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New therapies are being developed for breast cancer, and in this process, some "old" biomarkers are reutilized and given a new purpose. It is not always recognized that by changing a biomarker's intended use, a new biomarker assay is created. The Ki-67 biomarker is typically assessed by immunohistochemistry (IHC) to provide a proliferative index in breast cancer. Canadian laboratories assessed the analytical performance and diagnostic accuracy of their Ki-67 IHC laboratory-developed tests (LDTs) of relevance for the LDTs' clinical utility. Canadian clinical IHC laboratories enrolled in the Canadian Biomarker Quality Assurance Pilot Run for Ki-67 in breast cancer by invitation. The Dako Ki-67 IHC pharmDx assay was employed as a study reference assay. The Dako central laboratory was the reference laboratory. Participants received unstained slides of breast cancer tissue microarrays with 32 cases and performed their in-house Ki-67 assays. The results were assessed using QuPath, an open-source software application for bioimage analysis. Positive percent agreement (PPA, sensitivity) and negative percent agreement (NPA, specificity) were calculated against the Dako Ki-67 IHC pharmDx assay for 5%, 10%, 20%, and 30% cutoffs. Overall, PPA and NPA varied depending on the selected cutoff; participants were more successful with 5% and 10%, than with 20% and 30% cutoffs. Only 4 of 16 laboratories had robust IHC protocols with acceptable PPA for all cutoffs. The lowest PPA for the 5% cutoff was 85%, for 10% was 63%, for 20% was 14%, and for 30% was 13%. The lowest NPA for the 5% cutoff was 50%, for 10% was 33%, for 20% was 50%, and for 30% was 57%. Despite many years of international efforts to standardize IHC testing for Ki-67 in breast cancer, our results indicate that Canadian clinical LDTs have a wide analytical sensitivity range and poor agreement for 20% and 30% cutoffs. The poor agreement was not due to the readout but rather due to IHC protocol conditions. International Ki-67 in Breast Cancer Working Group (IKWG) recommendations related to Ki-67 IHC standardization cannot take full effect without reliable fit-for-purpose reference materials that are required for the initial assay calibration, assay performance monitoring, and proficiency testing.
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Neoplasias de la Mama , Inmunohistoquímica , Antígeno Ki-67 , Humanos , Antígeno Ki-67/metabolismo , Antígeno Ki-67/análisis , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Femenino , Inmunohistoquímica/métodos , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisis , Canadá , Sensibilidad y Especificidad , Análisis de Matrices Tisulares/métodosRESUMEN
BACKGROUND: Copy number alterations (CNA) are acquired during the evolution of cancers from their early stage to metastatic stage. This study aims at analysing the clinical value of the identified metastasis-associated CNAs both in metastatic breast cancers (mBCs) and early breast cancers (eBCs). METHODS: Single-nucleotide polymorphism (SNP)-array was performed on 926 biopsies from mBC patients, enrolled in SAFIR02-BREAST prospective trial. CNA profiles of eBCs from The Cancer Genome Atlas Breast Invasive Carcinoma (n = 770), Molecular Taxonomy of Breast Cancer International Consortium (n = 1620) and PACS04 trial (n = 243) cohorts were used as references for comparing mBCs and eBCs CNA profiles. Overall survival was the considered survival endpoint. RESULTS: Among the twenty-one genes frequently altered in ER + /HER2- mBCs: focal amplification of TERT was associated with poor outcome in the ER + /HER2- mBC population. Among the ER + /HER2- mBCs patients for whom CDK4/6 inhibitors information before biopsies collection was available: we identified seven genes on post-treatment biopsies, including the cyclin-dependent kinase 4 (CDK4), which was amplified in 9.8% of the ER + /HER2- mBCs pretreated population, as compared to 1.5% in the ER + /HER2- mBCs unpretreated population (P = 2.82E-04) as well as the 3 eBC populations. CDK4 amplification was associated with poor outcome in the ER + /HER2- eBCs. CONCLUSIONS: This study provides insights into the biology of mBCs and identifies clinically useful genomic features for future improvement of breast cancer patient management.
