Prediction of Oncotype DX Recurrence Score Using Clinicopathological Variables in Estrogen Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer.

PURPOSE: Oncotype DX (ODX) is a well-validated multigene assay that is increasingly used in Korean clinical practice. This study aimed to develop a clinicopathological prediction (CPP) model for the ODX recurrence scores (RSs). METHODS: A total of 297 patients (study group, n = 175; external validation group, n = 122) with estrogen receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative, T1-3N0-1M0 breast cancer, and available ODX test results were included in the study. Risk categorization as determined by ODX RSs concurred with the TAILORx study (low-risk, RS ≤ 25; high-risk, RS > 25). Univariate and multivariate logistic regression analyses were used to assess the relationships between clinicopathological variables and risk stratified by the ODX RSs. A CPP model was constructed based on regression coefficients (ß values) for clinicopathological variables significant by multivariate regression analysis. RESULTS: Progesterone receptor (PR) negativity, high Ki-67 index, and nuclear grade (NG) 3 independently predicted high-risk RS, and these variables were used to construct the CPP model. The C-index, which represented the discriminatory ability of our CPP model for predicting a high-risk RS, was 0.915 (95% confidence interval [CI], 0.859-0.971). When the CPP model was applied to the external validation group, the C-index was 0.926 (95% CI, 0.873-0.978). CONCLUSION: Our CPP model based on PR, Ki-67 index, and NG could aid in the selection of patients with breast cancer requiring an ODX test.

A logarithmic model for hormone receptor-positive and breast cancer patients treated with neoadjuvant chemotherapy

SUMMARY OBJECTIVE: The aim of this study was to investigate the predictive importance of the previously validated log(ER)*log(PgR)/Ki-67 predictive model in a larger patient population. METHODS: Patients with hormone receptor positive/HER-2 negative and clinical node positive before chemotherapy were included. Log(ER)*log(PgR)/Ki-67 values of the patients were determined, and the ideal cutoff value was calculated using a receiver operating characteristic curve analysis. It was analyzed with a logistic regression model along with other clinical and pathological characteristics. RESULTS: A total of 181 patients were included in the study. The ideal cutoff value for pathological response was 0.12 (area under the curve=0.585, p=0.032). In the univariate analysis, no statistical correlation was observed between luminal subtype (p=0.294), histological type (p=0.238), clinical t-stage (p=0.927), progesterone receptor level (p=0.261), Ki-67 cutoff value (p=0.425), and pathological complete response. There was a positive relationship between numerical increase in age and residual disease. As the grade of the patients increased, the probability of residual disease decreased. Patients with log(ER)*log(PgR)/Ki-67 above 0.12 had an approximately threefold increased risk of residual disease when compared to patients with 0.12 and below (odds ratio: 3.17, 95% confidence interval: 1.48-6.75, p=0.003). When age, grade, and logarithmic formula were assessed together, the logarithmic formula maintained its statistical significance (odds ratio: 2.47, 95% confidence interval: 1.07-5.69, p=0.034). CONCLUSION: In hormone receptor-positive breast cancer patients receiving neoadjuvant chemotherapy, the logarithmic model has been shown in a larger patient population to be an inexpensive, easy, and rapidly applicable predictive marker that can be used to predict response.

Cáncer de mama metastásico y embarazo: reporte de caso / Metastatic breast cancer and pregnancy: a case report

Resumen ANTECEDENTES: El cáncer de mama es la segunda neoplasia maligna más común asociada con el embarazo. Su tratamiento es complejo debido a los riesgos en el feto en el contexto del tratamiento de la madre. CASO CLÍNICO: Paciente de 28 años, enviada del Hospital Naval de Chetumal, Quintana Roo, con 13.1 semanas de embarazo por fecha de la última menstruación. En la tomografía computada se advirtió la existencia de un derrame pleural del 70%, otro pericárdico y sospecha de metástasis osteoblástica a la columna torácica. En la exploración física se encontró con dinámica ventilatoria, amplexión y amplexación disminuida derecha, hipoventilación interescapular y basal derecha, con disminución a la trasmisión de voz, submatidez basal derecha y, hacia el lado izquierdo, un murmullo vesicular. Los estudios citoquímico y citológico de líquido pericárdico y pleural se reportaron positivos para malignidad. En la resonancia magnética de la columna se encontraron lesiones sugerentes de actividad tumoral en los cuerpos vertebrales T12 a L5. Debido al avanzado estado metastásico del cáncer se propuso la interrupción del embarazo con el propósito de no retrasar el tratamiento. El perfil biológico reportó: inmunofenotipo triple negativo (receptores de estrógeno y progesterona: negativo, HER2: negativo en células neoplásicas). Se le indicó tratamiento con quimioterapia sistémica (carboplatino-paclitaxel). CONCLUSIÓN: El diagnóstico de cáncer de mama durante el embarazo dificulta la detección e interpretación de las anormalidades mamarias, retrasa el diagnóstico, permite el crecimiento del tumor y se incrementa el riesgo metastásico de la enfermedad. El tratamiento oncológico adecuado y su valoración multidisciplinaria son decisivos para favorecer la supervivencia.

