| 1. |
- Bengtsson, Ylva, et al.
(författare)
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Serum copper, zinc and copper/zinc ratio in relation to survival after breast cancer diagnosis: A prospective multicenter cohort study
- 2023
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Ingår i: Redox Biology. - 2213-2317. ; 63
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThe essential trace elements copper and zinc, and their ratio (copper/zinc), are important for maintaining redox homeostasis. Previous studies suggest that these elements may impact breast cancer survival. However, no epidemiological study has so far been conducted on the potential association between copper and copper/zinc levels and survival after breast cancer diagnosis. In this study, we aimed to examine the relationship between serum copper, zinc and copper/zinc levels and survival following breast cancer diagnosis.Patients and methodsThe Sweden Cancerome Analysis Network – Breast Initiative (SCAN-B) is a population-based cohort study including multiple participating hospitals in Sweden. A total of 1998 patients diagnosed with primary invasive breast cancer were followed for approximately nine years. Serum levels of copper and zinc and their ratio at the time of diagnosis was analyzed in relation to breast cancer survival using multivariate Cox regression, yielding hazard ratios (HR) with 95% confidence intervals.ResultsA higher copper/zinc ratio was associated with lower overall survival after breast cancer diagnosis. Comparing patients with a copper/zinc ratio in quartile 4 vs 1, the crude HR was 2.29 (1.65–3.19) (Ptrend ConclusionThere is evidence that the serum copper/zinc ratio provides an independent predictive value for overall survival following breast cancer diagnosis.
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| 2. |
- Brueffer, Christian, et al.
(författare)
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Abstract P4-09-03: On the development and clinical value of RNA-sequencing-based classifiers for prediction of the five conventional breast cancer biomarkers: A report from the population-based multicenter SCAN-B study
- 2018
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Ingår i: Cancer research. Supplement. - 1538-7445. ; 78:4
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Konferensbidrag (refereegranskat)abstract
- Background:In early breast cancer, five histopathological biomarkers are part of current clinical routines and used for determining prognosis and treatment: estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (ERBB2/HER2), Ki67, and Nottingham histological grade (NHG). We aimed to develop classifiers for these biomarkers based on tumor mRNA-sequencing (RNA-seq), compare classification performance to conventional histopathology, and test whether RNA-seq-based predictors could add value for patient risk-stratification.Patients and Methods:In total, 3678 breast tumors were studied. For 405 breast tumors in the training cohort, a comprehensive histopathological biomarker evaluation was performed by three pathology readings to estimate inter-pathologist variability on the original diagnostic slides as well as on repeat immunostains for this study, and the consensus biomarker status for all five conventional biomarkers was determined. Whole transcriptome gene expression profiling was performed by RNA-sequencing on the Illumina platform. Using RNA-seq-derived tumor gene expression data as input, single-gene classifiers (SGC) and multi-gene classifiers (MGC) were trained on the consensus pathology biomarker labels. The trained classifiers were tested on an independent prospective population-based series of 3273 primary breast cancer cases from the multicenter SCAN-B study with median 41 months follow-up (ClinicalTrials.gov identifier NCT02306096), and classifications were evaluated by agreement statistics and by Kaplan-Meier and Cox regression survival analyses.Results:For the histopathological evaluation, pathologist evaluation concordance was high for ER, PgR, and HER2 (average kappa values of .920, .891, and .899, respectively), but moderate for Ki67 and NHG (.734 and .581). Classification concordance between RNA-seq classifiers and histopathology for the independent 3273-cohort was similar to that within histopathology assessments, with SGCs slightly outperforming MGCs. Importantly, patients with discordant results, classified as hormone responsive (HoR+) by histopathology but non-hormone responsive by MGC, presented with significantly inferior overall survival compared to patients with concordant results. These results extended to patients with no adjuvant systemic therapy (hazard ratio, HR, 4.54; 95% confidence interval, CI, 1.42-14.5), endocrine therapy alone (HR 3.46; 95% CI, 2.01-5.95), or receiving chemotherapy (HR 2.57; 95% CI 1.13-5.86). For HoR+ cases receiving endocrine therapy alone, the MGC HoR classifier remained significant after multivariable adjustment (HR 3.14; 95% CI, 1.75-5.65).Conclusions:RNA-seq-based classifiers for the five key early breast cancer biomarkers were generally equivalent to conventional histopathology with regards to classification error rate. However, when benchmarked using overall survival, our RNA-seq classifiers provided added clinical value in particular for cases that are determined by histopathology to be hormone-responsive but by RNA-seq appear hormone-insensitive and have a significantly poorer outcome when treated with endocrine therapy alone
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| 3. |
- Brueffer, Christian, et al.
