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Importance: There has been little consideration of genomic risk of recurrence by breast cancer subtype despite evidence of racial disparities in breast cancer outcomes. Objective: To evaluate associations between clinical trial end points, namely pathologic complete response (pCR) and distant recurrence-free survival (DRFS), and race and examine whether gene expression signatures are associated with outcomes by race. Design, Setting, and Participants: This retrospective cohort study used data from the Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2 (I-SPY 2) multicenter clinical trial of neoadjuvant chemotherapy with novel agents and combinations for patients with previously untreated stage II/III breast cancer. Analyses were conducted of associations between race and short- and long-term outcomes, overall and by receptor subtypes, and their association with 28 expression biomarkers. The trial enrolled 990 female patients between March 30, 2010, and November 5, 2016, with a primary tumor size of 2.5 cm or greater and clinical or molecular high risk based on MammaPrint or hormone receptor (HR)-negative/ERBB2 (formerly HER2 or HER2/neu)-positive subtyping across 9 arms. This data analysis was performed between June 10, 2021, and October 20, 2022. Exposure: Race, tumor receptor subtypes, and genomic biomarker expression of early breast cancer. Main Outcomes and Measures: The primary outcomes were pCR and DRFS assessed by race, overall, and by tumor subtype using logistic regression and Cox proportional hazards regression models. The interaction between 28 expression biomarkers and race, considering pCR and DRFS overall and within subtypes, was also evaluated. Results: The analytic sample included 974 participants (excluding 16 self-reporting as American Indian or Alaska Native, Native Hawaiian or Other Pacific Islander, or multiple races due to small sample sizes), including 68 Asian (7%), 120 Black (12%), and 786 White (81%) patients. Median (range) age at diagnosis was 47 (25-71) years for Asian, 49 (25-77) for Black, and 49 (23-73) years for White patients. The pCR rates were 32% (n = 22) for Asian, 30% for Black (n = 36), and 32% for White (n = 255) patients (P = .87). Black patients with HR-positive/ERBB2-negative tumors not achieving pCR had significantly worse DRFS than their White counterparts (hazard ratio, 2.28; 95% CI, 1.24-4.21; P = .01), with 5-year DRFS rates of 55% (n = 32) and 77% (n = 247), respectively. Black patients with HR-positive/ERBB2-negative tumors, compared with White patients, had higher expression of an interferon signature (mean [SD], 0.39 [0.87] and -0.10 [0.99]; P = .007) and, compared with Asian patients, had a higher mitotic score (mean [SD], 0.07 [1.08] and -0.69 [1.06]; P = .01) and lower estrogen receptor/progesterone receptor signature (mean [SD], 0.31 [0.90] and 1.08 [0.95]; P = .008). A transforming growth factor ß signature had a significant association with race relative to pCR and DRFS, with a higher signature associated with lower pCR and worse DRFS outcomes among Black patients only. Conclusions and Relevance: The findings show that women with early high-risk breast cancer who achieve pCR have similarly good outcomes regardless of race, but Black women with HR-positive/ERBB2-negative tumors without pCR may have worse DRFS than White women, highlighting the need to develop and test novel biomarker-informed therapies in diverse populations.
