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Relationship of Estrogen and Progesterone Receptors to Clinical Gynecologic Oncology 106 (2007) 325–333 www.elsevier.com/locate/ygyno Relationship of estrogen and progesterone receptors to clinical outcome in metastatic endometrial carcinoma: A Gynecologic Oncology Group Study ⁎ Meenakshi Singh a, Richard J. Zaino b, Virginia J. Filiaci c, Kimberly K. Leslie d, a Department of Pathology, The University of Colorado Health Sciences Center, Denver, CO 80262, United States b Department of Pathology, Hershey Medical Center, Hershey, PA 17033, United States c Gynecologic Oncology Group Statistical and Data Center, Roswell Park Cancer Institute, Buffalo, NY 14263, United States d Departments of Obstetrics and Gynecology and Biochemistry and Molecular Biology, the University of New Mexico, Albuquerque, NM 87131, United States Received 18 January 2007 Available online 25 May 2007 Abstract Introduction. The goal of this study was to explore the relationship between the expression of hormone receptors in metastatic endometrial tumors and clinical response to daily tamoxifen citrate and intermittent weekly medroxyprogesterone acetate. Study design. Patients with measurable recurrent or advanced endometrial cancer were enrolled on a clinical trial, Gynecologic Oncology Group Study 119. A pretreatment tumor biopsy was obtained and subjected to immunohistochemical analyses. Estrogen receptor-α (ER-α) and progesterone receptor (PR) were assessed on frozen tissues, and PR isoforms A and B were detected on fixed tissues. The receptors were scored using a semi-quantitative HSCORE, with a cut off greater than 75 considered positive. Results. Of the 60 eligible patients, 45 had evaluable tissues for all receptors. For ER, 40% of the cases were positive; for PR, 45% were positive. The sub-cellular distribution of PRA was exclusively nuclear, and 16% of the tumors demonstrated positive staining. PRB was nuclear and cytoplasmic, with 22% of the tumors staining for nuclear PRB and 36% of the tumors staining for cytoplasmic PRB. ER and PR from frozen tissues and PRA and cytoplasmic PRB from fixed tissues significantly decreased with increasing tumor grade. The co-expression of ER-α with PR from the frozen tissues (r = 0.68, p b 0.001) and PRA (r = 0.58, p b 0.001) from the fixed tissues was statistically significant. The ER HSCORE was related to both response and overall survival; there was no statistically significant correlation of PR with clinical response in this small number of patients. Conclusion. ER-α measured in metastatic endometrial carcinoma tissue prior to hormonal therapy was statistically significantly related to clinical response to daily tamoxifen and intermittent medroxyprogesterone acetate. © 2007 Elsevier Inc. All rights reserved. Keywords: Uterus; Estrogen; Medroxyprogesterone acetate; Receptors; Tamoxifen; Endometrial; Cancer Introduction terone mediates both proliferative and anti-proliferative effects [2,3]. Therefore, the study of progestin action in the endome- The role of progesterone in the glandular epithelium of the trium has particular importance because the epithelium relies on endometrium is primarily antagonistic to estrogen-mediated cell progesterone to induce cell differentiation and to counter uncon- proliferation [1]; this is in contrast to the breast, where proges- trolled growth. While progestins have been used with great success to reverse endometrial hyperplasia [4,5] they are not consistently effective in the treatment of primary endometrial cancer. Progestins as single agents have been used traditionally ⁎ Corresponding author. University of New Mexico, The Division of Maternal-Fetal Medicine, The Department of OB/GYN2211 Lomas Blvd., NE in the treatment of recurrent or metastatic endometrial adeno- ACC-4, Albuquerque, NM 87131, United States. carcinoma. However, the overall response rates range from only E-mail address: [email protected] (K.K. Leslie). 8% to 55% [6–11]. Progestin exposure results in a rapid and 0090-8258/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.ygyno.2007.03.042 326 M. Singh et al. / Gynecologic Oncology 106 (2007) 325–333 predictable ligand-dependent loss of progesterone receptors Materials and methods (PR) in both normal and neoplastic endometrial glands [12]. Two recent publications of Gynecologic Oncology Group Patient population (GOG) studies, 119 and 153, reported attempts to circumvent Between 1991 and 1996, the GOG conducted a prospective phase II trial of PR down-regulation with a strategy combining tamoxifen, as an tamoxifen combined with intermittent MPA. This trial included patients with estrogen surrogate to induce PR, and intermittent progestin histologically-confirmed advanced, persistent or recurrent endometrial carcino- treatment [13,14]. However, neither of these