(författare)
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Clinical Value of RNA Sequencing–Based Classifiers for Prediction of the Five Conventional Breast Cancer Biomarkers: A Report From the Population-Based Multicenter Sweden Cancerome Analysis Network—Breast Initiative
- 2018
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Ingår i: JCO Precision Oncology. - 2473-4284. ; 2, s. 1-18
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Tidskriftsartikel (refereegranskat)abstract
- PurposeIn early breast cancer (BC), five conventional biomarkers—estrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2), Ki67, and Nottingham histologic grade (NHG)—are used to determine prognosis and treatment. We aimed to develop classifiers for these biomarkers that were based on tumor mRNA sequencing (RNA-seq), compare classification performance, and test whether such predictors could add value for risk stratification.MethodsIn total, 3,678 patients with BC were studied. For 405 tumors, a comprehensive multi-rater histopathologic evaluation was performed. Using RNA-seq data, single-gene classifiers and multigene classifiers (MGCs) were trained on consensus histopathology labels. Trained classifiers were tested on a prospective population-based series of 3,273 BCs that included a median follow-up of 52 months (Sweden Cancerome Analysis Network—Breast [SCAN-B], ClinicalTrials.gov identifier: NCT02306096), and results were evaluated by agreement statistics and Kaplan-Meier and Cox survival analyses.ResultsPathologist concordance was high for ER, PgR, and HER2 (average κ, 0.920, 0.891, and 0.899, respectively) but moderate for Ki67 and NHG (average κ, 0.734 and 0.581). Concordance between RNA-seq classifiers and histopathology for the independent cohort of 3,273 was similar to interpathologist concordance. Patients with discordant classifications, predicted as hormone responsive by histopathology but non–hormone responsive by MGC, had significantly inferior overall survival compared with patients who had concordant results. This extended to patients who received no adjuvant therapy (hazard ratio [HR], 3.19; 95% CI, 1.19 to 8.57), or endocrine therapy alone (HR, 2.64; 95% CI, 1.55 to 4.51). For cases identified as hormone responsive by histopathology and who received endocrine therapy alone, the MGC hormone-responsive classifier remained significant after multivariable adjustment (HR, 2.45; 95% CI, 1.39 to 4.34).ConclusionClassification error rates for RNA-seq–based classifiers for the five key BC biomarkers generally were equivalent to conventional histopathology. However, RNA-seq classifiers provided added clinical value in particular for tumors determined by histopathology to be hormone responsive but by RNA-seq to be hormone insensitive.
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| 4. |
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| 5. |
- Brueffer, Christian, et al.
(författare)
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The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome
- 2020
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Breast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. Within the Sweden Cancerome Analysis Network–Breast project (SCAN-B; ClinicalTrials.govNCT02306096), an ongoing study elucidating the tumor transcriptomic profiles for thousands of breast cancers prospectively, we developed an optimized pipeline for detection of single nucleotide variants and small insertions and deletions from RNA sequencing (RNA-seq) data, and profiled a large real-world population-based cohort of 3,217 breast tumors. We use it to describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population-based cohort of patients, and relate it to patient overall survival. We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such asPIK3CA,TP53, andERBB2, as well as the status of key molecular pathways and tumor mutational burden, and identify potentially druggable genes in 86.8% percent of tumors. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source web-based application, the SCAN-B MutationExplorer, accessible athttp://oncogenomics.bmc.lu.se/MutationExplorer. These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling.
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| 6. |
- Brueffer, Christian, et al.
(författare)
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The mutational landscape of the SCAN‐B real‐world primary breast cancer transcriptome
- 2020
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Ingår i: EMBO Molecular Medicine. - : EMBO. - 1757-4684 .- 1757-4676. ; 12:10
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Tidskriftsartikel (refereegranskat)abstract
- Breast cancer is a disease of genomic alterations, of which the panorama of somatic mutations and how these relate to subtypes and therapy response is incompletely understood. Within SCAN‐B (ClinicalTrials.gov: NCT02306096), a prospective study elucidating the transcriptomic profiles for thousands of breast cancers, we developed a RNA‐seq pipeline for detection of SNVs/indels and profiled a real‐world cohort of 3,217 breast tumors. We describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population‐based cohort and relate it to patient survival. We demonstrate that RNA‐seq can be used to call mutations in genes such as PIK3CA, TP53, and ERBB2, as well as the status of molecular pathways and mutational burden, and identify potentially druggable mutations in 86.8% of tumors. To make this rich dataset available for the research community, we developed an open source web application, the SCAN‐B MutationExplorer (http://oncogenomics.bmc.lu.se/MutationExplorer). These results add another dimension to the use of RNA‐seq as a clinical tool, where both gene expression‐ and mutation‐based biomarkers can be interrogated in real‐time within 1 week of tumor sampling.
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| 7. |
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| 8. |
- Dahlgren, Malin, et al.
