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With the approval of trastuzumab deruxtecan for treating advanced human epidermal growth factor receptor-2 (HER2) low breast cancer (BC), it has become increasingly important to develop more accurate and reliable methods to identify HER2-low BC. In addition, HER2 immunohistochemistry (IHC) has limitations for quantification of HER2. We explored the relationship between HER2 IHC and mRNA levels and evaluated whether HER2 IHC scores and mRNA levels are associated with clinicopathologic features and Oncotype DX Recurrence Score (RS) in estrogen receptor (ER)-positive, HER2-negative BCs. A total of 750 BCs sent for Oncotype DX (ODX) testing were included in this study, and 559 with HER2 mRNA levels were available. There were no statistically significant differences between HER2 0 and HER2-low BC in clinicopathologic variables or ODX RS using HER2 IHC. There was a significant difference in median HER2 mRNA values between HER2 0 and HER2-low (8.7 vs 9.3, P < .001); however, the HER2 mRNA distribution had substantial overlap between these 2 groups with a suboptimal area under the receiver operating characteristic curve (area under the receiver operating characteristic curve = 0.68). A HER2 mRNA value of 9.2 was generated as the optimal cutoff for distinguishing HER2 0 and HER2-low BC. Comparing ER+ BCs with HER2 mRNA high (>9.2) and low (≤9.2) revealed a statistically significant difference in most clinicopathologic variables and ODX RS. From this large cohort of ER-positive, HER2-negative BC, our results demonstrated that HER2 mRNA levels correlated better with clinicopathologic features and recurrence risk as assessed by ODX RS than HER2 IHC scores. Our findings suggest that HER2 mRNA-detecting methods could potentially serve as a quantitative and reliable method for identifying a biologically meaningful group of HER2-low BC. Further study is needed to determine whether HER2 mRNA levels could be more reliable than IHC for identifying which patients will be most likely to benefit from trastuzumab deruxtecan.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Imuno-Histoquímica , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Curva ROC , Prognóstico , Biomarcadores Tumorais/genéticaRESUMO
Breast cancer (BC) with average human epidermal growth factor receptor 2 (HER2) signals/cell ≥6 and HER2/chromosome enumeration probe 17 (CEP17) ratio <2 (in situ hybridization [ISH] group 3) is very rare, accounting for 0.4% to 3.0% of cases sent for the dual-probe ISH assay. Although such patients are currently eligible for treatment with HER2-targeted therapy, their characteristics and outcomes remain poorly understood. Sixty-two BCs with equivocal HER2 immunohistochemical score (2+) and reflex ISH group 3 results were identified across 4 institutions. Available clinicopathologic characteristics, MammaPrint and BluePrint molecular results, and follow-up information were retrospectively analyzed. Most BCs with HER2 equivocal immunohistochemical and ISH group 3 results were histologic grade 2 or 3 (100%), estrogen receptor (ER) positive (90.3%), with an average HER2 signals/cell of 7.3. Molecular profiles revealed that 80% (16/20) of tumors were luminal subtypes, and HER2 molecular subtype was identified in 10% of tumors (2/20). Twelve (19.4%) out of 62 patients developed local recurrence and/or distant metastasis with a median follow-up of 50 months. One (10%) of 10 patients achieved pathologic complete response after neoadjuvant chemotherapy. Forty-nine (79%) out of 62 patients completed anti-HER2 agents, and exploratory analysis showed no statistically significant difference in disease outcomes between patients who completed anti-HER2 treatment and those who did not. Univariate analysis revealed advanced clinical stage, and ER/progesterone receptor negativity was associated with unfavorable disease outcomes, and exploratory multivariate analysis demonstrated that clinical stage was the most significant factor associated with disease outcomes in the studied population. These findings increase our understanding of this rare, but clinically important HER2 category. Large-scale prospective randomized studies are needed to further evaluate the role of perioperative HER2-targeted therapy in this patient population.
