455:Cell Division; D003131:Combined Modality Therapy; D004958:Estradiol / Q000008:administration & dosage / Q000097:blood* / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D005640:Follicle Stimulating Hormone / Q000097:blood*; D006801:Humans; D009367:Neoplasm Staging; D011960:Receptors, Estrogen / Q000032:analysis; D016196:S Phase / Q000187:drug effects*; D013488:Suppositories
D011960:Receptors, Estrogen; D013488:Suppositories; D004958:Estradiol; D005640:Follicle Stimulating Hormone