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CONTEXT.: Recently, a new type of antibody-drug conjugate, trastuzumab-deruxtecan (T-DXd), has been approved for the treatment of metastatic breast cancer with low level of human epidermal growth factor receptor 2 (HER2) gene expression. Thereby, eligibility relies on an accurate diagnosis of HER2-low status defined by immunohistochemistry IHC 1+/2+ with no gene amplification. OBJECTIVE.: To assess pathologists' accuracy and training efficacy in the diagnosis of HER2-low. DESIGN.: Agreement rates of HER2-low scoring in breast cancer tissue were assessed between expert consensus and real-world pathologists (n = 77 from 14 countries) before and after a specific 4-hour training for HER2-low detection. Two assays were evaluated, the Ventana Pathway 4B5 CDx and the Dako HercepTest (polyclonal). Concordance of the pathologists with consensus score and efficacy of training were measured by Cohen κ, overall rater agreement, and receiver operating characteristic (ROC) curve statistics. RESULTS.: In the Ventana 4B5 HER2-low category, baseline agreement rates were >80% but <90%. Negative percentage agreement was improved from 80.6% to 91.1% by training. In the HER2-0 category, positive percentage agreement (74.6%) was the only parameter below the 80% benchmark but was significantly improved to 89.2% after training. Training efficacy was confirmed by ROC curve analysis, which shows improvement for the identification of HER2-0 and HER2-low cases. Finally, in-depth examination of cases with discordant HER2 status disclosed specific issues of HER2-low underscoring and overscoring. CONCLUSIONS.: The ability of pathologists to achieve acceptable diagnostic accuracy in identifying patients with HER2-low breast cancer could be enhanced by short-term training. Potential routes to improve the quality of HER2-low scoring in clinical practice have been identified.
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Claudin-18.2 (CLDN18.2) expression evaluated by immunohistochemistry is a new biomarker for gastric and gastroesophageal junction adenocarcinomas that will soon have market authorization for implementation into routine clinical practice. Despite successful testing in the setting of clinical trials, no specific practical testing guidelines have been proposed. Several pre-analytical and analytical variables may interfere with adequate CLDN18.2 staining interpretation, thus this article provides practical guidance on CLDN18.2 testing and scoring in gastric/gastroesophageal junction adenocarcinomas in order to identify patients who may respond to targeted therapy with monoclonal antibodies directed against CLDN18.2. Based on available data, moderate to strong (2+/3+) membrane staining in ≥75% of adenocarcinoma cells is the proposed cut-off for clinical use of the monoclonal antibody anti-CLDN18.2 (zolbetuximab).
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Assessing programmed death ligand 1 (PD-L1) expression on tumor cells (TCs) using Food and Drug Administration-approved, validated immunoassays can guide the use of immune checkpoint inhibitor (ICI) therapy in cancer treatment. However, substantial interobserver variability has been reported using these immunoassays. Artificial intelligence (AI) has the potential to accurately measure biomarker expression in tissue samples, but its reliability and comparability to standard manual scoring remain to be evaluated. This multinational study sought to compare the %TC scoring of PD-L1 expression in advanced urothelial carcinoma, assessed by either an AI Measurement Model (AIM-PD-L1) or expert pathologists. The concordance among pathologists and between pathologists and AIM-PD-L1 was determined. The positivity rate of ≥ 1%TC PD-L1 was between 20-30% for 8/10 pathologists, and the degree of agreement and scoring distribution for among pathologists and between pathologists and AIM-PD-L1 was similar both scored as a continuous variable or using the pre-defined cutoff. Numerically higher score variation was observed with the 22C3 assay than with the 28-8 assay. A 2-h training module on the 28-8 assay did not significantly impact manual assessment. Cases exhibiting significantly higher variability in the assessment of PD-L1 expression (mean absolute deviation > 10) were found to have patterns of PD-L1 staining that were more challenging to interpret. An improved understanding of sources of manual scoring variability can be applied to PD-L1 expression analysis in the clinical setting. In the future, the application of AI algorithms could serve as a valuable reference guide for pathologists while scoring PD-L1.