Abstract BACKGROUND: Breast cancer is the second most common malignancy associated with pregnancy. Its treatment is complex due to fetal risks in the context of treatment of the mother. CLINICAL CASE: 28-year-old patient, referred from the Naval Hospital of Chetumal, Quintana Roo, with 13.1 weeks of pregnancy by date of last menstrual period. The CT scan showed a 70% pleural effusion, another pericardial effusion and suspicion of osteoblastic metastasis to the thoracic spine. Physical examination showed ventilatory dynamics, decreased right amplexion and amplexation, interscapular and right basal hypoventilation, with decreased voice transmission, right basal submatitis and, to the left side, a vesicular murmur. Cytochemical and cytological studies of pericardial and pleural fluid were positive for malignancy. MRI of the spine showed lesions suggestive of tumor activity in the vertebral bodies T12 to L5. Due to the advanced metastatic stage of the cancer, termination of pregnancy was proposed in order not to delay treatment. The biological profile reported: triple negative immunophenotype (estrogen and progesterone receptors: negative, HER2: negative in neoplastic cells). Treatment with systemic chemotherapy (carboplatin-paclitaxel) was indicated. CONCLUSION: The diagnosis of breast cancer during pregnancy hinders the detection and interpretation of breast abnormalities, delays diagnosis, allows tumor growth and increases the metastatic risk of the disease. Adequate oncologic treatment and its multidisciplinary assessment are decisive in favoring survival.

[Clinicopathological features and prognosis of hormone receptor-positive/human epidermal growth factor receptor 2-negative breast cancer].

OBJECTIVE: To investigate the clinicopathological features and prognosis of hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2 -) breast cancer. METHODS: In the study, 3 035 consecutive breast cancer patients diagnosed in Breast Disease Center, Peking University First Hospital from January 2008 to December 2017 were collected. The prognostic signi-ficance of important pathological factors in HR +/HER2 - patients with complete clinicopathological information was analyzed. RESULTS: Within the 1 920 (63.26%) cases of HR +/HER2 - breast cancer, there were 1 624 cases with complete clinicopathological data, of which, 124 cases (7.64%) recurred and/or metastasized and 63 cases died of the disease, and the 5-year overall survival (OS) rate and disease-free survival (DFS) rate was 93.0% and 92.6% respectively. The stage of pT1-2 was 92.80%, while pN0 was 69.03%. 89.66% cases belonged to histologically non-specific type and 30.11%, 55.60%, 14.29% were credited to Grade 1, 2 and 3 respectively. The distribution of ER negative, low or high expression groups were 1.60%, 2.09% and 96.31%, while PR were 6.83%, 10.47%, 82.70%, respectively. The group of Ki67 index < 10% was 19.52%, ≥10% & < 20% for 32.02%, ≥20% for 48.46%. Survival analysis showed that cases with pT1 stage had lower risk of recurrence than those with pT3, while cases with pT2 and pT3 had shorter DFS than those with pT1, with higher risk of recurrence and metastasis. Analysis proved that both pN stage and histological grade were negatively correlated with DFS. The cases with pN0, pN1 and pN2 were lower risk of recurrence than those with pN3, while cases with Grade 1 and 2 had lower risk of recurrence than cases with Grade 3. And the group of Ki67 index ≥20% showed higher risk of recurrence and metastasis. The prognostic significance of ER expression in HR+/HER2- breast cancer was not significant. However, the negative/low PR expression groups showed higher risk of recurrence and metastasis, of which PR < 10% group had shortest DFS and OS, followed by 10%-60% group and then > 60% group. The most common site of metastasis was bone (55 cases, 44.35%), while cases with liver metastasis (30 cases, 24.20%) had the worst outcome. CONCLUSION: Our study revealed that pT, pN, Grade, HR expression level and Ki67 index were important prognostic factors for HR +/HER2 - breast cancer, although there are variables in prognostic value. Factors of pN and Grade showed independent prognostic significance. PR expression level had prognostic significance for the risk of recurrence and metastasis. The stratified level of PR expression (< 10%, 10%-60%, >60%) had independent prognostic value, showing successively longer DFS and OS, lower risk of recurrence. PR>60% group had the longest DFS and OS as well as the lowest risk of recurrence.

