Neoadjuvant chemotherapy with trastuzumab in HER2-positive breast cancer: pathologic complete response rate, predictive and prognostic factors

The purpose of this study was to retrospectively review the pathologic complete response (pCR) rate from patients (n=86) with stage II and III HER2-positive breast cancer treated with neoadjuvant chemotherapy at our institution from 2008 to 2013 and to determine possible predictive and prognostic factors. Immunohistochemistry for hormone receptors and Ki-67 was carried out. Clinical and pathological features were analyzed as predictive factors of response to therapy. For survival analysis, we used Kaplan-Meier curves to estimate 5-year survival rates and the log-rank test to compare the curves. The addition of trastuzumab to neoadjuvant chemotherapy significantly improved pCR rate from 4.8 to 46.8%, regardless of the number of preoperative trastuzumab cycles (P=0.0012). Stage II patients achieved a higher response rate compared to stage III (P=0.03). The disease-free and overall survivals were not significantly different between the group of patients that received trastuzumab in the neoadjuvant setting (56.3 and 70% at 5 years, respectively) and the group that initiated it post-operatively (75.8 and 88.7% at 5 years, respectively). Axillary pCR post neoadjuvant chemotherapy with trastuzumab was associated with reduced risk of recurrence (HR=0.34; P=0.03) and death (HR=0.21; P=0.02). In conclusion, we confirmed that trastuzumab improves pCR rates and verified that this improvement occurs even with less than four cycles of the drug. Hormone receptors and Ki-67 expressions were not predictive of response in this subset of patients. Axillary pCR clearly denotes prognosis after neoadjuvant target therapy and should be considered to be a marker of resistance, providing an opportunity to investigate new strategies for HER2-positive treatment.

Eficacia y seguridad de fulvestrant en pacientes con cáncer de mama metastásico con receptores hormonales positivos, no tributarios a quimioterapia, que ha progresado a inhibidores de aromatasa no esteroideos / Efficacy and safety of fulvestrant in patients with metastatic breast cancer with hormone receptor positive, non-tributary to chemotherapy, who has progressed to non-steroidal aromatase inhibitors

INTRODUCCIÓN: Antecedentes: El presente informe expone la evaluación de eficacia y seguridad del uso de fulvestrant en el manejo de pacientes post-menopáusicas, con diagnóstico de cáncer de mama metastásico con receptores hormonales positivos, progresivo a inhibidores de aromatasa no esteroideos con control de enfermedad visceral y de partes blandas con quimioterapia basada en taxanos con toxicidad limitante (i.e., no tributarios a quimioterapia sistémica). Aspectos Generales: El cáncer de mama es el tipo de cáncer que se diagnostica con mayor frecuencia entre mujeres a nivel mundial. En el Perú, del total de cánceres reportados entre los años 2006 a 2011, el cáncer de mama fue el tercer tipo de cáncer más frecuente en toda la población (10.3%) y el segundo tipo de cáncer más frecuente entre mujeres (16.6%). Aproximadamente 34 de cada 100 mil mujeres al año es diagnosticada con cáncer de mama, con una tasa de mortalidad de 14 por cada 100 mil mujeres diagnosticadas. El cáncer de mama metastásico es la principal causa de muerte dentro de los pacientes con cáncer de mama. Más del 90% de pacientes con cáncer de mama muere por metástasis. Tecnologia Sanitaria de Interés: Fulvestrant (nombre comercial Faslodex), es una terapia antiestrogénica de tipo SERDs. Esta terapia está indicada para el tratamiento de cáncer de mama metastásico con receptores estrogénicos positivos en mujeres post-menopáusicas que han progresado luego de terapia antiestrogénica. Fulvestrant disminuye la actividad de los receptores de estrógeno, presenta actividad anti-proliferativa, induce apoptosis, no posee actividad agonista de estrógeno y carece de resistencia cruzada con otras terapias antiestrogénicas, tales como los SERMs. METODOLOGIA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad de fulvestrant para el tratamiento de cáncer de mama con receptores estrogénicos positivos metastásico, en pacientes no tributarios a quimioterapia, que han progresado a inhibidores de aromatasa no esteroideos. Esta búsqueda se realizó utilizando los meta-buscadores: Translating Research into Practice (TRIPDATABASE), National Library of Medicine (Pubmed-Medline) y Health Systems Evidence. RESULTADOS: Sinopsis de la Evidencia: Se realizó la búsqueda bibliográfica y de evidencia científica hasta Junio 2016 para el sustento del uso de fulvestrant en el tratamiento de cáncer de mama positivo a receptores hormonales metastásico, en pacientes no tributarios a quimioterapia que han progresado a inhibidores de aromatasa no esteroideos. Se presenta la evidencia\r\ndisponible según el tipo de publicación priorizada en los criterios de inclusión (i.e., GP, ETS, RS y ECA fase III). CONCLUSIONES: El presente documento evaluó la evidencia científica publicada hasta Julio del 2016 para el uso fulvestrant en mujeres post-menopáusicas con cáncer de mama metastásico con receptores hormonales positivos que han progresado a tratamientos previos con inhibidores de aromatasa no esteroideos. Existen pacientes con cáncer de mama metastásico con receptores hormonales positivos que progresan a terapia hormonal estándar con inhibidores de aromatasa no esteroideos, en quienes la quimioterapia no está indicada, dejando limitadas alternativas para su tratamiento. En la actualidad, el Petitorio Farmacológico de EsSalud cuenta con exemestano, un inhibidor de aromatasa esteroideo, por lo tanto es necesario probar que fulvestrant es una alternativa superior a exemestano en relación a los desenlaces considerados en el presente dictamen. Fulvestrant, es una alternativa de terapia hormonal se segunda línea. Sin embargo, esta no ha probado ser mejor que exemestano para ninguno de los desenlaces de interés, a pesar de ello, el costo de este medicamento es considerablemente elevado en relación al que actualmente se encuentra en el petitorio farmacológico de EsSalud. El Instituto de evaluación de Tecnologías en Salud e Investigación (IETSI) no aprueba el uso de fulvestrant para el tratamiento endocrino de cancer de mama con receptores hormonales positivos metastásico en mujeres post-menopaúsicas no tributarias a quimioterapia que han progresado a terapia con inhibidores de aromatasa no esteroideos.

