Luiz Henrique Gebrim

Effects of low dose tamoxifen on normal breast tissue from premenopausal women

The aim of this study was to determine the effects of low doses of tamoxifen (5 and 10mg/day) for 50 days compared with the standard dose (20 mg/day) on breast biomarkers measured in normal breast tissue from premenopausal patients. A randomised double-blind study was performed using tissue from 56 premenopausal women with a diagnosis of fibroadenoma of the breast. Excisional biopsy was performed on the 50th day of therapy. Normal breast tissue samples were collected during surgery. The patients were divided in groups: A (placebo, n=11); group B (5 mg, n=16), group C (10 mg, n=14) and group D (20 mg, n=15). In this cross-sectional study, differences in the expression of Oestrogen Receptor alpha (ERalpha), Progesterone Receptor (PR), Ki-67, apoptotic bodies and mitotic index between the different groups after treatment can be seen on the normal breast tissue. We believe that a lower dose of tamoxifen could reduce the side-effects associated with treatment without affecting its chemopreventive activity in the breast.

Effect of a half dose of tamoxifen on proliferative activity in normal breast tissue.

Objectives: To investigate the proliferative activity of the mammary gland epithelium and plasma levels of progesterone, estradiol, prolactin, luteinizing hormone (LH), follicle‐stimulating hormone (FSH) and sex hormone‐binding globulin (SHBG) in premenopausal women treated with 10 and 20 mg of tamoxifen (TAM) for 22 days. Patients and methods: A randomized double‐blind study was performed with 43 premenopausal women with a diagnosis of fibroadenoma of the breast. The patients were divided into three groups: A (n=15, placebo); B (n=15, TAM 10 mg/day) and C (n=13, TAM 20 mg/day). They started taking an oral dose of TAM or placebo on the very first day of the menstrual cycle. Lumpectomy was performed on the 22nd day of therapy. Normal breast tissue samples were collected during surgery, immediately immersed in 10% buffered formalin, processed for routine histology and immunohistochemistry for proliferating cell nuclear antigen (PCNA) detection. Two peripheral blood samples were collected, both on the 22nd day of the menstrual cycle, in order to evaluate the hormone levels. PCNA expressing epithelial cells were quantified by using a digital program Kontron Image System KS‐300 in 1000 cells (400×). Results: The percentage of cells expressing PCNA was significantly higher in the group receiving placebo (group A, 50.3%) when compared to groups receiving TAM 10 or 20 mg/day (group B, 24.1%; and group C, 23.2%, respectively) (P<0.001). Differences between groups B and C were not significant. Levels of progesterone, estradiol and SHBG were significantly higher in B and C groups compared to group A. Increasing concentrations of FSH (P<0.0045) and lower levels of prolactin (P<0.0055) were only found in the group receiving 20 mg/day of TAM (group C). Conclusions: A 22‐day TAM therapy, either with 10 or 20 mg/day, significantly reduced the PCNA expression and therefore the proliferative activity of the normal human breast tissue. Increasing levels of estradiol, progesterone and SHBG were associated with TAM therapy at 10 or 20 mg/day. However, a significant change of the level of FSH and prolactin was reached only with a 20‐mg/day dose.