Elastosis in Breast Cancer as a Surrogate Marker for Estrogen Receptor Positivity.

OBJECTIVES: We sought to describe the occurrence of stromal elastosis in breast carcinoma among Omani female patients using semi-quantitative methods. We also sought to investigate the relationship between stromal elastosis and estrogen receptor (ER), progesterone receptor (PR), HER2/neu receptor tumor grade, and Ki-67 index. Furthermore, we evaluated the diagnostic accuracy of hematoxylin and eosin (H&E) stain method in quantifying elastosis compared to Elastin van Gieson (EVG) stain and if elastosis can be used as prognostic marker for overall survival. METHODS: The content of elastic tissue in primary infiltrating carcinomas of the breast was assessed using semi-quantitative methods (H&E and EVG stains) in 80 female Omani patients by two independent pathologists. Data of primary breast cancer patients who were not treated with neoadjuvant therapy from 2009 to 2019 at the Armed Forces Hospital of Oman were collected from medical records. Demographic and clinical data, including age, menstrual status, tumor type and grade, ER, PR, HER2/neu status, and Ki-67 index were obtained. Follow-up data, including clinical remission, evidence of metastasis, death, or lost follow-up were traced from medical records. RESULTS: Among the 80 cases studied, 80.0% were diagnosed with invasive ductal carcinoma, not otherwise specified, while 12.6% were diagnosed with infiltrating lobular carcinoma. Interobserver agreement of grading elastosis on H&E and EVG was strong (Kappa coefficient = 0.858). Using EVG, absent elastosis, grade 1, grade 2, and grade 3 were observed in 12.5%, 37.5%, 30.0%, and 20.0%, respectively. A statistically significant relationship between high elastosis and ER positivity (p = 0.015) and negative HER2/neu receptor (p = 0.045) was observed. No statistically significant relationship between elastosis and other entities, including menopausal status, tumor type and grade, PR, Ki-67, and prognosis. The sensitivity and specificity of quantifying elastosis on H&E stained sections compared to EVG stain (the gold standard) were 68.75% and 96.88%, respectively. CONCLUSIONS: Elastosis occurrence varies in different breast cancer populations. Elastosis can be considered a surrogate marker for estrogen positivity and HER2/neu negativity in breast cancer patients. In addition, H&E stain is considered an accurate method for quantifying elastosis compared to the EVG staining method.

[Consensus recommendations for the clinical application of CDK4/6 inhibitors in patients with hormone receptor positive, human epidermal growth factor receptor 2 negative advanced breast cancer].

The introduction of cyclin-dependent kinase (CDK) 4/6 inhibitors has revolutionized the clinical management paradigm of hormone receptor (HR) positive/human epidermal growth factor receptor (HER) 2 negative breast cancer. As of today, CDK 4/6 inhibitors including Palbociclib, Ribociclib, and Abemaciclib have been widely approved by regulatory agencies. Randomized clinical trials demonstrated that CDK 4/6 inhibitors in combination with an aromatase inhibitor (AI) or fulvestrant in the first-, second- or later-line setting for HR positive/HER2 negative locally advanced or metastatic breast cancer led to substantial reduction in the risk of disease progression or death. Adverse effects of treatment were manageable and as or better than expected in terms of patient satisfaction. Considering CDK4/6 inhibitors in combination with endocrine therapy being a novel approach in China clinical practice, the panel developed the consensus comprehensively describing the pharmacology properties, monitoring strategy during treatment and adverse events management, to facilitate greater understanding in Chinese oncologists of a whole new therapeutic class of drug, promote accuracy of clinical decision and help reach the ultimate goal of improving survival and quality of life of the target patient population.

Immunohistochemical and clinicopathologic features of estrogen receptor-negative, progesterone receptor-positive, HER-2 negative breast carcinomas

