Higher risk of recurrence in early-stage breast cancer patients with increased levels of ribosomal protein S6.

PI3K/AKT/mTOR pathway is implicated in breast cancer progression and recurrence. The identification of PIK3CA and AKT1 mutations and loss of PTEN serve as selection criterion for targeted therapies involving selective inhibitors. However, they do not consistently align with pathway activation, and high-cost determinations limit their routine application. PI3K-downstream epigenetic regulatory mechanisms broaden the alterations that amplify pathway activity and, consequently, sensitivity to selective inhibitors. In this retrospective observational study, conducted within a cohort of early-stage breast cancer patients, we determined phosphorylated ribosomal protein S6 (pS6) at Ser240/244 by immunohistochemistry as an indicator of PI3K pathway activation. Log-Rank test and Cox proportional hazards regression were used to analyze the clinical relevance of pS6, alone and together with clinicopathological variables, regarding recurrence-free survival. ROC curves and the area under the curves were used to evaluate the calibration and discrimination properties of uni- and multivariate models. Our results show that a high percentage of pS6 positive tumor cells was associated with an unfavorable prognosis in a cohort of 129 hormone receptor positive/HER2 negative breast cancer patients (Hazard Ratio = 5.92; Log-Rank p = 9.5e-08; median follow-up = 53 months). When assessed in combination with lymph node status, the predictive capacity was higher compared to both univariate models individually. In conclusion, pS6 could represent a novel independent marker for predicting recurrence risk in luminal breast cancer.

Deciphering the causes of advanced-stage disease at diagnosis among breast cancer patients who attended a suburban hospital in Buenos Aires.

INTRODUCTION: Breast cancer is still one of the main causes of cancer mortality in women worldwide, and death rates are even greater in vulnerable populations. A delay in diagnosis usually comes with advanced-stage disease, which impacts patient survival. The aim of this study was to evaluate the time for first medical consultation among women with breast cancer attending the Magdalena V. de Martínez Hospital and to determine the causes that may influence patient delay and its impact on cancer stage at diagnosis. MATERIALS AND METHODS: Three hundred and six breast cancer patients were interviewed using a self-report questionnaire, and socioeconomic and demographic variables, namely, highest education level completed, employment status and breast cancer awareness, were collected. The answers were associated with patient clinical records, such as clinical staging and tumor size. RESULTS: Forty-nine percent of the patients were diagnosed with advanced-stage disease. These women had either a deficiency in breast cancer awareness, did not visit a gynecologist after age 40 or, were unemployed, while those patients diagnosed with early-stage breast cancer had nonpalpable tumors, declared a sufficient household income or delayed less than four weeks in seeking medical attention. Moreover, the delay in the first medical visit was more than one month in 78% of the patients, being disregard the most common cause of postponement. Additionally, patient delays were associated with larger tumors and with incomplete education. DISCUSSION: These results indicate that early detection efforts should be made to reduce the disease stage at diagnosis, which may impact on overall survival.

Introducción: El cáncer de mama (CM) es una de las principales causas de mortalidad por cáncer en mujeres, y las tasas de mortalidad son aún mayores en poblaciones vulnerables. Un retraso en el diagnóstico suele acompañarse con estadios avanzados de la enfermedad, lo que impacta en la supervivencia del paciente. El objetivo fue evaluar el tiempo transcurrido para la primera consulta médica entre mujeres con CM que asisten al Hospital Magdalena V. de Martínez y determinar las causas que pueden influir en la demora del paciente y su impacto en el estadio al momento del diagnóstico. Materiales y métodos: Se entrevistaron 306 pacientes con CM utilizando un cuestionario autoinformado, y se recopilaron variables socioeconómicas y demográficas, entre ellas, nivel educativo más alto completado, situación laboral y conocimiento sobre el CM. Las respuestas se asociaron con los registros clínicos de las pacientes. Resultados: El 49% de las pacientes fueron diagnosticadas con enfermedad en estadios avanzados. Estas mujeres tenían deficiencias en el conocimiento sobre el CM, no consultó al ginecólogo después de los 40 años o estaba desempleada, mientras que aquellas diagnosticadas con CM en estadios tempranos tenían tumores no palpables, declaraban un ingreso familiar suficiente o demoraban menos de cuatro semanas en buscar atención médica. Además, la demora en la primera visita médica fue de más de un mes en el 78% de las pacientes, siendo el desinterés la causa más común de postergación. Asimismo, las demoras estaban asociadas con tumores más grandes y con una educación incompleta. Discusión: Este estudio sugiere la necesidad de desarrollar estrategias de sensibilización y educación sobre el CM, así como de políticas para mejorar el acceso a la atención médica, especialmente para poblaciones vulnerables, con el fin de reducir el retraso en el diagnóstico y mejorar la salud de las pacientes con CM.

