Treatment of palbociclib in hormone receptor positive breast cancer: a real-world study and efficacy prediction model / 中华肿瘤杂志

Objective: To summarize the clinical use of palbociclib and evaluate its efficacy and safety in hormone-receptor (HR)-positive advanced breast cancer patients. Methods: We retrospectively analyzed data from 66 HR-positive metastatic breast cancer patients treated with palbociclib and endocrine therapy at the Department of Oncology in the First Affiliated Hospital with Nanjing Medical University between 2018 and 2020. We evaluated the factors affecting the efficacy of palbociclib using Kaplan-Meier method and Log-rank test for survival analysis and Cox regressions for multivariate analysis. Nomogram model was built for predicting prognosis among HR-positive breast cancer patients who received palbociclib. Concordance index (C-index) and calibration curve were used for internal validation to assess the predictive ability and conformity of the model. Results: Of the 66 patients treated with palbociclib, 33.3%(22), 42.4%(28) and 24.2%(16) patients were treated without endocrine therapy, first-line endocrine therapy, second-line or above endocrine therapy after recurrence, respectively. 36.4%(24) patients had hepatic metastasis, 16.7% (11) patients were sensitive to previous endocrine therapy, 27.3%(18/66) patients had primary resistance to endocrine therapy, while 56.1% (37) patients had secondary resistance to endocrine therapy. The overall response rate was 14.3% (95% CI: 6.7%, 25.4%) and clinical benefit rate was 58.7% (95% CI: 45.6%, 71.0%). Better clinical outcomes were associated with non-hepatic metastasis (P=0.001), sensitive/secondary resistant to previous endocrine therapy (P=0.004), no or only one line of chemotherapy for metastatic breast cancer (P=0.004), recent pathological confirmation of immunohistochemical analysis (P=0.025). Hepatic metastasis (P=0.005) and primary resistance to endocrine therapy (P=0.016) were the independent risk factors of progression free survival. The C-index of predictive probability for the nomogram constructed from the patient clinical characteristics (whether liver metastasis, whether primary endocrine resistance, lines of chemotherapy after metastasis, lines of endocrine therapy, number of metastatic sites, and time to last immunohistochemistry) to predict the progression-free survival at 6 and 12 months for patients was 69.7% and 72.1%, respectively. The most common adverse events were hematologic toxicities. Conclusions: Our report indicates that palbociclib combined with endocrine therapy for HR-positive recurrent metastatic breast cancer is effective and safe; patients with hepatic metastases and primary resistance to endocrine therapy have worse prognoses and are independent risk factors for progression after palbociclib therapy. The constructed nomogram could help predict the survival and guide the use of palbociclib.

Impact of HER2 receptor status on axillary nodal burden in patients with non-luminal A invasive ductal breast carcinoma / Receptores HER2, compromiso ganglionar axilar y sobrevida en mujeres con cáncer de mama ductal invasivo

ABSTRACT Background: Breast cancer (BC) is the most common malignancy in women. Aim: To assess the impact of HER2 status on axillary lymph node (ALN) involvement in patients with invasive ductal carcinoma of no special type (IDC-NST) both at diagnosis and during the 4-year postoperative period. Patients and Methods: We retrospectively included 375 women with an early clinical stage of non-luminal IDC-NST who between 2007 and 2013 underwent breast surgery at a clinical hospital. They were divided into phenotype-based groups: HR+HER2-, HR+HER2+, HR-HER2+ and HR-HER2-. Only patients with sentinel lymph node (SLN) macrometastases underwent ALN dissection. If > 3 ALNs were positive, radiotherapy was delivered. All patients were treated with chemotherapy, HER2+ BC patients received trastuzumab, and hormone receptor (HR)-positive BC patients received hormonal therapy. Results: Larger tumor size, higher grade, HR+, HER2+ status, and lymphovascular invasion (LVI) were predictive for ALN metastases at diagnosis. The poorest overall, disease-free, and distant recurrence-free survival (OS, DFS, DRFS) were found in the HR-HER2- group, while the poorest locoregional recurrence-free survival (LRFS) was observed in HR-HER2+ and HR-HER2- groups. HER2 status was not predictor of survival. Conclusions: HER2+ status was predictive for ALN involvement at diagnosis but had no effect on 4-year LRFS in these patients.

