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PURPOSE: Immunohistochemistry (IHC) is a newer technique for assessing the estrogen receptor (ER) status of breast cancers, with the potential to overcome many of the shortcomings associated with the traditional ligand-binding assay (LBA). The purpose of this study was to evaluate the ability of ER status determination by IHC, compared with LBA, to predict clinical outcome-especially response to adjuvant endocrine therapy-in a large number of patients with long-term clinical follow-up. PATIENTS AND METHODS: ER status was evaluated in 1,982 primary breast cancers by IHC on formalin-fixed paraffin-embedded tissue sections, using antibody 6F11 and standard methodology. Slides were scored on a scale representing the estimated proportion and intensity of positive-staining tumor cells (range, 0 to 8). Results were compared with ER values obtained by the LBA in the same tumors and to clinical outcome. RESULTS: An IHC score of greater than 2 (corresponding to as few as 1% to 10% weakly positive cells) was used to define ER positivity on the basis of a univariate cut-point analysis of all possible scores and disease-free survival (DFS) in patients receiving any adjuvant endocrine therapy. Using this definition, 71% of all tumors were determined to be ER-positive by IHC, and the level of agreement with the LBA was 86%. In multivariate analyses of patients receiving adjuvant endocrine therapy alone, ER status determined by IHC was better than that determined by the LBA at predicting improved DFS (hazard ratios/P = 0.474/.0008 and 0.707/.3214, respectively) and equivalent at predicting overall survival (0.379/.0001 and 0.381/.0003, respectively). CONCLUSION: IHC is superior to the LBA for assessing ER status in primary breast cancer because it is easier, safer, and less expensive, and has an equivalent or better ability to predict response to adjuvant endocrine therapy.
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Myoepithelial cells play key roles in normal mammary gland development and in limiting pre-invasive to invasive breast tumor progression, yet their differentiation and perturbation in ductal carcinoma in situ (DCIS) are poorly understood. Here, we investigated myoepithelial cells in normal breast tissues of BRCA1 and BRCA2 germline mutation carriers and in non-carrier controls, and in sporadic DCIS. We found that in the normal breast of non-carriers, myoepithelial cells frequently co-express the p63 and TCF7 transcription factors and that p63 and TCF7 show overlapping chromatin peaks associated with differentiated myoepithelium-specific genes. In contrast, in normal breast tissues of BRCA1 mutation carriers the frequency of p63+TCF7+ myoepithelial cells is significantly decreased and p63 and TCF7 chromatin peaks do not overlap. These myoepithelial perturbations in normal breast tissues of BRCA1 germline mutation carriers may play a role in their higher risk of breast cancer. The fraction of p63+TCF7+ myoepithelial cells is also significantly decreased in DCIS, which may be associated with invasive progression.
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Proteína BRCA1/metabolismo , Proteína BRCA2/metabolismo , Carcinoma Ductal de Mama/metabolismo , Mutación/genética , Animales , Proteína BRCA1/genética , Proteína BRCA2/genética , Carcinoma Ductal de Mama/genética , Línea Celular Tumoral , Proliferación Celular/genética , Proliferación Celular/fisiología , Femenino , Técnica del Anticuerpo Fluorescente , Mutación de Línea Germinal/genética , Humanos , Inmunohistoquímica , Ratones , Factor 1 de Transcripción de Linfocitos T/genética , Factor 1 de Transcripción de Linfocitos T/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/genética , Proteínas Supresoras de Tumor/metabolismoRESUMEN
To investigate immune escape during breast tumor progression, we analyzed the composition of leukocytes in normal breast tissues, ductal carcinoma in situ (DCIS), and invasive ductal carcinomas (IDC). We found significant tissue and tumor subtype-specific differences in multiple cell types including T cells and neutrophils. Gene expression profiling of CD45+CD3+ T cells demonstrated a decrease in CD8+ signatures in IDCs. Immunofluorescence analysis showed fewer activated GZMB+CD8+ T cells in IDC than in DCIS, including in matched DCIS and recurrent IDC. T-cell receptor clonotype diversity was significantly higher in DCIS than in IDCs. Immune checkpoint protein TIGIT-expressing T cells were more frequent in DCIS, whereas high PD-L1 expression and amplification of CD274 (encoding PD-L1) was only detected in triple-negative IDCs. Coamplification of a 17q12 chemokine cluster with ERBB2 subdivided HER2+ breast tumors into immunologically and clinically distinct subtypes. Our results show coevolution of cancer cells and the immune microenvironment during tumor progression.Significance: The design of effective cancer immunotherapies requires the understanding of mechanisms underlying immune escape during tumor progression. Here we demonstrate a switch to a less active tumor immune environment during the in situ to invasive breast carcinoma transition, and identify immune regulators and genomic alterations that shape tumor evolution. Cancer Discov; 7(10); 1098-115. ©2017 AACR.See related commentary by Speiser and Verdeil, p. 1062This article is highlighted in the In This Issue feature, p. 1047.