SUMMARY OBJECTIVE: Currently, there is an ongoing debate whether progesterone receptor positive and estrogen receptor negative breast carcinomas represent a true distinct subtype of tumor or a mere immunohistochemical artifact. In this study, we conducted an immunohistochemistry panel with the antibodies TFF1, EGFR, and CK5 to reclassify this phenotype in a luminal or basal-like subtype. METHODS: Tumors estrogen receptor -/progesterone receptor +, Her-2 - from a large population of breast cancer patients were selected to be studied. Immunohistochemistry with the antibodies TFF1, EGFR, and CK5 was performed. Tumors showing positivity for TFF1, regardless of EGFR and CK5 results, were classified as luminal-like carcinomas. Those lesions that were negative for TFF1, but were positive for EGFR and/or CK5, were classified as basal-like triple-negative carcinomas. When the three markers were negative, tumors were classified as undetermined. Clinical pathologic characteristics of patients and tumor recurrence were evaluated. RESULTS: Out of 1188 breast carcinomas investigated, 30 cases (2.5%) presented the estrogen receptor -/progesterone receptor +/HER2- phenotype. Of them, 27 tumors (90%) were classified as basal-like triple-negative carcinomas, one as luminal-like (3.3%), and two as undetermined tumors (6.7%). The mean follow-up for the study group was 27.7 (2.7 to 50) months. Out of the 26 patients, 6 had cancer recurrence: 2 local and 4 systemic recurrences. The average time for recurrence was 17 (8 to 38) months. CONCLUSION: Estrogen receptor -/progesterone receptor +/tumors exhibit aggressive behavior, similar to triple-negative tumors. An appropriate categorization of these tumors should be made to improve their therapeutic management.

Consensus recommendations for the clinical application of CDK4/6 inhibitors in patients with hormone receptor positive, human epidermal growth factor receptor 2 negative advanced breast cancer / 中华肿瘤杂志

The introduction of cyclin-dependent kinase (CDK) 4/6 inhibitors has revolutionized the clinical management paradigm of hormone receptor (HR) positive/human epidermal growth factor receptor (HER) 2 negative breast cancer. As of today, CDK 4/6 inhibitors including Palbociclib, Ribociclib, and Abemaciclib have been widely approved by regulatory agencies. Randomized clinical trials demonstrated that CDK 4/6 inhibitors in combination with an aromatase inhibitor (AI) or fulvestrant in the first-, second- or later-line setting for HR positive/HER2 negative locally advanced or metastatic breast cancer led to substantial reduction in the risk of disease progression or death. Adverse effects of treatment were manageable and as or better than expected in terms of patient satisfaction. Considering CDK4/6 inhibitors in combination with endocrine therapy being a novel approach in China clinical practice, the panel developed the consensus comprehensively describing the pharmacology properties, monitoring strategy during treatment and adverse events management, to facilitate greater understanding in Chinese oncologists of a whole new therapeutic class of drug, promote accuracy of clinical decision and help reach the ultimate goal of improving survival and quality of life of the target patient population.

Factors That Predict Biological Aggressiveness in Estrogen Receptor-Positive / Human Epidermal Growth Factor Receptor 2-Negative / Lymph Node-Negative Breast Cancer.

Background: Traditionally, breast cancer is staged using TNM criteria: tumor size (T), nodal status (N), and metastasis (M). The Oncotype DX assay provides a recurrence score (RS) based on genomics that predicts the likelihood of distant recurrence in estrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-)/lymph node-negative (LN-) tumors. Methods: We retrospectively reviewed the medical records of patients with ER+/HER2-/LN- breast cancer tumors who were evaluated between 2007 and 2017 with Oncotype DX RS. We compared the RS to tumor size, patient age, progesterone receptor (PR) status, and LN immunohistochemistry to assess for factors that may independently predict recurrence risk. We also compared tumor size to tumor grade. Results: The data set included 296 tumors: 248 ER+/PR-positive (PR+)/HER2- and 48 ER+/PR-negative (PR-)/HER2-. RS ranged from 0 to 66, patient age ranged from 33 to 77 years, and tumor size ranged from 1 to 65 mm. No significant correlation was found between age and RS (r=-0.073, P=0.208). PR- tumors had a significantly higher RS regardless of size (PR- mean RS 30.8 ± 12.7; PR+ mean RS 16.3 ± 7.3; t(53)=7.6, P<0.0001). No significant correlation was seen between tumor size and RS for all tumors (r=-0.028, P=0.635), and this finding remained true for the PR+ tumor subgroup (r=0.114, P=0.072). However, a significant negative correlation was seen between tumor size and RS in the PR- subgroup (r=-0.343, P=0.017). Further analysis to ensure that differences in tumor grade did not account for this correlation showed equal distribution of well differentiated, moderately differentiated, and poorly differentiated tumors with no significant correlation between tumor size and grade. Conclusion: Increasing tumor size may not be associated with increasing biological aggressiveness. Traditionally, smaller tumors are thought to be lower risk and larger tumors higher risk, with a tendency to use chemotherapy with large tumors. However, our data showed a negative correlation between tumor size and RS in the PR- subgroup. A tumor with PR negativity that reaches a large size without metastasizing may suggest a favorable tumor biology. These tumors may not receive as much benefit from chemotherapy as previously thought. Also, the higher RS seen in smaller PR- tumors may demonstrate PR- status as a predictor for higher risk of distant recurrence. We propose that all tumors meeting the ER+/PR-/LN- criteria, regardless of size, should be considered for genotyping, with the RS used to guide chemotherapy benefit.

