Lymph node metastases in breast cancer : investigating associations with tumor characteristics, molecular subtypes, and polygenic risk score using a continuous growth model

DATA AVAILABILITY STATEMENT The data that support the findings of this study are available from the corresponding author on request, after ethical approvals have been obtained from the Swedish ethical review board. Funding information: Cancerfonden, Grant/Award Number: 2020/0716; Vetenskapsrådet, Grant/Award Number: 2020-01302Peer reviewedPublisher PD

Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance

Acknowledgements: The computations and data handling were enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC) at UPPMAX, Uppsala University, partially funded by the Swedish Research Council through grant agreement no. 2018-05973. This research has been conducted using the UK Biobank Resource under Application Number 22224. Funding: Open Access funding provided by Karolinska Institute. Open Access funding provided by Karolinska Institute. This work was financed by the Swedish Research Council (Grant 2018-02547, 2015-03255, 2019-01272, 2018-02077), the Swedish Cancer Society (Grants CAN 2016/684), the Stockholm County Council (Grant no. 20170088), the Karolinska Institutet’s Research Foundation (Grant 2018-02146), Karolinska Institutet’s Strategic Research Program in Epidemiology, King Gustaf V:s and Queen Victoria's Foundation of Freemasons, and the Åke Wibergs Foundation (M19-0294). FG was a Leopoldina Postdoctoral Fellow (Grant no. LPDS 2018-06) funded by the Academy of Sciences Leopoldina. Correction to: Deciphering the genetic and epidemiological landscape of mitochondrial DNA abundance (Human Genetics, (2020), 10.1007/s00439-020-02249-w) The data were exclusively retrieved from the UK Biobank and can be accessed upon request from the UK Biobank. The mitochondrial DNA abundance as computed in this manuscript will be reported back to the UK Biobank upon publication. The scripts to compute the weights and the weighted mtDNA abundance in the UKB dataset will be published at https://github.com/GrassmannLab/MT_UKB.Peer reviewedPublisher PD

Determining breast cancer histological grade from RNA-sequencing data

BACKGROUND: The histologic grade (HG) of breast cancer is an established prognostic factor. The grade is usually reported on a scale ranging from 1 to 3, where grade 3 tumours are the most aggressive. However, grade 2 is associated with an intermediate risk of recurrence, and carries limited information for clinical decision-making. Patients classified as grade 2 are at risk of both under- and over-treatment. METHODS: RNA-sequencing analysis was conducted in a cohort of 275 women diagnosed with invasive breast cancer. Multivariate prediction models were developed to classify tumours into high and low transcriptomic grade (TG) based on gene- and isoform-level expression data from RNA-sequencing. HG2 tumours were reclassified according to the prediction model and a recurrence-free survival analysis was performed by the multivariate Cox proportional hazards regression model to assess to what extent the TG model could be used to stratify patients. The prediction model was validated in N=487 breast cancer cases from the The Cancer Genome Atlas (TCGA) data set. Differentially expressed genes and isoforms associated with HGs were analysed using linear models. RESULTS: The classification of grade 1 and grade 3 tumours based on RNA-sequencing data achieved high accuracy (area under the receiver operating characteristic curve = 0.97). The association between recurrence-free survival rate and HGs was confirmed in the study population (hazard ratio of grade 3 versus 1 was 2.62 with 95 % confidence interval = 1.04-6.61). The TG model enabled us to reclassify grade 2 tumours as high TG and low TG gene or isoform grade. The risk of recurrence in the high TG group of grade 2 tumours was higher than in low TG group (hazard ratio = 2.43, 95 % confidence interval = 1.13-5.20). We found 8200 genes and 13,809 isoforms that were differentially expressed between HG1 and HG3 breast cancer tumours. CONCLUSIONS: Gene- and isoform-level expression data from RNA-sequencing could be utilised to differentiate HG1 and HG3 tumours with high accuracy. We identified a large number of novel genes and isoforms associated with HG. Grade 2 tumours could be reclassified as high and low TG, which has the potential to reduce over- and under-treatment if implemented clinically.NonePublishe

Predictors for discontinuation of adjuvant hormone therapy in breast cancer patients