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Neoplasias de la Mama/inmunología , Carcinoma Ductal de Mama/inmunología , Carcinoma Intraductal no Infiltrante/inmunología , Perfilación de la Expresión Génica/métodos , Linfocitos T/inmunología , Antígeno B7-H1/genética , Biomarcadores de Tumor/genética , Neoplasias de la Mama/genética , Complejo CD3/genética , Carcinoma Ductal de Mama/genética , Carcinoma Intraductal no Infiltrante/genética , Progresión de la Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Antígenos Comunes de Leucocito/genética , Receptor ErbB-2/genética , Microambiente TumoralRESUMEN
Purpose To determine the pathologic complete response (pCR) rate in estrogen receptor (ER) -positive primary breast cancer triaged to chemotherapy when the protein encoded by the MKI67 gene (Ki67) level was > 10% after 2 to 4 weeks of neoadjuvant aromatase inhibitor (AI) therapy. A second objective was to examine risk of relapse using the Ki67-based Preoperative Endocrine Prognostic Index (PEPI). Methods The American College of Surgeons Oncology Group (ACOSOG) Z1031A trial enrolled postmenopausal women with stage II or III ER-positive (Allred score, 6 to 8) breast cancer whose treatment was randomly assigned to neoadjuvant AI therapy with anastrozole, exemestane, or letrozole. For the trial ACOSOG Z1031B, the protocol was amended to include a tumor Ki67 determination after 2 to 4 weeks of AI. If the Ki67 was > 10%, patients were switched to neoadjuvant chemotherapy. A pCR rate of > 20% was the predefined efficacy threshold. In patients who completed neoadjuvant AI, stratified Cox modeling was used to assess whether time to recurrence differed by PEPI = 0 score (T1 or T2, N0, Ki67 < 2.7%, ER Allred > 2) versus PEPI > 0 disease. Results Only two of the 35 patients in ACOSOG Z1031B who were switched to neoadjuvant chemotherapy experienced a pCR (5.7%; 95% CI, 0.7% to 19.1%). After 5.5 years of median follow-up, four (3.7%) of the 109 patients with a PEPI = 0 score relapsed versus 49 (14.4%) of 341 of patients with PEPI > 0 (recurrence hazard ratio [PEPI = 0 v PEPI > 0], 0.27; P = .014; 95% CI, 0.092 to 0.764). Conclusion Chemotherapy efficacy was lower than expected in ER-positive tumors exhibiting AI-resistant proliferation. The optimal therapy for these patients should be further investigated. For patients with PEPI = 0 disease, the relapse risk over 5 years was only 3.6% without chemotherapy, supporting the study of adjuvant endocrine monotherapy in this group. These Ki67 and PEPI triage approaches are being definitively studied in the ALTERNATE trial (Alternate Approaches for Clinical Stage II or III Estrogen Receptor Positive Breast Cancer Neoadjuvant Treatment in Postmenopausal Women: A Phase III Study; clinical trial information: NCT01953588).