Analysis of the molecular subtypes of preoperative core needle biopsy and surgical specimens in invasive breast cancer.

BACKGROUND: Accurate molecular classification of breast core needle biopsy (CNB) tissue is important for determining neoadjuvant systemic therapies for invasive breast cancer. The researchers aimed to evaluate the concordance rate (CR) of molecular subtypes between CNBs and surgical specimens. METHODS: This study was conducted with invasive breast cancer patients who underwent surgery after CNB at Seoul St. Mary's Hospital between December 2014 and December 2017. Estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki67 were analyzed using immunohistochemistry. ER and PR were evaluated by Allred score (0-8). HER2 was graded from 0 to +3, and all 2+ cases were reflex tested with silver in situ hybridization. The labeling index of Ki67 was counted by either manual scoring or digital image analysis. Molecular subtypes were classified using the above surrogate markers. RESULTS: In total, 629 patients were evaluated. The CRs of ER, PR, HER2, and Ki67 were 96.5% (kappa, 0.883; p<.001), 93.0% (kappa, 0.824; p<.001), 99.7% (kappa, 0.988; p<.001), and 78.7% (kappa, 0.577; p<.001), respectively. Digital image analysis of Ki67 in CNB showed better concordance with Ki67 in surgical specimens (CR, 82.3%; kappa, 0.639 for digital image analysis vs. CR, 76.2%; kappa, 0.534 for manual counting). The CRs of luminal A, luminal B, HER2, and triple negative types were 89.0%, 70.0%, 82.9%, and 77.2%, respectively. CONCLUSIONS: CNB was reasonably accurate for determining ER, PR, HER2, Ki67, and molecular subtypes. Using digital image analysis for Ki67 in CNB produced more accurate molecular classifications.

Expression of female sex hormone receptors and its relation to clinicopathological characteristics and prognosis of lung adenocarcinoma.

BACKGROUND: Adenocarcinoma (ADC) of the lung exhibits different clinicopathological characteristics in men and women. Recent studies have suggested that these differences originate from the expression of female sex hormone receptors in tumor cells. The aim of the present study was to evaluate the immunohistochemical expression of female sex hormone receptors in lung ADC and determine the expression patterns in patients with different clinicopathological characteristics. METHODS: A total of 84 patients with lung ADC who underwent surgical resection and/or core biopsy were recruited for the present study. Immunohistochemical staining was performed for estrogen receptor α (ERα), estrogen receptor ß (ERß), progesterone receptor (PR), epidermal growth factor receptor (EGFR), EGFR E746- A750 del, and EGFR L858R using tissue microarray. RESULTS: A total of 39 (46.4%) ERα-positive, 71 (84.5%) ERß-positive, and 46 (54.8%) PR-positive lung ADCs were identified. In addition, there were 81 (96.4%) EGFR-positive, 14 (16.7%) EGFR E746-A750 del-positive, and 34 (40.5%) EGFR L858R-positive cases. The expression of female sex hormone receptors was not significantly different in clinicopathologically different subsets of lung ADC. CONCLUSIONS: Expression of female sex hormone receptors is not associated with the prognosis and clinicopathological characteristics of patients with lung ADC.

Risk factors for paclitaxel-induced peripheral neuropathy in patients with breast cancer.

BACKGROUND: Paclitaxel induced peripheral neuropathy (PIPN) is a major debilitating side effect of paclitaxel in patients with breast cancer with no fully known mechanisms. The aim of the study was to find out the possible risk factors for PIPN. METHODS: Eligible patients with node positive breast cancer undergoing chemotherapy with paclitaxel were assessed. They belonged to an initial randomized controlled trial in which the effectiveness of omega-3 fatty acids in preventing and reducing severity of PIPN was evaluated (protocol ID: NCT01049295). Reduced total neuropathy score (r-TNS) was used for measuring PIPN. All analyses were performed adjusting for intervention effect. The association between age, BMI, BSA, pathological grade, molecular biomarkers and PIPN was evaluated. RESULTS: Fifty-seven patients with breast cancer were investigated. Age was significantly associated with risk of PIPN (RR:1.50, P value = .024). Body mass index and BSA had significant association with severity of PIPN (B:1.28, P = .025; and B: 3.88, P = .010 respectively). Also, BSA showed a significant association with the risk of PIPN (RR: 2.28, P = .035; B: 3.88, P = .035). Incidence and severity of PIPN were much more pronounced in progesterone receptor positive (PR+) patients (RR:1.88, P = .015 and B:1.54, P = .012). Multivariate analysis showed that age and the status of PR+ were independent risk factor for incidence and the status of PR+ was the only independent risk factor for severity of PIPN. CONCLUSION: Age, BSA and the status of PR+, should be considered as the risk factors for PIPN before commencement of chemotherapy with paclitaxel in patients with breast cancer. Older patients, those with greater BSA and PR+ patients may need closer follow up and more medical attention due to greater incidence and severity of PIPN.