Adjuvant treatment delay in breast cancer patients / Atraso no tratamento adjuvante em pacientes com câncer de mama

Summary Background: to evaluate if time between surgery and the first adjuvant treatment (chemotherapy, radiotherapy or hormone therapy) in patients with breast cancer is a risk factor for lower overall survival (OS). Method: data from a five-year retrospective cohort study of all women diagnosed with invasive breast cancer at an academic oncology service were collected and analyzed. Results: three hundred forty-eight consecutive women were included. Time between surgery and the first adjuvant treatment was a risk factor for shorter overall survival (HR=1.3, 95CI 1.06-1.71, p=0.015), along with negative estrogen receptor, the presence of lymphovascular invasion and greater tumor size. A delay longer than 4 months between surgery and the first adjuvant treatment was also associated with shorter overall survival (cumulative survival of 80.9% for delays ≤ 4 months vs. 72.6% for delays > 4 months; p=0.041, log rank test). Conclusion: each month of delay between surgery and the first adjuvant treatment in women with invasive breast cancer increases the risk of death in 1.3-fold, and this effect is independent of all other well-established risk factors. Based on these results, we recommend further public strategies to decrease this interval.

Resumo Objetivo: avaliar se o tempo da cirurgia até o primeiro tratamento adjuvante (quimioterapia, radioterapia ou hormonioterapia) em pacientes com câncer de mama é um fator de risco para pior sobrevivência global (SG). Métodos: estudo retrospectivo em que foram coletados dados dos prontuários de todas as mulheres com câncer de mama invasivo, diagnosticadas entre janeiro de 2005 e dezembro de 2010, atendidas consecutivamente em um serviço acadêmico de oncologia. Resultados: foram incluídas 348 mulheres, com mediana de tempo entre a cirurgia e o primeiro tratamento adjuvante de 2 meses. A sobrevivência global foi pior entre as mulheres com maior tempo entre a cirurgia e o primeiro tratamento adjuvante. Após análise multivariada, essa variável permaneceu como fator de risco independente para SG, juntamente com receptor de estrógeno negativo, presença de invasão angiolinfática e maior tamanho tumoral. Conclusão: o tempo entre a cirurgia e o primeiro tratamento adjuvante é um fator de risco independente para a sobrevivência global de mulheres com câncer de mama invasivo.

Expression of cancer-testis associated antigen MAGE-1 in relation to CD8+ T lymphocytes in breast infiltrating duct carcinoma [NOS]

Breast cancers are known to frequently [over] express several well-characterized tumor-associated antigens [TAAs] such as members of the MAGE-family. In the present study we are aiming to evaluate MAGE-1 expression in breast infiltrating duct carcinoma [NOS] in relation to some other known prognostic factors. We will compare this with MAGE-1 expression in some of the benign breast tumors and tumor-like lesions. We are also aiming to study the relation between MAGE-1 expression and lymphocytic response specifically CD8+ T lymphocytes as a hope for further breast cancer immunotherapy. After obtaining informed consent, tissues were obtained from patients undergoing breast lumpectomy or mastectomy. 132 patients of breast infiltrating duct carcinoma [IDC] [NOS] and 65 benign breast lesions were enrolled in this study. The cases were evaluated clinically by the surgeon and physician and any other information was added from the accompanying clinical data. All cases were studied by the histopathologist and immunostain was done for MAGE-1 and CDS. The malignant cases were additionally stained by estrogjenj-eceptors, progesterone receptors and Her-2 as a prognostic markers. The results were statistically studied and tabulated. In the present study we classified the patients into two groups. Group I: Include patients with breast carcinomas of IDC [NOS] type and group II: Include patients with benign breast lesions. The total number of cases was 197, 35 were males while 162 were females. Age ranged between 18-88.132 of the cases were with IDC [NOS] and 65 were with benign breast lesions. There was a significant difference in V1AGE-1 expression between the both groups, it was more expressed in group I and there was a highly significant relation between MAGE-1 expression in IDC [NOS] and the score of CD8+lymphocytes. On the other hand the relation between MAGE-1 and CD8+ lymphocytes was not significant in group II. In fibrocytic disease [FCD], MAGE was +2 in most of FCD cases and CD8+ lymphocytes scored +4 in four cases, but still the relation between the both variables non significant. We have demonstrated in the present study that MAGE-1 is expressed in some of benign breast lesions and at a high proportion in high-grade, hormone receptor-negative breast cancer, suggesting that MAGE-1 could be an indicator of aggressive diseases and can be a promising tumor antigen for immunotherapy of breast cancer with poor prognosis. On the other hand we suggest further studies to evaluate the rule of MAGE-1 vaccine in benign breast lesions as a preventive therapy

