Prognosis, stage and oestrogen receptor status of contralateral breast cancer in relation to characteristics of the first tumour, prior endocrine treatment and radiotherapy.

A contralateral breast cancer (CBC) is today treated as an independent primary tumour, although recent data suggest risk and prognosis of CBC to be influenced by characteristics of and treatment given for the first tumour (BC1). We hereby investigate phenotypical and prognostic features of the second tumour (BC2) in relation to prior endocrine treatment and radiotherapy

The G protein-coupled estrogen receptor 1 (GPER/GPR30) does not predict survival in patients with ovarian cancer

<p>Abstract</p> <p>Background</p> <p>Even though ovarian tumors are not generally considered estrogen-sensitive, estrogens may still have an impact on ovarian tumor progression. The recently identified trans-membrane estrogen receptor GPER is involved in rapid estrogen signaling. Furthermore, it binds selective estrogen receptor modulators with agonistic effect, which could explain tamoxifen controversies.</p> <p>Methods</p> <p>GPER mRNA was assayed with quantitative real-time PCR (qPCR) in 42 primary ovarian tumors and 7 ovarian cancer cell lines. ERα and ERβ mRNA were analyzed for comparison. GPER protein was semi-quantified with densitometric scanning of Western blots and its tissue distribution analyzed with immunohistochemistry (IHC) in 40 ovarian tumors. In addition, IHC was evaluated in a tissue microarray (TMA) of 150 primary malignant ovarian tumors.</p> <p>Results</p> <p>All tumor samples contained GPER mRNA. The content of mRNA was not different between benign and malignant tumors, but one third of malignant samples over-expressed GPER mRNA. The content of ERα mRNA was higher in malignant than in benign tumors, whereas ERβ mRNA was higher in benign than in malignant tumors. GPER mRNA was detected in all seven ovarian cancer cell lines with highest levels in TOV21G and TOV112D cells. Similar expression pattern was seen for ERβ mRNA. Western blot demonstrated GPER protein in all tumor samples. Semi-quantification showed no difference between benign and malignant tumors, but about one third of malignant samples over-expressed GPER protein. GPER staining was localized mainly in epithelial cells. In the TMA study we found no correlation between GPER staining and clinical stage, histological grade or patient survival.</p> <p>Conclusions</p> <p>GPER mRNA as well as GPER protein is present in both benign and malignant ovarian tumor tissue. About one third of malignant tumors over-expressed both GPER mRNA and protein. This, however, correlated neither with histological or clinical parameters nor with patient survival.</p

Histological grade provides significant prognostic information in addition to breast cancer subtypes defined according to St Gallen 2013

Background: The St Gallen surrogate definition of the intrinsic subtypes of breast cancer consist of five subgroups based on estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor type 2 (HER2), and Ki-67. PgR and Ki-67 are used for discriminating between the ‘Luminal A-like’ and ‘Luminal B-like (HER2-negative)’ subtypes. Histological grade (G) has prognostic value in breast cancer; however, its relationship to the St Gallen subtypes is not clear. Based on a previous pilot study, we hypothesized that G could be a primary discriminator for ER-positive/HER2-negative breast cancers that were G1 or G3, whereas Ki-67 and PgR could provide additional prognostic information specifically for patients with G2 tumors. To test this hypothesis, a larger patient cohort was examined. Patients and methods: Six hundred seventy-one patients (≥35 years of age, pT1-2, pN0-1) with ER-positive/HER2-negative breast cancer and complete data for PgR, Ki-67, G, lymph node status, tumor size, age, and distant disease-free survival (DDFS; median follow-up 9.2 years) were included. Results: ‘Luminal A-like’ tumors were mostly G1 or G2 (90%) whereas ‘Luminal B-like’ tumors were mostly G2 or G3 (87%) and corresponded with good and poor DDFS, respectively. In ‘Luminal B-like’ tumors that were G1 (n = 23), no metastasis occurred, whereas 14 of 40 ‘Luminal A-like’ tumors that were G3 metastasized. In the G2 subgroup, low PgR and high Ki-67 were associated with an increased risk of distant metastases, hazard ratio (HR) and 95% confidence interval (CI) 1.8 (0.95–3.4) and 1.5 (0.80–2.8), respectively. Conclusions: Patients with ER-positive/HER2-negative/G1 breast cancer have a good prognosis, similar to that of ‘Luminal A-like’, while those with ER-positive/HER2-negative/G3 breast cancer have a worse prognosis, similar to that of ‘Luminal B-like’, when assessed independently of PgR and Ki-67. Therapy decisions based on Ki-67 and PgR might thus be restricted to the subgroup G2