Estrogen Receptor-α Correlates with Higher Fungal Cell Number in Oral Paracoccidioidomycosis in Women.

BACKGROUND: Paracoccidioidomycosis is a neglected tropical fungal infection with great predilection for adult men, indicating the participation of female hormone estrogen in preventing paracoccidioidomycosis development in women. Estrogen has an immunologic effect leading to polarization toward the Th2 immune response, which favors the disease evolution. OBJECTIVES: To evaluate estrogen and progesterone receptors in oral paracoccidioidomycosis lesions and to verify any association with tissue fungi counting in women and men. METHODS: Thirty-two cases of chronic oral paracoccidioidomycosis were included. Immunohistochemical analyses for anti-estrogen receptor-α, anti-progesterone receptor and anti-Paracoccidioides brasiliensis antibodies were performed. The differences between women and men and the relations among the immunomarkers for each gender were also evaluated. RESULTS: A significant positive correlation was observed between estrogen receptor-α and the amount of fungi in women. In addition, estrogen receptor-α was mildly expressed in the inflammatory cells of female patients, while progesterone receptor was expressed in both genders, with similar expression between women and men. Moreover, fungi counting revealed no differences between genders. CONCLUSIONS: Estrogen receptor-α was expressed only in women and showed a positive correlation with the amount of fungi in oral paracoccidioidomycosis, while progesterone receptor was observed in both genders and exhibited no correlation with estrogen receptor-α or fungi counting.

Re-Appraisal of Estrogen Receptor Negative/Progesterone Receptor Positive (ER-/PR+) Breast Cancer Phenotype: True Subtype or Technical Artefact?

Expression of the ER and PR receptors is routinely quantified in breast cancer as a predictive marker of response to hormonal therapy. Accurate determination of ER and PR status is critical to the optimal selection of patients for targeted therapy. The existence of an ER-/PR+ subtype is controversial, with debate centred on whether this represents a true phenotype or a technical artefact on immunohistochemistry (IHC). The aim of this study was to investigate the true incidence and clinico-pathological features of ER-/PR+ breast cancers in a tertiary referral symptomatic breast unit. Clinico-pathological data were collected on invasive breast cancers diagnosed between 1995 and 2005. IHC for ER and PR receptors was repeated on all cases which were ER-/PR+, with the same paraffin block used for the initial diagnostic testing. Concordance between the diagnostic and repeat IHC was determined using validated testing. Complete data, including ER and PR status were available for 697 patients diagnosed during the study period. On diagnostic IHC, the immunophenotype of the breast tumours was: ER+/PR+ in 396 (57%), ER-/PR- in 157 (23%), ER+/PR- in 88 (12%) and ER-/PR+ in 56 (8.6%) patients. On repeat IHC of 48/56 ER-/PR+ tumours 45.8% were ER+/PR+, 6% were ER+/PR- and 43.7% were ER-/PR- None of the cases were confirmed to be ER-/PR+. The ER-/PR+ phenotypic breast cancer is likely to be the result of technical artefact. Prompt reassessment of patients originally assigned to this subtype who re-present with symptoms should be considered to ensure appropriate clinical management.

Hormone-like activities of Kuntai capsule in the uteri of ovariectomized rats and immature rabbits.