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AIMS: Over 50% of breast cancer cases are "Human epidermal growth factor receptor 2 (HER2) low breast cancer (BC)", characterized by HER2 immunohistochemistry (IHC) scores of 1+ or 2+ alongside no amplification on fluorescence in situ hybridization (FISH) testing. The development of new anti-HER2 antibody-drug conjugates (ADCs) for treating HER2-low breast cancers illustrates the importance of accurately assessing HER2 status, particularly HER2-low breast cancer. In this study we evaluated the performance of a deep-learning (DL) model for the assessment of HER2, including an assessment of the causes of discordances of HER2-Null between a pathologist and the DL model. We specifically focussed on aligning the DL model rules with the ASCO/CAP guidelines, including stained cells' staining intensity and completeness of membrane staining. METHODS AND RESULTS: We trained a DL model on a multicentric cohort of breast cancer cases with HER2-IHC scores (n = 299). The model was validated on two independent multicentric validation cohorts (n = 369 and n = 92), with all cases reviewed by three senior breast pathologists. All cases underwent a thorough review by three senior breast pathologists, with the ground truth determined by a majority consensus on the final HER2 score among the pathologists. In total, 760 breast cancer cases were utilized throughout the training and validation phases of the study. The model's concordance with the ground truth (ICC = 0.77 [0.68-0.83]; Fisher P = 1.32e-10) is higher than the average agreement among the three senior pathologists (ICC = 0.45 [0.17-0.65]; Fisher P = 2e-3). In the two validation cohorts, the DL model identifies 95% [93% - 98%] and 97% [91% - 100%] of HER2-low and HER2-positive tumours, respectively. Discordant results were characterized by morphological features such as extended fibrosis, a high number of tumour-infiltrating lymphocytes, and necrosis, whilst some artefacts such as nonspecific background cytoplasmic stain in the cytoplasm of tumour cells also cause discrepancy. CONCLUSION: Deep learning can support pathologists' interpretation of difficult HER2-low cases. Morphological variables and some specific artefacts can cause discrepant HER2-scores between the pathologist and the DL model.
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Biomarcadores de Tumor , Neoplasias de la Mama , Aprendizaje Profundo , Inmunohistoquímica , Receptor ErbB-2 , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Femenino , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Patólogos , Hibridación Fluorescente in Situ , Persona de Mediana EdadRESUMEN
PURPOSE: We aimed to determine the pattern of isolated local recurrences (ILR) in women with stage II-III hormone receptor-positive and human epidermal growth factor receptor 2 breast cancer (HR + /HER2-BC) after 10-year follow-up. METHODS: UNICANCER-PACS 01 and PACS 04 trials included 5,008 women with T1-T3 and N1-N3 to evaluate the efficacy of different anthracycline ± taxanes-containing regimens after modified mastectomy or lumpectomy plus axillary lymph node dissection. We analyzed the data from 2,932 women with HR + /HER2- BC to evaluate the cumulative incidence of ILR and describe the factors associated with ILR. RESULTS: After a median follow-up of 9.1 years (95% CI 9.0-9.2 years), the cumulative incidence of ILR increased steadily between 1 and 10 years from 0.2% to 2.5%. The multivariable analysis showed that older age (subhazard ratios [sHR] = 0.95, 95% CI 0.92-0.99) and mastectomy (sHR = 0.39, 95% CI 0.17-0.86) were associated with lower risk of ILR, and no adjuvant endocrine therapy (sHR = 2.73, 95% CI 1.32 7-5.67) with increased risk of ILR. CONCLUSION: In this population of high-risk patients with localized HR + /HER2- BC, the risk of ILR was low but remained constant over 10 years. Younger age at diagnosis, breast-conserving surgery, and adjuvant endocrine therapy were independent risk factors of ILR.