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Biomarcadores Tumorais , Neoplasias da Mama , Imuno-Histoquímica , Receptor ErbB-2 , Humanos , Feminino , Neoplasias da Mama/patologia , Neoplasias da Mama/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Receptor ErbB-2/análise , Pessoa de Meia-Idade , Adulto , Idoso , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Estudos Retrospectivos , Idoso de 80 Anos ou mais , Hibridização In Situ , Cromossomos Humanos Par 17/genéticaRESUMO
The significant clinical benefits of human epidermal growth factor receptor 2 (HER2)-targeted therapeutic agents have revolutionized the clinical treatment landscape in a variety of human solid tumours. Accordingly, accurate evaluation of HER2 status in these different tumour types is critical for clinical decision making to select appropriate patients who may benefit from life-saving HER2-targeted therapies. HER2 biomarker scoring criteria is different in different organ systems, and close adherence to the corresponding HER2 biomarker testing guidelines and their updates, if available, is essential for accurate evaluation. In addition, knowing the unusual patterns of HER2 expression is also important to avoid inaccurate evaluation. In this review, we discuss the key considerations when evaluating HER2 status in solid tumours for clinical decision making, including tissue handling and preparation for HER2 biomarker testing, as well as pathologist's readout of HER2 testing results in breast carcinomas, gastroesophageal adenocarcinomas, colorectal adenocarcinomas, gynaecologic carcinomas, and non-small cell lung carcinomas.
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Biomarcadores Tumorais , Tomada de Decisão Clínica , Receptor ErbB-2 , Humanos , Receptor ErbB-2/metabolismo , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , Neoplasias/patologia , Neoplasias/diagnóstico , Neoplasias/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Feminino , Imuno-HistoquímicaRESUMO
AIMS: Human epidermal growth factor receptor 2 (HER2) expression is an important biomarker in breast cancer (BC). Most BC cases categorised as HER2-negative (HER2-) express low levels of HER2 [immunohistochemistry (IHC) 1+ or IHC 2+/in-situ hybridisation not amplified (ISH-)] and represent a clinically relevant therapeutic category that is amenable to targeted therapy using a recently approved HER2-directed antibody-drug conjugate. A group of practising pathologists, with expertise in breast pathology and BC biomarker testing, outline best practices and guidance for achieving consensus in HER2 IHC scoring for BC. METHODS AND RESULTS: The authors describe current knowledge and challenges of IHC testing and scoring of HER2-low expressing BC and provide best practices and guidance for accurate identification of BCs expressing low levels of HER2. These expert pathologists propose an algorithm for assessing HER2 expression with validated IHC assays and incorporate the 2023 American Society of Clinical Oncology and College of American Pathologist guideline update. The authors also provide guidance on when to seek consensus for HER2 IHC scoring, how to incorporate HER2-low into IHC reporting and present examples of HER2 IHC staining, including challenging cases. CONCLUSIONS: Awareness of BC cases that are negative for HER protein overexpression/gene amplification and the related clinical relevance for targeted therapy highlight the importance of accurate HER2 IHC scoring for optimal treatment selection.
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Biomarcadores Tumorais , Neoplasias da Mama , Imuno-Histoquímica , Patologistas , Receptor ErbB-2 , Humanos , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Feminino , Imuno-Histoquímica/métodos , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/análise , ConsensoRESUMO
Recently, clinical trials have demonstrated promising efficacy for novel HER2-targeted therapies in HER2-low breast cancers, raising the prospect of including a HER2-low category (immunohistochemical [IHC] score of 1+, or 2+ with non-amplified in-situ hybridization [ISH]) in the HER2 evaluation of breast cancers. In order to better understand this newly-proposed HER2 category, we investigated the incidence, HER2 staining patterns, clinicopathologic features, and genomic profile of HER2-low breast cancers. HER2-stained slides of 281 consecutive breast cancers were re-reviewed and the clinicopathologic information, MammaPrint, and BluePrint results of these cases were retrospectively analyzed. HER2-low breast cancers were identified in 31% of cases and were more common in estrogen receptor (ER)-positive than ER-negative breast cancers (33.6% vs 15%, p = 0.017). HER2-low cancers were generally clinical stages I-II (79%), ER-positive (93.1%), had homogenous HER2 staining (59.2%), HER2 IHC score of 1+ (87.4%), ductal phenotype (81.6%), histologic grades of 1 or 2 (94.2%) and luminal molecular subtypes (94.3%). Three HER2-low patients received neoadjuvant chemotherapy and none of them achieved pathologic complete response. When compared to HER2-negative (IHC of 0+) and HER2-positive (IHC of 3+ or IHC of 2+ with amplified ISH) cancers, HER2-low breast cancers had significantly lower Ki-67 (p = 0.03 and p < 0.01, respectively) and higher ER positivity (p = 0.01 and p = 0.03, respectively). HER2-low breast cancers were less likely to be basal molecular subtype when compared to HER2-negative cancers (p < 0.01) and were less likely to have a HER2 molecular subtype when compared to HER2-positive cancers (p < 0.01). When adjusted for ER status, there was no significant difference on all the examined variables between HER2-low and HER2-negative groups. Our study provides valuable baseline characteristics of HER2-low breast cancers deriving from consecutive, real-world cases with a consensus confirmation of HER2 status, and would help to increase our understanding of this newly-proposed HER2 category in breast cancers.