Steroid profile in patients with breast cancer and in mice treated with mifepristone.

Progesterone receptors (PRs) are biomarkers used as prognostic and predictive factors in breast cancer, but they are still not used as therapeutic targets. We have proposed that the ratio between PR isoforms A and B (PRA and PRB) predicts antiprogestin responsiveness. The MIPRA trial confirmed the benefit of 200 mg mifepristone, administered to patients with tumors with a high PRA/PRB ratio, but dose-ranging has not been conducted. The aim of this study was to establish the plasma mifepristone levels of patients from the MIPRA trial, along with the resultant steroid profiles, and compare these with those observed in mifepristone-treated mice using therapeutic schemes able to induce the regression of experimental mammary carcinomas with high PRA/PRB ratios: 6 mg pellets implanted subcutaneously, or daily doses of 12 mg/kg body weight. The plasma levels of mifepristone and other 19 plasma steroids were measured by liquid chromatography-tandem mass spectometry. In mifepristone-treated mice, plasma levels were lower than those registered in mifepristone-treated patients (i.e. day 7 after treatment initiation, pellet-treated mice: 8.4 ± 3.9 ng/mL; mifepristone-treated patients: 300.3 ± 31.7 ng/mL (mean ± s.d.; P < 0.001)). The increase in corticoid related steroids observed in patients was not observed in mifepristone-treated mice. The increase in progesterone levels was the most significant side effect detected in mifepristone-treated mice after 14 or 21 days of treatment, probably due to an ovarian compensatory effect not observed in postmenopausal patients. We conclude that in future clinical trials using mifepristone, the possibility of lowering the standard daily dose of 200 mg should be considered.

Beneficial Effects of Mifepristone Treatment in Patients with Breast Cancer Selected by the Progesterone Receptor Isoform Ratio: Results from the MIPRA Trial.

PURPOSE: Preclinical data suggest that antiprogestins inhibit the growth of luminal breast carcinomas that express higher levels of progesterone receptor isoform A (PRA) than isoform B (PRB). Thus, we designed a presurgical window of opportunity trial to determine the therapeutic effects of mifepristone in patients with breast cancer, based on their high PRA/PRB isoform ratio (MIPRA; NCT02651844). PATIENTS AND METHODS: Twenty patients with luminal breast carcinomas with PRA/PRB > 1.5 (determined by Western blots), and PR ≥ 50%, naïve from previous treatment, were included for mifepristone treatment (200 mg/day orally; 14 days). Core needle biopsies and surgical samples were formalin fixed for IHC studies, while others were snap-frozen to perform RNA sequencing (RNA-seq), proteomics, and/or Western blot studies. Plasma mifepristone levels were determined using mass spectrometry. The primary endpoint was the comparison of Ki67 expression pretreatment and posttreatment. RESULTS: A 49.62% decrease in Ki67 staining was observed in all surgical specimens compared with baseline (P = 0.0003). Using the prespecified response parameter (30% relative reduction), we identified 14 of 20 responders. Mifepristone induced an increase in tumor-infiltrating lymphocytes; a decrease in hormone receptor and pSer118ER expression; and an increase in calregulin, p21, p15, and activated caspase 3 expression. RNA-seq and proteomic studies identified downregulated pathways related to cell proliferation and upregulated pathways related to immune bioprocesses and extracellular matrix remodeling. CONCLUSIONS: Our results support the use of mifepristone in patients with luminal breast cancer with high PRA/PRB ratios. The combined effects of mifepristone and estrogen receptor modulators warrant clinical evaluation to improve endocrine treatment responsiveness in these patients. See related commentary by Ronchi and Brisken, p. 833.