Antecedentes: El cáncer de mama es el tumor maligno más común en mujeres. Objetivo: Conocer el impacto del estado HER2 sobre el compromiso ganglionar axilar al momento del diagnóstico y durante los primeros cuatro años después de la cirugía en mujeres con carcinoma ductal invasivo de tipo no especial (IDC-NST). Pacientes y Métodos: Incluimos retrospectivamente a 375 mujeres en etapas clínicas iniciales de IDC-NST que fueron operadas en un hospital clínico. Ellas se dividieron en grupos de acuerdo al fenotipo: HR+HER2-, HR+HER2+, HR-HER2+y HR-HER2-. La disección de ganglios axilares se efectuó solo en las pacientes con macrometástasis en el ganglio centinela. Si había más de tres ganglios comprometidos, se efectuó radioterapia. Todas las pacientes se trataron con quimioterapia. Las pacientes HER2+ recibieron trastuzumab y las pacientes HR+ recibieron hormonoterapia. Resultados: Tumores más grandes, de mayor grado de malignidad, HR+, HER2+ y la invasión linfovascular fueron predictivos de la presencia de metástasis axilares al momento del diagnóstico. La sobrevida más baja se observó en pacientes HR-HER2+. La sobrevida libre de recurrencia locorregional más baja, se observó en pacientes HR-HER2+ y HR-HER2-. HER2 no fue predictor de sobrevida. Conclusiones: En estas mujeres, HER2+fue predictor de la presencia de compromiso ganglionar axilar al momento del diagnóstico pero no de la sobrevida a cuatro años.

Supervivencia en cáncer de mama por subtipo mediante inmunohistoquímica: Un estudio retrospectivo / Survival in breast cancer by subtype by immunohistochemistry: A retrospective study

Resumen Antecedentes: La clasificación del cáncer de mama en subtipos mediante la expresión de receptores hormonales (RH) y del receptor 2 del factor de crecimiento epidérmico humano (HER2) por inmunohistoquímica (IHQ) es una práctica estándar para la toma de decisiones terapéuticas. Objetivo: Conocer las características y supervivencia de cada subtipo de pacientes, que es indispensable para poder diseñar futuros estudios. Método: Realizamos un estudio retrospectivo evaluando las características clinicopatológicas y la supervivencia por subtipo mediante IHQ en mujeres con cáncer de mama. Resultados: 211 mujeres con cáncer de mama RH(+)/HER2(-), 53 con RH(+)/HER2(+), 16 con HER2(+) y 23 con RH(-)/HER2(-), con una mediana de supervivencia global en meses de 39 (20.5-62.7), 42 (25.5-65), 42 (13.7-67.7) y 26 (11-78), respectivamente, para un cociente de riesgo (HR por sus siglas en inglés, Hazard Ratio): 3.7 (IC 95%: 1.3-10.3) en el grupo triple negativo comparado con RH(+)/HER2(-) (p = 0.01). Conclusión: Los subtipos con RH positivos por IHQ son los más frecuentes y este grupo de pacientes tienen una mejor supervivencia global comparada con las pacientes triple negativo.

Abstract Background: Breast cancer subtype classification according to hormone receptors (HR) and human epidermal growth factor receptor 2 (HER2) using immunohistochemistry is the standard practice for therapeutic decision making. Objective: To design future studies information on characteristics and survival of each subtype is essential. Method: We conducted a retrospective study to analyze clinical and pathologic features as well as survival data according to breast cancer immunohistochemistry subtype. Results: There were 211 women with a RH(+)/HER2(-) breast cancer subtype, 53 HR(+)/HER2(+), 16 HER2(+) and 23 HR(-)/HER2(-), with a median overall survival in months of 39 (20.5-62.7), 42 (25.5-65), 42 (13.7-67.7) and 26 (11-78), respectively, for a 3.7 hazard ratio of death (95% Confidence Interval [CI]: 1.3-10.3) for the triple negative group as compared to the HR(+)/HER2(-) group (p = 0.01). Conclusions: HR positive subtypes by immunohistochemistry where most frequent and showed a greater overall survival compared to the triple negative subtype.

Características clínicas y pronóstico de pacientes con cáncer de mama HER2 positivo avanzado, en la era antes y después de terapias anti-HER2 / Survival of patients with advanced HER2+ breast cancer. Analysis of a cancer center database

Background: HER2+ breast cancer (BC) subtype overexpresses the Human Epidermal growth factor Receptor type-2 (HER2) and is characterized by its aggressiveness and its high sensitivity to monoclonal antibody-based HER2-targeted therapies. Aim: To assess the prognosis and evaluate the impact of novel anti-HER2 therapies on advanced HER2+ BC patients treated at our institution over the last decades. Material and Methods: Analysis of the patient database at a cancer center of a university hospital. Information about the subtype of cancer was obtained in 2,149 of 2,724 patients in the database. Eighteen percent of the latter were HER2+. We analyzed data of 83 of these patients with advanced disease. Results: Median overall survival (OS) was 24 months. For patients treated between 1997-2006 median OS was 17 months and for those treated in the period 2007-2017 median OS was 32 months (p = 0.09). Conclusions: A non-significant trend towards better survival in the last decade was observed. HER2+ BC overall survival has improved in our center. This can be probably attributed to the use of novel more effective anti-HER2 therapies.