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Inteligência Artificial , Antígeno B7-H1 , Biomarcadores Tumorais , Variações Dependentes do Observador , Humanos , Antígeno B7-H1/análise , Antígeno B7-H1/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/metabolismo , Reprodutibilidade dos Testes , Carcinoma de Células de Transição/patologia , Carcinoma de Células de Transição/metabolismo , Carcinoma de Células de Transição/diagnóstico , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias Urológicas/patologia , Neoplasias Urológicas/metabolismo , Imuno-Histoquímica/métodos , Patologistas , Urotélio/patologia , Urotélio/metabolismoRESUMO
Testing to detect mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) has become an integral part of the routine diagnostic workup for colorectal cancer (CRC). While MSI was initially considered to be a possible indicator of a hereditary disposition to cancer (Lynch syndrome, LS), today the prediction of the therapy response to immune checkpoint inhibitors (ICI) is in the foreground. Corresponding recommendations and testing algorithms are available for use in primary diagnosis (reviewed in: Rüschoff et al. 2021).Given the increasing importance for routine use and the expanding indication spectrum of ICI therapies for non-CRCs, such as endometrial, small intestinal, gastric, and biliary tract cancers, an updated review of dMMR/MSI testing is presented. The focus is on the challenges in the assessment of immunohistochemical stains and the value of PCR-based procedures, considering the expanded ICI indication spectrum. A practice-oriented flowchart for everyday diagnostic decision-making is provided that considers new data on the frequency and type of discordances between MMR-IHC and MSI-PCR findings, and the possible role of Next Generation Sequencing in clarifying them. Reference is made to the significance of systematic quality assurance measures (e.g., QuIP MSI portal and multicenter proficiency testing), including regular continued training and education.
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Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Humanos , Reparo de Erro de Pareamento de DNA/genética , Instabilidade de Microssatélites , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Estudos Multicêntricos como AssuntoRESUMO
Testing to detect mismatch repair deficiency (dMMR) and high-grade microsatellite instability (MSI-H) has become an integral part of the routine diagnostic workup for colorectal cancer (CRC). While MSI was initially considered to be a possible indicator of a hereditary disposition to cancer (Lynch syndrome, LS), today the prediction of the therapy response to immune checkpoint inhibitors (ICI) is in the foreground. Corresponding recommendations and testing algorithms are available for use in primary diagnosis (reviewed in: Rüschoff et al. 2021).Given the increasing importance for routine use and the expanding indication spectrum of ICI therapies for non-CRCs, such as endometrial, small intestinal, gastric, and biliary tract cancers, an updated review of dMMR/MSI testing is presented. The focus is on the challenges in the assessment of immunohistochemical stains and the value of PCR-based procedures, considering the expanded ICI indication spectrum. A practice-oriented flowchart for everyday diagnostic decision-making is provided that considers new data on the frequency and type of discordances between MMR-IHC and MSI-PCR findings, and the possible role of Next Generation Sequencing in clarifying them. Reference is made to the significance of systematic quality assurance measures (e.g., QuIP MSI portal and multicenter proficiency testing), including regular continued training and education.
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Neoplasias Colorretais Hereditárias sem Polipose , Neoplasias Colorretais , Humanos , Reparo de Erro de Pareamento de DNA/genética , Instabilidade de Microssatélites , Neoplasias Colorretais/diagnóstico , Neoplasias Colorretais Hereditárias sem Polipose/diagnóstico , Estudos Multicêntricos como AssuntoRESUMO
In the treatment of most newly discovered solid cancerous tumors, surgery remains the first treatment option. An important factor in the success of these operations is the precise identification of oncological safety margins to ensure the complete removal of the tumor without affecting much of the neighboring healthy tissue. Here we report on the possibility of applying femtosecond Laser-Induced Breakdown Spectroscopy (LIBS) combined with Machine Learning algorithms as an alternative discrimination technique to differentiate cancerous tissue. The emission spectra following the ablation on thin fixed liver and breast postoperative samples were recorded with high spatial resolution; adjacent stained sections served as a reference for tissue identification by classical pathological analysis. In a proof of principle test performed on liver tissue, Artificial Neural Networks and Random Forest algorithms were able to differentiate both healthy and tumor tissue with a very high Classification Accuracy of around 0.95. The ability to identify unknown tissue was performed on breast samples from different patients, also providing a high level of discrimination. Our results show that LIBS with femtosecond lasers is a technique with potential to be used in clinical applications for rapid identification of tissue type in the intraoperative surgical field.
