José Ignacio Arias

THE VARIANT E233G OF THE RAD51D GENE COULD BE A LOW-PENETRANCE ALLELE IN HIGH-RISK BREAST CANCER FAMILIES WITHOUT BRCA1/2 MUTATIONS

Six SNPs have been detected in the DNA repair genes RAD51C and RAD51D, not previously characterized. The novel variant E233G in RAD51D is more highly represented in high‐risk, site‐specific, familial breast cancer cases that are not associated with the BRCA1/2 genes, with a frequency of 5.74% (n = 174) compared to a control population (n = 567) and another subset of breast cancer patients (n = 765) with a prevalence of around 2% only (comparison to controls, OR = 2.6, 95% CI 1.12–6.03; p < 0.021). We found that the immunohistochemical profile detected in available tumors from these patients differs slightly from those described in non‐BRCA1/2 tumors. Finally, the structural prediction of the putative functional consequence of this change indicates that it can diminish protein stability and structure. This suggests a role for E233G as a low‐penetrance susceptibility gene in the specific subgroup of high‐risk familial breast cancer cases that are not related to BRCA1/2.

Carcinoma ductal infiltrante de mama. Diferencias clinicobiológicas entre mujeres mayores de 70 años y aquéllas de entre 60 y 70 años

BACKGROUND: There is discrepancy in the literature regarding the behavior of breast cancer in elderly women. For this reason we decided to study the possible clinical and biological differences of infiltrative ductal breast carcinoma between women over 70 years and those aged between 60 and 70 years. PATIENTS AND METHOD: The study group included 181 women with infiltrative ductal carcinomas (IDCs) who were referred from a breast clinic (BC) and a breast cancer screening campaign (BCS). 67 of them were older than 70 and 114 were between 60 and 70 years old. Estrogen receptors (ER), progesterone receptors (PR), pS2 and cathepsin D cytosolic levels were determined, as well as levels of epidermal growth factor receptor (EGFR) in cell surfaces. Likewise, size, axillary lymph node involvement, distant metastasis, histological grade, ploidy and cellular S-phase fraction were also considered as variables of the study. RESULTS: IDCs in women older than 70 had greater size (p 14% (p = 0.093). However, when we considered only women referred from BCS, no differences in the parameters studied between women older than 70 and those aged between 60 and 70 years were observed. When only patients coming from BC were considered, women older than 70 had a greater number of axillary lymph nodes involved (p= 0.027). Patients older than 70 years from BC showed greater size (p= 0.054) and more common distant metastasis (p= 0.075) than those from BCS. Also, patients between 60 and 70 referred from BC had tumors with greater size (p <0.001), nodal involvement (p= 0.022), number of lymph nodes involved (p= 0.022) and distant metastasis (p= 0.048) than those from BCS with the same age. CONCLUSIONS: Our results suggest that IDCs in women older than 70 years show clinical and biological features associated with a worse behaviour. However, this is only observed in women referred from BC but not in those coming from BCS. For this reason, the patients referral site seems to be essential for the observed clinical and biological differences of breast carcinomas in the elderly.

CA 15-3 serum levels in patients with ductal breast carcinoma: relationship with clinicopathological parameters and tumor markers.

Introduction Cancer antigen 15–3 (CA 15–3) is the most widely used serum marker in diagnosing and monitoring breast cancer. The aim of this work was to analyze preoperative CA 15–3 serum levels in patients with ductal breast carcinoma in relation to 1) clinicopathological parameters, 2) hormone receptors, and 3) tissue-based tumor markers. Methods A group of 340 women with infiltrating ductal carcinoma of the breast who had undergone no prior treatment was studied. These women ranged in age between 27 and 83 years (mean age 61.5±9.9 years). Preoperative CA 15–3 serum levels were determined by an immunoradiometric method. Hormone receptors (estrogen, progesterone and androgen receptors), p53, bcl-2 and Ki67 were determined by different immunohistochemical methods. Epidermal growth factor receptor (EGFR) was analyzed in the cell membranes by radioligand assay whereas cathepsin D and pS2 were determined by immunoradiometric analysis. Tumor ploidy and S-phase fraction were studied by flow cytometry. Results CA 15–3 serum levels were higher in postmenopausal women (p=0.032), in patients with tumors exceeding 2 cm (p=0.003), lymph node involvement (p=0.026), distant metastases (M1) (p<0.0001), S-phase fraction <7% (p=0.015), EGFR <6 fmol/mg protein (p=0.025), and cathepsin D <50 pmol/mg protein (p=0.023). Conclusions Preoperative CA 15–3 serum levels were associated with cell proliferation determined by the S-phase fraction, the concentration of cathepsin D in the cytosol, and the EGFR concentration in the cell membrane.