Assessment of HER-2 status in invasive breast cancer in Brazil / Avaliação de HER-2 no câncer de mama invasivo no Brasil

Summary Objective: To characterize the frequency of HER-2-positive breast cancer in Brazil. Method: In this prospective observational study, we first ascertained the HER-2 status of invasive breast cancer specimens by automated immunohistochemistry (IHC). For specimens classified as 2+ by IHC, we performed in situ hybridization (ISH). Results: From February, 2011 to December, 2012, 1,495 breast specimens were registered, and 1,310 samples collected at 24 centers were analyzed. Median patient age was 54 years, and the majority of samples were obtained from segmental (46.9%) or radical mastectomy (34.4%). The predominant histological type was invasive breast carcinoma of no special type (85%), 64.3% had tubule formation (grade 3), and estrogen/progesterone receptors (ER/PR) were positive in 77.4/67.8% of the specimens analyzed, respectively. Using IHC, we found a negative HER-2 status (0 or 1+) in 72.2% of specimens, and 3+ in 18.5%; the 9.3% scored as 2+ were further analyzed by ISH, of which 15.7% were positive (thus, 20.0% of samples were HER-2- -positive by either method). We found no association between HER-2 scores and menopausal status or histological type. Tumors classified as 3+ came from younger patients, and had higher histological grade and less frequent expression of ER/PR. In the North region of Brazil, 34.7% of samples were 3+, with lower frequencies in the other four regions of the country. Conclusion: Our findings provide estimates for the frequency of HER-2 positivity in Brazil and raise the hypothesis that biological differences may underlie the different distribution of breast-cancer phenotypes among different Brazilian regions.

Resumo Objetivo: Estimar a frequência de câncer de mama positivo para HER-2 no Brasil. Método: Neste estudo observacional e prospectivo, verificamos o escore de HER-2 de espécimes de câncer de mama invasivo por imuno-histoquímica automatizada (IHQ). Para amostras classificadas como 2+ por IHQ, fizemos hibridização in situ (HIS). Resultados: De fevereiro de 2011 a dezembro de 2012, 1.495 espécimes de mama foram registrados, e 1.310 amostras coletadas por 24 centros foram analisadas. A idade mediana das pacientes foi 54 anos, e a maioria das amostras foram obtidas a partir de mastectomia segmentar (46,9%) ou radical (34,4%). O tipo histológico predominante foi o carcinoma invasivo da mama, sem tipo especial (85%); 64,3% tinham formação de túbulos (grau 3); e os receptores de estrógeno (RE)/progesterona (RP) foram positivos em 77,4%/67,8% das amostras analisadas. Por IHQ, encontramos HER-2 negativo (0 ou 1+) em 72,2% das amostras, e 3+ em 18,5%; os 9,3% de casos classificados como 2+ foram analisados por HIS, e 15,7% deles foram positivos (assim, 20,0% das amostras foram positivas para HER-2 por qualquer método). Não encontramos associação entre escores de HER-2 e estado menopausal ou tipo histológico. Tumores classificados como 3+ vieram de pacientes mais jovens, tinham maior grau histológico e foi menos frequente a expressão de RE/RP. Na região Norte do Brasil, 34,7% das amostras foram 3+, com frequências mais baixas nas outras quatro regiões do país. Conclusão: Nossos resultados permitem estimar a frequência de positividade do HER-2 no Brasil, gerando a hipótese de que pode haver diferenças biológicas subjacentes à distribuição dos fenótipos de câncer de mama entre as diferentes regiões brasileiras.

Increased Expression of Forkhead Box M1 Is Associated with Aggressive Phenotype and Poor Prognosis in Estrogen Receptor-Positive Breast Cancer

Fox transcription factors play a critical role in the regulation of a variety of biological processes. While FoxM1 behaves like the oncogenic transcription factor, FoxO3a is known as a tumor suppressor by inhibiting FoxM1. This study aimed to investigate the clinicopathological significance of FoxM1 and FoxO3a expression in breast cancer. Expression of FoxM1 and FoxO3a were analyzed by immunohistochemical staining on tissue microarray sections from 236 breast cancer patients, and correlated with various clinicopathological characteristics. Overexpression of FoxM1 correlated with adverse clinicopathological features, such as larger tumor size, lymph node metastasis, advanced tumor stage, and lymphovascular invasion. The Kaplan-Meier survival curves revealed no prognostic significance of FoxM1 expression. However, in subgroup analyses with patients of estrogen receptor (ER) positive breast cancers, FoxM1 overexpression associated with poor disease free and overall survival. No association was found between FoxO3a and FoxM1 expression. Regarding clinicopathological variables, the only association between histologic grade and FoxO3a was observed. In conclusion, FoxM1 overexpression was significantly associated with aggressive phenotypes and poor prognosis of ER-positive breast cancer. These findings suggest the possible role of FoxM1 as a prognostic biomarker and putative target of anti-cancer therapy.