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/química , Neoplasias de la Mama/tratamiento farmacológico , Antígeno Ki-67/análisis , Recurrencia Local de Neoplasia , Anciano , Anastrozol , Androstadienos/uso terapéutico , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Toma de Decisiones Clínicas , Femenino , Estudios de Seguimiento , Humanos , Antígeno Ki-67/genética , Letrozol , Persona de Mediana Edad , Índice Mitótico , Terapia Neoadyuvante/métodos , Metástasis de la Neoplasia , Estadificación de Neoplasias , Nitrilos/uso terapéutico , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Receptores de Estrógenos/análisis , Receptores de Estrógenos/genética , Receptores de Progesterona/genética , Tasa de Supervivencia , Transcriptoma , Triazoles/uso terapéuticoRESUMEN
Fibroblast growth factor receptor 1 (FGFR1) amplification drives poor prognosis and is an emerging therapeutic target. We sought to construct a multigene mRNA expression signature to efficiently identify FGFR1-amplified estrogen receptor-positive (ER+) breast tumors. Five independent breast tumor series were analyzed. Genes discriminative for FGFR1 amplification were screened transcriptome-wide by receiver operating characteristic analyses. The METABRIC series was leveraged to construct/evaluate four approaches to signature composition. A locked-down signature was validated with 651 ER+ formalin-fixed, paraffin-embedded tissues (the University of British Columbia-tamoxifen cohort). A NanoString nCounter assay was designed to profile selected genes. For a gold standard, FGFR1 amplification was determined by fluorescent in situ hybridization (FISH). Prognostic effects of FGFR1 amplification were assessed by survival analyses. Eight 8p11-12 genes (ASH2L, BAG4, BRF2, DDHD2, LSM1, PROSC, RAB11FIP1, and WHSC1L1) together with the a priori selected FGFR1 gene, highly discriminated FGFR1 amplification (area under the receiver operating characteristic curve ≥0.82, all genes and all cohorts). The nine-gene signature Call-FGFR1-amp accurately identified FGFR1 FISH-amplified ER+ tumors in the University of British Columbia-tamoxifen cohort (specificity, 0.94; sensitivity, 0.96) and exhibited prognostic effects (disease-specific survival hazard ratio, 1.57; 95% CI, 1.14-2.16; P = 0.005). Call-FGFR1-amp includes several understudied 8p11-12 amplicon-driven oncogenes and accurately identifies FGFR1-amplified ER+ breast tumors. Our study demonstrates an efficient approach to diagnosing rare amplified therapeutic targets with FISH as a confirmatory assay.
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Neoplasias de la Mama/genética , Perfilación de la Expresión Génica , ARN Mensajero/metabolismo , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Receptores de Estrógenos/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Estudios de Cohortes , Femenino , Amplificación de Genes , Humanos , Estimación de Kaplan-Meier , Modelos de Riesgos Proporcionales , ARN Mensajero/genética , Curva ROC , TranscriptomaRESUMEN
HER2 gene-protein assay (GPA) is a new method for the simultaneous evaluation of HER2 immunohistochemistry (IHC) and HER2 dual in situ hybridization (DISH) on single tissue sections of breast cancer. We investigated the presence of HER2 gene and protein discrepancy and HER2-heterogeneity using HER2-GPA. HER2 status was analyzed for the correlation between the presence of HER2-heterogeneity and patient prognosis. Consecutive 280 invasive breast cancer were examined. Statuses of HER2 protein and gene were evaluated in whole tumor sections of HER2 GPA slides. HER2 protein and gene combination patterns were classified to six phenotypic and genotypic types for each case, as well as at individual cell levels: (A) IHC and DISH positive; (B) IHC positive and DISH negative; (C) IHC equivocal and DISH positive; (D) IHC equivocal and DISH negative; (E) IHC negative and DISH positive; and (F) IHC and DISH negative. The presence of HER2-heterogeneity was determined by the existence of at least two of six types within one tumor. HER2-IHC positive patients had significantly worse survival than IHC negative patients and HER2-DISH positive patients had significantly worse survival than DISH negative patients. HER2 IHC negative and DISH positive patients had significantly worse recurrence-free survival than IHC and DISH negative patients. In the HER2 IHC and DISH negative group, the HER2 heterogeneous group had significantly worse survival than the nonheterogeneous group. Notably, among triple negative breast cancer (TNBC), the HER2 heterogeneous group had significantly worse survival than the nonheterogeneous group. Our study suggests that the presence of HER2-heterogeneity might be a prognostic factor in HER2 negative breast cancer patients, especially in TNBC.