Clear cell lesions of the head and neck: The spectrum of histological features

Objective: Estrogen receptor (ER) positive breast cancer (BC) can havean insidious course with disease-relapse decades after primary surgery.New analysis performed on archived formalin-fixed paraffin-embedded(FFPE) tissue are important for disease-management in late BC-relapseand an important tool in BC-research. However, although loss of immunoreactivityin tissue slides after sectioning has been shown, little isknown of the preservation of biomarker-expression in FFPE tumourblocks.We aim to investigate the quality of immunohistochemical(IHC) ER-evaluation in FFPE-tissue over time (1978–2000).Method: Tissue-microarrays from a Swedish multicenter cohort of 728patients with contralateral BC was used for ER IHC-evaluation. BC wasstudied in three periods (1958–1985, 1986–1993, 1994–2000), and retrospectiveER IHC-data was correlated to corresponding prospective ERcytosol-analysis performed on fresh BC-tissue.Results: The concordance between the original ER cytosol-analysis andthe new IHC was substantial (1978–1985: 82 %, (117/142), Kappa 0.52.1986–1993: 91 %, (194/213), Kappa 0.72. 1994–2000: 86 %, (187/218),Kappa 0.61). Discrepancies were mostly found for tumours with ERvaluesclose to cutoff for one or both of the methods.Conclusion: FFPE BC-tissue from the late 70s to millennium showspreserved ER-antigenicity up to 35 years later

Striking parallels between carotid body glomus cell and adrenal chromaffin cell development

Carotid body glomus cells mediate essential reflex responses to arterial blood hypoxia. They are dopaminergic and secrete growth factors that support dopaminergic neurons, making the carotid body a potential source of patient-specific cells for Parkinson’s disease therapy. Like adrenal chromaffin cells, which are also hypoxia-sensitive, glomus cells are neural crest-derived and require the transcription factors Ascl1 and Phox2b; otherwise, their development is little understood at the molecular level. Here, analysis in chicken and mouse reveals further striking molecular parallels, though also some differences, between glomus and adrenal chromaffin cell development. Moreover, histology has long suggested that glomus cell precursors are ‘émigrés’ from neighbouring ganglia/nerves, while multipotent nerve-associated glial cells are now known to make a significant contribution to the adrenal chromaffin cell population in the mouse. We present conditional genetic lineage-tracing data from mice supporting the hypothesis that progenitors expressing the glial marker proteolipid protein 1, presumably located in adjacent ganglia/nerves, also contribute to glomus cells. Finally, we resolve a paradox for the ‘émigré’ hypothesis in the chicken - where the nearest ganglion to the carotid body is the nodose, in which the satellite glia are neural crest-derived, but the neurons are almost entirely placode-derived - by fate-mapping putative nodose neuronal 'émigrés' to the neural crest

Molecular Monitoring after Autologous Stem Cell Transplantation and Preemptive Rituximab Treatment of Molecular Relapse; Results from the Nordic Mantle Cell Lymphoma Studies (MCL2 and MCL3) with Median Follow-Up of 8.5 Years