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Neoplasias de la Mama , Femenino , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/cirugía , Neoplasias de la Mama/metabolismo , Mastectomía , Estudios de Seguimiento , Recurrencia Local de Neoplasia/epidemiología , Recurrencia Local de Neoplasia/cirugía , Ganglios Linfáticos/patología , Factores de RiesgoRESUMEN
Predictive biomarkers for tumor response to neoadjuvant chemotherapy are needed in breast cancer. This study investigates the predictive value of 280 genes encoding proteins that regulate microtubule assembly and function. By analyzing 3 independent multicenter randomized cohorts of breast cancer patients, we identified 17 genes that are differentially regulated in tumors achieving pathological complete response (pCR) to neoadjuvant chemotherapy. We focused on the MTUS1 gene, whose major product, ATIP3, is a microtubule-associated protein down-regulated in aggressive breast tumors. We show here that low levels of ATIP3 are associated with an increased pCR rate, pointing to ATIP3 as a predictive biomarker of breast tumor chemosensitivity. Using preclinical models of patient-derived xenografts and 3-dimensional models of breast cancer cell lines, we show that low ATIP3 levels sensitize tumors to the effects of taxanes but not DNA-damaging agents. ATIP3 silencing improves the proapoptotic effects of paclitaxel and induces mitotic abnormalities, including centrosome amplification and multipolar spindle formation, which results in chromosome missegregation leading to aneuploidy. As shown by time-lapse video microscopy, ATIP3 depletion exacerbates cytokinesis failure and mitotic death induced by low doses of paclitaxel. Our results favor a mechanism by which the combination of ATIP3 deficiency and paclitaxel treatment induces excessive aneuploidy, which in turn results in elevated cell death. Together, these studies highlight ATIP3 as an important regulator of mitotic integrity and a useful predictive biomarker for a population of chemoresistant breast cancer patients.
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Aneuploidia , Antineoplásicos Fitogénicos/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Proteínas de Neoplasias/fisiología , Paclitaxel/farmacología , Proteínas Supresoras de Tumor/fisiología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Línea Celular Tumoral , Citocinesis/efectos de los fármacos , ADN de Neoplasias/efectos de los fármacos , Perfilación de la Expresión Génica , Xenoinjertos , Humanos , Microtúbulos/efectos de los fármacos , Microtúbulos/fisiología , Estudios Multicéntricos como Asunto/estadística & datos numéricos , Terapia Neoadyuvante , Invasividad Neoplásica/genética , Trasplante de Neoplasias , Interferencia de ARN , Ensayos Clínicos Controlados Aleatorios como Asunto/estadística & datos numéricos , Huso Acromático/efectos de los fármacos , Huso Acromático/ultraestructura , Taxoides/farmacología , Imagen de Lapso de Tiempo , Proteínas Supresoras de Tumor/antagonistas & inhibidores , Proteínas Supresoras de Tumor/genéticaRESUMEN
High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from -0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the 'ideal' sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.
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Linfocitos Infiltrantes de Tumor/patología , Células del Estroma/patología , Neoplasias de la Mama Triple Negativas/patología , Microambiente Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Australia , Quimioterapia Adyuvante , Toma de Decisiones Clínicas , Europa (Continente) , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Mastectomía , Persona de Mediana Edad , Terapia Neoadyuvante , Invasividad Neoplásica , América del Norte , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Células del Estroma/efectos de los fármacos , Células del Estroma/inmunología , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/terapia , Microambiente Tumoral/inmunologíaRESUMEN
The last international guidelines on HER2 determination in breast cancer have been updated in 2018 by the American Society of Clinical Oncology and College of American Pathologists, on the basis of a twenty-year practice and results of numerous clinical trials. Moreover, the emerging HER2-low concept for 1+ and 2+ non amplified breast cancers lead to refine French practices for HER2 status assessment. The GEFPICS group, composed of expert pathologists, herein presents the latest French recommendations for HER2 status evaluation in breast cancer, taking into account the ASCO/CAP guidelines and introducing the HER2-low concept. In the era of personalized medicine, HER2 status assessment remains one of the most important biomarkers in breast cancer and its quality guaranties the optimal patients' care. French pathologists' commitment in theranostic biomarker quality is more than ever required to provide the most efficient cares in oncology.