The Expression of Multiple Proteins as Prognostic Factors in Colorectal Cancer: Cathepsin D, p53, COX-2, Epidermal Growth Factor Receptor, C-erbB-2, and Ki-67

BACKGROUND/AIMS: A single gene mutation alone cannot explain the poor prognosis of colorectal cancer. This study aimed to establish a correlation between the expression of six proteins and the prognosis of colorectal cancer patients. METHODS: Tissue samples were collected from 266 patients who underwent surgery for colorectal cancer at our institution from January 2006 to December 2007. The expression of six proteins were determined using immunohistochemical staining of specimens. RESULTS: Cathepsin D, p53, COX-2, epidermal growth factor receptor, c-erbB-2, and Ki-67 expression were detected in 38.7%, 60.9%, 37.6%, 35.7%, 30.1%, and 74.4% of the samples, respectively. The expression of cathepsin D was significantly correlated with reduced cancer-free survival (p=0.036) and colorectal cancer-specific survival (p=0.003), but the other expression levels were not. In a multivariate analysis, cathepsin D expression was found to be an independent prognostic factor for poorer colorectal cancer-specific survival (hazard ratio, 8.55; 95% confidence interval, 1.07 to 68.49). Furthermore, patients with tumors expressing four or more of the proteins had a significantly decreased cancer-free survival rate (p=0.006) and colorectal cancer-specific survival rate (p=0.002). CONCLUSIONS: Patients with cathepsin D positivity had a poorer outcome than patients who were cathepsin D-negative. Thus, cathepsin D may provide an indicator for appropriate intensive follow-up and adjuvant chemotherapy.

Expression of procaspase 3 and activated caspase 3 and its relevance in hormone-responsive gallbladder carcinoma chemotherapy

BACKGROUND/AIMS: The higher incidence of gallbladder cancer (GBC) in females has been accredited to the involvement of hormones. The clinical implications of sex hormone receptors in GBC are well established. Cysteine proteases (such as caspase-3-9, etc.) are known to play a central role in the apoptotic pathway. Of these, the downstream enzyme caspase-3 is often activated in the apoptotic pathway. The aim of this work was to examine the status of apoptosis (which directly correlated with the level of active caspase-3) in hormone-responsive GBC. METHODS: We used 10 androgen receptor (AR)-positive, 14 estrogen receptor (ER)-positive, 12 HER/neu-positive, eight triple positive, and 10 triple negative malignant GBC human tissue samples. We isolated the total cellular protein from tumor tissues and carried out Western blotting using antipro-caspase-3 and anti-activated caspase-3 antibodies. RESULTS: ER and HER/neu-positive GBC exhibited high caspase-3 activity and low procaspase-3 activity, whereas AR-positive GBC showed no significant level of apoptosis. We also evaluated the apoptosis status of triple positive GBC and triple negative GBC, and found significant apoptosis in triple positive GBC. CONCLUSIONS: The results indicate that ER and HER/neu-positive GBCs had active apoptosis, whereas AR-positive GBC was highly resistant to apoptosis.

Evaluation of HER-2/neu status in breast cancer specimens using immunohistochemistry (IHC) & fluorescence in-situ hybridization (FISH) assay.

Background & objectives: Fluorescence in situ hybridization (FISH) is increasingly being recognized as the most accurate and predictive test for HER2/neu gene amplification and response to therapy in breast cancer. In the present study we investigated HER-2/neu gene amplification by FISH in breast carcinoma tissue specimens and compared the results with that of immunohistochemical (IHC) analysis. Methods: A total of 90 breast carcinoma tissue samples were used for immunohistochemical (IHC) and FISH analysis. IHC was performed by using mouse monoclonal antibody to the intracellular domain of HER-2/neu protein. Each slide was scored in a blinded fashion by two pathologists according to the manufacturer's recommended criteria. FISH analysis was performed on paraffin embedded breast tumour tissue sections. The polysomy for centromere 17 (Spec green signal) was read as green signals less than 4 as moderate polysomy, and more than 4 as highly polysomy. Results: Thirty of the 90 patients had negative results by IHC and FISH. Of the 28 patients with the score of 2+ by IHC, 20 were FISH positive for HER-2/neu gene amplification, three were FISH negative and five patients showed equivocal (1.8-2.2) results by FISH. These five cases were retested for IHC and FISH on different paraffin embedded tissue blocks, and all five were found positive for HER-2/neu gene amplification. Twenty five patients with the score of 3+ by IHC were FISH positive for HER-2/neu gene amplification (>2.2). Seven cases with the score of 3+ by IHC were FISH negative for HER-2/neu gene amplification (>2.2), and showed polysomy of chromosome number 17 high polysomy > 4. Interpretation & conclusions: Our results indicated that HER-2/neu status by FISH should be performed in all cases of breast tumour with a 2+ score by IHC. Cases demonstrating a 3+ score by IHC may be subjected to FISH to rule out polysomy of chromosome 17 which could be falsely interpreted as HER-2/neu overexpression by IHC analysis. There is also a need for establishing a clinically validated cut-off value for HER-2/neu FISH amplification against IHC which may be further compared and calibrated.

Molecular phenotypes of ductal carcinoma-in-situ and invasive ductal carcinoma: A comparative study.