The main objectives of the present study were to monitor minimal residual disease (MRD) in the bone marrow of patients with mantle cell lymphoma (MCL) to predict clinical relapse and guide preemptive treatment with rituximab. Among the patients enrolled in 2 prospective trials by the Nordic Lymphoma Group, 183 who had completed autologous stem cell transplantation (ASCT) and in whom an MRD marker had been obtained were included in our analysis. Fresh samples of bone marrow were analyzed for MRD by a combined standard nested and quantitative real-time PCR assay for Bcl-1/immunoglobulin heavy chain gene (IgH) and clonal IgH rear-rangements. Significantly shorter progression-free survival (PFS) and overall survival (OS) was demonstrated for patients who were MRD positive pre-ASCT (54 patients) or in the first analysis post-ASCT (23 patients). The median PFS was only 20 months in those who were MRD-positive in the first sample post-ASCT, compared with 142 months in the MRD-negative group (PPeer reviewe

Comprehensive molecular comparison of BRCA1 hypermethylated and BRCA1 mutated triple negative breast cancers

Funder: The Governmental Funding for Young Clinical Researchers within the National Health Service (ALF) 2017-2019Funder: Shamik Mitra is financially supported by the funding received from the European Community’s Horizon 2020 Framework Program for Research and Innovation (H2020-MSCA-ITN-2014) under Grant Agreement no. 247634Funder: Vetenskapsrådet (Swedish Research Council); doi: https://doi.org/10.13039/501100004359Funder: The Governmental Funding within the National Health Service (ALF)Funder: - The Governmental Funding of Clinical Research within the National Health Service (ALF), grant nbr 2018/40612 - The Gustav V:s Jubilee Foundation (174271 and 187041) - The research foundation at Department of Oncology in LundAbstract: Homologous recombination deficiency (HRD) is a defining characteristic in BRCA-deficient breast tumors caused by genetic or epigenetic alterations in key pathway genes. We investigated the frequency of BRCA1 promoter hypermethylation in 237 triple-negative breast cancers (TNBCs) from a population-based study using reported whole genome and RNA sequencing data, complemented with analyses of genetic, epigenetic, transcriptomic and immune infiltration phenotypes. We demonstrate that BRCA1 promoter hypermethylation is twice as frequent as BRCA1 pathogenic variants in early-stage TNBC and that hypermethylated and mutated cases have similarly improved prognosis after adjuvant chemotherapy. BRCA1 hypermethylation confers an HRD, immune cell type, genome-wide DNA methylation, and transcriptional phenotype similar to TNBC tumors with BRCA1-inactivating variants, and it can be observed in matched peripheral blood of patients with tumor hypermethylation. Hypermethylation may be an early event in tumor development that progress along a common pathway with BRCA1-mutated disease, representing a promising DNA-based biomarker for early-stage TNBC

Analytical validation of a standardised scoring protocol for Ki67 immunohistochemistry on breast cancer excision whole sections: an international multicentre collaboration

Aims The nuclear proliferation marker Ki67 assayed by immunohistochemistry has multiple potential uses in breast cancer, but an unacceptable level of interlaboratory variability has hampered its clinical utility. The International Ki67 in Breast Cancer Working Group has undertaken a systematic programme to determine whether Ki67 measurement can be analytically validated and standardised among laboratories. This study addresses whether acceptable scoring reproducibility can be achieved on excision whole sections. Methods and results Adjacent sections from 30 primary ER+ breast cancers were centrally stained for Ki67 and sections were circulated among 23 pathologists in 12 countries. All pathologists scored Ki67 by two methods: (i) global: four fields of 100 tumour cells each were selected to reflect observed heterogeneity in nuclear staining; (ii) hot-spot: the field with highest apparent Ki67 index was selected and up to 500 cells scored. The intraclass correlation coefficient (ICC) for the global method [confidence interval (CI) = 0.87; 95% CI = 0.799-0.93] marginally met the prespecified success criterion (lower 95% CI >= 0.8), while the ICC for the hot-spot method (0.83; 95% CI = 0.74-0.90) did not. Visually, interobserver concordance in location of selected hot-spots varies between cases. The median times for scoring were 9 and 6 min for global and hot-spot methods, respectively. Conclusions The global scoring method demonstrates adequate reproducibility to warrant next steps towards evaluation for technical and clinical validity in appropriate cohorts of cases. The time taken for scoring by either method is practical using counting software we are making publicly available. Establishment of external quality assessment schemes is likely to improve the reproducibility between laboratories further