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Neoplasias de la Mama/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/genética , Femenino , Heterogeneidad Genética , Humanos , Persona de Mediana Edad , Pronóstico , Análisis de SupervivenciaRESUMEN
BACKGROUND: For women with hormone receptor-positive, operable breast cancer, surgical oophorectomy plus tamoxifen is an effective adjuvant therapy. We conducted a phase III randomized clinical trial to test the hypothesis that oophorectomy surgery performed during the luteal phase of the menstrual cycle was associated with better outcomes. METHODS: Seven hundred forty premenopausal women entered a clinical trial in which those women estimated not to be in the luteal phase of their menstrual cycle for the next one to six days (n = 509) were randomly assigned to receive treatment with surgical oophorectomy either delayed to be during a five-day window in the history-estimated midluteal phase of the menstrual cycles, or in the next one to six days. Women who were estimated to be in the luteal phase of the menstrual cycle for the next one to six days (n = 231) were excluded from random assignment and received immediate surgical treatments. All patients began tamoxifen within 6 days of surgery and continued this for 5 years. Kaplan-Meier methods, the log-rank test, and multivariable Cox regression models were used to assess differences in five-year disease-free survival (DFS) between the groups. All statistical tests were two-sided. RESULTS: The randomized midluteal phase surgery group had a five-year DFS of 64%, compared with 71% for the immediate surgery random assignment group (hazard ratio [HR] = 1.24, 95% confidence interval [CI] = 0.91 to 1.68, P = .18). Multivariable Cox regression models, which included important prognostic variables, gave similar results (aHR = 1.28, 95% CI = 0.94 to 1.76, P = .12). For overall survival, the univariate hazard ratio was 1.33 (95% CI = 0.94 to 1.89, P = .11) and the multivariable aHR was 1.43 (95% CI = 1.00 to 2.06, P = .05). Better DFS for follicular phase surgery, which was unanticipated, proved consistent across multiple exploratory analyses. CONCLUSIONS: The hypothesized benefit of adjuvant luteal phase oophorectomy was not shown in this large trial.
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Antineoplásicos Hormonales/administración & dosificación , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/cirugía , Fase Luteínica , Ovariectomía , Premenopausia , Tamoxifeno/administración & dosificación , Adulto , Neoplasias de la Mama/sangre , Neoplasias de la Mama/química , Neoplasias de la Mama/mortalidad , Supervivencia sin Enfermedad , Esquema de Medicación , Estrógenos/sangre , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Ciclo Menstrual , Oportunidad Relativa , Progesterona/sangre , Pronóstico , Modelos de Riesgos Proporcionales , Resultado del TratamientoRESUMEN
The mechanisms by which tumour cells metastasize and the role that cell polarity proteins play in this process are not well understood. We report that partitioning defective protein 3 (Par3) is dysregulated in metastasis in human breast cancer, and is associated with a higher tumour grade and ErbB2-positive status. Downregulation of Par3 cooperated with ErbB2 to induce cell invasion and metastasis in vivo. Interestingly, the metastatic behaviour was not associated with an overt mesenchymal phenotype. However, loss of Par3 inhibited E-cadherin junction stability, disrupted membrane and actin dynamics at cell-cell junctions and decreased cell-cell cohesion in a manner dependent on the Tiam1/Rac-GTP pathway. Inhibition of this pathway restored E-cadherin junction stability and blocked invasive behaviour of cells lacking Par3, suggesting that loss of Par3 promotes metastatic behaviour of ErbB2-induced tumour epithelial cells by decreasing cell-cell cohesion.