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Neoplasias de la Mama , Biomarcadores de Tumor , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/genética , Femenino , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Receptor ErbB-2/genéticaRESUMEN
Histopathological assessment of ductal carcinoma in situ, a nonobligate precursor of invasive breast cancer, is characterized by considerable interobserver variability. Previously, post hoc dichotomization of multicategorical variables was used to determine the "ideal" cutoffs for dichotomous assessment. The present international multicenter study evaluated interobserver variability among 39 pathologists who performed upfront dichotomous evaluation of 149 consecutive ductal carcinomas in situ. All pathologists independently assessed nuclear atypia, necrosis, solid ductal carcinoma in situ architecture, calcifications, stromal architecture, and lobular cancerization in one digital slide per lesion. Stromal inflammation was assessed semiquantitatively. Tumor-infiltrating lymphocytes were quantified as percentages and dichotomously assessed with a cutoff at 50%. Krippendorff's alpha (KA), Cohen's kappa and intraclass correlation coefficient were calculated for the appropriate variables. Lobular cancerization (KA = 0.396), nuclear atypia (KA = 0.422), and stromal architecture (KA = 0.450) showed the highest interobserver variability. Stromal inflammation (KA = 0.564), dichotomously assessed tumor-infiltrating lymphocytes (KA = 0.520), and comedonecrosis (KA = 0.539) showed slightly lower interobserver disagreement. Solid ductal carcinoma in situ architecture (KA = 0.602) and calcifications (KA = 0.676) presented with the lowest interobserver variability. Semiquantitative assessment of stromal inflammation resulted in a slightly higher interobserver concordance than upfront dichotomous tumor-infiltrating lymphocytes assessment (KA = 0.564 versus KA = 0.520). High stromal inflammation corresponded best with dichotomously assessed tumor-infiltrating lymphocytes when the cutoff was set at 10% (kappa = 0.881). Nevertheless, a post hoc tumor-infiltrating lymphocytes cutoff set at 20% resulted in the highest interobserver agreement (KA = 0.669). Despite upfront dichotomous evaluation, the interobserver variability remains considerable and is at most acceptable, although it varies among the different histopathological features. Future studies should investigate its impact on ductal carcinoma in situ prognostication. Forthcoming machine learning algorithms may be useful to tackle this substantial diagnostic challenge.
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Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Patólogos , Biopsia , Neoplasias de la Mama/cirugía , Calcinosis/patología , Carcinoma Intraductal no Infiltrante/cirugía , Núcleo Celular/patología , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/patología , Necrosis , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Pronóstico , Reproducibilidad de los Resultados , Medición de Riesgo , Factores de RiesgoRESUMEN
Breast cancer (BC) remains the primary cause of death from cancer among women worldwide. Cholesterol-5,6-epoxide (5,6-EC) metabolism is deregulated in BC but the molecular origin of this is unknown. Here, we have identified an oncometabolism downstream of 5,6-EC that promotes BC progression independently of estrogen receptor α expression. We show that cholesterol epoxide hydrolase (ChEH) metabolizes 5,6-EC into cholestane-3ß,5α,6ß-triol, which is transformed into the oncometabolite 6-oxo-cholestan-3ß,5α-diol (OCDO) by 11ß-hydroxysteroid-dehydrogenase-type-2 (11ßHSD2). 11ßHSD2 is known to regulate glucocorticoid metabolism by converting active cortisol into inactive cortisone. ChEH inhibition and 11ßHSD2 silencing inhibited OCDO production and tumor growth. Patient BC samples showed significant increased OCDO levels and greater ChEH and 11ßHSD2 protein expression compared with normal tissues. The analysis of several human BC mRNA databases indicated that 11ßHSD2 and ChEH overexpression correlated with a higher risk of patient death, highlighting that the biosynthetic pathway producing OCDO is of major importance to BC pathology. OCDO stimulates BC cell growth by binding to the glucocorticoid receptor (GR), the nuclear receptor of endogenous cortisol. Interestingly, high GR expression or activation correlates with poor therapeutic response or prognosis in many solid tumors, including BC. Targeting the enzymes involved in cholesterol epoxide and glucocorticoid metabolism or GR may be novel strategies to prevent and treat BC.