Estrogen receptors in adult Egyptians with gynecomastia with or without schistosomiasis

Idiopathic gynecomastia occurs with persistence of low T/E1 and T/E2 ratios after puberty. Men with liver disease have gynecomastia, as a consequence of impaired hepatic steroid metabolism. In Egyptian patients with schistosomal hepatic fibrosis, gynecomastia is not an uncommon condition. To study the estrogen receptors in breast tissue in gynecomastia associated with schistosomal hepatic fibro sis compared to idiopathic gynecomastia. The study included 10 males with gynecomastia associated with schistosomal hepatic fibrosis [group A] and 8 patients with idiopathic gynecomastia free of liver disease. Mammary tissue, obtained via surgical excision was submitted to histopathological examination. The mean values of the plasma testosterone in the groups A and B, were 8 +/- 2.6 ng/ml and 5.7 +/- 2 ng/ml respectively. The difference was statistically insignificant [p = 0.058]. The mean values of serum estradiol were 45 +/- 24 pg/ml for group A and 24 +/- 9 pg/ml for group B. In group A there was characteristic lymphocytic and histocytic infiltration, with less fibrous reaction in the stromal tissue than it was in group B. ER status showed positivity in 67% of cases including 5/10 [50%] in group A and 7/8 [88%] in group B. It appeared in the form of reddish nuclear staining in 10 patients and cytoplasmic in two patients who were both in group B. The ER positivity was found to be significantly lower in patients of group A than it is in those of group B

Hormonal receptors in mammary carcinoma: comparison between quantitative and qualitative methods

Alternatives to the traditional hormone receptor dosages for prognostic evaluation and clinical approach to breast cancer have been proposed for immunohistochemical determinations. For correlation purposes, such procedures were compared in 37 patients presenting 5 to 15 years of survival. Considering 30 fm/mg as the positivity index, the disagreement between both methods reached 35.1 percent with estrogen and 48.5 percent with progesterone receptors. When the positiveness level was changed to 20 fm/mg, the discrepancies were reduced to 32 percent with ER and increased to 57 percent with PgR. This study leads us to not recommend the immunohistochemical method applied to paraffin sections as an alternative procedure to the dextran-charcoal dosage for prognosis and therapeutic management of mammary carcinoma.

Immunohistochemical study of estrogen and progesterone receptors in normal, hyperplastic and malignant endometrium

A series of 44 cases of various human endometrial tissues were immunohistochemically stained for estrogen receptor [ER] and progesterone receptor [PR] using formalin -fixed, paraffin - embedded sections. ER/PR content was evaluated in the epithelium, stroma and myometrium according to the percentage of positive cells and the intensity of nuclear stain. The receptor content was highest in the proliferative epithelium and decreased gradually throughout the postovulatory phase of the menstrual cycle in both the epithelium and the stroma. ER / PR content was high both in the epithelium and stroma of hyperplasia without atypia and was thus similar to that of the proliferative endometrium. The receptor content was very low in the epithelium and stroma of hyperplasia with cytologic atypia. In carcinomas, there was a heterogeneous distribution of ER and PR both in the epithelium and stroma, but in general, the receptor content was low as compared with normal proliferative or hyperplastic endometrium without atypia. Endometrioidtype adenocarcinomas including those with squamous differentiation had the highest degree of positivity for both receptors. Tumors with architectural grade 3 were significantly immunostained less than those with 2 or 1 grades. Carcinomas with nuclear grade 3 were unstaind. The low grade endometrial stromal sarcoma was positive for both receptors, while the high - grade one was negative. The degrees of ER and PR positivity correlated with each other. There was no correlation between the patient's age and ER / PR categories. The results of this study indicate that immunohistochemical analysis of sex steroid receptor status on formalin -fixed, paraffin - embedded tissues offers good alternative to the standard biochemical procedure

Prognostic value of activated complement 3 and oestrogen receptors in cases of cancer breast

Despite the classic prognostic factors for evaluation of cancer breast cases were used for longterm, but still insufficient and less reliable for this evaluation. Use of oestrogen receptor [ER] and complement 3 [C[3]] gave a good prognostic indicator for different cases of cancer breast