479 research outputs found
HER2 and ESR1 mRNA expression levels and response to neoadjuvant trastuzumab plus chemotherapy in patients with primary breast cancer
No full textIntroduction: Recent data suggest that benefit from trastuzumab and chemotherapy might be related to expression of HER2 and estrogen receptor (ESR1). Therefore, we investigated HER2 and ESR1 mRNA levels in core biopsies of HER2-positive breast carcinomas from patients treated within the neoadjuvant GeparQuattro trial.
Methods: HER2 levels were centrally analyzed by immunohistochemistry (IHC), silver in-situ hybridization (SISH) and qRT-PCR in 217 pretherapeutic formalin-fixed, paraffin-embedded (FFPE) core biopsies. All tumors had been HER2-positive by local pathology and had been treated with neoadjuvant trastuzumab/ chemotherapy in GeparQuattro.
Results: Only 73% of the tumors (158 of 217) were centrally HER2-positive (cHER2-positive) by IHC/SISH, with cHER2-positive tumors showing a significantly higher pCR rate (46.8% vs. 20.3%, p<0.0005). HER2 status by qRT-PCR showed a concordance of 88.5% with the central IHC/SISH status, with a low pCR rate in those tumors that were HER2-negative by mRNA analysis (21.1% vs. 49.6%, p<0.0005). The level of HER2 mRNA expression was linked to response rate in ESR1-positive tumors, but not in ESR1-negative tumors. HER2 mRNA expression was significantly associated with pCR in the HER2-positive/ESR1-positive tumors (p=0.004), but not in HER2-positive/ESR1-negative tumors.
Conclusions: Only patients with cHER2-positive tumors - irrespective of the method used - have an increased pCR rate with trastuzumab plus chemotherapy. In patients with cHER2-negative tumors the pCR rate is comparable to the pCR rate in the non-trastuzumab treated HER-negative population. Response to trastuzumab is correlated to HER2 mRNA levels only in ESR1-positive tumors. This study adds further evidence to the different biology of both subsets within the HER2-positive group
Tumor infiltrating lymphocytes in early breast cancer
No full textImmunoediting represents a complex and dynamic process involving cancer and immune system cells, composed by three intertwined phases: elimination, equilibrium and escape. A large number of immune cell subtypes are involved, each playing a peculiar role in interacting with cancer cells: cytotoxic CD8(+) T cells play a main role in cancer killing by inducing tumor cell death, while FOXP3(+) T-regulatory cells represent an immune-inhibitory cell subtype. The evaluation of tumor infiltrating lymphocytes (TILs) in H&E routine samples has been shown to represent a reliable surrogate of the immune anti-tumor activity and a robust independent prognostic biomarker in breast cancer (BC) patients, especially in the Tripe Negative and HER2thorn subtypes. The present review addresses the mechanisms of breast cancer immunoediting, its cell complexity and prognostic/predictive relevance, providing evidence that TILs represent one the most promising biomarkers for BC patients
Class I histone deacetylases 1, 2 and 3 are highly expressed in renal cell cancer
No full textBackground Enhanced activity of histone deacetylases (HDAC) is associated with more aggressive tumour behaviour and tumour progression in various solid tumours. The over-expression of these proteins and their known functions in malignant neoplasms has led to the development of HDAC inhibitors (HDI) as new anti-neoplastic drugs. However, little is known about HDAC expression in renal cell cancer. Methods We investigated the expression of HDAC 1, 2 and 3 in 106 renal cell carcinomas and corresponding normal renal tissue by immunohistochemistry on tissue micro arrays and correlated expression data with clinico-pathological parameters including patient survival. Results Almost 60% of renal cell carcinomas expressed the HDAC isoforms 1 and 2. In contrast, HDAC 3 was only detected in 13% of all renal tumours, with particular low expression rates in the clear cell subtype. HDAC 3 was significantly higher expressed in pT1/2 tumours in comparison to pT3/4 tumours. Expression of class I HDAC isoforms correlated with each other and with the proliferative activity of the tumours. We found no prognostic value of the expression of any of the HDAC isoforms in this tumour entity. Conclusion Class I HDAC isoforms 1 and 2 are highly expressed in renal cell cancer, while HDAC 3 shows low, histology dependent expression rates. These unexpected differences in the expression patterns suggests alternative regulatory mechanisms of class I HDACs in renal cell cancer and should be taken into account when trials with isoform selective HDI are being planned. Whether HDAC expression in renal cancers is predictive of responsiveness for HDI will have to be tested in further studies
A histological comparison of the osteocyte lacunar density in the trabeculae of human cervical, thoracic and lumbar vertebrae