Assuntos
Neoplasias da Mama , Grupos Raciais , Feminino , Humanos , Neoplasias da Mama/genética , Estudos Retrospectivos , Transcriptoma , Resposta Patológica Completa , Intervalo Livre de DoençaRESUMO
IMPORTANCE: Residual cancer burden (RCB) distributions may improve the interpretation of efficacy in neoadjuvant breast cancer trials. OBJECTIVE: To compare RCB distributions between randomized control and investigational treatments within subtypes of breast cancer and explore the relationship with survival. DESIGN, SETTING, AND PARTICIPANTS: The I-SPY2 is a multicenter, platform adaptive, randomized clinical trial in the US that compares, by subtype, investigational agents in combination with chemotherapy vs chemotherapy alone in adult women with stage 2/3 breast cancer at high risk of early recurrence. Investigational treatments graduated in a prespecified subtype if there was 85% or greater predicted probability of higher rate of pathologic complete response (pCR) in a confirmatory, 300-patient, 1:1 randomized, neoadjuvant trial in that subtype. Evaluation of a secondary end point was reported from the 10 investigational agents tested in the I-SPY2 trial from March 200 through 2016, and analyzed as of September 9, 2020. The analysis plan included modeling of RCB within subtypes defined by hormone receptor (HR) and ERBB2 status and compared control treatments with investigational treatments that graduated and those that did not graduate. INTERVENTIONS: Neoadjuvant paclitaxel plus/minus 1 of several investigational agents for 12 weeks, then 12 weeks of cyclophosphamide/doxorubicin chemotherapy followed by surgery. MAIN OUTCOMES AND MEASURES: Residual cancer burden (pathological measure of residual disease) and event-free survival (EFS). RESULTS: A total of 938 women (mean [SD] age, 49 [11] years; 66 [7%] Asian, 103 [11%] Black, and 750 [80%] White individuals) from the first 10 investigational agents were included, with a median follow-up of 52 months (IQR, 29 months). Event-free survival worsened significantly per unit of RCB in every subtype of breast cancer (HR-positive/ERBB2-negative: hazard ratio [HZR], 1.75; 95% CI, 1.45-2.16; HR-positive/ERBB2-positive: HZR, 1.55; 95% CI, 1.18-2.05; HR-negative/ERBB2-positive: HZR, 2.39; 95% CI, 1.64-3.49; HR-negative/ERBB2-negative: HZR, 1.99; 95% CI, 1.71-2.31). Prognostic information from RCB was similar from treatments that graduated (HZR, 2.00; 95% CI, 1.57-2.55; 254 [27%]), did not graduate (HZR, 1.87; 95% CI, 1.61-2.17; 486 [52%]), or were control (HZR, 1.79; 95% CI, 1.42-2.26; 198 [21%]). Investigational treatments significantly lowered RCB in HR-negative/ERBB2-negative (graduated and nongraduated treatments) and ERBB2-positive subtypes (graduated treatments), with improved EFS (HZR, 0.61; 95% CI, 0.41-0.93) in the exploratory analysis. CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, the prognostic significance of RCB was consistent regardless of subtype and treatment. Effective neoadjuvant treatments shifted the distribution of RCB in addition to increasing pCR rate and appeared to improve EFS. Using a standardized quantitative method to measure response advances the interpretation of efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01042379.
Assuntos
Neoplasias da Mama , Terapia Neoadjuvante , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante/métodos , Neoplasia Residual , Prognóstico , Intervalo Livre de Progressão , Receptor ErbB-2/análiseRESUMO
Importance: Pathologic complete response (pCR) is a known prognostic biomarker for long-term outcomes. The I-SPY2 trial evaluated if the strength of this clinical association persists in the context of a phase 2 neoadjuvant platform trial. Objective: To evaluate the association of pCR with event-free survival (EFS) and pCR with distant recurrence-free survival (DRFS) in subpopulations of women with high-risk operable breast cancer treated with standard therapy or one of several novel agents. Design, Setting, and Participants: Multicenter platform trial of women with operable clinical stage 2 or 3 breast cancer with no prior surgery or systemic therapy for breast cancer; primary tumors were 