OBJECTIVE: To investigate the hormone-like activities of Kuntai capsule (KTC) in the uteri of ovariectomized rats and immature rabbits. METHODS: Following bilateral ovariectomy, rats were randomly divided into six groups including sham group, control group, estradiol valerate group, KTC 0.24, 0.6, and 1.5 g/kg groups. The rats were treated with 0.5% CMC-Na, estradiol valerate and KTC (0.24, 0.6, and 1.5 g/kg), respectively for 28 consecutive days. Then the estrous cycle, uterine changes and pathological changes were examined. Serum levels of estradiol (E2), and progesterone (P4) were measured by enzyme-linked immunosorbent assay (ELISA). Protein levels of estradiol receptor (ER), progesterone receptor (PR), vascular endothelial growth factor (VEGF), proliferating cell nuclear antigen (PCNA) and nuclear-associated antigen-67 (Ki-67) in uterine tissues were detected by western blot. Immature rabbits were estrogen-primed prior to intragastric administration with KTC for 6 d consecutively. Then, the uteri underwent hematoxylin-eosin staining to observe endometrial transformation. RESULTS: Compared with the control group, 0.6 and 1.5 g/kg KTC markedly decreased the uterine organ coefficient and endometrial thickness (P < 0.05). The serum level of P4 was increased in the KTC 0.6 g/kg group (P < 0.05). There were no significant variations in the serum level of E2 in the KTC groups compared with the control group. ER¦Â, but not ER¦Á, was markedly upregulated after KTC administration (P < 0.05). Furthermore, 1.5 g/kg KTC significantly decreased the protein level of PRA (P < 0.05) and 0.6 g/kg KTC increased the protein level of PRB in the uteri (P < 0.05). VEGF was highly expressed after treatment with 0.24 and 0.6 g/kg KTC, and Ki-67 was markedly reduced in ovariectomized rats treated with 1.5 g/kg KTC. No difference was found in the expression of PCNA. KTC 0.24 and 0.6 g/kg promoted endometrial transformation in immature rabbit uteri. CONCLUSION: KTC does not demonstrate obvious estrogen-like effect on uteri after ovariectomy, but it does exhibit weak progestogen-like effect, by which mechanism of action is yet to be further investigated.

PROGNOSTIC IMPACT OF LOW ESTROGEN AND PROGESTERONE POSITIVITY IN LUMINAL B (HER2 NEGATIVE) BREAST CANCER.

- Luminal B (HER2 negative) subtype is the most diversiform type of breast cancers, with a high Ki-67 proliferation index (>20%) or/and low progesterone (PR; <20%) with various intensity and distribution of hormone receptors. Considerable difference has also been noticed in disease outcome, wherefore there is the need for a more detailed classification of this tumor subtype. The clinical and pathologic parameters of 147 luminal B (HER2 negative) breast cancers were examined. The expression of hormone receptors in correlation with other prognostic factors and disease outcome was analyzed by Kaplan-Meier curves and multivariate Cox regression analysis. The Kaplan-Mayer analysis showed that low positivity of estrogen (ER) and PR receptors in tumors was associated with a significantly worse disease outcome (overall survival (ER), p=0.020; disease free survival (ER), p=0.019; overall survival (PR), p=0.026; disease free survival (PR), p=0.038)), unlike Ki-67, which did not show a statistically significant connection (overall survival, p=0.343; disease free survival, p=0.322). The intensity of receptor staining and Ki-67 relative to other histopathologic prognostic factors showed a statistically significant correlation solely with histologic grade of tumor. By using the Cox regression model, PR proved to be an independent prognostic factor for overall survival (p=0.004) and disease free survival (p=0.029). The luminal B (HER2 negative) breast cancer with low expression of hormone receptors, independent of the Ki-67 proliferation index, and in correlation with a higher histologic grade, could be a unique subtype of cancer.

Expression and correlation of Fascin-1 and EGFR in hormone receptor-positive breast cancer / 中国医师杂志

Objective To explore the expression and correlation of Fascin-1 and epidermal growth factor receptor (EGFR) in hormone receptor-positive breast cancer.Methods The immunohistochemical technique,EnVision method,was used to evaluate the expression of Fascin-1 and EGFR in 294 cases of hormone receptor-positive breast cancer,which contains 290 cases of estrogen receptor (ER) positive and 244 cases of progestrone receptor (PR) positive.According to ER,PR,Epidermal growth factor receptor 2 (HER2),and Ki-67 status,all cases of hormone receptor-positive breast cancer were categorized into 2 subtypes:160 cases of luminal A and 134 cases of luminal B.Results Fascin-1 and EGFR protein positive rates in hormone receptor-positive breast cancer was 13.9％ (41/294) and 30.6％ (90/294),respectively.Fascin-1 positive rate was significantly higher in EGFR positive cases (30.0％,27/90) than in EGFR negative cases (6.9％,14/204) (x2 =27.857,P =0.000).In the ER positive and PR positive cases,Fascin-1 positive rates were both significantly higher in EGFR positive cases than in EGFR negative cases (x2 =29.23,P =0.000;x2 =27.596,P =0.000,respectively).In the Luminal A and Luminal B subtype,Fascin-1 positive rates were also both significantly higher in EGFR positive cases than in EGFR negative cases (x2 =23.247,P=0.000;x2 =5.325,P=0.021,respectively).Conclusions EGFR signal pathway may positive regulate Fascin-1 expression in hormone receptor-positive breast cancer.

[Study on the changes of gonadotropin releasing hormone agonist in pinopodes].