PURPOSE: To identify predictors of discontinuation of adjuvant hormone therapy in patients with breast cancer. PATIENTS AND METHODS: We conducted a record-linkage study based on data from Stockholm-Gotland Breast Cancer Register, Swedish Prescribed Drug Register, and self-reported questionnaire. Women diagnosed with breast cancer between 2005 and 2008 in Stockholm, Sweden, were prospectively followed for 5 years until 2013, starting from their first prescription of tamoxifen or aromatase inhibitors (N = 3,395). RESULTS: Family history of ovarian cancer (hazard ratio [HR], 1.55; 95% CI, 1.19 to 2.02); younger (< 40 years; HR, 1.39; 95% CI, 1.08 to 1.78) and older (>/= 65 years; HR, 1.15; 95% CI, 1.03 to 1.28) age; higher Charlson comorbidity index (>/= 2 v 0; HR, 1.35; 95% CI, 1.03 to 1.76); and use of analgesics (HR, 1.33; 95% CI, 1.16 to 1.52), hypnotics/sedatives (HR, 1.24; 95% CI, 1.07 to 1.43), GI drugs (HR, 1.25; 95% CI, 1.08 to 1.43), and hormone replacement therapy (HR, 1.27; 95% CI, 1.08 to 1.49) were identified as baseline predictors for hormonal treatment discontinuation. Use of analgesics (HR, 1.22; 95% CI, 1.08 to 1.37), hypnotics/sedatives (HR, 1.21; 95% CI, 1.07 to 1.37), antidepressants (HR, 1.22; 95% CI, 1.06 to 1.40), or GI drugs (HR, 1.27; 95% CI, 1.13 to 1.43), and switching therapy between tamoxifen and aromatase inhibitors (HR, 1.50; 95% CI, 1.23 to 1.83) during the first year of hormonal treatment were associated with increased risk of discontinuation during the next 4 years. CONCLUSION: Predictors identified in our study can be used in developing targeted intervention to prevent adjuvant hormone therapy discontinuation and subsequently to improve breast cancer outcomes.Swedish Research CouncilSwedish Cancer SocietyFORTESwedish Society of Medical Research (SSMF)Accepte

Interval breast cancer is associated with other types of tumors

Contributions: F.G. and K.C. conceived and designed the project; K.C. acted as the principal investigator; P.H., M.E, M.G., Women’s Health Initiative organized patient recruitment and sample collection; F.G. and W.H. analyzed the data; W.H., M.G., P.H., K.C. contributed to data interpretation; F.G. and K.C. wrote the manuscript with input from all authors. All authors approved of the final manuscript. Acknowledgements: This work was financed by the Swedish Research Council (Grant 2018-02547), the Swedish Cancer Society (grants CAN 2016/684 and 2013/469), the Cancer Society in Stockholm (Grant 141092), the Stockholm County Council (Grant No. LS 1211–1594), and the Karolinska Institutet’s Research Foundation (Grant 2018-02146). The KARMA study is supported by the Märit and Hans Rausing Initiative Against Breast Cancer and the Cancer and Risk Prediction Center (CRisP), a Linnaeus center (grant 70867902) financed by the Swedish Research Council. F.G. was a Leopoldina Postdoctoral Fellow (Grant No. LPDS 2018-06) funded by the Academy of Sciences Leopoldina. W.H. was supported by the Swedish Research Council for Health, Working Life and Welfare (FORTE, 2018-00877). We thank Dr. Johanna Holm for her valuable contribution to the manuscript. Genotyping of the OncoArray was principally funded by three sources: the PERSPECTIVE project, funded by the Government of Canada through Genome Canada and the Canadian Institutes of Health Research, the Ministère de l’Économie, de la Science et de l’Innovation du Québec through Genome Québec, and the Quebec Breast Cancer Foundation; the National Cancer Institute Genetic Associations and Mechanisms in Oncology (GAME-ON) initiative and Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) projects (National Institutes of Health [NIH] grants U19 CA148065 and X01HG007492); and Cancer Research UK (C1287/A10118 and C1287/A16563). Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175); Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program; and the Ministry of Economic Development, Innovation and Export Trade of Quebec (grant PSR-SIIRI-701). Combination of the GWAS data was supported in part by NIH Cancer Post-Cancer GWAS initiative grant U19 CA148065 (DRIVE, part of the GAME-ON initiative). All studies and funders are listed in ref. 60. The WHI program is funded by the National Heart, Lung, and Blood Institute, National Institutes of Health, US Department of Health and Human Services through contracts N01WH22110, 24152, 32100–2, 32105–6, 32108–9, 32111–13, 32115, 32118–32119, 32122, 42107–26, 42129–32, and 44221. This manuscript was not prepared in collaboration with investigators of the WHI, has not been reviewed, and/or approved by the WHI, and does not necessarily reflect the opinions of the WHI investigators or the NHLBI. The study sponsors had no role in the design of the study, the collection, analysis, or interpretation of the data, the writing of the manuscript, or the decision to submit the manuscript for publication. Open access funding provided by Karolinska InstitutePeer reviewedPublisher PD

Time from breast cancer diagnosis to therapeutic surgery and breast cancer prognosis : a population-based cohort study

Theoretically, time from breast cancer diagnosis to therapeutic surgery should affect survival. However, it is unclear whether this holds true in a modern healthcare setting in which breast cancer surgery is carried out within weeks to months of diagnosis. This is a population- and register-based study of all women diagnosed with invasive breast cancer in the Stockholm-Gotland healthcare region in Sweden, 2001 - 2008, and who were initially operated. Follow-up of vital status ended 2014. 7017 women were included in analysis. Our main outcome was overall survival. Main analyses were carried out using Cox proportional hazards models. We adjusted for likely confounders and stratified on mode of detection, tumor size and lymph node metastasis. We found that a longer interval between date of morphological diagnosis and therapeutic surgery was associated with a poorer prognosis. Assuming a linear association, the hazard rate of death from all causes increased by 1.011 (95% CI 1.006 to 1.017) per day. Comparing, e.g., surgery 6 weeks after diagnosis to surgery 3 weeks after diagnosis, thereby confers a 1.26-fold increased hazard rate. The increase in hazard rate associated with surgical delay was strongest in women with largest tumors. Whilst there was a clear association between delays and survival in women without lymph node metastasis, the association may be attenuated in subgroups with increasing number of lymph node metastases. We found no evidence of an interaction between time to surgery and mode of detection. In conclusion, unwarranted delays to primary treatment of breast cancer should be avoided.Swedish Research CouncilSwedish Cancer SocietyStockholm County CouncilFORTEAccepte