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Neoplasias da Mama , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Feminino , Genômica , Humanos , Imuno-Histoquímica , Hibridização In Situ , Incidência , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Estudos RetrospectivosRESUMO
In light of the significant clinical benefits of novel HER2-targeting antibody-drug conjugates in advanced HER2-low expressing breast cancers in recent phases I and III clinical trials, particularly trastuzumab-deruxtecan (T-Dxd), the new "HER2-low" category in breast cancers (breast cancer with a HER2 IHC score of 1+, or 2+ without gene amplification) has gained increasing attention. In the past year, "HER2-low" breast cancers have been under active investigation by both oncologists and pathologists. In this current review, we update the recent cutting-edge research on HER2-low breast cancers, with a focus on the biology of HER2-low breast cancers, the issues on the identification of HER2-low breast cancers by immunohistochemistry in current practice of pathology, and the future directions in this emerging category in breast cancers.
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Neoplasias da Mama , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapêuticoRESUMO
PURPOSE OF REVIEW: The human epidermal growth factor receptor 2 (HER2) is an important prognostic and predictive biomarker in the breast cancer. The American Society of Clinical Oncology/College of American Pathology (ASCO/CAP) has published HER2 testing guidelines in breast cancer. We herein reviewed the HER2 testing guidelines in breast cancer with a focus on the application of the current guidelines. RECENT FINDINGS: The continual investigation of HER2 testing in breast cancer has resulted in updates in the HER2 testing guidelines. The current guidelines focus on the uncommon clinical scenarios and emphasize the coordination between immunohistochemistry and in situ hybridization results, in an effort to improve clarity and accuracy. The ASCO/CAP guidelines provide valuable recommendations to ensure the accurate evaluation of HER2 status in breast cancer patients through standardization. Additional studies, particularly those with long-term outcome data are still needed to validate the guideline recommendations, especially the uncommon cases.
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Neoplasias da Mama/química , Receptor ErbB-2/análise , Osso e Ossos/química , Feminino , Humanos , Guias de Prática Clínica como AssuntoRESUMO
BACKGROUND: Clinical assays for the assessment of the human epidermal growth factor receptor-2 (HER2) status in breast cancer include immunohistochemistry (IHC) and in situ hybridization (ISH), both of which have limitations. Recent studies have suggested that a more quantitative approach to the measurement of HER2 protein expression may improve specificity in selecting patients for HER-2 targeted therapy. In the current study, we have used HER2 expression in breast cancer cell lines and clinical samples as a model to explore the potential utility of a novel immunodetection technique, using streptavidin coated Phosphor Integrated Dot fluorescent nanoparticles (PID), which can be quantitatively measured using computer analysis. METHODS: The expression of HER2 protein in cell lines was evaluated with antibody-binding capacity using fluorescence-activated cell sorting (FACS) for comparison with PID measurements to test for correlations with existing quantitative protein analysis methodologies. Various other analytic validation tests were also performed, including accuracy, precision, sensitivity, robustness and reproducibility. A methods comparison study investigated correlations between PID versus IHC and ISH in clinical samples. Lastly, we measured HER2 protein expression using PID in the pretreatment biopsies from 34 HER2-positive carcinomas that had undergone neoadjuvant trastuzumab-based chemotherapy. RESULTS: In the analytic validation, PID HER2 measurements showed a strong linear correlation with FACS analysis in breast cell lines, and demonstrated significant correlations with all aspects of precision, sensitivity, robustness and reproducibility. PID also showed strong correlations with conventional HER2 testing methodologies (IHC and ISH). In the neoadjuvant study, patients with a pathologic complete response (pCR) had a significantly higher PID score compared with patients who did not achieve a pCR (p = 0.011), and was significantly correlated to residual cancer burden (RCB) class (p = 0.026, R2 = 0.9975). CONCLUSIONS: Analytic testing of PID showed that it may be a viable testing methodology that could offer advantages over other experimental or conventional biomarker diagnostic methodologies. Our data also suggests that PID quantitation of HER2 protein may offer an improvement over conventional HER2 testing in the selection of patients who will be the most likely to benefit from HER2-targeted therapy. Further studies with a larger cohort are warranted.