2.5 cm or larger. Women with tumors that were ERBB2 negative/hormone receptor (HR) positive with low 70-gene assay score were excluded. Participants were adaptively randomized to one of several different investigational regimens or control therapy within molecular subtypes from March 2010 through 2016. The analysis included participants with follow-up data available as of February 26, 2019. Interventions: Standard-of-care neoadjuvant therapy consisting of taxane treatment with or without (as control) one of several investigational agents or combinations followed by doxorubicin and cyclophosphamide. Main Outcomes and Measures: Pathologic complete response and 3-year EFS and DRFS. Results: Of the 950 participants (median [range] age, 49 [23-77] years), 330 (34.7%) achieved pCR. Three-year EFS and DRFS for patients who achieved pCR were both 95%. Hazard ratios for pCR vs non-pCR were 0.19 for EFS (95% CI, 0.12-0.31) and 0.21 for DRFS (95% CI, 0.13-0.34) and were similar across molecular subtypes, varying from 0.14 to 0.18 for EFS and 0.10 to 0.20 for DRFS. Conclusions and Relevance: The 3-year outcomes from the I-SPY2 trial show that, regardless of subtype and/or treatment regimen, including 9 novel therapeutic combinations, achieving pCR after neoadjuvant therapy implies approximately an 80% reduction in recurrence rate. The goal of the I-SPY2 trial is to rapidly identify investigational therapies that may improve pCR when validated in a phase 3 confirmatory trial. Whether pCR is a validated surrogate in the sense that a therapy that improves pCR rate can be assumed to also improve long-term outcome requires further study. Trial Registration: ClinicalTrials.gov Identifier: NCT01042379.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante/efeitos adversos , Recidiva Local de Neoplasia/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Hidrocarbonetos Aromáticos com Pontes/administração & dosagem , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Intervalo Livre de Doença , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Intervalo Livre de Progressão , Modelos de Riscos Proporcionais , Receptor ErbB-2/genética , Taxoides/administração & dosagem , Taxoides/efeitos adversos , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Resultado do TratamentoRESUMO
PURPOSE: The phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin is a key pathway of survival and therapeutic resistance in breast cancer. We evaluated the pan-Akt inhibitor MK-2206 in combination with standard therapy in patients with high-risk early-stage breast cancer. PATIENTS AND METHODS: I-SPY 2 is a multicenter, phase II, open-label, adaptively randomized neoadjuvant platform trial that screens experimental therapies and efficiently identifies potential predictive biomarker signatures. Patients are categorized by human epidermal growth factor receptor 2 (HER2), hormone receptor (HR), and MammaPrint statuses in a 2 × 2 × 2 layout. Patients within each of these 8 biomarker subtypes are adaptively randomly assigned to one of several experimental therapies, including MK-2206, or control. Therapies are evaluated for 10 biomarker signatures, each of which is a combination of these subtypes. The primary end point is pathologic complete response (pCR). A therapy graduates with one or more of these signatures if and when it has an 85% Bayesian predictive probability of success in a hypothetical phase III trial, adjusting for biomarker covariates. Patients in the current report received standard taxane- and anthracycline-based neoadjuvant therapy without (control) or with oral MK-2206 135 mg/week. RESULTS: MK-2206 graduated with 94 patients and 57 concurrently randomly assigned controls in 3 graduation signatures: HR-negative/HER2-positive, HR-negative, and HER2-positive. Respective Bayesian mean covariate-adjusted pCR rates and percentage probability that MK-2206 is superior to control were 0.48:0.29 (97%), 0.62:0.36 (99%), and 0.46:0.26 (94%). In exploratory analyses, MK-2206 evinced a numerical improvement in event-free survival in its graduating signatures. The most significant grade 3-4 toxicity was rash (14% maculopapular, 8.6% acneiform). CONCLUSION: The Akt inhibitor MK-2206 combined with standard neoadjuvant therapy resulted in higher estimated pCR rates in HR-negative and HER2-positive breast cancer. Although MK-2206 is not being further developed at this time, this class of agents remains of clinical interest.