Progesterone receptor isoform ratio dictates antiprogestin/progestin effects on breast cancer growth and metastases: A role for NDRG1.

Progesterone receptors (PRs) ligands are being tested in luminal breast cancer. There are mainly two PR isoforms, PRA and PRB, and their ratio (PRA/PRB) may be predictive of antiprogestin response. Our aim was to investigate: the impact of the PR isoform ratio on metastatic behaviour, the PR isoform ratio in paired primary tumours and lymph node metastases (LNM) and, the effect of antiprogestin/progestins on metastatic growth. Using murine and human metastatic models, we demonstrated that tumours with PRB > PRA (PRB-H) have a higher proliferation index but less metastatic ability than those with PRA > PRB (PRA-H). Antiprogestins and progestins inhibited metastatic burden in PRA-H and PRB-H models, respectively. In breast cancer samples, LNM retained the same PRA/PRB ratio as their matched primary tumours. Moreover, PRA-H LNM expressed higher total PR levels than the primary tumours. The expression of NDRG1, a metastasis suppressor protein, was higher in PRB-H compared to PRA-H tumours and was inversely regulated by antiprogestins/progestins. The binding of the corepressor SMRT at the progesterone responsive elements of the NDRG1 regulatory sequences, together with PRA, impeded its expression in PRA-H cells. Antiprogestins modulate the interplay between SMRT and AIB1 recruitment in PRA-H or PRB-H contexts regulating NDRG1 expression and thus, metastasis. In conclusion, we provide a mechanistic interpretation to explain the differential role of PR isoforms in metastatic growth and highlight the therapeutic benefit of using antiprogestins in PRA-H tumours. The therapeutic effect of progestins in PRB-H tumours is suggested.

Increased androgen receptor expression in estrogen receptor-positive/progesterone receptor-negative breast cancer.

PURPOSE: Expression of estrogen receptor alpha (ER) and/or progesterone receptor (PR) defines luminal breast cancer. Even though androgen (AR) and glucocorticoid receptors (GR) are highly expressed in luminal breast cancers, prognostic value remains uncertain and concomitant expression of these four hormone receptors is still unexplored. METHODS: Here, we evaluated ER, PR, AR, and GR expression, using immunohistochemistry, in a cohort of 169 breast cancer patients and correlated these findings with clinical and pathological parameters. RESULTS: We found that AR is more frequently expressed and at higher levels in the ER+PR- subset compared to ER+PR+ tumors. There were no significant differences in GR expression between tumor subsets. Moreover, most luminal tumors also expressed either AR or GR and most basal tumors were also negative for AR and GR. CONCLUSION: These data suggest that targeting AR in ER+PR- tumors may represent a promising therapeutic alternative in hormonal refractory tumors.