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Neoplasias da Mama/genética , Citometria de Fluxo , Nanopartículas/química , Receptor ErbB-2/genética , Biomarcadores Tumorais/genética , Biópsia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Hibridização in Situ Fluorescente , Terapia de Alvo Molecular , Nanopartículas/administração & dosagem , Terapia Neoadjuvante , Inclusão em Parafina , Trastuzumab/administração & dosagemRESUMO
Individualized targeted therapies for cancer patients require accurate and reproducible assessment of biomarkers to be able to plan treatment accordingly. Recent studies have shown highly variable effects of preanalytical variables on gene expression profiling and protein levels of different tissue types. Several publications have described protein degradation of tissue samples as a direct result of delay of formalin fixation of the tissue. Phosphorylated proteins are more labile and epitope degradation can happen within 30 min of cold ischemic time. To address this issue, we evaluated the change in antigenicity of a series of phosphoproteins in paraffin-embedded samples from breast tumors as a function of time to formalin fixation. A tissue microarray consisting of 93 breast cancer specimens with documented time-to-fixation was used to evaluate changes in antigenicity of 12 phosphoepitopes frequently used in research settings as a function of cold ischemic time. Analysis was performed in a quantitative manner using the AQUA technology for quantitative immunofluorescence. For each marker, least squares univariate linear regression was performed and confidence intervals were computed using bootstrapping. The majority of the epitopes tested revealed changes in expression levels with increasing time to formalin fixation. Some phosphorylated proteins, such as phospho-HSP27 and phospho-S6 RP, involved in post-translational modification and stress response pathways increased in expression or phosphorylation levels. Others (like phospho-AKT, phosphor-ERK1/2, phospho-Tyrosine, phospho-MET, and others) are quite labile and loss of antigenicity can be reported within 1-2 h of cold ischemic time. Therefore specimen collection should be closely monitored and subjected to quality control measures to ensure accurate measurement of these epitopes. However, a few phosphoepitopes (like phospho-JAK2 and phospho-ER) are sufficiently robust for routine usage in companion diagnostic testing.
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Neoplasias da Mama/metabolismo , Isquemia Fria , Epitopos/metabolismo , Fosfoproteínas/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/diagnóstico , Feminino , Imunofluorescência/métodos , Formaldeído , Humanos , Inclusão em Parafina , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Manejo de Espécimes/métodos , Fatores de Tempo , Análise Serial de Tecidos , Fixação de TecidosRESUMO
Oncotype DX (Genomic Health, Redwood City, CA, USA, current list price $4,350.00) is a multigene quantitative reverse transcription-polymerase chain reaction-based assay that estimates the risk of distant recurrence and predicts chemotherapy benefit for patients with estrogen receptor (ER)-positive breast cancers. Studies have suggested that standard histologic variables can provide similar information. Klein and Dabbs et al have shown that Oncotype DX recurrence scores can be estimated by incorporating standard histologic variables into equations (Magee equations). Using a simple modification of the Magee equation, we predict the Oncotype DX recurrence score in an independent set of 283 cases. The Pearson correlation coefficient (r) for the Oncotype DX and average modified Magee recurrence scores was 0.6644 (n=283; P<0.0001). 100% of cases with an average modified Magee recurrence score>30 (n=8) or an average modified Magee recurrence score<9 (with an available Ki-67, n=5) would have been correctly predicted to have a high or low Oncotype DX recurrence score, respectively. 86% (38/44) of cases with an average modified Magee recurrence score≤12, and 89% (34/38) of low grade tumors (NS<6) with an ER and PR≥150, and a Ki-67<10%, would have been correctly predicted to have a low Oncotype DX recurrence score. Using an algorithmic approach to eliminate high and low risk cases, between 5% and 23% of cases would potentially not have been sent by our institution for Oncotype DX testing, creating a potential cost savings between $56,550.00 and $282,750.00. The modified Magee recurrence score along with histologic criteria may be a cost-effective alternative to the Oncotype DX in risk stratifying certain breast cancer patients. The information needed is already generated by many pathology laboratories during the initial assessment of primary breast cancer, and the equations are free.