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Neoplasias de la Mama/metabolismo , Moléculas de Adhesión Celular/metabolismo , Adhesión Celular , Comunicación Celular , Proteínas de Ciclo Celular/metabolismo , Uniones Intercelulares/metabolismo , Proteínas de la Membrana/metabolismo , Citoesqueleto de Actina/metabolismo , Proteínas Adaptadoras Transductoras de Señales , Animales , Neoplasias de la Mama/genética , Neoplasias de la Mama/secundario , Cadherinas/metabolismo , Moléculas de Adhesión Celular/genética , Proteínas de Ciclo Celular/genética , Línea Celular Tumoral , Movimiento Celular , Forma de la Célula , Regulación hacia Abajo , Femenino , Regulación Neoplásica de la Expresión Génica , Genotipo , Factores de Intercambio de Guanina Nucleótido/metabolismo , Uniones Intercelulares/patología , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos NOD , Ratones SCID , Invasividad Neoplásica , Fenotipo , Interferencia de ARN , Receptor ErbB-2/metabolismo , Transducción de Señal , Proteína 1 de Invasión e Inducción de Metástasis del Linfoma-T , Factores de Tiempo , Transfección , Células Tumorales Cultivadas , Proteínas de Unión al GTP rac/metabolismoRESUMEN
The incidence of invasive breast cancer (IBC) can be dramatically reduced by improving our abilities to detect and treat ductal carcinoma in situ (DCIS). Progress will be based on a detailed understanding of molecular mechanisms responsible for tumor progression. An interesting study by Jang and colleagues evaluated and compared the frequency of amplification of four oncogenes (HER2, c-MYC, CCND1 and FGFR1) in large cohorts of pure DCIS, in the DCIS component of IBC, and in corresponding IBC. Of particular interest, they found a twofold increase in FGFR1 amplification in IBC versus pure DCIS, and significantly reduced disease-free survival in amplified versus unamplified IBC - leading the authors to conclude that FGFR1 plays an important role in the development and progression of IBC. These observations indeed provide hints that FGFR1 is important in this setting, although the issue is very complex and far from resolved.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Amplificación de Genes , Receptor Tipo 1 de Factor de Crecimiento de Fibroblastos/genética , Femenino , HumanosRESUMEN
PURPOSE: To determine the upstage rate from nonmalignant papillary breast lesions obtained at imaging-guided core needle biopsy (CNB) and if there are any clinical, imaging, or pathologic features that can be used to predict eventual upstaging to malignancy. MATERIALS AND METHODS: This retrospective case review was institutional review board approved and HIPAA compliant, with a waiver of informed consent. A database search (from January 2001 to March 2010) was performed to find patients with a nonmalignant papillary breast lesion diagnosed at CNB. Of the resulting 128 patients, 86 (67%) underwent surgical excision; 42 (33%) patients were observed with imaging, for a median observation time of 4.1 years (range, 1.0-8.6 years). Chart review was performed to determine pertinent features of each case. RESULTS: Fourteen of 128 patients were subsequently found to have malignancy at excision, for an upstage rate of 11%. Nine (7%) of the 128 patients were subsequently found to have atypia at excision. Comparisons between patients with upstaged lesions and patients whose lesions were not upstaged demonstrated patients with upstaged lesions to be slightly older (65 vs 56 years, P=.01), more likely to have a mass than calcifications at imaging (P=.03), and to have had less tissue obtained at biopsy (three vs five cores obtained, P=.02; 14- vs 9-gauge needle used, P<.01; no vacuum assistance used, P<.01). Most strongly predictive of eventual malignancy, however, was whether the interpreting pathologist qualified the benign diagnosis at CNB with additional commentary (P<.01). CONCLUSION: Given the substantial upstage rate (11%) of papillary lesions diagnosed at imaging-guided CNB, surgical excision is an appropriate management decision; however, careful evaluation in concert with an expert breast pathologist may allow for observation in appropriately selected patients.
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Biopsia con Aguja Gruesa/métodos , Neoplasias de la Mama/patología , Biopsia Guiada por Imagen/métodos , Mamografía/métodos , Papiloma Intraductal/patología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , Reproducibilidad de los Resultados , Sensibilidad y EspecificidadRESUMEN
These NCCN Guidelines Insights highlight the important updates/changes specific to the management of metastatic breast cancer in the 2012 version of the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer. These changes/updates include the issue of retesting of biomarkers (estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2) on recurrent disease, new information regarding first-line combination endocrine therapy for metastatic disease, a new section on monitoring of patients with metastatic disease, and new information on endocrine therapy combined with an mTOR inhibitor as a subsequent therapeutic option.
