Delayed diagnosis and increased mortality risk: Assessing the effects of the COVID-19 pandemic on breast cancer recurrence.

OBJECTIVES: The COVID-19 pandemic has had a significant global impact since its declaration in March 2020. The COVID-19 pandemic has disproportionately impacted cancer patients, particularly those with breast cancer. This study aims to analyze the effects of the pandemic on women diagnosed with breast cancer recurrence. METHODS: A cohort study was conducted at a tertiary public hospital in São Paulo State, Brazil. Data were collected from electronic records. Patients diagnosed with breast cancer and experiencing recurrence between January 2011 and March 2022 were included. Survival analysis was performed using the Kaplan-Meier estimator and Cox regression. RESULTS: The study included 187 patients, 45 in the pandemic group (recurrence after March 23, 2020) and 142 in the pre-pandemic group. Distant recurrences were more frequent in both groups (pre-pandemic: 62.7 %, pandemic: 75.5 %). Compared to the pre-pandemic group (1.8 years), the pandemic group experienced a longer mean time to recurrence detection (2.9 years) and significantly decreased median survival (9 months vs. 22 months). The Cox regression analysis confirmed an increased risk of death for women diagnosed with breast cancer recurrence during the pandemic period (HR = 1.92, 95 % CI 1.19‒3.12). CONCLUSION: The present study is among the first to investigate the pandemic's specific effects on breast cancer recurrence, revealing concerning delays in detection and a decrease in survival rates. Prompt diagnosis, timely treatment initiation, and comprehensive support are crucial during public health crises. These findings urge healthcare systems to prioritize tailored care for breast cancer patients during pandemics.

Intestinal P-gp activity is reduced in postmenopausal women under breast cancer therapy.

Intestinal P-glycoprotein (P-gp) activity plays a crucial role in modulating the oral bioavailability of its substrates. Fexofenadine has commonly been used as a P-gp probe, although it is important to note the involvement of other drug transporters like, OATP1B1, OATP1B3, and OATP2B1. In vitro studies demonstrated an upregulation of P-gp protein in response to exposure to pregnancy-related hormones. The objective of this study was to investigate how intestinal P-gp activity is impacted by menopausal status. This study sampled fexofenadine plasma concentrations over 0-12 h after probe drug administration from two groups of patients with breast cancer: premenopausal (n = 20) and postmenopausal (n = 20). Fexofenadine plasma concentrations were quantified using liquid-chromatography tandem mass spectrometry. Area under the plasma concentration-time curve from zero to infinity (AUCinf ) was calculated through limited sampling strategies equation. Multiple linear regression was applied on AUCinf , maximum plasma concentration (Cmax ), and time to Cmax . Postmenopausal patients showed a significant increase in Cmax (geometric mean and 95% confidence interval [CI] 143.54, 110.95-176.13 vs. 223.54 ng/mL, 161.02-286.06 and in AUCinf 685.55, 534.98-878.50 vs. 933.54 ng·h/mL 735.45-1184.99) compared to premenopausal patients. The carriers of the ABCB1 3435 allele T displayed higher Cmax values of 166.59 (95% CI: 129.44-214.39) compared to the wild type at 147.47 ng/mL (95% CI: 111.91-194.34, p = 0.02). In postmenopausal individuals, the decrease in P-gp activity of ~40% may lead to an increased plasma exposure of orally administered P-gp substrates.

10-year opportunistic mammographic screening scenario in Brazil and its impact on breast cancer early detection: a nationwide population-based study.