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Algoritmos , Lasers , Humanos , Análise Espectral/métodos , Redes Neurais de Computação , Aprendizado de MáquinaRESUMO
The antibody-drug conjugate trastuzumab emtansine (T-DM1) is approved for human epidermal growth factor receptor 2 (HER2/ERBB2)-positive breast cancer. We aimed to study tumor HER2 expression and its effects on T-DM1 responses in patients with HER2-positive urothelial bladder cancer (UBC) or pancreatic cancer (PC)/cholangiocarcinoma (CC). In the phase II KAMELEON study (NCT02999672), HER2 status was centrally assessed by immunohistochemistry, with positivity defined as non-focal homogeneous or heterogeneous overexpression of HER2 in ≥30% of stained cells. We also performed exploratory biomarker analyses (e.g., gene-protein assay) on tissue samples collected from study participants and consenting patients who failed screening. Of the 284 patients successfully screened for HER2 status (UBC, n = 69; PC/CC, n = 215), 13 with UBC, four with PC, and three with CC fulfilled eligibility criteria. Due to recruitment difficulty, the sponsor terminated KAMELEON prematurely. Of the five responders in the UBC cohort (overall response rate, 38.5%), HER2 expression was heterogeneous in two and homogeneous in three. The one responder in the PC/CC cohort had PC, and the tumor displayed homogeneous expression. In the biomarker-evaluable population, composed of screen-failed and enrolled patients, 24.3% (9/37), 1.5% (1/66), and 8.2% (4/49) of those with UBC, PC, or CC, respectively, had HER2-positive tumors. In a gene-protein assay combining in situ hybridization with immunohistochemistry, greater HER2 homogeneity was associated with increased ERBB2 amplification ratio. In conclusion, KAMELEON showed that some patients with HER2-positive UBC or PC can respond to T-DM1 and provided insight into the prevalence of HER2 positivity and expression patterns in three non-breast tumor types.
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Neoplasias dos Ductos Biliares , Neoplasias da Mama , Carcinoma de Células de Transição , Colangiocarcinoma , Maitansina , Neoplasias Pancreáticas , Neoplasias da Bexiga Urinária , Humanos , Feminino , Trastuzumab , Anticorpos Monoclonais Humanizados , Ado-Trastuzumab Emtansina , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Neoplasias da Mama/patologia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/genética , Neoplasias da Bexiga Urinária/tratamento farmacológico , Neoplasias da Bexiga Urinária/genética , Ductos Biliares Intra-Hepáticos/patologia , Neoplasias PancreáticasRESUMO
Reliable, reproducible methods to interpret programmed death ligand-1 (PD-L1) expression on tumor cells (TC) and immune cells (IC) are needed for pathologists to inform decisions associated with checkpoint inhibitor therapies. Our international study compared interpathologist agreement of PD-L1 expression using the combined positive score (CPS) under standardized conditions on samples from patients with gastric/gastroesophageal junction/esophageal adenocarcinoma. Tissue sections from 100 adenocarcinoma pretreatment biopsies were stained in a single laboratory using the PD-L1 immunohistochemistry 28-8 and 22C3 (Agilent) pharmDx immunohistochemical assays. PD-L1 CPS was evaluated by 12 pathologists on scanned whole slide images of these biopsies before and after a 2-hour CPS training session by Agilent. Additionally, pathologists determined PD-L1-positive TC, IC, and total viable TC on a single tissue fragment from 35 of 100 biopsy samples. Scoring agreement among pathologists was assessed using the intraclass correlation coefficient (ICC). Interobserver variability for CPS for 100 biopsies was high, with only fair agreement among pathologists both pre- (range, 0.45-0.55) and posttraining (range, 0.56-0.57) for both assays. For the 35 single biopsy samples, poor/fair agreement was also observed for the total number of viable TC (ICC, 0.09), number of PD-L1-positive IC (ICC, 0.19), number of PD-L1-positive TC (ICC, 0.54), and calculated CPS (ICC, 0.14), whereas calculated TC score (positive TC/total TC) showed excellent agreement (ICC, 0.82). Retrospective histologic review of samples with the poorest interpathologist agreement revealed the following as possible confounding factors: (1) ambiguous identification of positively staining stromal cells, (2) faint or variable intensity of staining, (3) difficulty in distinguishing membranous from cytoplasmic tumor staining, and (4) cautery and crush artifacts. These results emphasize the need for objective techniques to standardize the interpretation of PD-L1 expression when using the CPS methodology on gastric/gastroesophageal junction cancer biopsies to accurately identify patients most likely to benefit from immune checkpoint inhibitor therapy.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Antígeno B7-H1/metabolismo , Estudos Retrospectivos , Variações Dependentes do Observador , Patologistas , Biomarcadores Tumorais , Adenocarcinoma/patologia , Junção Esofagogástrica/metabolismo , Junção Esofagogástrica/patologia , Neoplasias Gástricas/patologiaRESUMO
The overexpression of HER2 in breast cancer is a classic example for molecular targeted therapy, and it has been shown that classical anti-HER2 therapeutics were only effective in patients with HER2 overexpressing tumors. Therefore, in recent decades, pathologists have been focused on the reliable identification of HER2 overexpressing tumors. Based on the results of recent clinical trials in metastatic breast cancer with antibody-drug conjugates (ADCs), this diagnostic strategy for evaluation of HER2 is currently changing. It has been shown that the ADC trastuzumab-deruxtecan is effective not only against tumors with classical HER2 overexpression, but also against HER2-low tumors. These clinical trial results lead to a paradigm shift in the treatment of patients whose tumours were previously classified as HER2 negative. In addition to the identification of HER2 (score 3+) overexpressing tumors, it is necessary to identify HER2-low expressing tumors (defined as an immunohistochemistry (IHC) score of 1+ or IHC2+ with negative in situ hybridization).Due to the therapeutic consequences, it is important to quickly adapt the diagnostic workup and reporting to the new requirements. In addition, the new therapeutic options for anti-HER2 therapy lead to new challenges for standardization as well as to new scientific questions for the characterization of tumors with low HER2 expression.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/diagnóstico , Receptor ErbB-2/genética , Anticorpos Monoclonais Humanizados/uso terapêutico , Imuno-Histoquímica , Terapia de Alvo MolecularRESUMO
The overexpression of HER2 in breast cancer is a classic example for molecular targeted therapy, and it has been shown that classical anti-HER2 therapeutics were only effective in patients with HER2 overexpressing tumors. Therefore, in recent decades, pathologists have been focused on the reliable identification of HER2 overexpressing tumors. Based on the results of recent clinical trials in metastatic breast cancer with antibody-drug conjugates (ADCs), this diagnostic strategy for evaluation of HER2 is currently changing. It has been shown that the ADC trastuzumab-deruxtecan is effective not only against tumors with classical HER2 overexpression, but also against HER2-low tumors. These clinical trial results lead to a paradigm shift in the treatment of patients whose tumours were previously classified as HER2 negative. In addition to the identification of HER2 (score 3+) overexpressing tumors, it is necessary to identify HER2-low expressing tumors (defined as an immunohistochemistry (IHC) score of 1+ or IHC2+ with negative in situ hybridization).Due to the therapeutic consequences, it is important to quickly adapt the diagnostic workup and reporting to the new requirements. In addition, the new therapeutic options for anti-HER2 therapy lead to new challenges for standardization as well as to new scientific questions for the characterization of tumors with low HER2 expression.