(författare)
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Preexisting Somatic Mutations of Estrogen Receptor Alpha (ESR1) in Early-Stage Primary Breast Cancer
- 2021
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Ingår i: JNCI Cancer Spectrum. - : Oxford University Press (OUP). - 2515-5091. ; 5:2
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Tidskriftsartikel (refereegranskat)abstract
- More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1), the most important factor for directing anti-estrogenic endocrine therapy (ET). Recently, mutations in ESR1 were identified as acquired mechanisms of resistance to ET, found in 12% to 55% of metastatic breast cancers treated previously with ET. We analyzed 3217 population-based invasive primary (nonmetastatic) breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096), sampled from initial diagnosis prior to any treatment, for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by droplet digital polymerase chain reaction on tumor and normal DNA. Patient outcomes were analyzed using Kaplan-Meier estimation and a series of 2-factor Cox regression multivariable analyses. We identified ESR1 resistance mutations in 30 tumors (0.9%), of which 29 were ER positive (1.1%). In ET-treated disease, presence of ESR1 mutation was associated with poor relapse-free survival and overall survival (2-sided log-rank test P < .001 and P = .008, respectively), with hazard ratios of 3.00 (95% confidence interval = 1.56 to 5.88) and 2.51 (95% confidence interval = 1.24 to 5.07), respectively, which remained statistically significant when adjusted for other prognostic factors. These population-based results indicate that ESR1 mutations at diagnosis of primary breast cancer occur in about 1% of women and identify for the first time in the adjuvant setting that such preexisting mutations are associated to eventual resistance to standard hormone therapy. If replicated, tumor ESR1 screening should be considered in ER-positive primary breast cancer, and for patients with mutated disease, ER degraders such as fulvestrant or other therapeutic options may be considered as more appropriate.
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| 9. |
- Demircan, Kamil, et al.
(författare)
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Autoimmunity to selenoprotein P predicts breast cancer recurrence
- 2022
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Ingår i: Redox Biology. - : Elsevier BV. - 2213-2317. ; 53
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundLow concentrations of serum selenium (Se) and its main transporter selenoprotein P (SELENOP) are associated with a poor prognosis following breast cancer diagnosis. Recently, natural autoantibodies (aAb) with antagonistic properties to SELENOP uptake have been identified in healthy subjects, and in patients with thyroid disease. Given the potential transport disrupting properties, we hypothesized that breast cancer patients with SELENOP-aAb may have a poor prognosis.MethodsSELENOP-aAb along with serum Se, SELENOP and GPX3 activity were determined in serum samples of 1988 patients with a new diagnosis of breast cancer enrolled in the multicentre SCAN-B study. Patients were followed for ∼9 years and multivariate Cox regression models were applied to assess hazard ratios.ResultsApplying a cut-off based on outlier detection, we identified 7.65% of patients with SELENOP-aAb. Autoantibody titres correlated positively to total Se and SELENOP concentrations, but not to GPX3 activity, supporting a negative role of SELENOP-aAb on Se transport. SELENOP-aAb were associated with age, but independent of tumor characteristics. After fully adjusting for potential confounders, SELENOP-aAb were associated with higher recurrence, HR(95%CI) = 1.87(1.17–2.99), particularly in patients with low Se concentrations, HR(95%CI) = 2.16(1.20–3.88). Associations of SELENOP-aAb with recurrence and mortality were linear and dose-dependent, with fully adjusted HR(95%CI) per log increase of 1.25(1.01–1.55) and 1.31(1.13–1.51), respectively.ConclusionOur results indicate a prognostic and pathophysiological relevance of SELENOP-aAb in breast cancer, with potential relevance for other malignancies. Assessment of SELENOP-aAb at time of diagnosis identifies patients with a distinctly elevated risk for a poor prognosis, independent of established prognostic factors, who may respond favourably to Se supplementation.
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| 10. |
- Demircan, Kamil, et al.
(författare)
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Matched analysis of circulating selenium with the breast cancer selenotranscriptome: a multicentre prospective study
- 2023
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Ingår i: Journal of Translational Medicine. - 1479-5876.
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Tidskriftsartikel (refereegranskat)abstract
- IntroductionLow serum selenium and altered tumour RNA expression of certain selenoproteins are associated with a poor breast cancer prognosis. Selenoprotein expression stringently depends on selenium availability, hence circulating selenium may interact with tumour selenoprotein expression. However, there is no matched analysis to date.MethodsThis study included 1453 patients with newly diagnosed breast cancer from the multicentric prospective Sweden Cancerome Analysis Network – Breast study. Total serum selenium, selenoprotein P and glutathione peroxidase 3 were analysed at time of diagnosis. Bulk RNA-sequencing was conducted in matched tumour tissues. Fully adjusted Cox regression models with an interaction term were employed to detect dose-dependent interactions of circulating selenium with the associations of tumour selenoprotein mRNA expression and mortality.Results237 deaths were recorded within ~ 9 years follow-up. All three serum selenium biomarkers correlated positively (p ConclusionsThis first unbiased analysis of serum selenium with the breast cancer selenotranscriptome identified an effect-modification of selenium on the associations of DIO1, SELENOM, and DIO3 with prognosis. Selenium substitution in patients with DIO1-expressing tumours merits consideration to improve survival.
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