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Antineoplásicos Hormonales/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Biomarcadores de Tumor , Neoplasias de la Mama/metabolismo , Femenino , Humanos , Metástasis de la Neoplasia , Serina-Treonina Quinasas TOR/antagonistas & inhibidoresRESUMEN
Molecular mechanisms mediating the progression of ductal carcinoma in situ (DCIS) to invasive breast cancer remain largely unknown. We used gene expression profiling of human DCIS (n = 53) and invasive breast cancer (n = 51) to discover uniquely expressed genes that may also regulate progression. There were 470 total differentially expressed genes (≥2-fold; P < 0.05). Elevated expression of genes involved in synthesis and organization of extracellular matrix was particularly prominent in the epithelium of invasive breast cancer. The degree of overlap of the genes with nine similar studies in the literature was determined to help prioritize their potential importance, resulting in 74 showing overlap in ≥2 studies (average 3.6 studies/gene; range 2-8 studies). Using hierarchical clustering, the 74-gene profile correctly categorized 96% of samples in this study and 94% of samples from 3 similar independent studies. To study the progression of DCIS to invasive breast cancer in vivo, we introduced human DCIS cell lines engineered to express specific genes into a "mammary intraductal DCIS" xenograft model. Progression of xenografts to invasive breast cancer was dramatically increased by suppressing four genes that were usually elevated in clinical samples of DCIS, including a protease inhibitor (CSTA) and genes involved in cell adhesion and signaling (FAT1, DST, and TMEM45A), strongly suggesting that they normally function to suppress progression. In summary, we have identified unique gene expression profiles of human DCIS and invasive breast cancer, which include novel genes regulating tumor progression. Targeting some of these genes may improve the detection, diagnosis, and therapy of DCIS.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/patología , Regulación Neoplásica de la Expresión Génica , Animales , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal no Infiltrante/metabolismo , Línea Celular , Análisis por Conglomerados , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Genes Supresores de Tumor , Humanos , Ratones , Ratones SCID , Anotación de Secuencia Molecular , Invasividad Neoplásica/genética , Estadificación de Neoplasias , Trasplante HeterólogoRESUMEN
To correlate the variable clinical features of oestrogen-receptor-positive breast cancer with somatic alterations, we studied pretreatment tumour biopsies accrued from patients in two studies of neoadjuvant aromatase inhibitor therapy by massively parallel sequencing and analysis. Eighteen significantly mutated genes were identified, including five genes (RUNX1, CBFB, MYH9, MLL3 and SF3B1) previously linked to haematopoietic disorders. Mutant MAP3K1 was associated with luminal A status, low-grade histology and low proliferation rates, whereas mutant TP53 was associated with the opposite pattern. Moreover, mutant GATA3 correlated with suppression of proliferation upon aromatase inhibitor treatment. Pathway analysis demonstrated that mutations in MAP2K4, a MAP3K1 substrate, produced similar perturbations as MAP3K1 loss. Distinct phenotypes in oestrogen-receptor-positive breast cancer are associated with specific patterns of somatic mutations that map into cellular pathways linked to tumour biology, but most recurrent mutations are relatively infrequent. Prospective clinical trials based on these findings will require comprehensive genome sequencing.
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Inhibidores de la Aromatasa/uso terapéutico , Aromatasa/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Genoma Humano/genética , Anastrozol , Androstadienos/farmacología , Androstadienos/uso terapéutico , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Reparación del ADN , Exoma/genética , Exones/genética , Femenino , Variación Genética/genética , Humanos , Letrozol , MAP Quinasa Quinasa 4/genética , Quinasa 1 de Quinasa de Quinasa MAP/genética , Mutación/genética , Nitrilos/farmacología , Nitrilos/uso terapéutico , Receptores de Estrógenos/metabolismo , Resultado del Tratamiento , Triazoles/farmacología , Triazoles/uso terapéuticoRESUMEN
Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer. Although there is extensive information on the cellular and molecular changes in DCIS, there is limited ability to functionally test. The critical changes in premalignant progression. This review summarizes our experience with a recently developed method which provides. The opportunity to functionally test the molecular events occuring to functionally test the molecular events occurring in the initial changes in premaligant progression; i.e., the step from non-invasive to invasive behavior.