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Neoplasias de la Mama/metabolismo , Carcinógenos/metabolismo , Colesterol/metabolismo , Receptores de Glucocorticoides/metabolismo , 11-beta-Hidroxiesteroide Deshidrogenasa de Tipo 2/metabolismo , Animales , Línea Celular , Línea Celular Tumoral , Colesterol/análogos & derivados , Epóxido Hidrolasas/metabolismo , Receptor alfa de Estrógeno/metabolismo , Femenino , Células HEK293 , Humanos , Células MCF-7 , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Desnudos , ARN Mensajero/metabolismoRESUMEN
PURPOSE: The identification of molecular biomarkers for classification of breast cancer is needed to better stratify the patients and guide therapeutic decisions. The aim of this study was to investigate the value of MAPRE1 gene encoding microtubule-end binding proteins EB1 as a biomarker in breast cancer and evaluate whether combinatorial expression of MAPRE1 and MTUS1 gene encoding EB1-negative regulator ATIP3 may improve breast cancer diagnosis and prognosis. METHODS: Probeset intensities for MAPRE1 and MTUS1 genes were retrieved from Exonhit splice array analyses of 45 benign and 120 malignant breast tumors for diagnostic purposes. Transcriptomic analyses (U133 Affymetrix array) of one exploratory cohort of 150 invasive breast cancer patients and two independent series of 130 and 155 samples were compared with clinical data of the patients for prognostic studies. A tissue microarray from an independent cohort of 212 invasive breast tumors was immunostained with anti-EB1 and anti-ATIP3 antibodies. RESULTS: We show that MAPRE1 gene is a diagnostic and prognostic biomarker in breast cancer. High MAPRE1 levels correlate with tumor malignancy, high histological grade and poor clinical outcome. Combination of high-MAPRE1 and low-MTUS1 levels in tumors is significantly associated with tumor aggressiveness and reduced patient survival. IHC studies of combined EB1/ATIP3 protein expression confirmed these results. CONCLUSIONS: These studies emphasize the importance of studying combinatorial expression of EB1 and ATIP3 genes and proteins rather than each biomarker alone. A population of highly aggressive breast tumors expressing high-EB1/low-ATIP3 may be considered for the development of new molecular therapies.
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Biomarcadores de Tumor , Neoplasias de la Mama/genética , Neoplasias de la Mama/mortalidad , Expresión Génica , Proteínas Asociadas a Microtúbulos/genética , Proteínas Supresoras de Tumor/genética , Neoplasias de la Mama/diagnóstico , Femenino , Humanos , Clasificación del Tumor , Pronóstico , Recurrencia , Análisis de SupervivenciaRESUMEN
Salivary gland-like tumours are described in the breast but remain very rare and difficult to diagnose in this location. Only 37 cases of mucoepidermoid carcinoma have been described in the literature. We report the challenging diagnosis of a mucoepidermoid carcinoma sampled by core biopsy in a 51-year-old woman.