papers provided the ma considered incurable by local therapy or refractory to local therapy. In steroid hormone receptor expression data needed to correlate addition, all patients were to have disease that was measurable in 2 dimensions by clinical response with these variables. This report now provides palpation or imaging. Any lesion imaged by CT scan or ultrasound was to have a minimum diameter of 3 cm. The measurable tumor to be followed from entry information on the link between hormone receptor status and must not have received radiation therapy within 3 months prior to entry. Prior clinical response in one of these trials, GOG 119. therapy with cytotoxic drugs or hormonal therapy for endometrial cancer was not Two isoforms of PR, PRA and PRB, are expressed in humans: allowed. Normal hepatic, renal and hematologic functions, the absence of PRA encodes a 90 kDa protein, and PRB encodes a 120 kDa significant infection and GOG performance status 0–2 were required. Patients protein. Both forms arise from alternative promoters on the same with past or concomitant malignancy, other than non-melanoma skin cancer, were ineligible. Awritten informed consent conforming to federal, state and local gene and can form homo (A/A, B/B) or hetero (A/B) dimeric regulations was obtained from all participants prior to study entry. units. The isoforms are identical except that PRB has a longer N- terminus consisting of 164 amino acids not present in PRA. The Tissue requirements unique PRB N-terminus encodes a third activating domain, AF-3, that confers different functional characteristics to the isoforms. Pre-treatment tumor tissue from the metastatic or recurrent lesion was required for all patients for analysis of estrogen and progesterone receptors. A portion of the PRB is a stronger transcriptional activator of many genes com- fresh tumor, greater than 3×5×5 mm, was to be immediately placed in OCTor other pared to PRA [15,16]; PRA also has been reported to repress PRB embedding media into a foil cup or on cork or cardboard, rapidly frozen and [17]. A number of studies suggest that a relative change in PR maintained at a temperature of no more than −20 °C. The labeled vial of frozen tissue isoform expression may be as important as the total level of PR in was to be shipped on dry ice by overnight carrier to the initial testing laboratory. the genesis of endometrial cancer [15,16,18]. ER and PR immunohistochemistry on frozen tissue Tamoxifen is a complex nonsteroidal compound, structur- ally similar to diethylstilbestrol, which binds to the estrogen First, ER and PR were assessed directly on the frozen specimens. Frozen receptor (ER). The ability of tamoxifen-bound ER to activate sections were cut at 5 μM in a cryostat, and thaw mounted onto poly-L-lysine gene transcription appears to be gene and tissue-specific and coated glass slides. The slides were placed in Zamboni's fixative at 4 ° C for 15 min determines whether the drug acts as an estrogen agonist then rinsed twice in PBS for 5 min. Immunohistochemistry was performed manually for both of the antibodies. (tamoxifen-bound ER is capable of activating gene transcrip- The primary antibody to ER was the D222 clone, which recognizes ER-α, with tion) or as an antagonist (competes for ER binding with other little or no affinity for ER-β. For ER, the reagents provided by the manufacturer of estrogens, but forms complexes that are incapable of inducing the ER-ICA kit (Abbott, Chicago, IL) were used as recommended for the blocking transcription). The estrogen-like effects of tamoxifen on steroid step and the control or the ER primary antibody, with avidin and biotin used for hormone receptor expression in the endometrium were amplification of the reaction, using a rat peroxidase kit (Vector, Burlingame, CA). For PR, the primary antibody used on the frozen tissue was mPRI. Mouse IgG exploited in this phase II clinical trial of tamoxifen plus was used in place of the primary antibody as a negative control. Endogenous intermittent weeks of MPA, GOG 119, where tamoxifen was peroxidase was blocked with 1% hydrogen peroxide. and biotin was used for used in theory as an estrogen surrogate to induce PR and amplification of the reaction using the Mouse IgG Elite Vectastain kit (Vector, maintain its up-regulation [13]. Patients were treated with Burlingame, CA). tamoxifen citrate, 20 mg, p.o. twice daily. On alternating (even- For immunolocalization of both ER and PR, 3,3-diaminbenizidine was used as the chromogen, and the slides were coverslipped with permount mounting numbered) weeks, they also received medroxyprogesterone solution. Non-gravid rabbit uterus was used as the positive control tissue for acetate (MPA), 100 mg, p.o., twice daily. The clinical results of both ER and PR, since there was a known,
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