Pregnancy outcomes in women with a prior cervical intraepithelial neoplasia grade 3 diagnosis : a nationwide population-based cohort study with sibling comparison design

Background: Treatment of cervical intraepithelial neoplasia grade 3 (CIN3) removes or destroys part of the cervix and might subsequently influence pregnancy outcomes. Objective: To investigate pregnancy outcomes in women diagnosed with CIN3. Design: Population- and sibling-matched cohort study. Setting: Sweden, 1973-2018. Participants: General population comparison included 78 450 singletons born to women diagnosed with CIN3 and 784 500 matched singletons born to women in the general population who had no CIN3 diagnosis; sibling comparison included 23 199 singletons born to women diagnosed with CIN3 and 28 135 singletons born to their sisters without a CIN3 diagnosis. Measurements: Preterm birth, including spontaneous or iatrogenic preterm birth; Infection-related outcomes, including chorioamnionitis and infant sepsis; and early neonatal death, defined as death during the first week after birth. Results: Compared with the matched general population, women previously diagnosed with CIN3 were more likely to have a preterm birth especially extremely preterm (22-28 weeks; OR, 3.00; 95% CI, 2.69-3.34) and spontaneous preterm (OR, 2.12; 95% CI, 2.05-2.20) birth, infection-related outcomes including chorioamnionitis (OR, 3.23; 95% CI, 2.89-3.62) and infant sepsis (OR, 1.72; 95% CI, 1.60-1.86), and early neonatal death (OR, 1.83; 95% CI, 1.61-2.09). Sibling comparison analyses rendered largely similar results. Over time the risk difference attenuated for all outcomes and disappeared for early neonatal death. Limitations: Lack of data on CIN3 treatment and spontaneous abortion. Conclusion: Prior history of CIN 3 is associated with adverse pregnancy outcomes even after accounting for familial factors. Decreasing risk estimates over time suggest that adverse pregnancy outcomes among women diagnosed with CIN3 may be minimized by improving treatment modalities.Swedish Research Council, 2018-02547Swedish Cancer Society, 19 0266Swedish Research Council for Health, Working Life and Welfare, 2016-00081 and 2018-00877Zhejiang University through the Hundred Talents ProgramManuscrip

Mammographic features are associated with cardiometabolic disease risk and mortality

Open Access via the OUP Open Access Agreement Acknowledgements: The authors thank all the participants in the KARMA study and personnel for their devoted work during data collection. They also would like to acknowledge Jose ́ Tapia for helping in data management. Funding: This work was supported by “Ma ̈rit and Hans Rausing’s Initiative Against Breast Cancer” and was financed by the Swedish Research Council (Grant 2018-02547 to K.C.), the Swedish Cancer Society (Grant 19 0266 and 19 0267 to K.C.), FORTE (Grant 2016-00081 to K.C.), and the Karolinska Institutet’s Research Foundation (Grant 2018-02146 to F.G.). F.G. was a Leopoldina Postdoctoral Fellow (Grant No. LPDS 2018-06) funded by the Academy of Sciences Leopoldina. H.Y. was supported by Start-up Fund for high-level talents of Fujian Medical University (Grant .No. XRCZX2020007) and Start-up Fund for Scientific Research, Fujian Medical University (Grant No. 2019QH1002). The funding agency had no role in the study design, data collection, analyses, and data interoperation, in writing the manuscript, or in the decision to submit the manuscript for publication.Peer reviewedPublisher PD

Exome sequencing of contralateral breast cancer identifies metastatic disease

Women with contralateral breast cancer (CBC) have significantly worse prognosis compared to women with unilateral cancer. A possible explanation of the poor prognosis of patients with CBC is that in a subset of patients, the second cancer is not a new primary tumor but a metastasis of the first cancer that has potentially obtained aggressive characteristics through selection of treatment. Exome and whole-genome sequencing of solid tumors has previously been used to investigate the clonal relationship between primary tumors and metastases in several diseases. In order to assess the relationship between the first and the second cancer, we performed exome sequencing to identify somatic mutations in both first and second cancers, and compared paired normal tissue of 25 patients with metachronous CBC. For three patients, we identified shared somatic mutations indicating a common clonal origin thereby demonstrating that the second tumor is a metastasis of the first cancer, rather than a new primary cancer. Accordingly, these patients all developed distant metastasis within 3 years of the second diagnosis, compared with 7 out of 22 patients with non-shared somatic profiles. Genomic profiling of both tumors help the clinicians distinguish between true CBCs and subsequent metastasesVetenskapsrådetForteAccepte