Background: Mammographic screening has been used to reduce breast cancer mortality worldwide and remains the main modality for the early detection of this disease. Women from low- and middle-income countries still lack access to periodic mammograms and efficient health care. This cross-sectional study aimed to explore opportunistic mammographic coverage in Brazil, while considering the privately insured population and its association with early breast cancer (EBC) detection. Methods: Data on population, gross domestic product (GDP), number of mammograms performed under the Sistema Único de Saúde (SUS) public health system or private system, and women diagnosed with early-stage breast cancer from 2010 to 2019 were retrieved from publicly available databases. Results: A total of 39 555 636 mammograms with an average of 3 955 564 ± 395 704 mammograms were obtained per year from 2010 to 2019 in Brazil. Most examinations (58.6%) were performed in the target population (50-69 years old), while 32% were performed in women aged 40-49, and 9.4% were performed in women <40 years or >70 years of age. The 10-year mammogram coverage was 30.6% in the target population and 24.8% in the population aged 40-49 years, with significant variation across states and municipalities. The overall EBC detection rates in Brazil were 30.6% in populations aged 50-70 and 24.8% in those aged 40-50 years. We observed a positive correlation between coverage and EBC detection rate (r = 0.68; P = 0.0001 (50-70 years) and r = 0.75; P < 0.0001 (40-50 years)). According to the GDP, the municipalities with higher GDP per capita had higher mammogram coverage (P < 0.0001). Conclusions: The coverage of mammographic screening for women under the SUS is far below the international guidelines. Additionally, a significant number of mammograms have been performed in non-target populations. This scenario reflects the problematic screening programs in developing countries and reflects low rates of EBC diagnosis. As Brazil is a continental country with heterogeneous socioeconomic indicators, we observed significant variations in the number of mammograms performed by age groups when separated by states and municipalities. Even when considering supplemental health system coverage, municipalities with higher GDP per capita were associated with higher mammogram coverage.

Axillary ultrasound and fine-needle aspiration cytology to predict clinically relevant nodal burden in breast cancer patients.

BACKGROUND: Axillary lymph node involvement is one important prognostic factor in breast cancer, but the way to access this information has been modified over the years. This study evaluated if axillary ultrasound (US) coupled with fine-needle aspiration cytology (FNAC) can accurately predict clinically relevant node metastasis in patients with breast cancer, and thus assist clinical decisions METHODS: This is a cross-sectional study with retrospective data collection of 241 individuals (239 women and 2 men) with unilateral operable breast cancer who were submitted to preoperative axillary assessment by physical exam, US and FNAC if suspicious nodes by imaging. We calculated sensitivity, specificity, and accuracy of the methods. We compared the patient's characteristics using chi-square test, parametrics and non-parametrics statistics according to the variable. RESULTS: The most sensible method was US (0.59; 95% CI, 0.50-0.69), and the most specific was US coupled with FNAC (0.97; 95% CI, 0.92-0.99). Only 2.7% of the patients with normal axillary US had more than 2 metastatic nodes in the axillary lymph node dissection, against 50% of the patients with suspicious lymph nodes in the US and positive FNAC. CONCLUSIONS: Axillary US coupled with FNAC can sort patients who have a few metastatic nodes at most from those with heavy axillary burden and could be one more tool to initially evaluate patients and define treatment strategies.

Epidemiological Analyses Reveal a High Incidence of Breast Cancer in Young Women in Brazil.

PURPOSE: Breast cancer screening is not recommended for young women (< 40 years old); therefore, those diagnosed are more likely to have advanced and metastatic disease, reducing treatment outcomes. This study aimed to investigate breast cancer epidemiology among young women in Brazil. METHODS: Data from three publicly available databases and a cohort from a university hospital in Brazil were analyzed in a retrospective study. Descriptive statistics was performed on disease prevalence and stage distribution across age groups. Incidence was estimated using age-standardized incidence ratio. The impact of age in disease-specific survival was also analyzed. RESULTS: Invasive breast cancer prevalence data by age group revealed that 4.4% and 20.6% of patients were < 35 and < 45 years old, respectively. In the United States, this prevalence was 1.85% and 11.5%, respectively (odds ratio [OR], 2.2; P < .0001). The percentage of regional and metastatic diseases were higher in São Paulo State (Fundação Oncocentro de São Paulo [FOSP]) compared with the United States (45% and 9.8% v 29% and 5.7%, respectively; P < .0001). In FOSP, regional and metastatic disease prevalence were higher among young patients (53.5% and 11.3%, respectively). The median tumor size in patients < 40 years old was higher (25.0 mm × 20.9 mm; P < .0001), and young patients have higher risk to be diagnosed with positive lymph nodes (OR, 1.5; P = .004) and higher proportion of luminal-B and triple-negative (TNBC) tumors. Young patients have a poor disease-specific survival because of late-stage diagnosis and more aggressive breast cancer subtypes (human epidermal growth factor receptor 2-enriched and TNBC) (P < .0001). CONCLUSION: In Brazil, breast cancer prevalence among young patients and late-stage incidence during this age span is higher. Advanced disease and more aggressive subtypes lead to a significant impact on breast cancer-specific survival in young patients.

