IMPACT OF MENOPAUSAL HORMONE-REPLACEMENT THERAPY ON CLINICAL AND LABORATORY CHARACTERISTICS OF BREAST CANCER Pascal BONNIER 1 *, Fre ´ de ´ ric BESSENAY 1 , Annie J. SASCO 4 , Bassodeo BEEDASSY 1 , Christiane LEJEUNE 1 , Sylvie ROMAIN 2 , Colette CHARPIN 3 , Lucien PIANA 1 and Pierre-Marie MARTIN 2 1 Department of Gynecology and Obstetrics, Marseille Public Hospital System (APHM), Marseille, France 2 Oncology Biopathology Laboratory, Marseille Public Hospital System (APHM), Marseille, France 3 Laboratory of Histology, Marseille Public Hospital System (APHM), Marseille, France 4 Program of Epidemiology for Cancer Prevention, International Agency for Research on Cancer and Institut National de la Sante ´ et de la Recherche Me ´dicale, Lyon, France Hormone-replacement therapy (HRT) is widely used by post-menopausal women. Although this treatment may slightly increase the incidence of breast cancer, more and more cases are diagnosed while women are taking H RT . T he purpose of this study was to ascertain the influence of H RT on prognostic factors and outcome of breast cancer. Data on all breast-cancer patients, including precise information on H RT , was prospectively and systematically recorded in a data base. From 1985 to 1995, 1379 post-menopausal women fulfilled the eligibility criteria for this study. All were treated by us (P.B. and L.P.) in our ward of a large public hospital of Marseilles, France. The clinical features, laboratory findings and survival rates in 142 HRT users who developed breast cancer while being treated were compared with those of 284 matched never user breast-cancer patients. Patients who developed breast cancer during HRT had fewer locally ad- vanced cancersand smaller and better-differentiated cancers. Lymph-node involvement was significantly less frequent in the user group than in the non-user group (non-significant). Estradiol receptivity was both qualitatively and quantitatively lower in users. T here wasno significant difference with regard to recurrence and metastasis-free survival and overall sur- vival. W e conclude that H RT does not affect the prognosis of breast cancer. Regular surveillance during H RT allows early detection of smaller lesions. The higher number of well- differentiated cancers and the distribution of hormone recep- tivity may reflect interaction between neoplastic tissue and exogenous hormones. Int. J. Cancer (Pred. Oncol.) 79:278–282, 1998.  1998 Wiley-Liss, Inc. Hormone-replacement therapy (HRT) is widely used by post- menopausal women. It has little effect on the risk of breast cancer, but more and more cases are diagnosed in women under hormone- replacement treatment. Numerous epidemiological studies have studied the risk of breast cancer associated with estrogen- replacement therapy (Brinton et al., 1986; Bergkvist et al., 1989b; Colditz et al.,1995; Dupont and Page, 1991; Henderson, 1989; Steinberg et al., 1991). Previous data concerning the characteristics and outcome of breast cancer in patients undergoing replacement therapy suggest that prognosis is better for HRT users. However, data are scarce and incomplete. The purpose of this study was to determine whether concurrent HRT affects prognosis and survival. To answer this question, we compared clinical features, laboratory findings and survival rates in 142 patients taking replacement therapy at the time they developed breast cancer with those of 284 matched breast-cancer patients who had never received HRT. Mean follow-up was 55.2 months. PATIENTS AND METHODS All breast-cancer patients treated at our institution from 1985 onwards have been systematically and prospectively entered in a computerized data base. In addition to details concerning the cancer, treatment and follow-up, precise information about HRT was recorded. From 1985 to 1995, 1490 post-menopausal women were included in the data base. Our definition of menopause required ovariectomy or a 6-month period of amenorrhea. For women without ovariectomy, menopausal status was based on measurement of follicle-stimulating hormone (FSH) and luteiniz- ing hormone (LH). We excluded 76 patients with a prior history of cancer (39 breast cancers, 37 other cancers), 4 with lobular carcinoma in situ and 1 with sarcoma. In addition, we excluded 6 patients because of incomplete data on HRT and 18 patients who stopped taking hormone-replacement treatment more than a year before diagnosis. The study population was 1385 women, i.e., 92.9% of the total population. We compared 2 groups of patients: users and non-users. Users were defined as any patients in whom breast cancer was diagnosed during post-menopausal HRT, while never-users were defined as any patients with no previous exposure to HRT who developed cancer. For each user, 2 never-users treated at the same age and in the same year were selected.The user/non-user ratio was 1 to 2 in the study population. The following clinical data were noted: weight, height, and body-mass index, modality that allowed diagnosis (clinical exami- nation or X-ray), delay between the first sign and histological confirmation of cancer, clinical tumor size, disease stage and surgical methods. The histological data were anatomical size, histological type, degree of infiltration, histoprognostic grade (Scarff, Bloom and Richardson) and lymph-node involvement. Estradiol-receptor and progesterone-receptor assays were car- ried out in the same laboratory (Romain et al., 1995), either by radioligand-binding assay or by enzyme immuno-assay. Both techniques measure bound and unbound receptors. Cut-off points were 10 fmol/mg protein for the radioligand-binding assay and 15 fmol/mg protein for the enzyme immuno-assay. Radioligand bind- ing was performed using the dextran-coated-charcoal exchange technique with a single saturating dose assay. The Enzyme immuno-assay was performed using Abbott kits (Abbott, Chicago, IL). Quality control was ensured by frequent testing according to the criteria of the European Organization for Research and Treatment of Cancer (EORTC) and by internal laboratory standards according to the recommendations of the Receptors and Biomark- ers EORTC Group. The statistical analysis was done using Medlog software (Infor- mationAnalysis, Mountain View, CA). Variables frequencies were compared using the Chi-squared test and medians using the Wilcoxon test. Survival curves were calculated according to the Kaplan-Meier method and compared using the log-rank test. In most patients, surveillance consisted of clinical examination 3 times a year and annual mammography, liver ultrasonography and bone scintiscan. Tumor-marker assays, Computerized tomography scan and Magnetic resonance imaging were performed only in symptomatic patients. The duration of recurrence-free survival, metastasis-free survival and overall survival were calculated from the date of initiation of cancer treatment. Local recurrence was *Correspondence to: Service de Gyne ´cologie et Obstetrique A, Ho ˆpital de la Conception, 147, boulevard Baille, 13385 Marseille Cedex 5, France. Fax: (33)4-9138-3030. Received 5 December 1997; Revised 9 February 1998 Int. J. Cancer (Pred. Oncol.): 79, 278–282 (1998)  1998 Wiley-Liss, Inc. Publication of the International Union Against Cancer Publication de l’Union Internationale Contre le Cancer