Rastreamento do câncer de mama no Brasil

Atualmente o câncer de mama e um problema de saude publica, nao so em paises em desenvolvimento, como e o caso do Brasil, mas tambem em paises desenvolvidos, como Estados Unidos e paises da Europa Ocidental. Tal situacao deve-se a difi culdade de prevencao primaria (eliminar fatores de risco ou diagnosticar e tratar lesoes precursoras), observando-se como consequencia aumento signifi cativo na incidencia e mortalidade decorrentes desta neoplasia. Segundo a Organizacao Mundial de Saude (OMS), observou-se nas decadas de 60 e 70 aumento de dez vezes nas taxas de incidencia ajustadas por idade nos Registros de Câncer de Base Populacional de diversos continentes1. O aumento na incidencia pode ser explicado, em parte, por alteracoes nos habitos reprodutivos, como postergacao do primeiro parto, e nutricionais (considerando que a obesidade eleva o risco de câncer na pos-menopausa). Nos Estados Unidos, a American Cancer Society estimou que ocorram em 2006 cerca de 212.930 casos novos e 40.870 mortes por carcinoma de mama. Entretanto, apesar da tendencia gradual do aumento na incidencia, observa-se nesse pais, bem como nos paises da Uniao Europeia, uma diminuicao na mortalidade por esta neoplasia de ate 2,3 % ao ano2, 3. Apesar da reducao da mortalidade por câncer de mama nos Estados Unidos o numero de pacientes em estadios avancados nao sofreu alteracao4. A reducao provavelmente foi obtida pelo aumento na proporcao de mulheres com diagnosticos iniciais (carcinoma “in situ” e estadio clinico I) oriundas de camadas de maior poder aquisitivo, que passaram a realizar a prevencao secundaria (diagnostico na fase pre-clinica por mamografi a), aliado a reducao de mortalidade obtida pela hormonioterapia adjuvante com tamoxifeno4. No Brasil, o câncer de mama tambem apresenta alta incidencia entre as mulheres. Segundo o Instituto Nacional do Câncer de Ministerio da Saude (INCA), para uma populacao feminina de cerca de 93 milhoes, estima-se que ocorrerao 48.930 casos em 2006, com incidencia de 52 casos a cada 100 mil mulheres. Tanto a incidencia como a taxa bruta de mortalidade vem apresentando aumento signifi cativo nas ultimas decadas5, com crescimento de 76% entre os anos de 1979 e 2004, passando de 5,7 para 10,1 mortes por 100.000 mulheres (Figura 1).

Effects of tamoxifen on the breast in the luteal phase of the menstrual cycle

Objectives: The effect of tamoxifen on cyclic mastalgia and on chemoprophylaxis against breast cancer is little known, mainly due to the difficulties in studying the normal human gland. We proposed to evaluate the mitotic index and the nuclear volume of the lobule of women medicated with tamoxifen only during the luteal phase of the menstrual cycle in order to observe the effect of tamoxifen on the normal human mammary gland. Methods: Twenty‐four premenopausal women with fibroadenoma diagnosed via biopsy were studied. The phase of the cycle was determined by the date of menstruation and serum progesterone level in the luteal phase (≥3 ng/ml). The patients admitted to the study and were given written informed consent to participate in the investigation, which was previously approved of by the hospital Ethics Committee. Patients were divided at random into two groups: Group I consisted of 12 untreated women (control) and Group II consisted of 12 patients treated with 20 mg/day tamoxifen for 10 consecutive days beginning on the 13th day of the menstrual cycle. In both groups, the patients were submitted to biopsies of the nodule and of a 1‐cm3 fragment of adjacent mammary parenchyma between the 23rd and 26th day of the cycle. The mitotic index (number of mitoses/1000 nuclei counted) and mean nuclear volume (mean of 10 nuclear volumes for each case) were measured. Results: No mitosis was observed in Group II. There was a reduction in the mean nuclear volume in Group II (Mann–Whitney test). Conclusions: Tamoxifen, when administered only during the luteal phase of the menstrual cycle, significantly reduces the nuclear volume and mitotic activity of the epithelium. This data demonstrates an antagonistic action of tamoxifen on estrogen even when administered for short periods of time.

The effect of tamoxifen on PCNA expression in fibroadenomas.

Abstract:  For almost three decades, tamoxifen has been used in the adjuvant treatment of breast cancer. It has also proven effective in the chemoprophylaxis of this disease and in the treatment of cyclic mastalgia. Since a fibroadenoma is a benign hormone‐dependent neoplasm which contains estrogen receptor (ER) levels higher than in the mammary lobule, an evaluation of the effect of this drug on the proliferative activity of both the epithelium and the stroma of fibroadenomas in premenopausal women following the administration of 10 or 20 mg/day over 22 days was proposed. Forty women with fibroadenoma were selected for a randomized double‐blind trial. They had regular menstrual cycles and had received neither hormones nor become pregnant 12 months prior to this study. Patients were divided into three groups: A (n = 14; placebo), B (n = 13; tamoxifen 10 mg/day), and C (n = 13; tamoxifen 20 mg/day). The treatment was initiated on the first day of their menstrual cycle and the surgeries were performed on the 22nd day. Estradiol, progesterone, and steroid hormone binding globulin (SHBG) were measured twice. The first measurement was performed on the 22nd day of the previous menstrual cycle and the second one was performed on the day of surgery. The fibroadenoma was fixed in 10% formaldehyde solution and stained with hematoxylin and eosin and then processed through immunohistochemical reaction (PC‐10, DAKO code number M879, Denmark A/S). The immunoexpression of the proliferative cell nuclear antigen (PCNA) of at least 500 epithelial and 500 stromal cells was evaluated. Such cells were interactively counted using the Kontron Imaging System KS‐300 computerized analysis system, with ×400 magnification. As to PCNA expression in the fibroadenomas’ epithelium, the average percentage of stained nuclei in groups A, B, and C was 25.2, 19.3, and 18.0, respectively. However, no significant difference was found in the variance analysis of these data (p = 0.168). As to the study of the fibroadenomas’ stroma, the average percentage of stained nuclei found in groups A, B, and C was 32.4, 23.2, and 18.4, respectively. The variance analysis (p = 0.031) and Fishers multiple comparison test (1.39; 26.67 confidence interval [CI]) confirmed that the number of PCNA‐expressing nuclei in the stroma was significantly lower in group C (20 mg/day) compared to group A (control). However, there was no significant difference between group B (10 mg/day) and group C (20 mg/day). It was found that tamoxifen reduced the expression of PCNA in the epithelium and the stroma of the fibroadenoma. However, the effect was only statistically significant in the stroma when a 20 mg/day dose was administered.