Analysis of the relationship between hospital characteristics and survival in ovarian cancer: A historical cohort.

BACKGROUND AND OBJECTIVES: The management of ovarian cancer requires complex surgical and medical interventions. Specialized care is associated with superior outcomes in early and advanced stages. This study aimed to estimate the effect of hospital characteristics on the overall survival of women with epithelial ovarian cancer. METHODS: We established a cohort with data recorded by the Fundação Oncocentro de São Paulo cancer registry. We included 6111 women treated for ovarian cancer in the state of Sao Paulo from January 2000 to December 2018. From 76 hospitals analyzed, 7 were high volume (20 or more cases a year) and 69 low volume. Twenty-nine were teaching and 47 community hospitals. A 10-year survival was analyzed using the Kaplan-Meyer estimator and the Cox model. RESULTS: Fifty-two percent of the epithelial ovarian cancer patients were treated in high-volume hospitals. High-volume - (HR, 0.86; 95% CI, 0.8-0.92; P < .001) and teaching - (HR, 0.91; 95% CI, 0.85-0.99; P = .019) were hospital characteristics associated with low risk of death in 10 years. CONCLUSIONS: High-volume and teaching hospitals are associated with better overall survival in ovarian cancer. Our data suggest that both hospital characteristics are important indicators of good quality of care in ovarian cancer treatment.

Total, renal and hepatic clearances of doxorubicin and formation clearance of doxorubicinol in patients with breast cancer: Estimation of doxorubicin hepatic extraction ratio.

Doxorubicin (DOX) is a cytotoxic drug which has remained as an essential component of chemotherapy regiment for breast cancer. The cardiotoxicity of DOX is related to the accumulation of its main metabolite doxorubicinol (DOXOL) in the cardiac tissue. Although the pharmacokinetics of DOX shows high interindividual variability, there are no significant covariates to improve dose adjustment. The present study reports the pharmacokinetics of both DOX and DOXOL in a homogeneous population of young female patients with breast cancer (n = 12) making use of a standardized drug association, evaluated in the very first chemotherapy cycle, using plasma and urine data that allowed the calculation of the renal clearance of DOX, the formation clearance of DOXOL and the hepatic clearance of DOX. The extensive data availability also made it possible to estimate the hepatic extraction ratio of DOX for the investigated population, as well as to determine DOXOL unbound fraction in plasma for the first time in humans. DOX and DOXOL simultaneous analysis in plasma, plasma ultrafiltrate, and urine were performed by liquid chromatography coupled to mass spectrometry (LC-MS/MS). The pharmacokinetics profile of both DOX and DOXOL showed high variability (geometric coefficient of variation of area under the plasma concentration versus time curve extrapolated to infinity was approximately 215 %). The geometrics means were 0.26 for DOXOL/DOX AUC ratio, 15 % and 17 % for unbound fractions of DOX and DOXOL, respectively, 30.70 L⋅h-1 for total clearance, 0.66 L⋅h-1 for renal clearance, 29.97 L⋅h-1 for hepatic clearance and 0.39 L⋅h-1 for the formation clearance of the metabolite DOXOL. The 95 % confidence interval of the estimated hepatic extraction ratio of DOX ranged from 0.14 to 0.79, which characterizes DOX as a drug of low, intermediate or high hepatic extraction ratio.

Hormonal status affects plasma exposure of tamoxifen and its main metabolites in tamoxifen-treated breast cancer patients.