Aims and Objectives: This study was aimed at analyzing the prevalence of molecular phenotypes in invasive ductal carcinoma (IDC) and coexisting ductal carcinoma-in-situ (DCIS) and to correlate with clinicopathological features. Materials and Methods: In this study, 75 cases of IDC with coexisting DCIS were included. Molecular phenotype was determined using expression of estrogen receptor, progesterone receptor, HER2/neu, and cytokeratin 5/6. Statistical analysis was performed for correlation between molecular phenotypes and clinicopathologic parameters. Results: Of the 75 cases, the invasive component in all cases was IDC-not otherwise specified. About one-third of our patients were post-menopausal. The most common molecular phenotype was luminal A (45.3%) followed by HER2-expressing type (24%). In all cases, the molecular phenotype was identical in DCIS and the invasive component. HER2-expressing tumors were found to be larger in size with frequent nodal involvement. On statistical analysis, tumor size and grade were found to correlate with the molecular phenotype. Conclusion: In conclusion, the molecular phenotype in DCIS correlates well with that of coexisting IDC, suggesting that DCIS is a precursor lesion in these tumors. This correlation of molecular phenotype can be utilized in prediction of phenotype of the invasive component in a case with in-situ carcinoma.

Core biopsies of the breast: Diagnostic pitfalls.

The incidence of breast cancer is increasing worldwide. In this review article, the authors compare and contrast the incidence of breast cancer, and the inherent differences in the United States (US) and India in screening techniques used for diagnosing breast cancer. In spite of these differences, core biopsies of the breast are common for diagnosis of breast cancer in both countries. The authors describe "Best Practices" in the reporting and processing of core biopsies and in the analysis of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor Receptor 2 (Her2/neu). The pitfalls in the diagnosis of fibroepithelial lesions of the breast on core biopsy are discussed, as also the significance of pseudoangiomatous stromal hyperplasia of the breast (PASH) is discussed in core biopsy. In this review, the management and diagnosis of flat epithelial atypia and radiation atypia are elaborated and the use of immunohistochemistry (IHC) in papillary lesions, phyllodes tumor, and complex sclerosing lesions (radial scars) is illustrated. Rarer lesions such as mucinous and histiocytoid carcinoma are also discussed.

Assessment of HER-2/neu status in breast cancer using fluorescence in situ hybridization & immunohistochemistry: Experience of a tertiary cancer referral centre in India.

Background & objective: Determination of HER2 status in breast cancer has become important to identify potential candidates for anti-HER2 therapy. In this study we compared fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for the determination of HER2 status in breast cancer patients referred to a tertiary care referral centre. Methods: A total of 200 cases of invasive breast cancer were evaluated for HER2 status using IHC and FISH and results were compared. Results: The IHC 3+ (93.9%) and IHC negative (85.9%) cases showed good concordance with the corresponding FISH results; while 66.6 per cent of IHC 2+ cases showed gene amplification by FISH. In addition, hormone receptor expression and HER2 gene status showed a statistically significant inverse association (P<0.05). Interpretation & conclusion: These findings reaffirm IHC as a prudent first-step to screen tissue samples for HER2 status and to determine suitability for technically demanding FISH test and the dual coloured FISH as a gold standard for determination of HER2/neu status in IHC equivocal cases of breast carcinoma.

Expresión tumoral de HER-2, receptores de estrógenos y de progesterona y su relación con características clínico-patológicas en pacientes uruguayas con cáncer de mama / Tumor expression of HER-2, estrogen and progesterone receptors and their relationship with clinical-pathological characteristics in Uruguayan patients with breast cancer

Introducción: el cáncer de mama (CM), principal causa de muerte por cáncer en la mujer uruguaya, constituye una enfermedad heterogénea. El estudio de la expresión tumoral del receptor del factor de crecimiento epidérmico-2 (HER2), el receptor de estrógenos (RE) y el receptor de progesterona (RP) permite reconocer subtipos con diferentes características clínico-patológicas y evolutivas. Objetivos: conocer el perfil de expresión tumoral de HER2, RE y RP y su relación con características clínico-patológicas en pacientes uruguayas con CM. Material y método: se revisaron las historias clínicas de pacientes intervenidas quirúrgicamente por CM invasivo en un período de dos años, seleccionándose las que contaban con la determinación de RE, RP y HER2 mediante inmunohistoquímica. Se comparó el perfil de expresión de estos marcadores con la edad al diagnóstico, tipo y grado histológico (GH) y estadio patológico (TNM). Resultados: se seleccionaron 197 pacientes cuyas características fueron edad media: 55 años, carcinoma ductal: 85%, GH 1-2: 59%, estadio: I-II: 75%, metástasis axilares: 51%, RE/RP+: 78%, HER2+: 10%. Se definieron tres subtipos: HER2- RE/RP+ (73%), HER2+ (10%) y triple negativo (TN) (17%). Los subtipos TN y HER2+ se asociaron con mayor grado histológico (p<0,05) y el TN con menor edad al diagnóstico (p<0,05) que el subtipo HER2-, RE/RP+. Conclusiones: el porcentaje de pacientes con CM invasivo subtipo HER2+ (10%) es menor que el reportado por otros estudios (17%-28%). En concordancia con estudios previos, los subtipos TN y HER2+ se correlacionaron con tumores más indiferenciados y el TN se presentó en pacientes más jóvenes