Estrogenic activity of tamoxifen on normal mammary parenchyma in the luteal phase of the menstrual cycle

Objectives: Tamoxifen, an anti‐estrogenic drug used in the adjuvant treatment of breast cancer, deserves more investigation for the determination of its efficacy as a prophylactic agent against breast cancer in high risk women. Thus, the action of tamoxifen on the human mammary gland was studied by measuring the number of lysosomes in normal mammary epithelium during the administration of tamoxifen. Methods: Tamoxifen was administered only during the luteal phase of the menstrual cycle to avoid interference with corpus luteum formation. A fragment of breast tissue adjacent to a fibroadenoma was obtained during surgery from 35 premenopausal women aged 15 to 37 years who had been eumenorrheic for at least 6 months; 18 of these patients were treated with tamoxifen and 17 were used as controls. Lysosome counts were performed under the light microscope on slides submitted to the acid phosphatase cytochemical technique and the data were analyzed statistically by the Mann‐Whitney test. Results: The fragments from the group treated with tamoxifen showed a significant decrease in lysosome numbers. Conclusions: Tamoxifen administered after ovulation significantly decreases the number of lysosomes in the cells of normal mammary epithelium, demonstrating the antiestrogenic effect of the drug on this target tissue.

Estimativa de custo do rastreamento mamográfico em mulheres no climatério

PURPOSE: to evaluate the cost of preventive mammographic screening in climacteric women, as compared to the cost of breast cancer treatment in more advanced stages. METHODS: one thousand and fourteen patients attended at the Climacteric outpatient service of the Gynecology Department, Federal University of Sao Paulo Paulista School of Medicine, were included in the study and submitted to mammographic test. All mammographic tests were analyzed by the same two physicians and classified according to the BI-RADS (Breast Imaging Reporting and Data System American College of Radiology) categories. The detected lesions were submitted to cytological and histological examination. RESULTS: the final diagnostic impression of the 1014 examinations, according to the classification of BI-RADS categories was: 1=261, 2=671, 3=59, 4=22 and 5=1. The invasive procedures were performed through a needle guided by ultrasound or stereotactic examinations: 33 fine-needle aspiration biopsies, 6 core biopsies guided by ultrasound and 20 core biopsies guided by stereotactic examination. Five cancer diagnoses were established. The total cost of this screening based on Brazilian procedure values was R

Leiomyoma of the breast: a case report

76,593.79 (25,534 dollars). Therefore, the cost of the diagnosis of the five cases of cancer in this screening was R

Evaluation of Monoclonal Antibody MIB-1 in the Mammary Epithelium Adjacent to Fibroadenomas in Premenopausal Women Treated with Tamoxifen

15,318.75 (5,106 dollars) each. However, the average cost per patient screened was R

Evaluation of bone metastases from breast cancer by bone scintigraphy and positron emission tomography/computed tomography imaging.

75.53 (25 dollars). CONCLUSIONS: considering that the total treatment cost of only one case of breast cancer in advanced stage including hospital costs, surgery, chemotherapy, radiotherapy and hormonal treatment is similar to the cost of 1,000 mammographic screenings in climacteric women, it may be concluded that the cost of the early cancer diagnosis program is worth it and should be included in the public health program, as a way of lowering the public health expense.