BACKGROUND: Tamoxifen is considered a prodrug of its active metabolite endoxifen, which is dependent on the CYP2D6 and CYP3A enzymes. Tamoxifen pharmacokinetic variability influences endoxifen exposure and, consequently, its clinical outcome. This study investigated the impact of hormonal status on the pharmacokinetics of tamoxifen and its metabolites in TAM-treated breast cancer patients. METHODS: TAM-treated breast cancer patients (n = 40) previously believed to have CYP3A activity within the normal range based on oral midazolam and phenotyped as CYP2D6 normal metabolizers using oral metoprolol were divided into two groups according to premenopausal (n = 20; aged 35-50 years) or postmenopausal (n = 20; aged 60-79 years) status. All patients were treated with 20 mg/day tamoxifen for at least three months. Serial plasma samples were collected within the 24 h dose interval for analysis of unchanged tamoxifen, endoxifen, 4-hydroxytamoxifen and N-desmethyltamoxifen quantified by LC-MS/MS. CYP activities were assessed using midazolam apparent clearance (CYP3A) and the metoprolol/alfa-hydroxymetoprolol plasma metabolic ratio (CYP2D6). CYP3A4, CYP3A5 and CYP2D6 SNPs and copy number variation were investigated using TaqMan assays. RESULTS: Postmenopausal status increased steady-state plasma concentrations (Css) of tamoxifen (116.95 vs 201.23 ng/mL), endoxifen (8.01 vs 18.87 ng/mL), N-desmethyltamoxifen (485.16 vs 843.88 ng/mL) and 4-hydroxytamoxifen (2.67 vs 4.11 ng/mL). The final regression models included hormonal status as the only predictor for Css of tamoxifen [ß-coef ± SE, p-value (75.03 ± 17.71, p = 0.0001)] and 4-hydroxytamoxifen (1.7822 ± 0.4385, p = 0.0002), while endoxifen Css included hormonal status (8.578 ± 3.402, p = 0.02) and race (11.945 ± 2.836, p = 0.007). For N-desmethyltamoxifen Css, the final model was correlated with hormonal status (286.259 ± 76.766, p = 0.0007) and weight (- 8.585 ± 3.060, p = 0.008). CONCLUSION: The premenopausal status was associated with decreased endoxifen plasma concentrations by 135% compared to postmenopausal status. Thus, the endoxifen plasma concentrations should be monitored mainly in the premenopausal period to maintain plasma levels above the efficacy threshold value. TRIAL REGISTRATION: RBR-7tqc7k.

Development of New Formulations of Biologics: Expectations, Immunogenicity, and Safety for Subcutaneous Trastuzumab.

Subcutaneous (SC) trastuzumab has long been approved as a cancer treatment for early and advanced HER2-positive (HER2+) breast cancer by both the European Medicines Agency (EMA) and Agência Nacional de Vigilância Sanitária (ANVISA), the Brazilian National Health Surveillance Agency. A pivotal non-inferiority phase III trial, which aimed to provide a more convenient and cost-effective treatment in the HER2+ breast cancer neoadjuvant setting, showed that the SC group met prespecified efficacy endpoints and the SC formulation was considered as safe as the intravenous (IV) formulation. Considering the recent approval of several biosimilars, new SC formulations are also an interesting manufacturer strategy as these drugs can obtain patent protection. Despite being considered non-inferior to the IV formulation of trastuzumab, in clinical development, the SC formulation elicited higher immunogenicity, mainly related to overall anti-drug antibodies (ADAs); however, this finding was classified as clinically non-significant. In this article, we explore different aspects of the benefits and risks of the SC trastuzumab formulation according to published data.

Identification of a Subtype of Poorly Differentiated Invasive Ductal Carcinoma of the Breast Based on Vimentin and E-cadherin Expression.

OBJECTIVE: The use of molecular markers can identify a subgroup of tumors with distinct recurrence patterns. The present study aimed to characterize the immunohistochemical expression of vimentin (VIM), of E-cadherin (CDH1), and of cytokeratin 5 (CK5) in patients with invasive ductal carcinomas (IDCs). METHODS: We have constructed a tissue microarray (TMA) from 87 patients with IDC of the breast. Immunohistochemistry (IHC) was performed to study the expression of estrogen and progesterone receptors (ER and PgR), human epidermal growth factor receptor 2 (HER2), VIM, CDH1, CK5, and Ki67. The tumors were classified as luminal A and B (n = 39), HER2 enriched (n = 25), and triple-negative (TNBC) (n = 23), based on the IHC expression. RESULTS: We have observed that luminal A and B tumors lack the VIM+/CDH1-/low phenotype. This phenotype was observed in 16.5% of the HER2+ tumors and in 60% of the TNBC tumors (p = 0.0001). Out of a total of 20 TNBC tumors, the CK5 (basal-like marker) was positive in 11 of them. The VIM+/CDH1-/low phenotype was observed in 5 CK5+ TNBC tumors (45%) and in 7 out of 9 CK5- TNBC tumors (78%) (p = 0.02). The median Ki67 index in the VIM+/CDH1-/low tumors was 13.6 (range: 17.8-45.4) compared with 9.8 (range: 4.1-38.1) in other tumors (p = 0.0007). The presence of lymph node metastasis was less frequent in patients with VIM+/CDH1-/low tumors (23% versus 61%; X2 test; p = 0.01). CONCLUSION: Our findings suggest that the expression of VIM and CDH1 can identify a subset of IDCs of the breast with a mesenchymal phenotype associated with poor prognosis, high-grade lesion, and high mitotic index.