Cell surface CD44v5 levels correlate with progesterone receptors and a tumor size > 2 cm in infiltrating ductal carcinomas of the breast

Kaufmann et al (1) and Sinn et al (2) have reported that normal mammary ductal epithelial cells and cells derived from hyperplastic lesions do not express CD44vs, while Friedrichs et al (3) detected CD44v6 and v9 in the epithelium, and CD44s in stromal elements. Nevertheless, v5 and v6 epitopes are found in most tumor samples and all lymph node metastases. There are few papers concerning CD44v5 expression in breast carcinomas and its prognostic value, although its association with a poor overall survival and histological grade III has been described (1-2). The present study evaluates the CD44v5 cell surface levels in breast tissues, focusing on two main issues: 1) behavior in normal, non-malignant and malignant samples and 2) correlation with other clinical and biological parameters in order to define the possible existence of subgroups with different behavior. The study group included 225 breast tissues classified as follows: normal 26, fibroadenoma (FAD) 19, cystic breast disease (CBD) 3, intraductal carcinoma (IDC) 8 and infiltrating ductal carcinoma (IIDC) 169. In all cases there was histological confirmation, and cell surfaces and cytosols were obtained using standard criteria from EORTC. CD44v5 was carried out on cell surfaces by ELISA from Bender MedSystems (Austria) and the lowest level of sensitivity was established as 3 ng/mg prt. Other clinical and biological parameters included in this study were: estrogen receptors (ER), progesterone receptors (PR), pS2, cathepsin D, epidermal growth factor receptor (EGF-R), tissue-type plasminogen activator (t-PA), neu oncoprotein, menopausal status, histological grade, metastasis, lymph node involvement (N), size, ploidy and S-phase, both measured by FCM (Bencton Dickinson, Fascam) on fresh samples. Other technical aspects have been reported elsewhere (4). All statistical analyses were carried out us-

La concentración de ácido hialurónico citosólico define ciertas propiedades clinicobiológicas del carcinoma ductal infiltrante de mama CD44v5 positivo

Fundamento El acido hialuronico es uno de los ligandos de la molecula de adhesion CD44. En este estudio hemos querido analizar si su concentracion citosolica podia modular ciertos para-metros clinicobiologicos en el carcinoma ductal infiltrante (CDI) de mama CD44v5+. Pacientes y metodo Hemos determinado, mediante un metodo de radioligando, las concentra-ciones citosolicas de acido hialuronico en 127 casos. Asi mismo, dosificamos los valores cito-solicos de receptor de estrogenos, progesterona, pS2, catepsina D y activador del plasminogeno tipo tisular (t-AP), asi como las del receptor del factor de crecimiento epidermico (EGFR) en las membranas celulares. Se tuvieron presentes tambien el estado menopausico, tamano, invasion ganglionar axilar, grado histologico, ploidia y fase de sintesis celular. Resultados Los CDI con acido hialuronico positivo (> 4.800 ng/mg de proteina) que representa la mediana obtenida en 252 CDI, cursaron con mayores concentraciones de receptores de pro-gesterona (p = 0,035) y t-AP (p = 0,000), mientras que los CDI con acido hialuronico negativo mostraron con mayor frecuencia un tamano superior a 2 cm (p = 0,015), aneuploidia (p = 0,002) y una fase S mayor del 14% (p = 0,019), asi como un grado histologico 3 que rozo la significacion estadistica (p = 0,062), indicadores todos ellos de un peor comportamiento y evolucion. Conclusiones Los resultados anteriores indican que, como ocurre con el de membrana, la con-centracion del acido hialuronico citosolico parece modular ciertas propiedades clinicobiologicas del CDI/CD44v5+, lo que realza el papel de ambos parametros y podria ayudar a explicar algunas discordancias descritas en la bibliografia acerca de su interes practico cuando se consideran aisladamente cada uno de ellos.

Invasión de los ganglios axilares en el carcinoma mamario con receptores hormonales negativos

Fundamento y objetivo Estudiar la diseminacion ganglionar axilar en carcinomas ductales infiltrantes de mama con receptores hormonales negativos ( Pacientes y metodo El grupo de estudio incluyo 77 tumores con receptores de estrogeno negativos (RE–) y 47 con receptores de estrogenos y progesterona negativos (RE/RP–). Ambos re-ceptores hormonales se determinaron por enzimoinmunoanalisis Resultados En los tumores con RE– merecen destacarse las mayores concentraciones de catepsina D (> 50xa0pmol/mg de proteina) en los casos con diseminacion axilar (24 de 41 frente a 7 de 36 sin diseminacion ganglionar axilar; p Conclusiones Los resultados anteriores reflejan el posible interes clinico de la catepsina D en tumores mamarios con receptores hormonales negativos

CA15.3 Serum Concentrations in Older Women with Infiltrating Ductal Carcinomas of the Breast

Breast cancer is currently becoming a disease of the elderly. We have studied the relation between CA 15.3 serum concentrations and clinical-pathological parameters in 69 women with IDC aged over 70 years (76.3 ± 4.2; range: 71–88; median 76). A group of 205 women with the same tumor but aged <70 years (62.8 ± 4.0; range: 55–70; median 63) was also considered for comparison. Tumor size, axillary lymph node involvement, distant metastasis and histological grade were taken account. Serum CA 15.3 was determined by luminescence assay. CA 15.3 serum concentrations ranged between 6 and 85 U/mL (median 22.9 U/mL), and were higher only in patients with greater (qualitative and quantitative; p: 0.041) tumor size. Our results show that in women with IDCs, and aged over 70 years, serum CA 15.3 serum concentrations are associated exclusively with a greater tumor size, being these findings different to those described in women with the same subtype of tumor considered as a whole or with lower age.