Cáncer de mama bilateral / Bilateral breast cancer

Introducción: El cáncer de mama bilateral se define como la presencia de un tumor primario e independiente en cada mama. A pesar de que los factores ambientales, genéticos y bioquímicos, afectan ambas mamas por igual y cada vez son más las mujeres tratadas por cáncer de mama, la incidencia del cáncer de mama bilateral continúa siendo baja. Objetivo: El objetivo del presente trabajo es describir las características de las pacientes con carcinoma de mama bilateral tratadas en el Servicio de Ginecología y Mastología del Hospital Municipal Prof. Dr. Bernardo Houssay de Vicente López, en los últimos 15 años.Material y métodos: Entre enero de 1996 y diciembre de 2011, en el Servicio de Patología Mamariadel Hospital Municipal Prof. Dr. Bernardo Houssay de Vicente López, fueron tratadas 931 pacientes con cáncer de mama. Se realizó un estudio retrospectivo basado en datos de 28 historias clínicas de pacientes con cáncer de mama bilateral. Se analiza incidencia, edad y forma de presentación, características clínicas ehistológicas, intervalo entre el primero y el segundo tumor y su relación con el control, compromiso axilar y tratamientos realizados. Resultados: La incidencia de cáncer de mama bilateral en nuestro servicio es del 3%. El 57,1% de carcinomas sincrónicos y 42,9% de metacrónicos. La edad promedio de aparición de los sincrónicos fue de 65,75 años y su forma de presentación más frecuente fue la de tumor palpable bilateral. En los metacrónicos, la edad promedio de aparición fue de 56,75 años y su forma de presentación más frecuente fue la de tumor palpable, tanto en el primer tumor como en el segundo tumor; con un período promedio de aparición entre el primero y el segundo de 105,75 meses. El tipo histológico más frecuente fue el carcinoma ductal infiltrante, tanto en los simultáneos como en los sucesivos.

Características de los tumores mamarios en la primera consulta en el Hospital Provincial de Pacheco / Characteristics of breast tumors in the first consultation in the Hospital Provincial de Pacheco

Introducción: El Hospital Magdalena V. de Martínez (Pacheco) Tigre, abarca un amplia área de influencia com o la Región de Islas, así como también es cercano a C.A.B.A. (Ciudad Autónoma de Buenos Aires). Cuenta con consultorios de Patología Mamaria, que dependen del Servicio de Ginecología, allí se analizaron pacientes que presentaron tumores mamarios a la primera consulta. Objetivos: Identificar y evaluar la detección de cáncer de mama en pacientes que concurren al hospital. Al momento de la primera consulta se evaluó: Estadio de la presentación inicial. Características clínicas e imaginológicas de los mismos. Factores demográficos posiblemente asociados: grupo etario, lugar de residencia y demora a la primera consulta. Tratamientos quirúrgicos realizados. Material y métodos: Se evaluaron 179 casos de cáncer de mama durante el período 2009/2011; clasificán dose por edad de las pacientes (menores de 40 años, entre 40 y 50 años, mayores de 50 años); lugar de residencia (dentro o fuera del Partido de Tigre); y tiempo transcurrido hasta la primera consulta (menos de 2 meses, de 2 a 6 meses, más de 6 meses. Se analizaron las formas de presentación desde el aspecto clínico (nódulo, tumor, mastalgia, secreción del pezón, etc.) e imaginológico (mamográfico y/o ecográfico). Desde lo clínico-patológico se clasificó según estadio-estirpe y localización. El tratamiento se dividió en mastectomía radical modificada (Madden) y cirugía conservadora con ganglio centinela y/o vaciamiento axilar. Resultados: La edad de presentación: 8% menos de 40 años; 20% entre 40 y 50 años; 72% mayor de 50 años.

Cáncer de mama localmente avanzado. Características y manejo en el Hospital Magdalena V. de Martínez, Pacheco, Partido de Tigre / Locally advanced breast cancer. Characteristcs and managment in the Hospital V. Magdalena Martínez, Pacheco, Tigre