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Neoplasias da Mama/patologia , Recidiva Local de Neoplasia/patologia , Neoplasias da Mama/genética , Feminino , Perfilação da Expressão Gênica , Humanos , Recidiva Local de Neoplasia/genética , Prognóstico , Risco , Medição de RiscoRESUMO
BACKGROUND: The role of vitamin E in breast cancer prevention and treatment has been widely investigated, and the different tocopherols that comprise this nutrient have been shown to have divergent associations with cancer outcome. Our previous studies have shown that α-Tocopherol-associated protein (TAP), a vitamin E binding protein, may function as a tumor suppressor-like factor in breast carcinogenesis. The current study addresses the association of TAP expression with breast cancer clinical outcomes. METHODS: Immunohistochemical stain for TAP was applied to a tissue microarray from a breast cancer cohort consisting of 271 patients with a median follow-up time of 5.2 years. The expression of TAP in tumor cells was compared with patient's clinical outcome at 5 years after diagnosis. The potential role of TAP in predicting outcome was also assessed in clinically relevant subsets of the cohort. In addition, we compared TAP expression and Oncotype DX scores in an independent breast cancer cohort consisting of 71 cases. RESULTS: We demonstrate that the expression of TAP was differentially expressed within the breast cancer cohort, and that ER+/PR ± tumors were more likely to exhibit TAP expression. TAP expression was associated with an overall lower recurrence rate and a better 5-year survival rate. This association was primarily in patients with ER+ tumors; exploratory analysis showed that this association was strongest in patients with node-positive tumors and was independent of stage and treatment with chemotherapy. TAP expression in ER/PR negative or triple negative tumors had no association with clinical outcome. In addition, we did not observe an association between TAP expression and Oncotype DX recurrence score. CONCLUSIONS: The significant positive association we found for α-Tocopherol-associated protein with outcome in breast cancer may help to better define and explain studies addressing α-tocopherol's association with cancer risk and outcome. Additionally, further studies to validate and extend these findings may allow TAP to serve as a breast-specific prognostic marker in breast cancer patients, especially in those patients with ER+ tumors.
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While efforts are made to improve tissue quality and control preanalytical variables, pathologists are often confronted with the challenge of molecular analysis of patient samples of unknown quality. Here we describe a first attempt to construct a tissue quality index (TQI) or an intrinsic control that would allow a global assessment of protein status based on quantitative measurement of a small number of selected, informative epitopes. Quantitative immunofluorescence (QIF) of a number of proteins was performed on a series of 93 breast cancer cases where levels of expression were assessed as a function of delayed time to formalin fixation. A TQI was constructed based on the combination of proteins that most accurately reflect increased and decreased levels of expression in proportion to delay time. The TQI, defined by combinations of measurements of cytokeratin, ERK1/2 and pHSP-27 and their relationship to cold ischemic time were validated on a second build of the training series and on two independent breast tissue cohorts with recorded time to formalin fixation. We show an association of negative TQI values (an indicator for loss of tissue quality) with increasing cold ischemic time on both validation cohorts and an association with loss of ER expression levels on all three breast cohorts. Using expression levels of three epitopes, we can begin to assess the likelihood of delayed time to fixation or decreased tissue quality. This TQI represents a proof of concept for the use of epitope expression to provide a mechanism for monitoring tissue quality.