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Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Imunoconjugados/uso terapêutico , Receptor ErbB-2/genética , Trastuzumab/uso terapêutico , Ensaios Clínicos como AssuntoRESUMO
AIMS: A common concern among pathologists scoring PD-L1 immunohistochemical staining is interobserver and intraobserver variability. We assessed the interobserver and intraobserver reproducibility of PD-L1 scoring among trained pathologists using a combined positive score (CPS; tumour cell and tumour-associated immune cell staining). METHODS AND RESULTS: Data were collected for 2 years (2017-2019) from 456 pathologists worldwide. Digital training encompassed unique, tumour-specific training, and test sets. Samples were stained using PD-L1 IHC 22C3 pharmDx and evaluated at specific CPS cutoffs for gastric cancer (GC), cervical cancer (CC), urothelial cancer (UC), oesophageal cancer (OC), and head and neck squamous cell carcinoma (HNSCC). Pathologists underwent expert-to-peer training and scored 20 blinded samples on day 1 and 25 blinded samples on day 2 (including 15 of the day 1 samples). Interobserver and intraobserver reproducibility were assessed. For GC (120 observers) and CC (32 observers) samples assessed at CPS ≥1, average interobserver agreement was 91.5% and 91.0%, respectively, and average intraobserver agreement was 90.2% and 96.6%, respectively. For UC (139 observers) and OC (52 observers) samples measured at CPS ≥10, average interobserver agreement was 93.4% and 93.7%, respectively, and average intraobserver agreement was 92.0% and 92.5%, respectively. For HNSCC samples (113 observers), average interobserver agreement was 94.1% at CPS ≥1 and 86.5% at CPS ≥20; intraobserver agreement was 94.7% at CPS ≥1 and 90.5% at CPS ≥20. CONCLUSION: The consistently high interobserver and intraobserver concordance rates support the effectiveness of face-to-face training of many global pathologists for scoring PD-L1 CPS across multiple indications at several specific cutoffs.
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Carcinoma de Células de Transição , Neoplasias de Cabeça e Pescoço , Neoplasias Pulmonares , Neoplasias da Bexiga Urinária , Humanos , Antígeno B7-H1 , Patologistas , Carcinoma de Células Escamosas de Cabeça e Pescoço , Imuno-Histoquímica , Reprodutibilidade dos Testes , Biomarcadores Tumorais , Neoplasias Pulmonares/patologiaRESUMO
Performance of the new CE-IVD-marked HercepTest™ mAb pharmDx (Dako Omnis) assay (HercepTest (mAb)) was compared against the PATHWAY® anti-HER-2/neu (4B5) (PATHWAY 4B5) assay using 119 pre-selected breast cancer samples covering the entire range of HER2 immunohistochemistry (IHC) expression scores (0, 1 + , 2 + , 3 +). The sensitivity and specificity of both assays were assessed based on consensus IHC scores and amplification status, as determined by fluorescence in situ hybridization (FISH) according to 2018 ASCO/CAP testing guidelines. There was a high concordance between results from the HercepTest (mAb) and PATHWAY 4B5 assays for HER2-negative (IHC 0, 1 + , 2 + and FISH negative) and HER2-positive (IHC 3 + , 2 + and FISH positive) breast carcinomas (98.2%). Regarding individual IHC scores, complete agreement was achieved in 69.7% (83/119) of cases, and all but one of the discordant cases were due to higher HER2-status scoring using the HercepTest (mAb). Thus, more tumors were overscored as IHC 2 + by HercepTest (mAb) (27 versus 15) as evidenced by their lower FISH positivity rate (48.1% versus 80%). However, two amplified tumors identified as IHC 2 + by HercepTest (mAb) were missed by PATHWAY 4B5 (IHC 1 +). Four additional cases identified as IHC 2 + by HercepTest (mAb), with FISH ratio < 2 but elevated gene counts (≥ 4 to < 6), were recorded negative by PATHWAY 4B5. The HercepTest (mAb) detects HER2 expression with higher sensitivity in tumors with gene amplification (ISH group 1) and increased gene counts (ISH group 4) as well as in HER2-low tumors (HER2 IHC2 + /FISH negative or IHC 1 +). Future studies will demonstrate whether this translates into improved patient selection especially for new HER2-directed therapies.