Objetivos: Describir las características demográficas, epidemiológicas, clínico-patológicas y el perfil inmunohistoquímico de pacientes con cáncer de mama locamente avanzado (CMLA) asistidas en el hospital de Pacheco. Analizar los tratamientos implementados. Investigar la sobrevida general (SG) y la sobrevida libre de enfermedad (SLE) según diferentes características de las pacientes. Material y método: Análisis descriptivo, transversal y observacional de todas las pacientes con CMLA asistidas entre 2008 y 2011 inclusive. Se evaluó la incidencia, formas de presentación, las características anatomopatológicas y el perfil inmunohistoquímico. Se analizó el tratamiento quirúrgico implementado [mastectomía radical modificada (MRM) o cirugía conservadora (CC)] y su evolución. En cuanto al tratamientoneoadyuvante, las respuestas clínicas y patológicas se evaluaron mediante elcriterio de evaluación de respuesta a tumores sólidos (RECIST). Resultados: de 235 pacientes, 62 casos presentaron CMLA (26,38%). El tamaño tumoralde inicio promedio fue de 5,73 cm. Alrededor del 66% de las pacientes tenían cuatro o más ganglios afectados. En el 87% de los casos se realizó MRM y en el resto CC. Las recurrencias locales fueron 12,5% para CC y 0% con MRM. El 29,03% realizó quimioterapia neoadyuvante. El porcentaje de respuestas globales fue del 50% (44% parciales y 6% completas). El resto presentó enfermedad estable el 33% y enfermedad progresada 17%. El análisis de SG y SLE en la mayoría de las variables fue no significativo. Conclusiones: La incidencia de CMLA en nuestra serie evidencia no sólo la falta de programas de detección adecuados a nuestra población, sino también la falta de recursos fundamentales para ello; no obstante deberíamos, dentro de lo posible, diseñar un esquema de tratamiento acorde a nuestro medio que nos permita mejorar esta situación.

Presence of human papilloma virus in a series of breast carcinoma from Argentina.

BACKGROUND: The etiology and the molecular mechanisms related to breast carcinogenesis remain poorly understood. Some recent reports have examined the role of Human Papillomavirus (HPV) in this disease. The purpose of this study was to determine the prevalence of HPV in breast cancer. METHODS: Sixty one fresh frozen breast cancers samples were analyzed. Samples were tested for HPV by PCR, and products were automatically sequenced. Findings were correlated with clinical and pathological characteristics. RESULTS: The HPV DNA prevalence in the breast cancer samples was 26% (16/61). Clinical parameters were not statistically associated with HPV presence (p>0.05 χ(2) test). Sequence analysis in a subgroup of cases indicates the prevalence of low risk HPV11, followed by high risk HPV16. We found no HPV transcriptional activity. CONCLUSION: The present study demonstrated for the first time in Argentina the presence of HPV in a proportion of the malignant breast tissues. This finding suggests that HPV may have a biological significance in breast carcinogenesis.

Characterization of Epstein Barr virus latency pattern in Argentine breast carcinoma.

INTRODUCTION: Epstein-Barr virus (EBV)-associated tumors show different expression patterns of latency genes. Since in breast carcinoma this pattern is not yet fully described, our aim was to characterize EBV latency pattern in our EBV positive breast carcinoma series. METHODS: The study was conducted on 71 biopsies of breast carcinoma and in 48 non-neoplastic breast controls. EBNA1, LMP2A and LMP1 expression was assessed by immunohistochemistry with monoclonal antibodies, while viral genomic DNA and EBERs RNA transcripts expression was performed by in situ hybridization. EBV presence was confirmed by PCR. RESULTS: EBV genomic DNA and EBNA1 expression were detected in 31% (22/71) of patients specifically restricted to tumor epithelial cells in breast carcinoma while all breast control samples were negative for both viral DNA and EBNA1 protein. LMP2A was detected in 73% of EBNA1 positive cases, none of which expressed either LMP1 protein or EBERs transcripts. CONCLUSIONS: These findings suggest that EBV expression pattern in the studied biopsies could be different from those previously observed in breast carcinoma cell lines and lead us to suggest a new, EBNA1, LMP2A positive and LMP1 and EBERs negative latency profile in breast carcinoma in our population.