OBJETIVO: O uso de marcadores moleculares pode identificar subtipos tumorais com diferentes taxas de recidiva. O objetivo do presente estudo é caracterizar a expressão imunohistoquímica da vimentina (VIM), da E-caderina (CDH1) e de CK5 em pacientes com carcinoma ductal invasivo (CDI) da mama. MéTODOS: Utilizamos uma matriz de amostras teciduais (TMA, na sigla em inglês) de 87 pacientes com CDI da mama. Para avaliar a expressão dos receptores de estrogênio (RE) e receptores de progesterona (RP), HER2, VIM, CDH1, CK5 e Ki67, utilizamos imunohistoquímica. Os tumores foram classificados como luminal A e B (n = 39), HER2+ (n = 25) e triplo negativo (TNBC) (n = 23). RESULTADOS: Foi observado que tumores luminais A e B não expressaram o fenótipo VIM+/CDH1-/low. Este fenótipo foi observado em 16,5% dos tumores HER2+ e em 60% dos tumores TNBC (p = 0,0001). Dos 20 tumores TNBC, a CK5 (marcador de tumor basalóide) foi super expressa em 11 amostras. O fenótipo VIM+/CDH1-/low foi observado em 5 tumores CK5+ TNBC (45%) e em 7 dos 9 tumores CK5- TNBC (78%) (p = 0,02). A expressão média de Ki67 nos tumores VIM+/CDH1-/low foi 13.6 (amplitude de 17,8 a 45,4) comparado com 9,8 (amplitude de 4,1 a 38,1) nos outros tumores (p = 0,0007). A presença de metástase linfonodal foi menor em tumores com fenótipo VIM+/CDH1-/low (23% contra 61%; teste X2 ; p = 0,01). CONCLUSãO: Nossos achados sugerem que a expressão de VIM e CDH1 pode identificar um subtipo de CDI da mama com fenótipo mesenquimal associado a pior prognóstico, lesões de alto grau e alto índice mitótico.

Increased STAT1 Expression in High Grade Serous Ovarian Cancer Is Associated With a Better Outcome.

OBJECTIVE: Recently it has been demonstrated that constitutively activated signal transducer and activator of transcription 1 (STAT1) gene expression may act as a biomarker of ovarian cancer chemotherapy response. In this study, our objective was to validate the use of STAT1 immunohistochemistry as a prognostic biomarker for disease outcome using a cohort derived from Latin America. METHODS: We evaluated a cohort of Brazilian high-grade serous ovarian cancer, comprising 65 patients with outcome data covering more than 5 years to determine the prognostic and predictive value of STAT1 expression levels. High-grade serous ovarian cancer tumors were used to construct a tissue microarray. Exploratory analyses were conducted on clinical, histopathological, and STAT1 expression data that included descriptive statistics and Pearson correlative analyses. Survival curves for disease-free survival and overall survival were obtained by the Kaplan-Meier method, and the significance of homogeneity between the classes was assessed by log-rank statistics (Mantel-Cox). RESULTS: High expression of STAT1 in tumors was significantly associated with improved disease-free survival (P = 0.0256) and overall survival (P = 0.0193). Proportional hazards regression analysis showed STAT1 expression had an independent effect on both disease-free survival (P = 0.0358) and overall survival (P = 0.0469). CONCLUSIONS: These findings from a Brazilian cohort of patients with ovarian cancer reinforce the association of high STAT1 expression with better response to chemotherapy, providing additional validation of this protein as both a prognostic and predictive biomarker. Collectively, these results together with other recently published studies increase the feasibility of using the STAT1 pathway for the development of novel immunomodulator drugs that could enhance response to treatment.