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/biossíntese , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/enzimologia , Neoplasias da Mama/cirurgia , Doxorrubicina/administração & dosagem , Doxorrubicina/efeitos adversos , Feminino , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Proteínas Proto-Oncogênicas c-akt/antagonistas & inibidores , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores de Esteroides/metabolismo , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversosRESUMO
BACKGROUND: The VARK model categorizes learners by preferences for 4 modalities: visual, aural, read/write, and kinesthetic. Previous single-institution studies found that VARK preferences are associated with academic performance. This multi-institutional study was conducted to test the hypothesis that the VARK learning preferences of residents differ from the general population and that they are associated with performance on the American Board of Surgery In-Training Examination (ABSITE). METHODS: The VARK inventory was administered to residents at 5 general surgery programs. The distribution of the VARK preferences of residents was compared with the general population. ABSITE results were analyzed for associations with VARK preferences. χ2, Analysis of variance, and multiple linear regression were used for statistical analysis. RESULTS: A total of 132 residents completed the VARK inventory. The distribution of the VARK preferences of residents was different than the general population (P < .001). The number of aural responses on the VARK inventory was an independent predictor of ABSITE percentile rank (P = .03), percent of questions correct (P = .01), and standard score (P = .01). CONCLUSION: This study represents the first multi-institutional study to examine VARK preferences among surgery residents. The distribution of preferences among residents was different than that of the general population. Residents with a greater number of aural responses on VARK had greater ABSITE scores. The VARK model may have potential to improve learning efficiency among residents.
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Cirurgia Geral/educação , Internato e Residência , Aprendizagem , Cirurgiões/psicologia , Avaliação Educacional , Feminino , Humanos , Modelos Lineares , Masculino , Modelos Educacionais , Estudos Retrospectivos , Estados UnidosRESUMO
Importance: In the United States from 2009 to 2013, the incidence of breast cancer was the highest of any cancer and the death rate was second to that of lung cancer. Approximately 5% to 10% of breast cancers are inheritable. Observations: BRCA1 and BRCA2 germline mutations account for up to 30% of inheritable breast cancers and are the most commonly assessed mutations in patients presenting with early-onset breast cancer, triple-negative breast cancer, bilateral breast cancer, and a family history of breast cancer. Less common non-BRCA mutations have also been identified and contribute to hereditary breast cancer syndromes. Although established in BRCA mutations, indications and interpretations of genetic testing in non-BRCA mutations are not well defined. Furthermore, costs associated with genetic testing are highly variable and dependent on laboratory pricing, insurance coverage, and individual risk factors. Conclusions and Relevance: Genetic testing is a powerful tool that allows for the detection of BRCA and non-BRCA germline mutations in individuals with high risks of breast cancer, which in turn aids in the individualization of treatment. Given the magnitude of this disease, it is of great benefit for physicians, including general surgeons, to understand the indications, interpretations, and costs associated with genetic testing in patients with breast cancer. Cost is an especially important part of the genetic testing process and point of discussion with patients.