Summary Introduction: breast cancer, the main cause of death of Uruguayan women, is an heterogeneous disease. Study of the tumoral expression of the Human Epidermal growth factor Receptor-2 (HER2), the estrogen receptor and the progesterone receptor enables the recognition of sub-types with different clinical, and pathological characteristics and evolution. Objectives: to learn about the HER2, estrogen receptor and progesterone receptor tumoral expression profile and their relationship with clinical-pathological characteristics in Uruguayan patients with breast cancer. Method: we reviewed the medical record of patients who underwent surgery for invasive breast cancer within a two year period, and we selected those who had determination of estrogen receptor, progesterone receptor and HER2 through immune-histochemestry. We compared the expression profile of these markers with the age at the time of diagnosis, the histological type and degree and the pathological status. Results: we selected 197 patients with the following characteristics: average age: 55 years old, ductal carcinoma: 85%, histological degree 1-2: 59%; stage I-II: 75%, axillary metastasis: 51%, progesterone receptor/estrogen receptors+ (RE/RP+): 78%, HER2+: 10%. Three subtypes were defined: HER2- RE/RP+ (73%), HER2+ (10%) and triple negative (TN) (17%). Subtypes TN and HER2+ were associated with a greater histological degree (GH) (p<0,05) and the TN with lower age at the time of diagnosis than the HER2-, RE/RP+ subtype. Conclusions: the percentage of patients with HER2+ subtype invasive breast cancer (10%) is lower than the one reported in others studies. In accordance with previous studies, TN and HER2+ subtypes correlated with less differentiated tumors and TN subtype occurred in younger patients

Résumé Introduction: le cancer de sein (CS), principal responsable de mort par cancer des uruguayennes, est une maladie hétérogène. L’étude de l’expression tumorale du récepteur du facteur de croissance épidermique 2 (HER-2), le récepteur d’oestrogène (RE) et le récepteur de progestérone (RP) permet de reconnaître des sous-types à caractéristiques cliniques pathologiques et évolutives variées. Objectif: connaître le profil de expression tumorale de HER-2, RE et RP et leur lien avec des données cliniques pathologiques chez des patientes uruguayennes atteintes de cancer de sein. Matériel et méthode: on fait la révision clinique des patientes atteintes de CS ayant subi une intervention chirurgicale pour une période de deux ans, choisissant celles portant la détermination de HER-2, RP et RE par immunohistochimie. On compare le profil de manifestation de ces marqueurs à l’âge au diagnostic, type et degré histologique (GH) et stade pathologique (TNM). Résultats: 197 patientes furent sélectionnées dont voici les caractéristiques: 55 ans (moyenne), 85% carcinome ductal, 59% GH 1-2; 75% stade I- II; 51% métastase axillaire; 78% RE-RP +; 10% HER2+; trois sous-types furent définis: HER2- RE/RP+ (73%), HER2+ (10%) et triple négatif (TN) (17%). Les sous-types TN et HER2+ furent associés à un degré histologique plus grand (p<0,05) et le TN à un âge plus bas au diagnostic (p<0,05) que le sous-type HER2-, RE/RP+. Conclusions: le pourcentage de patientes avec CM invasif sous-type HER2+ (10%) est inférieur à celui reporté par d’autres études (17%-28%). En concordance avec des études préalables, les sous-types TN y HER2+ ont été mis en relation avec des tumeurs plus indifférenciées et le TN a été présent chez des patientes plus jeunes.

Resumo Introdução: o câncer de mama (CM), principal causa de morte por câncer em mulheres uruguaias, é uma doença heterogênea. O estudo da expressão tumoral do receptor do fator de crescimento epidérmico-2 (HER2), do receptor de estrógeno (RE) e do receptor de progesterona (RP) permite reconhecer subtipos com diferentes características clínico-patológicas e de evolução. Objetivos: conhecer o perfil de expressão tumoral de HER2, RE e RP e sua relação com as características clínico-patológicas em pacientes uruguaias com CM. Material e método: os prontuários de pacientes submetidas a cirurgia por CM invasivo em um período de dois anos foram revisados. Foram selecionadas as que incluíam a determinação de RE, RP e HER2 por imuno-histoquímica. O perfil de expressão destes marcadores foi comparado com a idade no momento do diagnóstico, tipo e grau histológico (GH) e estádio patológico (TNM). Resultados: foram selecionadas 197 pacientes cujas características eram idade media: 55 anos, carcinoma ductal: 85%, GH 1-2: 59%, estádio: I-II: 75%, metástases axilares: 51%, RE/RP+: 78%, HER2+: 10%. Foram definidos três subtipos: HER2- RE/RP+ (73%), HER2+ (10%) e triplo negativo (TN) (17%). Os subtipos TN e HER2+ estavam associados a um maior grau histológico (p<0,05) e o TN com menor idade no momento do diagnóstico (p<0,05) que o subtipo HER2-, RE/RP+. Conclusões: a porcentagem de pacientes com CM invasivo subtipo HER2+ (10%) é menor que o informado por outros estudos (17%-28%). No entanto houve concordância com estudos anteriores nos quais os subtipos TN e HER2+ estavam correlacionados com tumores mais indiferenciados e o TN em pacientes más jovens.