Quality of Life in Women With Breast Cancer Treated With or Without Chemotherapy.

BACKGROUND: The diagnosis and treatment of breast cancer may negatively affect the quality of life (QOL) of women. OBJECTIVES: The aim of this study is to assess QOL in women with breast cancer who were treated with or without chemotherapy and to identify factors associated with improved or worsening QOL in these women. METHODS: This cross-sectional study enrolled 112 women who were treated with chemotherapy (CTX group, with 85 [75.9%] women) or without chemotherapy (non-CTX group, with 27 [24.1%] women) for breast cancer. The Short-Form Health Survey (SF-36) assessed QOL and the Hospital Anxiety and Depression scale assessed anxiety and depression. RESULTS: The overall mean SF-36 score was below 50 in all domains. Relative to CTX women, non-CTX women were significantly older (P = .001) and more likely to engage in physical exercise (P = .002). The non-CTX group had higher scores in the Physical Functioning (P = .001) and Role-Physical (P = .0009) domains of the SF-36 relative to the CTX group, and the fluoruracil + epirubicin + cyclophosphamide group had significantly lower scores in the SF-36 domains Physical Functioning (P = .009) and Role-Physical (P = .02). CONCLUSION: Chemotherapy treatment for breast cancer worsens QOL in the Physical Functioning and the Role-Physical domains of the SF-36 relative to women treated without chemotherapy. IMPLICATIONS FOR PRACTICE: Nurses should assess Physical Functioning and the Role-Physical before treatment, as a woman who was not physically active before breast cancer is not likely to become physically active after treatment. Establishing support groups and providing educational sessions about the disease and its management, supportive care can improve the QOL of this population.

Detection of human mammaglobin A mRNA in peripheral blood of breast cancer patients before treatment and association with metastasis.

BACKGROUND: Mammaglobin A (MGA), mainly expressed in the breast epithelium, is overexpressed in breast cancer, and has been established as a tumor and promissory marker for the early detection of metastasis. AIM: The main aim of this study was to evaluate the association between the presence of the MGA transcript in the peripheral blood of Brazilian breast cancer patients and healthy women and the development of breast cancer and tumor progression. MATERIAL AND METHODS: The expression of the MGA transcript in peripheral blood of 102 breast cancer patients and 102 healthy women was assessed by RT-PCR. RESULTS: MGA mRNA was expressed in the peripheral blood of 39 breast cancer patients and in none of the women from the control group. The presence of MGA was significantly associated with presence of metastasis and age at onset after 60 years. The presence of MGA mRNA in peripheral blood displayed a sensitivity of 38.2%, specificity of 100.0%, positive predictive value (PPV) of 100.0%, and negative predictive value (NPV) of 61.8% as a breast cancer marker. CONCLUSION: This study provides additional evidence of the presence of MGA in the peripheral blood of breast cancer patients, and its applicability as an efficient biomarker for breast cancer (High specificity and PPV). To our knowledge, this is the first study to assess the expression of MGA mRNA in peripheral blood obtained from the Brazilian population.

ABCG2 is a potential marker of tumor-initiating cells in breast cancer.

The existence of tumor-initiating cells (TICs) within solid tumors has been hypothesized to explain tumor heterogeneity and resistance to cancer therapy. In breast cancer, the expression of CD44 and CD24 and the activity of aldehyde dehydrogenase 1 (ALDH1) can be used to selectively isolate a cell population enriched in TICs. However, the ideal marker to identify TICs has not been established. The aim of this study was to evaluate the expression of novel potential markers for TIC in breast carcinoma. We prospectively analyzed the expression of CD44, CD24, ABCG2, and CXCR4, and the activity of ALDH1 by using flow cytometry in 48 invasive ductal carcinomas from locally advanced and metastatic breast cancer patients who were administered primary chemotherapy. A mammosphere assay was employed in 30 samples. The relationship among flow cytometric analyses, ABCG2 gene expression, and clinical and pathological responses to therapy was analyzed. The GSE32646 database was analyzed in silico to identify genes associated with tumors with low and high ABCG2 expression. We observed that the presence of ABCG2(+) cells within the primary tumor was the only marker to predict the formation of mammospheres in vitro (R (2) = 0.15, p = 0.029). Quantitative polymerase chain reaction (qPCR) revealed a positive correlation between ABCG2 expression and the presence of ABCG2(+) cells within the primary tumor. The expression of ABCG2 was predictive of the response to neoadjuvant chemotherapy in our experiments and in the GSE32646 dataset (p = 0.04 and p = 0.002, respectively). The in silico analysis demonstrated that ABCG2(Up) breast cancer samples have a slower cell cycle and a higher expression of membrane proteins but a greater potential for chromosomal instability, metastasis, immune evasion, and resistance to hypoxia. Such genetic characteristics are compatible with highly aggressive and resistant tumors. Our results support the hypothesis that the presence of ABCG2(+) cells in breast carcinomas is a marker of resistance to chemotherapy, and based on in vitro assays and the genetic profile, we show, for the first time, that ABCG2 protein can be used as an independent marker for TIC identification in breast cancer.