Assuntos
Proteína BRCA1/genética , Proteína BRCA2/genética , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Testes Genéticos , Neoplasias da Mama/mortalidade , Feminino , Predisposição Genética para Doença/genética , Testes Genéticos/economia , Mutação em Linhagem Germinativa/genética , Custos de Cuidados de Saúde , Humanos , Neoplasias Primárias Múltiplas/genética , Educação de Pacientes como Assunto , Neoplasias de Mama Triplo Negativas/genética , Estados UnidosRESUMO
BACKGROUND: The heterogeneity of breast cancer makes identifying effective therapies challenging. The I-SPY 2 trial, a multicenter, adaptive phase 2 trial of neoadjuvant therapy for high-risk clinical stage II or III breast cancer, evaluated multiple new agents added to standard chemotherapy to assess the effects on rates of pathological complete response (i.e., absence of residual cancer in the breast or lymph nodes at the time of surgery). METHODS: We used adaptive randomization to compare standard neoadjuvant chemotherapy plus the tyrosine kinase inhibitor neratinib with control. Eligible women were categorized according to eight biomarker subtypes on the basis of human epidermal growth factor receptor 2 (HER2) status, hormone-receptor status, and risk according to a 70-gene profile. Neratinib was evaluated against control with regard to 10 biomarker signatures (prospectively defined combinations of subtypes). The primary end point was pathological complete response. Volume changes on serial magnetic resonance imaging were used to assess the likelihood of such a response in each patient. Adaptive assignment to experimental groups within each disease subtype was based on Bayesian probabilities of the superiority of the treatment over control. Enrollment in the experimental group was stopped when the 85% Bayesian predictive probability of success in a confirmatory phase 3 trial of neoadjuvant therapy reached a prespecified threshold for any biomarker signature ("graduation"). Enrollment was stopped for futility if the probability fell to below 10% for every biomarker signature. RESULTS: Neratinib reached the prespecified efficacy threshold with regard to the HER2-positive, hormone-receptor-negative signature. Among patients with HER2-positive, hormone-receptor-negative cancer, the mean estimated rate of pathological complete response was 56% (95% Bayesian probability interval [PI], 37 to 73%) among 115 patients in the neratinib group, as compared with 33% among 78 controls (95% PI, 11 to 54%). The final predictive probability of success in phase 3 testing was 79%. CONCLUSIONS: Neratinib added to standard therapy was highly likely to result in higher rates of pathological complete response than standard chemotherapy with trastuzumab among patients with HER2-positive, hormone-receptor-negative breast cancer. (Funded by QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Quinolinas/administração & dosagem , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Teorema de Bayes , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Quinolinas/efeitos adversos , Receptor ErbB-2 , Receptores de Estrogênio , Receptores de Progesterona , Trastuzumab/administração & dosagemRESUMO
BACKGROUND: The genetic and clinical heterogeneity of breast cancer makes the identification of effective therapies challenging. We designed I-SPY 2, a phase 2, multicenter, adaptively randomized trial to screen multiple experimental regimens in combination with standard neoadjuvant chemotherapy for breast cancer. The goal is to match experimental regimens with responding cancer subtypes. We report results for veliparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, combined with carboplatin. METHODS: In this ongoing trial, women are eligible for participation if they have stage II or III breast cancer with a tumor 2.5 cm or larger in diameter; cancers are categorized into eight biomarker subtypes on the basis of status with regard to human epidermal growth factor receptor 2 (HER2), hormone receptors, and a 70-gene assay. Patients undergo adaptive randomization within each biomarker subtype to receive regimens that have better performance than the standard therapy. Regimens are evaluated within 10 biomarker signatures (i.e., prospectively defined combinations of biomarker subtypes). Veliparib-carboplatin plus standard therapy was considered for HER2-negative tumors and was therefore evaluated in 3 signatures. The primary end point is pathological complete response. Tumor volume changes measured by magnetic resonance imaging during treatment are used to predict whether a patient will have a pathological complete response. Regimens move on from phase 2 if and when they have a high Bayesian predictive probability of success in a subsequent phase 3 neoadjuvant trial within the biomarker signature in which they performed well. RESULTS: With regard to triple-negative breast cancer, veliparib-carboplatin had an 88% predicted probability of success in a phase 3 trial. A total of 72 patients were randomly assigned to receive veliparib-carboplatin, and 44 patients were concurrently assigned to receive control therapy; at the completion of chemotherapy, the estimated rates of pathological complete response in the triple-negative population were 51% (95% Bayesian probability interval [PI], 36 to 66%) in the veliparib-carboplatin group versus 26% (95% PI, 9 to 43%) in the control group. The toxicity of veliparib-carboplatin was greater than that of the control. CONCLUSIONS: The process used in our trial showed that veliparib-carboplatin added to standard therapy resulted in higher rates of pathological complete response than standard therapy alone specifically in triple-negative breast cancer. (Funded by the QuantumLeap Healthcare Collaborative and others; I-SPY 2 TRIAL ClinicalTrials.gov number, NCT01042379.).