Objective: To study the changes of gonadotropin releasing hormone agonist (GnRH-a) in pinopodes during luteal phase and to explore the possible mechanism of GnRH-a in luteal phase support of assisted reproductive technology (ART). Methods: Totally 40 primary infertility women who were treated with ART due to male factors were enrolled, according to the order of the group they were randomly divided into experimental group and control group. On the 7th day after ovulation, the experimental group received a subcutaneous injection of 0.1 mg of GnRH-a, while the control group received a subcutaneous injection of placebo only (0.9% saline 2 ml), 3 days later they came to the clinic again. Serum estradiol and progesterone levels were measured before and after treatment in each group. Pinopodes were collected for electron microscopic examination. Levels of ER and PR were detected by western blot. Results: (1) There was no significant difference between the experimental group and the control group in the estrogen level before and after the treatment (all P>0.05). The level of progesterone in the experimental group after treatment [(66.8±14.9) nmol/L] was significantly higher than that before treatment(P<0.05); also significantly higher than the same period of the control group (P<0.05). (2) There was no significant difference in the expression of ER protein in the experimental group before and after treatment (P>0.05). The expression of PR in the experimental group after treatment was significantly lower than that before treatment (P<0.05); also lower than the same period of the control group (P<0.05). (3) Expression amount of pinopodes in the experimental group after treatment was significantly higher than that before treatment [65% (13/20) versus 25% (5/20), P<0.05], and the development trend was more mature [the percentage of maturation:75% (15/20) versus 35% (7/20), P<0.05]. Expression amount of pinopodes after treatment and the percentage of maturation in the experimental group were significantly higher than those in the same period of control group (P<0.05). Conclusion: GnRH-a in luteal phase support may play a role through the corpus luteum, which may promote the secretion of progesterone, downregulation of PR expression, promote the growth of pinopodes, and improve the endometrial receptivity.

Mammographic density among indigenous women in forested areas in the state of Amapá, Brazil: a cross-sectional study / Densidade mamográfica em mulheres indígenas de áreas da floresta do estado do Amapá, Brasil: estudo transversal

ABSTRACT CONTEXT AND OBJECTIVE: There is no register of breast cancer cases among indigenous populations in Brazil. The objective here was to evaluate the association of clinical and demographic characteristics with mammographic density among indigenous women. DESIGN AND SETTING: Cross-sectional analytical study conducted in indigenous territories in the state of Amapá, Brazil. METHODS: Women were recruited from three indigenous territories and underwent bilateral mammography and blood collection for hormonal analysis. They were interviewed with the aid of an interpreter. Mammographic density was calculated using computer assistance, and was expressed as dense or non-dense. RESULTS: A total of 137 indigenous women were included in this study, with an average age of 50.4 years, and an average age at the menarche of 12.8 years. Half (50.3%) of the 137 participants had not reached the menopause at the time of this study. The women had had an average of 8.7 children, and only two had never breastfed. The average body mass index of the population as a whole was 25.1 kg/m2. The mammographic evaluation showed that 82% of women had non-dense breasts. The clinical characteristics associated with mammographic density were age (P = 0.0001), follicle-stimulating hormone (FSH) (P < 0.001) and estrogen levels (P < 0.01). CONCLUSIONS: The majority of the indigenous women had non-dense breasts. Age, menopausal status and FSH and estrogen levels were associated with mammographic density.

RESUMO CONTEXTO E OBJETIVO: Não há registro de casos de câncer de mama em populações indígenas no Brasil. O objetivo foi avaliar a associação de características clínicas e demográficas com a densidade mamográfica em mulheres indígenas. TIPO DE ESTUDO E LOCAL: Estudo transversal, analítico, realizado em territórios indígenas no estado do Amapá, Brasil. MÉTODOS: Mulheres foram recrutadas de três territórios indígenas e submetidas a mamografia bilateral e a coleta de sangue para análise hormonal. As participantes foram entrevistadas com a ajuda de um intérprete. A densidade mamográfica foi calculada com assistência de computador, e expressa como densa ou não densa. RESULTADOS: 137 mulheres foram incluídas no estudo, com média de 50,4 anos e média de idade à menarca de 12,8 anos. Metade (50,3%) das 137 participantes não havia entrado na menopausa no momento do estudo. As mulheres tinham em média 8,7 filhos, e duas nunca haviam amamentado. O índice de massa corpórea médio da população como um todo foi de 25,1 kg/m2. A análise mamográfica mostrou que 82% das mulheres tinham mamas não densas. As características clínicas associadas com a densidade mamográfica foram idade (P = 0.0001), hormônio folículo-estimulante (FSH, P < 0,001) e níveis de estrogênio (P < 0,01). CONCLUSÕES: A maioria das indígenas tinha mamas não densas. Idade, status menopausal e níveis de estrógeno e FSH foram associados com a densidade mamográfica.