Signaling pathways in early onset sporadic breast cancer of patients in Indonesia.

AIM: to determine signaling pathways in breast cancers from patients aged 35 years old or younger and patients aged more than 35 years old. METHODS: this was a cross-sectional, comparative study of female breast cancer patients who were recruited and divided into two age groups, i.e. 35 years or younger and more than 35 years old. Specimens were obtained by biopsy or surgical removal of the tumors and were confirmed by histopathological examination. The expression of ER, IGF-1R, Her-2, MAPK, and cyclin D1 were measured using immunohistochemistry. RESULTS: ninety-three patients were recruited from September 2004 to December 2005. Forty-three patients were 35 years or younger. More than 90% of the patients within the two groups showed invasive ductal carcinomas and more than half of these tumors were grade 2. Immunohistochemical staining was successfully done in 90 patients. ER-alpha expression was negative in 33 breast cancers (78.6%) from patients less than 35 years old and 32 cancers (66.7%) of older patients. The expressions of IGF-1R, Her-2, MAPK, and cyclin D1 were positive, respectively in 17 (40.5%), 11 (26.2%), 28 (66.7%), and 7 (16.7%) cancers within the group of patients 35 years old or younger, and, respectively in 18 (37.5%), 11 (22.9%), 37 (77.1%), and 9 (18.8%) of cancers from patients more than 35 years old. CONCLUSION: there were no statistically significant differences in the expression of any of the biomarkers between the two groups. In all patients, ER was negative in 72.2% cases and MAPK was positive in 76.7% cases. Patients aged 35 years or younger showed similar ER, IGF-1R, Her-2, MAPK, and cyclin D1 expressions compared to cancers from patients more than 35 years old. These were predominantly ER-negative, suggesting that estrogen does not play a dominant role in their growth. The frequent expression of MAPK in these cancers raises the possibility that growth factors play a dominant role in their growth.

Comparison of Her-2, EGFR and Cyclin D1 in Primary Breast Cancer and Paired Metastatic Lymph Nodes: An Immunohistochemical and Chromogenic In Situ Hybridization Study

The significant advance in the development of molecular-targeting drugs has made an evaluation of Her-2, EGFR, and cyclin D1 an important clinical issue in breast cancer patients. This study compared the Her-2, EGFR, and cyclin D1 status of primary tumors as well as their matching lymph node metastases using immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) in 73 breast cancer patients. Her-2, EGFR, and cyclin D1 protein showed a concordance between the primary lesion and the metastatic regional lymph nodes in 82%, 90%, and 63%, respectively. CISH also revealed 92%, 93%, and 85% concordance in the gene amplification status of Her-2, EGFR, and cyclin D1, showing a reasonable agreement between primary tumors and metastatic regional lymph nodes. Although a statistically significant agreement was found in Her-2 expression, a relatively high discordance rate (18%) raises a little concern. Our findings suggest that the Her-2 status can be reliably assessed on primary tumor but a possible difference can be found in Her-2, EGFR, and cyclin D1 status between the primary and the metastatic sites and this possibility should be concerned in patients considering molecular targeted therapy or patients with progress of disease.

Expression of Epidermal Growth Factor Receptor, ErbB2 and Matrix Metalloproteinase-9 in Hepatolithiasis and Cholangiocarcinoma / 대한소화기학회지

BACKGROUND/AIMS: Hepatolithiasis is a common disease in East Asia and presents as a histological feature of proliferative glands containing mucin. 5-10% of hepatolithiasis is known to be associated with cholangiocarcinoma. Recent studies reported that epidermal growth factor receptor (EGFR) could be activated through heparin binding- EGF cleavage by metalloproteinases. Matrix metalloproteinases (MMPs) which digest the extracellular matrix are required for cancer cell invasion and the expression of MMP-9 is known to be increased in cholangiocarcinoma. However, there has been few studies on the expressions and roles of EGFR and MMP in hepatolithiasis. This study was performed to clarify and compare the expressions of EGFR, erbB2 and MMP-9 in hepatolithiasis and cholangiocarcinoma. METHODS: Surgically resected liver tissues with hepatolithiasis (n=14), cholangiocarcinoma (n=20) and trauma (n=2 as controls) were included. The expressions of EGFR, erbB2 and MMP-9 in tissue samples were examined by immunohistochemistry using respective monoclonal antibodies. RESULTS: In traumatic livers, the expressions of EGFR, erbB2 and MMP-9 were all negative. The expression of EGFR was increased in hepatolithiasis group (79%, 11/14) compared with cholangiocarcinoma group (25%, 5/20) (p0.05). CONCLUSIONS: EGFR expression appears to be the dominant component in periductular hyperplasia of hepatolithiasis and MMP-9 is upregulated not only in cholangiocarcinoma but also in hepatolithiasis. This study suggests that EGFR and MMP-9 are associated with cholangiocarcinoma and hepatolithiasis.