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzimidazóis/administração & dosagem , Carboplatina/administração & dosagem , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Teorema de Bayes , Benzimidazóis/efeitos adversos , Carboplatina/efeitos adversos , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Paclitaxel/administração & dosagem , Paclitaxel/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/administração & dosagem , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Neoplasias de Mama Triplo Negativas/cirurgiaRESUMO
BACKGROUND: The aim of our study was to determine if a fresh cadaver model is a viable method for teaching ultrasound (US)-guided breast biopsy of palpable breast lesions. METHODS: Third-year medical students were assessed both preinstruction and postinstruction on their ability to perform US-guided needle aspiration or biopsy of artificially created masses using a 10-item checklist. RESULTS: Forty-one third-year medical students completed the cadaver laboratory as part of the surgery clerkship. Eight items on the checklist were found to be significantly different between pre-testing and post-testing. The mean preinstruction score was 2.4, whereas the mean postinstruction score was 7.10 (P < .001). CONCLUSIONS: Fresh cadaver models have been widely used in medical education. However, there are few fresh cadaver models that provide instruction on procedures done in the outpatient setting. Our model was found to be an effective method for the instruction of US-guided breast biopsy among medical students.
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Mama/patologia , Competência Clínica , Educação de Graduação em Medicina/métodos , Cirurgia Geral/educação , Ultrassonografia Doppler , Biópsia por Agulha/métodos , Cadáver , Estágio Clínico/métodos , Avaliação Educacional , Feminino , Humanos , Biópsia Guiada por Imagem/métodos , Masculino , Modelos Educacionais , Melhoria de QualidadeRESUMO
Positive lymph node status in breast cancer is known to be an adverse prognostic factor, but the effect of lymph node (LN) status in inflammatory breast cancer (IBC) has not been evaluated. This study was designed to investigate the association between lymph node status and overall survival (OS) in individuals with IBC. Using the Surveillance, Epidemiology, and End Results (SEER) 18 registry, we collected data on 761 patients diagnosed with non-metastatic IBC from 2004 to 2008. Survival analysis was performed using the Kaplan-Meier method. Cox proportional hazard regression was performed to evaluate univariate and multivariate associations between estrogen and progesterone receptor (ER/PR) status, treatment, and OS. Positive nodal status was associated with a significant decrease in OS (p < 0.001). Five-year survival for LN-positive and LN-negative patients was 49 and 66 %, respectively. In node-positive patients, ER or PR positivity was associated with improved OS, (p = 0.025, p = 0.007). In node-positive patients, the combination of surgery and radiation therapy improved OS when compared with surgery alone (p = 0.002). Nearly 80 % of the patients in this study had nodal metastasis. Positive nodal status was found to be an adverse prognostic factor. ER/PR positivity and treatment with surgery and radiation in node-positive patients was found to improve outcomes. Further studies are required to characterize the biology of IBC and guide the optimal treatment of this disease.
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Neoplasias Inflamatórias Mamárias/patologia , Linfonodos/patologia , Metástase Linfática/patologia , Prognóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Neoplasias Inflamatórias Mamárias/epidemiologia , Neoplasias Inflamatórias Mamárias/genética , Pessoa de Meia-Idade , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genéticaRESUMO
The many improvements in breast cancer therapy in recent years have so lowered rates of recurrence that it is now difficult or impossible to conduct adequately powered adjuvant clinical trials. Given the many new drugs and potential synergistic combinations, the neoadjuvant approach has been used to test benefit of drug combinations in clinical trials of primary breast cancer. A recent FDA-led meta-analysis showed that pathologic complete response (pCR) predicts disease-free survival (DFS) within patients who have specific breast cancer subtypes. This meta-analysis motivated the FDA's draft guidance for using pCR as a surrogate endpoint in accelerated drug approval. Using pCR as a registration endpoint was challenged at ASCO 2014 Annual Meeting with the presentation of ALTTO, an adjuvant trial in HER2-positive breast cancer that showed a nonsignificant reduction in DFS hazard rate for adding lapatinib, a HER-family tyrosine kinase inhibitor, to trastuzumab and chemotherapy. This conclusion seemed to be inconsistent with the results of NeoALTTO, a neoadjuvant trial that found a statistical improvement in pCR rate for the identical lapatinib-containing regimen. We address differences in the two trials that may account for discordant conclusions. However, we use the FDA meta-analysis to show that there is no discordance at all between the observed pCR difference in NeoALTTO and the observed HR in ALTTO. This underscores the importance of appropriately modeling the two endpoints when designing clinical trials. The I-SPY 2/3 neoadjuvant trials exemplify this approach.