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Mama/patologia , Patologia/normas , Manejo de Espécimes/normas , Mama/metabolismo , Estudos de Casos e Controles , Linhagem Celular Tumoral , Feminino , Formaldeído , Humanos , Inclusão em Parafina , Estudos Prospectivos , Receptores de Estrogênio/metabolismo , Fatores de Tempo , Fixação de TecidosRESUMO
AIMS: Historically, nuclear staining of ≥10% of invasive tumour cells has been used for oestrogen receptor (ER) positivity. In 2010, ASCO/CAP guidelines recommended the cut-off value be changed to nuclear staining of ≥1%. This study will analyse the relationships between levels of ER expression and clinicopathological features and clinical outcomes, with an emphasis on the ER 1-10% subgroup. METHODS AND RESULTS: We analysed clinicopathological features in five subgroups based on ER expression levels in 1700 consecutive invasive breast cancer patients diagnosed and treated at our institution between 2000 and 2011. Of the cases, 24% had ER expression <1%, 2% were ER 1-10%, 5% were 11-50%, 5% were 51-70% and 64% were 71-100%. We observed four subgroups of patient cohorts (ER <1%, 1-10%, 11-70% and 71-100%) that were unique in Nottingham grade, nuclear grade, progesterone receptor expression and disease-free survival. Of the 341 patients with follow-up data, we found no significant differences in pathological features between patients in the ER 11-50% and ER 51-70% subgroups. CONCLUSION: These data support the important role of ER in breast cancer, and the importance of accurate testing and quantitative reporting for ER. Tumours with ER 1-10% are not common, and further studies are needed to understand more clearly this subgroup of breast cancer.
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Neoplasias da Mama/diagnóstico , Carcinoma Ductal de Mama/diagnóstico , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/classificação , Neoplasias da Mama/patologia , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/classificação , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/terapia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Receptores de Progesterona/metabolismo , Tamoxifeno/uso terapêutico , Adulto JovemRESUMO
Use of complementary approaches is common among breast cancer survivors. Potential interactions between aromatase inhibitors (AI) and high phytoestrogen foods, such as flaxseed (FS), are not often described. We conducted a pilot 2 × 2 factorial, randomized intervention study between tumor biopsy and resection, in 24 postmenopausal women with estrogen receptor positive (ER+) breast cancer, to assess the effects of FS and anastrozole, and possible interactions between them, on serum steroid hormone and tumor-related characteristics associated with long-term survival (Roswell Park Cancer Institute, 2007-2010). The effect of each treatment vs. placebo on outcomes was determined by linear regression adjusting for pretreatment measure, stage, and grade. Although not statistically significant, mean ERß expression was approximately 40% lower from pre- to postintervention in the FS + AI group only. We observed a statistically significant negative association (ß ± SE -0.3 ± 0.1; P = 0.03) for androstenedione in the FS + AI group vs. placebo and for DHEA with AI treatment (ß ± SE -1.6 ± 0.6; P = 0.009). Enterolactone excretion was much lower in the FS + AI group compared to the FS group. Our results do not support strong effects of FS on AI activity for selected breast tumor characteristics or serum steroid hormone levels but suggest AI therapy might reduce the production of circulating mammalian lignans from FS.
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Inibidores da Aromatase/farmacologia , Biomarcadores Tumorais/sangue , Neoplasias da Mama/tratamento farmacológico , Linho/química , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anastrozol , Índice de Massa Corporal , Neoplasias da Mama/sangue , Receptor beta de Estrogênio/genética , Receptor beta de Estrogênio/metabolismo , Feminino , Hormônios Esteroides Gonadais/sangue , Humanos , Lignanas/urina , Modelos Lineares , Pessoa de Meia-Idade , Nitrilas/farmacologia , Projetos Piloto , Resultado do Tratamento , Triazóis/farmacologia , Adulto JovemAssuntos
Neoplasias da Mama/patologia , Recidiva Local de Neoplasia/patologia , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Algoritmos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Feminino , Seguimentos , Perfilação da Expressão Gênica , Humanos , Linfonodos/patologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/genética , Prognóstico , Receptores de Progesterona/metabolismo , Adulto JovemRESUMO