The Usefulness of CDX-2 for Differentiating Primary and Metastatic Ovarian Carcinoma: An Immunohistochemical Study Using a Tissue Microarray

Distinguishing primary ovarian carcinoma from metastatic carcinoma to the ovary is often difficult by histologic examination alone. Recently an immunohistochemical marker CDX-2 was found to be of considerable diagnostic value in establishing the gastrointestinal origin of metastatic tumors. The aim of this study was to determine whether CDX-2 can distinguish between these malignancies. Paraffin-embedded tissue sections from 57 primary ovarian tumors and 40 metastatic tumors to the ovary were immunostained for CDX-2, and results were compared to the ancillary immunohistochemical results for CK7/CK20, CEA, CA125, and her-2/neu. CDX-2 immunoreactivity was observed in most of metastatic carcinomas with colorectal (91%) and appendiceal (100%) origin, however CDX-2 was negative in all primary ovarian carcinomas, except for the mucinous subtype. Almost all primary ovarian carcinomas including the mucinous subtype showed diffuse and strong immunoexpression for CK7. CEA and CA125 were mainly found in metastatic and primary ovarian carcinoma, respectively. Her-2/neu overexpression was only noted in a small proportion of primary and metastatic ovarian carcinomas. These results suggest that CDX-2 is very useful immunohistochemical marker for distinguishing metastatic colorectal carcinoma to the ovary from primary ovarian carcinoma, including the mucinous subtype. Furthermore, combination with CDX-2 and CK7 strengthen the differential diagnosis between these tumors.

Clinical Significance of HER-2/neu Expression in Colon Cancer / 대한소화기학회지

BACKGROUND/AIMS: The HER-2/neu protein is involved in normal cell proliferation and tissue growth because it is extensively homologous and related to epidermal growth factor receptor. As a prognostic marker, HER-2/neu is used to forecast the clinical course and poor outcome in breast cancer. As a predictive marker, HER-2/neu is used to predict the therapeutic response to adjuvant chemotherapy and endocrine therapy in breast cancer. In this study, we investigated the relationships between clinical and pathologic characteristics of tumor and prognosis according to the HER-2/neu expression in colon cancer. This study was conducted for the future introduction of Herceptin(r) therapy for colon cancer patients. METHODS: Overexpression of HER-2/neu was examined by semiquantitative standardized immunohistochemical staining kit in 88 patients with colon cancer. The patients underwent curative surgery at the Kangbuk Samsung Hospital. RESULTS: Overexpression of HER-2/neu was detected in 11 (12.5%) of 88 patients. Tumors with positive HER-2/neu staining showed a tendency for higher rates of nodal metastasis and poor mean survival (1,646 +/- 269 vs 2,631 +/- 141 days) and 5-year survival (65.5% vs 78.9%). CONCLUSIONS: Tumors with positive HER-2/neu staining showed a tendency for higher rates for nodal metastasis and poor clinical survival rate.

Study of HER2/neu status in Qatari women with breast carcinoma

The study is aimed at determining the prevalence of HER2/neu overexpression in Qatari women with breast cancer and to assess the survival in patients with HER2/neu positive tumors. This is a retrospective study of clinical data of 70 Qatari female patients diagnosed with breast cancer during the period 1991 through to 2001, at Hamad Medical Corporation, Doha, Qatar. We also performed a retrospective review of breast tissue sample for those patients using paraffin sections and applying immunohistochemistry staining-[Hercep test [DAKO Inc]] to determine the HER2/neu status. Eighteen patients [26%] were HER2/neu positive [2+ and 3+] with a mean age at diagnosis of 49.3years, and 52 [74%] were negative [0 and 1+] with mean age at diagnosis of 46.6 years. Of the patients with positive HER2/neu, 5 [28%] had a relapse of the disease and 4 [22%] died of the disease during follow up. Of the patients with HER2/neu, negative test 9 [17%] had a relapse of the disease and 10 [19%] died of the disease. The median survival function at mean of covariates for HER2/neu positive patients was 26 months, and for HER2/NEU negative patients was 28 months. The prevalence of HER2/neu over expression in Qatari female with breast cancer in this study is 26%, but due to a small sample size it may not reflect really the prevalence. Patient with HER2/neu positive were older at diagnosis than patients with HER2/neu negative, also they had higher relapse rate and mortality. Median survival function was better for HER2/neu negative patients