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Neoplasias da Mama , Receptor ErbB-2 , Humanos , Feminino , Receptor ErbB-2/metabolismo , Hibridização in Situ Fluorescente/métodos , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Imuno-Histoquímica , Neoplasias da Mama/patologia , Amplificação de GenesRESUMO
BACKGROUND: There is a paucity of knowledge regarding pediatric biomarkers, including the relevance of ErbB pathway aberrations in pediatric tumors. We investigated the occurrence of ErbB receptor aberrations across different pediatric malignancies, to identify patterns of ErbB dysregulation and define biomarkers suitable for patient enrichment in clinical studies. PROCEDURE: Tissue samples from 297 patients with nervous system tumors and rhabdomyosarcoma were analyzed for immunohistochemical expression or gene amplification of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). Exploratory analyses of HER3/HER4 expression, and mRNA expression of ErbB receptors/ligands (NanoString) were performed. Assay validation followed general procedures, with additional validation to address Clinical Laboratory Improvement Amendments (CLIA) requirements. RESULTS: In most tumor types, samples with high ErbB receptor expression were found with heterogeneous distribution. We considered increased/aberrant ErbB pathway activation when greater than or equal to two EGFR/HER2 markers were simultaneously upregulated. ErbB pathway dysregulation was identified in â¼20%-30% of samples for most tumor types (medulloblastoma/primitive neuroectodermal tumors 31.1%, high-grade glioma 27.1%, neuroblastoma 22.7%, rhabdomyosarcoma 23.1%, ependymoma 18.8%), 4.2% of diffuse intrinsic pontine gliomas, and no recurrent or refractory low-grade astrocytomas. In medulloblastoma/primitive neuroectodermal tumors and neuroblastoma, this was attributed mainly to high EGFR polysomy/HER2 amplification, whereas EGFR gene amplification was observed in some high-grade glioma samples. EGFR/HER2 overexpression was most prevalent in ependymoma. CONCLUSIONS: Overexpression and/or amplification of EGFR/HER2 were identified as potential enrichment biomarkers for clinical trials of ErbB-targeted drugs.
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Neoplasias do Sistema Nervoso , Rabdomiossarcoma , Criança , Receptores ErbB , HumanosRESUMO
In recent years, the treatment of non-small-cell lung cancer (NSCLC) has been fundamentally changed by immunotherapy where the immune system is reactivated using anti-programmed cell death protein 1/programmed death ligand 1 (PD1/PD-L1) checkpoint inhibition. With this, the immunohistological detection of PD-L1 has become one of the most important predictive biomarkers, leading pathologists to play a central role in the immuno-oncological therapy decisions. This has brought them the challenge of requiring the knowledge of relevant checkpoint inhibitors (CI), different PD-L1 scores and cut-offs as well as the choice of the right tissues and controls. Their involvement is also required in the careful validation of both clinical trial assays (CTAs) and laboratory developed tests (LDTs), in addition to the internal and external quality assessment and the interpretation and scoring of the staining based on specialist training. After the training of tumor proportion score (TPS) scoring in NSCLC, pathologists show a high level of concordance, with some variation between different cut-offs. Since not all patients benefit from immunotherapy, further research is needed to validate new predictive markers and optimize existing ones. In this context, these studies focus on a combination of PD-L1 and molecular signatures.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Antígeno B7-H1 , Biomarcadores Tumorais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Humanos , Imuno-Histoquímica , Neoplasias Pulmonares/tratamento farmacológico , PatologistasRESUMO