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Neoplasias de la Mama/patología , Carcinoma Mucoepidermoide/patología , Neoplasias de la Mama Triple Negativas/patología , Biomarcadores de Tumor/análisis , Neoplasias de la Mama/química , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/diagnóstico por imagen , Carcinoma Mucoepidermoide/química , Carcinoma Mucoepidermoide/diagnóstico , Carcinoma Mucoepidermoide/diagnóstico por imagen , Hibridación Genómica Comparativa , Diagnóstico Diferencial , Femenino , Humanos , Mamografía , Mastectomía Segmentaria , Persona de Mediana Edad , Especificidad de Órganos , Neoplasias de las Glándulas Salivales/patología , Biopsia del Ganglio Linfático Centinela , Transactivadores/genética , Neoplasias de la Mama Triple Negativas/química , Neoplasias de la Mama Triple Negativas/diagnósticoRESUMEN
Neoadjuvant therapy is an increasing treatment option in the management of breast cancer. The tumor response to neoadjuvant therapy, especially the pathological complete response, is a validated endpoint frequently used in clinical trials. However, there is still a lack of standardization for the surgical specimen management in the neoadjuvant setting. This leads to heterogeneity in the specimen handling and might lead to significant bias for the prognostic assessment of patients or in clinical trials. The GEFPICS group, composed of expert breast cancer pathologists, herein presents guidelines for the management of breast and axillary specimen before treatment (management of biopsy, items of the pathological report) and after neoadjuvant therapy (specimen handling, histological assessment of response, items of the pathological report and response grading systems).
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Neoplasias de la Mama/patología , Mama/patología , Ganglios Linfáticos/patología , Terapia Neoadyuvante , Manejo de Especímenes/normas , Biomarcadores de Tumor , Biopsia/métodos , Biopsia/normas , Neoplasias de la Mama/química , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/terapia , Quimioterapia Adyuvante/normas , Ensayos de Selección de Medicamentos Antitumorales , Femenino , Francia , Humanos , Ganglios Linfáticos/efectos de los fármacos , Ganglios Linfáticos/cirugía , Registros Médicos/normas , Microscopía , Neoplasia Residual/patología , Pronóstico , Biopsia del Ganglio Linfático Centinela/métodos , Manejo de Especímenes/métodos , Resultado del Tratamiento , Carga Tumoral/efectos de los fármacosRESUMEN
Solid papillary carcinoma with reverse polarity is a rare breast cancer of favorable prognosis that can be difficult to diagnose. We report here nine additional cases of this tumor, and we describe its morphologic, immunohistochemical and molecular profile in comparison to other types of papillary and micropapillary lesions of the breast that are intraductal papilloma with usual ductal hyperplasia, encapsulated papillary carcinoma, solid papillary carcinoma and invasive micropapillary carcinoma. We studied nine cases of this special papillary tumor and six of each other types mentioned above. We found that solid papillary carcinoma with reverse polarity harbor specific morphologic features as cuboid or tall cells with abundant eosinophilic cytoplasms located at the basal pole giving the impression of reverse nuclear polarity. Nuclei were sometimes grooved. Immunohistochemistry demonstrated the lack of myoepithelial cells, as in encapsulated papillary carcinoma and solid papillary carcinoma, questioning their invasive nature. Seven of nine solid papillary carcinoma with reverse polarity showed a low Ki67 proliferative index (Ki67 <5%). They showed expression of CK5/6 as in intraductal papilloma with usual ductal hyperplasia. They showed expression of calretinin and a low or lack of hormonal receptor (HR) expression that were not observed in other breast tumors studied. By whole-exome analysis, seven of nine solid papillary carcinomas with reverse polarity (78%) harbored a hotspot mutation in IDH2 (R172) that was totally absent in other groups. Six of nine tumors (67%) also harbored PRUNE2 mutation, including the two IDH2 wild-type cases. We also demonstrated for the first time in this breast tumor, immunostaining with a specific antibody IDH1/2 mutant R132/R172 (7/9) that can highlight IDH2 mutation. Moreover, transcriptomic analysis showed that proteoglycan pathway was significantly enriched. Our findings support the fact that solid papillary carcinoma with reverse polarity is a singular breast neoplasm that can be distinguished from other papillary breast tumors.