No full textDenkert K, Schroeder G, Schulze M, Schober H-C. A histological comparison of the osteocyte lacunar density in the trabeculae of human cervical, thoracic and lumbar vertebrae. In: ASBMR Annual Meeting Abstract Supplement 2021. Journal of Bone and Mineral Research. Vol 37. Hoboken: Wiley; 2022
Breast cancer
No full textBreast cancer is still the most common cancer worldwide. But the way breast cancer is viewed has changed drastically since its molecular hallmarks were extensively characterised, now including immunohistochemical markers (eg, ER, PR, HER2 [ERBB2], and proliferation marker protein Ki-67 [MKI67]), genomic markers (eg, BRCA1, BRCA2, and PIK3CA), and immunomarkers (eg, tumour-infiltrating lymphocytes and PD-L1). New biomarker combinations are the basis for increasingly complex diagnostic algorithms. Neoadjuvant combination therapy, often including targeted agents, is a standard of care (especially in HER2-positive and triple-negative breast cancer), and the basis for de-escalation of surgery in the breast and axilla and for risk-adapted post-neoadjuvant strategies. Radiotherapy remains an important cornerstone of breast cancer therapy, but de-escalation schemes have become the standard of care. ER-positive tumours are treated with 5-10 years of endocrine therapy and chemotherapy, based on an individual risk assessment. For metastatic breast cancer, standard therapy options include targeted approaches such as CDK4 and CDK6 inhibitors, PI3K inhibitors, PARP inhibitors, and anti-PD-L1 immunotherapy, depending on tumour type and molecular profile. This range of treatment options reflects the complexity of breast cancer therapy today
Abstract ES11-3: Novel approaches for selection of and monitoring treatment
No full textAbstract
With the introduction of new therapeutic options in advanced and metastatic breast cancer, there is a growing demand for new biomarkers to guide treatment decisions.
There are several differences compared to early breast cancer that have to be addressed to define the clinical use of precision medicine in advanced and metastatic breast cancer.
The current challenges include the limited availability of tissue in metastatic disease, the problems of spatial heterogeneity in large advanced tumors, as well as differences between different metastatic sites. In addition, it has been shown that in metastatic and recurrent tumors, new molecular alterations develop under therapeutic pressure, for example mutations in the ESR1 receptor.
The current guidelines suggest that the basic characterization of the tumor using the standard markers of hormone receptors and HER2 should be repeated in the metastatic setting, if possible. Differences between primary and recurrent tumors have been observed in a comparably small percentage of tumors, nevertheless these differences may open new therapeutic options. Therefore, rebiopsies should be performed, if possible, these biopsies are also highly relevant for the evaluation of new therapy strategies in clinical trials.
Another relevant challenge is the heterogeneity of the tumor cells at different metastatic sites, these different metastases originate from different cell clones and have therefore a different molecular background, in particular in those tumors that have a high intratumoral molecular diversity. Considering this heterogeneity between different metastases as well as technical difficulties in the conduction of biopsies, new technologies have been established to monitor tumor biomarkers on a systemic level. This includes the evaluation of circulating tumor cells as well as the evaluation of cell-free circulating DNA (cfDNA) in so called liquid-biopsies. Several translational studies shown that sequencing of cfDNA is suitable to detect tumor mutations that can be used distinguish different groups of tumors with different response rates, for example to PIK3CA inhibitors. Relevant mutations include ESR1 and PIK3CA, which are relevant for therapy resistance in breast cancer and can be measured by NGS-sequencing. In breast cancer, these investigations are currently not part of the clinical routine. In lung cancer, the analysis of T790M EGFR mutations in liquid biopies are routinely used to guide therapeutic decisions in recurrent disease, which shows that the introduction into the clinical setting is feasible. The presentation will discuss the advantages and limitations of the different methods, and give examples for biomarker strategies for different therapies including endocrine therapy, immune therapy and targeted therapy.
Citation Format: Denkert C. Novel approaches for selection of and monitoring treatment [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr ES11-3.</jats:p
Hrd1 forms the retrotranslocation pore regulated by auto-ubiquitination and binding of misfolded proteins.