Trastuzumab induced cardiotoxicity in HER2 positive breast cancer patients attended in a tertiary hospital.

BACKGROUND: The use of trastuzumab is associated with an increased survival rate in HER2 positive breast cancer patients. However, it is related to different levels of cardiotoxicity leading to treatment discontinuation, which can deprive patients of the benefits of this therapy. OBJECTIVE: This study aimed to identify the incidence of trastuzumab induced cardiotoxicity (TIC) and the rate of discontinuation of trastuzumab in clinical practice. Possible factors associated with TIC were also investigated. SETTING: This study was conducted in the General Hospital of the School of Medicine of Ribeirão Preto, University of São Paulo. METHODS: We retrospectively reviewed the medical records of patients without distant metastasis that started trastuzumab between 2007 and 2011 in the tertiary hospital. TIC was defined as symptomatic heart failure or a decrease in left ventricular ejection fraction (LVEF) by ≥10 % compared to the first echocardiography measurement or to <50 % at any time. Logistic regression models were used to estimate odds ratios and their respective 95 % confidence intervals for TIC associated with variables such as age, body mass index, smoking history, cardiac risks, type of surgery, presence of positive lymph nodes, chemotherapy regimen and epirubicin cumulative dose. MAIN OUTCOME MEASURE: The incidence and factors associated with TIC and the rate of discontinuation of trastuzumab in clinical practice. RESULTS: We analyzed the records of 79 patients. TIC developed in 26 (32.9 %) patients, being the LVEF decline by ≥10 % observed in 21 (26.6 %), a decreased to <50 % in four (5.1 %) and one (1.2 %) was symptomatic without LVEF decline. Thirteen (16.4 %) patients discontinued permanently the treatment, three (3.8 %) discontinued temporarily and 10 (12.6 %) finished it without interruption. None of the covariates influenced on the incidence of TIC in this population. CONCLUSION: Although most patients finished their treatment, TIC led to trastuzumab discontinuation in a significant proportion of patients suggesting the need of a closer cardiac monitoring. None of the covariates influenced on the incidence of TIC, which can be due to the relatively small sample. Thus, larger scale studies should be conducted in order to establish which specific factors are associated with the development of TIC in order to avoid it.

Epidemiological report on the treatment of patients with gestational trophoblastic disease in 10 Brazilian referral centers: results after 12 years since International FIGO 2000 Consensus.

OBJECTIVE: To evaluate treatment of Brazilian patients with gestational trophoblastic disease (GTD). STUDY DESIGN: A retrospective cohort study with analysis of medical reports performed in 10 Brazilian referral centers from January 2000 to December 2011. RESULTS: Of 5,250 patients 3 died (0.06%) at the time of uterine evacuation. Spontaneous remission of GTD (group G1) was observed in 4,103 cases, and 1,144 (21.8%) progressed to gestational trophoblastic neoplasia (GTN) (G2). In G1 2,716 (66.2%) had complete hydatidiform mole (HM) and 1,210, partial HM (29.5%); 3,772 patients (92.7%) recovered as noted in December 2012. In G2, of 1,118 patients treated, initial histopathological results of previous gestation were complete HM (77.5% [n = 886]), partial HM (8.8% [n = 100]), and choriocarcinoma (8.0% [n = 92]); 930 (81.3%) were low-risk, 200 (17.5%) were high-risk GTN, and 14 had placental site trophoblastic tumor (PSTT) (1.2%); cure was achieved in 1,078 cases (96.4%), but 26 patients (2.3%) died (4 low-risk [0.4%], 19 high-risk [9.5%], and 3 PSTT [21.4%]). CONCLUSION: The highest death rates were due to high-risk GTN and PSTT. Patients with molar pregnancy should be referred to a referral center for an early diagnosis and prompt treatment of GTN in order to reduce the morbidity and mortality found in advanced stages.