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Neoplasias de la Mama/patología , Carcinoma Papilar/patología , Isocitrato Deshidrogenasa/genética , Mutación , Anciano , Biomarcadores de Tumor , Mama/metabolismo , Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Carcinoma Papilar/genética , Carcinoma Papilar/metabolismo , Proliferación Celular , Femenino , Perfilación de la Expresión Génica , Humanos , Inmunohistoquímica , Isocitrato Deshidrogenasa/metabolismo , Persona de Mediana EdadRESUMEN
BACKGROUND: The 21-gene Recurrence Score (RS) result predicts outcome and chemotherapy benefit in node-negative and node-positive (N+), estrogen receptor-positive (ER+) patients treated with endocrine therapy. The purpose of this study was to evaluate the prognostic impact of RS results in N+, hormone receptor-positive (HR+) patients treated with adjuvant chemotherapy (6 cycles of FEC100 vs. 3 cycles of FEC100 followed by 3 cycles of docetaxel 100 mg/m2) plus endocrine therapy (ET) in the PACS-01 trial (J Clin Oncol 2006;24:5664-5671). METHODS: The current study included 530 HR+/N+ patients from the PACS-01 parent trial for whom specimens were available. The primary objective was to evaluate the relationship between the RS result and distant recurrence (DR). RESULTS: There were 209 (39.4%) patients with low RS (< 18), 159 (30%) with intermediate RS (18-30) and 162 (30.6%) with high RS (≥ 31). The continuous RS result was associated with DR (hazard ratio = 4.14; 95% confidence interval: 2.67-6.43; p < 0.001), adjusting for treatment. In multivariable analysis, the RS result remained a significant predictor of DR (p < 0.001) after adjustment for number of positive nodes, tumor size, tumor grade, Ki-67 (immunohistochemical status), and chemotherapy regimen. There was no statistically significant interaction between RS result and treatment in predicting DR (p = 0.79). CONCLUSIONS: After adjustment for clinical covariates, the 21-gene RS result is a significant prognostic factor in N+/HR+ patients receiving adjuvant chemoendocrine therapy. TRIAL REGISTRATION: Not applicable.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Pruebas Genéticas/métodos , Recurrencia Local de Neoplasia/diagnóstico , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa/métodos , Mama/patología , Mama/cirugía , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Ensayos Clínicos Fase III como Asunto , Supervivencia sin Enfermedad , Femenino , Estudios de Seguimiento , Humanos , Metástasis Linfática , Mastectomía , Persona de Mediana Edad , Estudios Multicéntricos como Asunto , Recurrencia Local de Neoplasia/genética , Pronóstico , Ensayos Clínicos Controlados Aleatorios como Asunto , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
With the major development of immunotherapies, evaluation of the immune response associated to cancer has become the new challenge for pathologists. In breast cancer, this perspective has been notably anticipated by the recent publication, in 2014, of international guidelines for assessment of tumor-infiltrating lymphocytes (TILs), on routine haematoxylin-eosin stains. This technical article aims at reviewing the main key points and different steps in evaluation of tumor-infiltrating lymphocytes, in order to allow an easy implementation of this putative biomarker in routine practice. Widespread diffusion of international guidelines is the key to development of a standardized and reproducible biomarker. This early learning phase is of particular importance, as immune response will probably play a major role as a prognostic and predictive biomarker, especially in triple-negative and HER2 positive breast cancer.