Ground breaking advances in medicine, driven in part by major technologic developments in molecular biology have led us to a new model for cancer care that has been termed personalized, or precision medicine. Precision medicine is a model for making medical decisions that employs an innovative clinical approach and advanced tumor testing methods that are tailored to understanding an individual patient's tumor biology and the molecular drivers of their disease. This medical model includes a combination of diagnostic testing and specific treatment options that can be offered to patients at presentation and in theory throughout the course of their disease as new mutations arise with the development of disease recurrence. Although the precision medicine model offers incredible potential to transform cancer care, these advances are only meaningful when they reach the correct patients. The evolving paradigm of precision medicine is changing the practice of pathology, and the pathology community needs to be mindful of these changes because every tissue specimen represents a patient's life, and those patients are depending on the pathology community to handle their tissue correctly. The diagnostic tests performed in the pathology laboratory for precision medicine are increasingly complex, and pathologists along with the entire laboratory and clinical communities need to take steps to ensure that the right diagnosis is given to the right patient to inform the right treatment options, at the right time, along every step of the continuum of care for cancer patients. While hormone receptors and human epidermal growth factor receptor 2 (HER2) overexpression and/or amplification have been the mainstay for risk-stratification, and treatment decision making in breast cancer since the early 2000's, the seminal work on gene expression by Perou and colleagues in the early 2000's opened the door for molecular testing in the prognostic and predictive assessment of breast cancer. Molecular testing is now part of the standard of care in the precision medicine model for breast cancer care. In this article, the reader will gain a better understanding of how the lack of standardization of pre-analytic factors has the potential to negatively impact the quality of the tissue specimen for downstream biomarker and molecular testing, which ultimately can negatively affect patient care. The reader will also gain insight into the current climate surrounding molecular testing in breast cancer.
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OBJECTIVES: Actionable, solid tumor activating neurotrophic receptor tyrosine kinase (NTRK) fusions are best detected via nucleic acid-based assays, while Pan-TRK immunohistochemistry (IHC) serves as a reasonable screening modality. We describe a practical and cost-effective approach to validate pan-TRK and discuss challenges that may be encountered. METHODS: Pan-TRK Clone EPR17341 was validated in accordance with the 2014 consensus statements set forth by the College of American Pathologists. Confirmation of IHC results were guided by the European Society of Medical Oncology recommendations for standard methods to detect NTRK fusions. RESULTS: Within 36 samples, ETV6-NTRK3 (n = 8) and TPM4-NTRK3 (n = 1) fusions were confirmed. ETV6-NTRK3 fusion positive cases revealed cytoplasmic and nuclear staining. A TPM4-NTRK3 fusion positive high grade malignant peripheral nerve sheath tumor revealed diffuse cytoplasmic staining. A high grade ovarian serous carcinoma revealed focal punctate staining and revealed a non-actionable NTRK1 truncation at intron 2. Diffuse cytoplasmic staining was observed in a case of fusion-negative polymorphous adenocarcinoma. Wild-type expression of TRK in pulmonary meningothelial-like nodules was discovered following a false-positive IHC interpretation. CONCLUSION: Pan-TRK IHC shows some utility as a diagnostic and surrogate marker for NTRK screening however, physiologic or non-specific expression may lead to false-positive results.
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Adenocarcinoma , Cistadenocarcinoma Seroso , Humanos , Citoplasma , Imuno-Histoquímica , Íntrons , Receptores Proteína Tirosina QuinasesRESUMO
CONTEXT.: Human epidermal growth factor receptor 2 (HER2) status in breast cancer is currently classified as negative or positive for selecting patients for anti-HER2 targeted therapy. The evolution of the HER2 status has included a new HER2-low category defined as an HER2 immunohistochemistry score of 1+ or 2+ without gene amplification. This new category opens the door to a targetable HER2-low breast cancer population for which new treatments may be effective. OBJECTIVE.: To review the current literature on the emerging category of breast cancers with low HER2 protein expression, including the clinical, histopathologic, and molecular features, and outline the clinical trials and best practice recommendations for identifying HER2-low-expressing breast cancers by immunohistochemistry. DATA SOURCES.: We conducted a literature review based on peer-reviewed original articles, review articles, regulatory communications, ongoing and past clinical trials identified through ClinicalTrials.gov, and the authors' practice experience. CONCLUSIONS.: The availability of new targeted therapy potentially effective for patients with breast cancers with low HER2 protein expression requires multidisciplinary recognition. In particular, pathologists need to recognize and identify this category to allow the optimal selection of patients for targeted therapy.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Hibridização in Situ Fluorescente , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Amplificação de Genes , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismoRESUMO
We compared the performance of two commonly-used HER2 immunohistochemistry (IHC) assays in uterine serous carcinomas (USC), correlating with HER2 gene amplification by fluorescence in-situ hybridization (FISH). Sixty-five USCs were stained by both HercepTest™ and PATHWAY 4B5 assays. FISH was performed by HER2 IQFISH pharmDx. Consensus HER2 IHC scoring was performed, and HER2 testing results were evaluated using USC-specific criteria. Complete concordance between HercepTest and 4B5 assays was achieved in 44/65 tumors (68%). The overall HER2 IHC/FISH concordance was 94% (45/48) by HercepTest and 91% (42/46) by 4B5. All HER2 IHC 3+ cases with HercepTest (n = 6) and 4B5 (n = 4) were gene-amplified, corresponding to specificities of 100%. For cases with IHC 2+, 41% (7/17) by HercepTest and 42% (8/19) by 4B5 had HER2 gene amplification. The sensitivity for HercepTest and 4B5 were 38% and 25%, respectively, at a cut-off of IHC 3+ (P = 0.50), and were 81% and 75%, respectively, at a cut-off of IHC 2+ (P > 0.99). Among HER2 IHC 0-1+ cases, 3/42 cases by HercepTest and 4/42 cases by 4B5 showed amplified FISH results, corresponding to overall false negative rates of 19% for HercepTest and 25% for 4B5. By using USC-specific IHC scoring criteria, both HercepTest and 4B5 assays showed high specificities (100%) for HER2 gene amplification in IHC 3+ cases, high IHC/FISH concordance, and comparable sensitivity for detecting HER2 gene amplification. The notable false negative rates using IHC 2+ as a cut-off for reflexing FISH analysis may warrant consideration for performing FISH in IHC 1+ cases until more data become available.
Assuntos
Biomarcadores Tumorais , Cistadenocarcinoma Seroso , Amplificação de Genes , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Receptor ErbB-2 , Neoplasias Uterinas , Humanos , Feminino , Neoplasias Uterinas/genética , Neoplasias Uterinas/patologia , Neoplasias Uterinas/diagnóstico , Receptor ErbB-2/genética , Receptor ErbB-2/análise , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Cistadenocarcinoma Seroso/genética , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/patologia , Sensibilidade e EspecificidadeRESUMO
The American Society of Clinical Oncology/College of American Pathologists ERBB2 testing guidelines address several pre-analytical variables known to affect ERBB2 testing accuracy. According to 2010 updated guidelines, the pre-analytical variable of time to tissue fixation (cold ischemia time) should be kept to <1 h, however, little has been published about cold ischemia time and its significance in ERBB2 testing. To that end, this study evaluated ERBB2 status using two different FDA-approved in-situ hybridization methods and an FDA-approved immunohistochemistry (IHC) assay in the largest cohort to date (n=84) of invasive breast carcinomas with tracked cold ischemia time. Cold ischemia time was stratified into four groups (<1 h (n=45), 1-2 h (n=27), 2-3 h (n=6), and >3 h (n=6)) and ERBB2 status was evaluated in each group by IHC (4B5) and by in-situ hybridization methodologies (PathVysion(®) fluorescence in situ hybridization and the INFORM HER2(®) dual in situ DNA probe assay). Both in-situ hybridization methods were evaluated using three ERBB2 scoring criteria (dual-probe guidelines, single-probe guidelines, and the FDA package insert scoring instructions). Fluorescence in-situ hybridization (FISH) and INFORM HER2(®) demonstrated 100% concordance in the detection of ERBB2 amplification by all three scoring guidelines at all cold ischemia time points. Agreement between in-situ hybridization methodologies and IHC was superior using single-probe guidelines compared with dual probe or FDA scoring instructions. In addition, Inform HER2(®) in-situ hybridization signals were significantly more intense than FISH at all cold ischemia time points, however, no significant loss of either chromosome 17 or ERBB2 signal was detected by FISH or Inform HER2(®) in-situ hybridization in cold ischemia times up to 3 h. On the basis of our findings, cold ischemia time up to 3 h has no deleterious effect on the detection of ERBB2 via in-situ hybridization or IHC.