Volume of breast tissue excised during breast-conserving surgery in patients undergoing preoperative systemic therapy.

PURPOSE: We aimed to determine whether clinical examination could adequately ascertain the volume of tissue to be resected during breast-conserving surgery after neoadjuvant therapy. METHODS: We reviewed the clinical reports of 279 patients with histologically diagnosed invasive breast carcinomas treated with neoadjuvant therapy followed by surgery or with primary surgery alone. We estimated volumes of excised tissues, the volume of the tumor mass and the optimal volume required for excision based on 1 cm of clear margins. The actual excess of resected volume was estimated by calculating the resection ratio measured as the volume of the resected specimen divided by the optimal specimen volume. The study endpoints were to analyze the extent of tissue resection and to ascertain the effect of excess resected tissue on surgical margins in both groups of patients. RESULTS: The median tumor diameter was 2.0 and 1.5 cm in the surgery and neoadjuvant therapy groups, respectively. The median volume of resected mammary tissue was 64.3 cm³ in the primary surgery group and 90.7 cm³ in the neoadjuvant therapy group. The median resection ratios in the primary surgery and neoadjuvant therapy groups were 2.0 and 3.3, respectively (p<0.0001). Surgical margin data were similar in both groups. Comparison of the volume of resected mammary tissues with the tumor diameters showed a positive correlation in the primary surgery group and no correlation in the neoadjuvant therapy group. CONCLUSION: Surgeons tend to excise large volumes of tissue during breast-conserving surgery after neoadjuvant therapy, thereby resulting in a loss of the correlation between tumor diameter and volume of the excised specimen.

Expression of aldehyde dehydrogenase after neoadjuvant chemotherapy is associated with expression of hypoxia-inducible factors 1 and 2 alpha and predicts prognosis in locally advanced breast cancer.

OBJECTIVE: To analyze the expression of hypoxia-inducible factors (hypoxia-inducible factor 1A and hypoxia-inducible factor 2A) and aldehyde dehydrogenase proteins in patients with locally advanced breast carcinoma who were subjected to neoadjuvant chemotherapy. METHODS: We included 90 patients with histologically confirmed stage II and III breast carcinoma who were treated with neoadjuvant chemotherapy between 2000 and 2005. Immunohistochemistry for aldehyde dehydrogenase, hypoxia-inducible factor 1A, and hypoxia-inducible factor 2A was performed before and after neoadjuvant chemotherapy. We analyzed the influence of clinical and pathological features on clinical and pathological response, disease-free survival, and overall survival. RESULTS: An objective clinical response to neoadjuvant chemotherapy was observed in 80% of patients, with 12% showing a complete pathological response. Among all clinical and pathological parameters, only the expression of hypoxia-inducible factor 1A was associated with a pathological response. A positive association was found between expression of aldehyde dehydrogenase and that of hypoxia-inducible factor 1A before and after chemotherapy. Aldehyde dehydrogenase expression was associated with expression of hypoxia inducible-factor 2A in tumors after neoadjuvant treatment. In a univariate analysis, prognosis was influenced by age, pathological response, metastasis to axillary lymph nodes after neoadjuvant chemotherapy, overexpression of hypoxia-inducible factor 2, and the presence of aldehyde dehydrogenase-positive cells within the primary tumor after neoadjuvant chemotherapy. In a multivariate analysis, only age and the presence of aldehyde dehydrogenase-positive cells after chemotherapy were associated with reduced overall survival. CONCLUSION: The presence of aldehyde dehydrogenase-positive cells within the residual tumor after neoadjuvant chemotherapy is associated with an increase in the expression of hypoxia-inducible factor 2A and with poor prognosis in patients with locally advanced breast cancer.