No full textDuring endoplasmic-reticulum-associated protein degradation (ERAD), misfolded proteins are polyubiquitinated, extracted from the ER membrane and degraded by the proteasome1-4. In a process called retrotranslocation, misfolded luminal proteins first need to traverse the ER membrane before ubiquitination can occur in the cytosol. It was suggested that the membrane-embedded ubiquitin ligase Hrd1 forms a retrotranslocation pore regulated by cycles of auto- and deubiquitination5-8. However, the mechanism by which auto-ubiquitination affects Hrd1 and allows polypeptides to cross the membrane and whether Hrd1 forms a membrane-spanning pore remained unknown. Here, using purified Hrd1 incorporated into different model membranes, we show that Hrd1 auto-ubiquitination leads to the opening of a pore. Substrate binding increases the pore size and its activity, whereas deubiquitination closes the pore and renders it unresponsive to substrate. We identify two binding sites for misfolded proteins in Hrd1, a low-affinity luminal site and a high-affinity cytoplasmic site formed following auto-ubiquitination of specific lysine residues in Hrd1's RING domain. We propose that the affinity difference between the luminal and cytoplasmic binding sites provides the initial driving force for substrate movement through Hrd1
Abstract ES4-3: Tumor-infiltrating lymphocytes (TILs) and genomic signatures of immune cells
No full textAbstract
Increased levels of tumor-infiltrating lymphocytes have been described in subsets of breast cancer, in particular triple-negative (TNBC) and HER2-positive (HER2+) tumors. Neoadjuvant therapy approaches in breast cancer have been used as a strategy to characterize subgroups of tumors with increased tumor-infiltrating lymphocytes (TILs). We have described tumor-infiltrating lymphocytes (TILs) as predictors of pathological complete response to neoadjuvant chemotherapy in breast cancer trials conducted by the German Breast Group. It has been shown that increased TILs are linked to an increased response rate to neoadjuvant therapy and improved prognosis after adjuvant therapy, in particular in triple-negative and HER2 positive breast cancer. In addition to tumor-infiltrating lymphocytes, immune mRNA markers have been studied in breast cancer and are associated with increased chemotherapy response and improved prognosis. These results suggest that some subtypes of breast cancer are immunogenic and that there is an ongoing low-level immune response present even in clinically progressing tumors.
Therapeutic approaches to modulate tumor-associated inflammation by immune checkpoint inhibitors have shown clinical responses in a subset of triple-negative breast cancers, and some of these responses were durable. These targeted therapies have stimulated interest in the interaction between immune cells and tumor cells. Based on the concept that conventional chemotherapy might be immunogenic, some studies are evaluating the combination of an immune checkpoint inhibitor and a chemotherapy. Considering the fact that responses to immune checkpoint inhibitors are observed in only a subset of tumors, biomarkers that will be able to identify those tumors are needed. Possible biomarkers include the therapeutic targets, in particular PD-L1 and PD1, tumor-infiltrating lymphocytes, predictive mRNA signatures, immunogenic neoepitope signatures that are generated by mutations as well as other factors. Due to the low costs of a simple H&E based test, tumor infiltrating lymphocytes might become a promising biomarker as part of the pathology report. In preparation for this, the international immune-oncology working group (TIL working group) has published standardized guidelines for TIL evaluation in breast cancer, and has conducted a first international TIL ring trial. This ring trial suggests that decentral TIL evaluation is feasible. In some situations, in particular in tumors with intermediate and heterogeneous TILs, additional tests, including gene expression signatures might be necessary. It should be emphasized that the clinical utility of TILs for current medical decisions is very limited at the present time, and the ultimate usefulness of these biomarker concepts will be obtained in the ongoing and future clinical immunotherapy trials.
The presentation will provide an overview on recent results on immune markers for prediction of response to neoadjuvant chemotherapy and prognosis with a focus in standardized histomorphological evaluation of tumor-infiltrating lymphocytes as well as clinical trials concepts and biomarker strategies for future immune checkpoint inhibitor therapies in breast cancer.
Citation Format: Denkert C. Tumor-infiltrating lymphocytes (TILs) and genomic signatures of immune cells [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES4-3.</jats:p
Molecular pathways: involvement of immune pathways in the therapeutic response and outcome in breast cancer.
No full textThe immune system could mediate the antitumor activity of several anticancer treatments. Several chemotherapy compounds, including anthracyclines and oxaliplatin, induce immunogenic cell death that in turn activates antitumor immune response. Trastuzumab induces antibody-dependant cell-mediated cytotoxicity. On the basis of this background, immune markers have recently been the focus of intense translational research to predict and monitor the efficacy of treatments. Gene expression arrays and immunohistochemistry have assessed immune activation and infiltration by macrophages, natural killer, and T and B lymphocytes. Using these approaches, several retrospective analyses of large trials have shown that activation of immune pathway may predict treatment efficacy and outcome in patients with breast cancers. As examples, intratumoral infiltration by lymphocytes and interferon-response in primary tumor predicted the efficacy of neoadjuvant chemotherapy. Intratumoral infiltration by lymphocytes was associated with good prognosis in patients with triple-negative breast cancer treated with adjuvant chemotherapy. More recently, it has been suggested that lymphocyte infiltration could also predict efficacy of trastuzumab. Finally, small retrospective studies have suggested that postchemotherapy lymphocyte infiltrates could be associated with better outcome in patients who did not reach pathologic complete response. This body of evidence suggests that assessing immune infiltration and activation could be useful in the future to stratify breast cancer patients. In addition, they provide evidence for the development of immunotherapies in breast cancer patients.Journal ArticleReviewSCOPUS: ar.jinfo:eu-repo/semantics/publishe
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