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Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Glándulas Mamarias Humanas/patología , Trasplante de Neoplasias/patología , Lesiones Precancerosas/patología , Ensayo de Tumor de Célula Madre , Animales , Progresión de la Enfermedad , Femenino , Humanos , Huésped Inmunocomprometido , Ratones , Ratones Endogámicos NOD , Ratones SCID , Invasividad Neoplásica/patologíaRESUMEN
PURPOSE: The NSABP (National Surgical Adjuvant Breast and Bowel Project) B-24 study demonstrated significant benefit with adjuvant tamoxifen in patients with ductal carcinoma in situ (DCIS) after lumpectomy and radiation. Patients were enrolled without knowledge of hormone receptor status. The current study retrospectively evaluated the relationship between receptors and response to tamoxifen. PATIENTS AND METHODS: Estrogen (ER) and progesterone receptors (PgR) were evaluated in 732 patients with DCIS (41% of original study population). An experienced central laboratory determined receptor status in all patient cases with available paraffin blocks (n = 449) by immunohistochemistry (IHC) using comprehensively validated assays. Results for additional patients (n = 283) determined by various methods (primarily IHC) were available from enrolling institutions. Combined results were evaluated for benefit of tamoxifen by receptor status at 10 years and overall follow-up (median, 14.5 years). RESULTS: ER was positive in 76% of patients. Patients with ER-positive DCIS treated with tamoxifen (v placebo) showed significant decreases in subsequent breast cancer at 10 years (hazard ratio [HR], 0.49; P < .001) and overall follow-up (HR, 0.60; P = .003), which remained significant in multivariable analysis (overall HR, 0.64; P = .003). Results were similar, but less significant, when subsequent ipsilateral and contralateral, invasive and noninvasive, breast cancers were considered separately. No significant benefit was observed in ER-negative DCIS. PgR and either receptor were positive in 66% and 79% of patients, respectively, and in general, neither was more predictive than ER alone. CONCLUSION: Patients in NSABP B-24 with ER-positive DCIS receiving adjuvant tamoxifen after standard therapy showed significant reductions in subsequent breast cancer. The use of adjuvant tamoxifen should be considered for patients with DCIS.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Carcinoma in Situ/tratamiento farmacológico , Carcinoma Intraductal no Infiltrante/tratamiento farmacológico , Recurrencia Local de Neoplasia/prevención & control , Receptores de Estrógenos/efectos de los fármacos , Tamoxifeno/administración & dosificación , Adulto , Factores de Edad , Anciano , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma in Situ/mortalidad , Carcinoma in Situ/patología , Carcinoma in Situ/cirugía , Carcinoma Intraductal no Infiltrante/mortalidad , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Intraductal no Infiltrante/cirugía , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Femenino , Estudios de Seguimiento , Humanos , Estimación de Kaplan-Meier , Mastectomía Segmentaria/métodos , Persona de Mediana Edad , Invasividad Neoplásica/patología , Recurrencia Local de Neoplasia/mortalidad , Estadificación de Neoplasias , Receptores de Estrógenos/análisis , Receptores de Progesterona/análisis , Receptores de Progesterona/efectos de los fármacos , Medición de Riesgo , Análisis de Supervivencia , Tamoxifeno/efectos adversos , Estados UnidosRESUMEN
About 50,000 U.S. women are diagnosed with breast atypical hyperplasia each year, giving them about a six-fold increased relative risk of developing invasive breast cancer (IBC) compared with age-matched controls. Still, only a small fraction of patients with atypical hyperplasia ever progress to IBC, which is a major reason why a large majority do not participate in breast cancer prevention, despite the remarkable effectiveness of currently available risk-reducing therapies. An interesting study reported by Radisky and colleagues in this issue of the journal (beginning on page 1953) evaluated expression levels of p16(ink4a) in atypical hyperplasia for more accurately predicting risk--hoping to identify high-risk patients who will benefit most from therapy while sparing those with lower risk from unnecessary therapy. Unfortunately, p16(ink4a) expression was not prognostic in this particular study, although research to identify powerful biomarkers of risk remains a high priority. Fortunately, there are many other promising biomarkers under investigation, as well as several underutilized experimental strategies which could help promote successful breast cancer prevention.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Inhibidor p16 de la Quinasa Dependiente de Ciclina/metabolismo , Hiperplasia/metabolismo , Lesiones Precancerosas/metabolismo , Femenino , HumanosRESUMEN