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Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Ensaios Clínicos como Assunto , Descoberta de Drogas , Feminino , Humanos , Terapia Neoadjuvante , Resultado do TratamentoRESUMO
BACKGROUND AND OBJECTIVES: This study was performed to investigate recent trends and factors associated with immediate breast reconstruction (IBR) using a large population-based registry. We hypothesized that rates of IBR have increased since passage of the Women's Health and Cancer Rights Act of 1998. METHODS: The SEER (surveillance, epidemiology and end results) database was used to evaluate Stage I-III breast cancer (BC) patients who underwent total mastectomy from 1998 to 2008. Univariate and multivariate analyses were performed to study predictors of IBR. RESULTS: Of 112,348 patients with BC treated by mastectomy 18,001 (16%) had IBR. Rates of IBR increased significantly from 1998 to 2008 (P < 0.0001). Use of IBR significantly decreased as patient age increased (P < 0.0001), as stage increased (P < 0.0001), and as the number of positive lymph nodes increased (P < 0.0001). Estrogen receptor+/progesterone receptor+ (ER+/PR+) patients had significantly higher IBR rates than ER-/PR-patients (P < 0.0001). IBR was used in 3,615 of 25,823 (14.0%) of patients having post-mastectomy radiation (XRT) and in 14,188 of 86,513 (16.4%) of those not having XRT (P < 0.0001). CONCLUSIONS: The utilization of IBR has increased significantly over the last decade. IBR was found to be significantly associated with age, race, geographical region, stage, ER, grade, LN status, and XRT (P < 0.0001).
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Neoplasias da Mama/cirurgia , Mamoplastia/tendências , Mastectomia , Programa de SEER , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Neoplasias da Mama/radioterapia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de NeoplasiasRESUMO
Cowden syndrome is caused by germline mutations in PTEN and clinically characterized by hamartomas, macrocephaly, classic dermatologic stigmata, and an estimated 85 % lifetime risk of female breast cancer. A young woman with macrocephaly, tricholemmomas, AV malformations, and mammary papillomatosis was found to be hemizygous for PTEN in her germline DNA. Using MLPA, comparative genomic hybridization, and DNA sequencing, we identified a 2-Mb deletion in chromosome 10 spanning 344-kb centromeric and 1.7-Mb telomeric of PTEN. Her father who has a clinical history including macrocephaly, Hashimoto's thyroiditis, colonic polyposis, acral keratoses, and goiter was also found to have the same deletion. In benign breast tissue from the hemizygous female, PTEN protein expression was significantly reduced in luminal and stromal cells but present in the myoepithelium. Compared with a typical papilloma of the breast which had intense cytoplasmic PTEN staining, the majority of the patient's papilloma had significantly decreased PTEN expression while some cells had mislocalized perinuclear PTEN expression. In addition to PTEN, 22 other protein-coding genes were deleted including two predicted haploinsufficient genes and five additional genes that have previously been associated with hereditary predispositions to certain diseases. However, because all significant clinical features of the proband and her father are common to patients with genetic alterations in PTEN, the other 22 hemizygous protein-coding genes appear to be haplosufficient.