Asunto(s)
Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Inmunohistoquímica/normas , Linfocitos Infiltrantes de Tumor/inmunología , Guías de Práctica Clínica como Asunto , Neoplasias de la Mama/terapia , Carcinoma/inmunología , Carcinoma/patología , Carcinoma/terapia , Femenino , Genes erbB-2 , Humanos , Inmunohistoquímica/métodos , Inmunoterapia , Ganglios Linfáticos/inmunología , Ganglios Linfáticos/patología , Metástasis Linfática , Neoplasias Hormono-Dependientes/inmunología , Neoplasias Hormono-Dependientes/patología , Neoplasias Hormono-Dependientes/terapia , Reproducibilidad de los Resultados , Coloración y Etiquetado/métodos , Células del Estroma/inmunología , Células del Estroma/patología , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/terapiaRESUMEN
BACKGROUND: Major advances have been achieved in the characterization of early breast cancer (eBC) genomic profiles. Metastatic breast cancer (mBC) is associated with poor outcomes, yet limited information is available on the genomic profile of this disease. This study aims to decipher mutational profiles of mBC using next-generation sequencing. METHODS AND FINDINGS: Whole-exome sequencing was performed on 216 tumor-blood pairs from mBC patients who underwent a biopsy in the context of the SAFIR01, SAFIR02, SHIVA, or Molecular Screening for Cancer Treatment Optimization (MOSCATO) prospective trials. Mutational profiles from 772 primary breast tumors from The Cancer Genome Atlas (TCGA) were used as a reference for comparing primary and mBC mutational profiles. Twelve genes (TP53, PIK3CA, GATA3, ESR1, MAP3K1, CDH1, AKT1, MAP2K4, RB1, PTEN, CBFB, and CDKN2A) were identified as significantly mutated in mBC (false discovery rate [FDR] < 0.1). Eight genes (ESR1, FSIP2, FRAS1, OSBPL3, EDC4, PALB2, IGFN1, and AGRN) were more frequently mutated in mBC as compared to eBC (FDR < 0.01). ESR1 was identified both as a driver and as a metastatic gene (n = 22, odds ratio = 29, 95% CI [9-155], p = 1.2e-12) and also presented with focal amplification (n = 9) for a total of 31 mBCs with either ESR1 mutation or amplification, including 27 hormone receptor positive (HR+) and HER2 negative (HER2-) mBCs (19%). HR+/HER2- mBC presented a high prevalence of mutations on genes located on the mechanistic target of rapamycin (mTOR) pathway (TSC1 and TSC2) as compared to HR+/HER2- eBC (respectively 6% and 0.7%, p = 0.0004). Other actionable genes were more frequently mutated in HR+ mBC, including ERBB4 (n = 8), NOTCH3 (n = 7), and ALK (n = 7). Analysis of mutational signatures revealed a significant increase in APOBEC-mediated mutagenesis in HR+/HER2- metastatic tumors as compared to primary TCGA samples (p < 2e-16). The main limitations of this study include the absence of bone metastases and the size of the cohort, which might not have allowed the identification of rare mutations and their effect on survival. CONCLUSIONS: This work reports the results of the analysis of the first large-scale study on mutation profiles of mBC. This study revealed genomic alterations and mutational signatures involved in the resistance to therapies, including actionable mutations.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Exoma , Mutación , Femenino , Humanos , Metástasis de la Neoplasia , Estudios Retrospectivos , Análisis de Secuencia de ADNRESUMEN
No specific biomarkers for prognostication or evaluation of tumour load in melanoma have been reported to our knowledge. MicroRNAs (miRNAs) are strongly implicated in oncogenesis and tumour progression, and their circulating forms have been studied as potential biomarkers in oncology. The aim of this prospective study was to identify a melanoma-specific profile of plasma miRNAs. A screening phase, using RNA microarray, was conducted on plasma from 14 patients with metastatic melanoma and 5 healthy subjects. Selected miRNAs were analysed by RTqPCR in 2 independent training and validation cohorts including, respectively, 29 and 31 patients and 16 and 43 control subjects. A profile of 2 miRNAs (miR-1246 and miR-185) significantly associated with metastatic melanoma with a sensitivity of 90.5% and a specificity of 89.1% was identified. This plasma miRNA profile may become an accurate non-invasive biomarker for melanoma.