Based on new trial data regarding immune checkpoint inhibitors (ICIs), the detection of high-grade microsatellite instability (MSI-H) or underlying deficient mismatch repair protein (dMMR) is now becoming increasingly important for predicting treatment response. For the first time, a PD1 ICI (pembrolizumab) has been approved by the European Medicines Agency (EMA) for first-line treatment of advanced (stage IV) dMMR/MSIH colorectal cancer (CRC). Further indications, such as dMMR/MSIH endometrial carcinoma (EC), have already succeeded (Dostarlimab, 2nd line treatment) and others are expected to follow before the end of 2021. The question of optimal testing in routine diagnostics should therefore be re-evaluated. Based on a consideration of the strengths and weaknesses of the widely available methods (immunohistochemistry and PCR), a test algorithm is proposed that allows quality assured, reliable, and cost-effective dMMR/MSIH testing. For CRC and EC, testing is therefore already possible at the primary diagnosis stage, in line with international recommendations (NICE, NCCN). The clinician is therefore enabled from the outset to consider not only the predictive but also the prognostic and predispositional implications of such a test when counseling patients and formulating treatment recommendations. As a basis for quality assurance, participation in interlaboratory comparisons and continuous documentation of results (e.g., QuIP Monitor) are strongly recommended.
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Instabilidade de Microssatélites , Neoplasias/tratamento farmacológico , Neoplasias/genética , Reparo de Erro de Pareamento de DNA , Feminino , Humanos , Inibidores de Checkpoint Imunológico/uso terapêutico , Imuno-Histoquímica , PrognósticoRESUMO
BACKGROUND: Breast cancer (BC) is the most frequent female cancer and preferentially metastasizes to bone. The transcription factor TGFB-induced factor homeobox 1 (TGIF) is involved in bone metabolism. However, it is not yet known whether TGIF is associated with BC bone metastasis or patient outcome and thus of potential interest. METHODS: TGIF expression was analyzed by immunohistochemistry in 1197 formalin-fixed, paraffin-embedded tissue samples from BC patients treated in the GAIN (German Adjuvant Intergroup Node-Positive) study with two adjuvant dose-dense schedules of chemotherapy with or without bisphosphonate ibandronate. TGIF expression was categorized into negative/low and moderate/strong staining. Endpoints were disease-free survival (DFS), overall survival (OS) and time to primary bone metastasis as first site of relapse (TTPBM). RESULTS: We found associations of higher TGIF protein expression with smaller tumor size (p = 0.015), well differentiated phenotype (p < 0.001) and estrogen receptor (ER)-positive BC (p < 0.001). Patients with higher TGIF expression levels showed a significantly longer disease-free (DFS: HR 0.75 [95%CI 0.59-0.95], log-rank p = 0.019) and overall survival (OS: HR 0.69 [95%CI 0.50-0.94], log-rank p = 0.019), but no association with TTPBM (HR 0.77 [95%CI 0.51-1.16]; p = 0.213). Univariate analysis in molecular subgroups emphasized that elevated TGIF expression was prognostic for both DFS and OS in ER-positive BC patients (DFS: HR 0.68 [95%CI 0.51-0.91]; log-rank p = 0.009, interaction p = 0.130; OS: HR 0.60 [95%CI 0.41-0.88], log-rank p = 0.008, interaction p = 0.107) and in the HER2-negative subgroup (DFS:HR 0.67 [95%CI 0.50-0.88], log-rank p = 0.004, interaction p = 0.034; OS: HR 0.57 [95%CI 0.40-0.81], log-rank p = 0.002, interaction p = 0.015). CONCLUSIONS: Our results suggest that moderate to high TGIF expression is a common feature of breast cancer cells and that this is not associated with bone metastases as first site of relapse. However, a reduced expression is linked to tumor progression, especially in HER2-negative breast cancer. TRIAL REGISTRATION: This clinical trial has been registered with ClinicalTrials.gov ; registration number: NCT00196872 .