Ductal carcinoma in situ (DCIS) is a non-obligate precursor of invasive breast cancer. The current recognition that DCIS lesions exhibit inter- and intra-lesion diversity suggests that the process of evolution to invasive breast cancer is more complex than previously recognized. Here we demonstrate the reproducible growth of primary DCIS cells derived from patient's surgical and biopsy samples by the mouse intraductal (MIND) model. MIND involves injection of cells into the NOD-SCID IL2Rgamma$^{{\rm{null}}}$ (NSG) mouse mammary ducts. Twelve (eight unique and four repeats) DCIS and two atypical hyperplasia specimens, heterogeneous with respect to biomarker expression and histology, were injected into 48 mouse mammary glands and analysed for successful xenotransplantation. Overall, 14/34 and 11/14 MIND xenotransplanted glands contained human DCIS and atypical hyperplastic cells, respectively, after 8 weeks, which formed single and multi-layered epithelium inside the ducts, and were heterogeneous with respect to expression of human cytokeratins, oestrogen receptor α (ER), and HER2. ER protein expression was recapitulated in MIND xenografts at ratios similar to the corresponding patient biopsies. In both patient biopsies and corresponding MIND xenografts, HER2 protein expression and nuclear HER2 gene overexpression were restricted to the DCIS lesions and were not found in the surrounding stroma or normal ducts. The xenografted DCIS lesions recapitulate the pathology and heterogeneity of human disease, thus providing a powerful tool for the characterization of the distinct cellular and molecular basis of inter- and intra-tumoural heterogeneity and the processes of DCIS to early invasive breast cancer progression.
Asunto(s)
Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Ensayos Antitumor por Modelo de Xenoinjerto/métodos , Adulto , Animales , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Carcinoma Intraductal no Infiltrante/genética , Carcinoma Intraductal no Infiltrante/metabolismo , Modelos Animales de Enfermedad , Femenino , Humanos , Hiperplasia , Hibridación Fluorescente in Situ , Ratones , Ratones Endogámicos NOD , Ratones SCID , Persona de Mediana Edad , Trasplante de Neoplasias , Células Tumorales CultivadasRESUMEN
PURPOSE: Preoperative aromatase inhibitor (AI) treatment promotes breast-conserving surgery (BCS) for estrogen receptor (ER)-positive breast cancer. To study this treatment option, responses to three AIs were compared in a randomized phase II neoadjuvant trial designed to select agents for phase III investigations. PATIENTS AND METHODS: Three hundred seventy-seven postmenopausal women with clinical stage II to III ER-positive (Allred score 6-8) breast cancer were randomly assigned to receive neoadjuvant exemestane, letrozole, or anastrozole. The primary end point was clinical response. Secondary end points included BCS, Ki67 proliferation marker changes, the Preoperative Endocrine Prognostic Index (PEPI), and PAM50-based intrinsic subtype analysis. RESULTS: On the basis of clinical response rates, letrozole and anastrozole were selected for further investigation; however, no other differences in surgical outcome, PEPI score, or Ki67 suppression were detected. The BCS rate for mastectomy-only patients at presentation was 51%. PAM50 analysis identified AI-unresponsive nonluminal subtypes (human epidermal growth factor receptor 2 enriched or basal-like) in 3.3% of patients. Clinical response and surgical outcomes were similar in luminal A (LumA) versus luminal B tumors; however, a PEPI of 0 (best prognostic group) was highest in the LumA subset (27.1% v 10.7%; P = .004). CONCLUSION: Neoadjuvant AI treatment markedly improved surgical outcomes. Ki67 and PEPI data demonstrated that the three agents tested are biologically equivalent and therefore likely to have similar adjuvant activities. LumA tumors were more likely to have favorable biomarker characteristics after treatment; however, occasional paradoxical increases in Ki67 (12% of tumors with > 5% increase after therapy) suggest treatment-resistant cells, present in some LumA tumors, can be detected by post-treatment profiling.