| 1. |
- Holm, Johanna, et al.
(författare)
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Assessment of breast cancer risk factors reveals subtype heterogeneity
- 2017
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Ingår i: Cancer Research. - Stockholm : Karolinska Institutet, Dept of Medical Epidemiology and Biostatistics. - 0008-5472. ; 77:13, s. 3708-3717
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Tidskriftsartikel (refereegranskat)abstract
- Subtype heterogeneity for breast cancer risk factors has been suspected, potentially reflecting etiological differences and implicating risk prediction. Reports are conflicting regarding presence of heterogeneity for many exposures. To examine subtype heterogeneity across known breast cancer risk factors, we conducted a case-control analysis of 2,632 breast cancers and 15,945 controls in Sweden. Molecular subtype was predicted from pathology-record derived immunohistochemistry markers by a classifier trained on PAM50 subtyping. Multinomial logistic regression estimated separate odds ratios for each subtype by the exposures parity, age at first birth, breastfeeding, menarche, HRT use, somatotype at age 18, benign breast disease, mammographic density, polygenic risk score, family history of breast cancer and BRCA mutations. We found clear subtype heterogeneity for genetic factors and breastfeeding. The polygenic risk score was associated with risk of all subtypes except for the basal-like (p heterogeneity < 0.0001). Parous women who never breastfed were at higher risk of basal-like subtype (OR 4.17; 95% CI 1.89 to 9.21) compared to both nulliparous (reference) and breastfeeding women. Breastfeeding was not associated with risk of HER2-overexpressing type, but protective for all other subtypes. The observed heterogeneity in risk of distinct breast cancer subtypes for germline variants supports heterogeneity in etiology and has implications for their use in risk prediction. The increased risk of basal-like subtype among women who never breastfed merits more research into potential causal mechanisms and confounders.
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| 2. |
- Mälarstig, Anders, et al.
(författare)
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Evaluation of circulating plasma proteins in breast cancer using Mendelian randomisation
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Biomarkers for early detection of breast cancer may complement population screening approaches to enable earlier and more precise treatment. The blood proteome is an important source for biomarker discovery but so far, few proteins have been identified with breast cancer risk. Here, we measure 2929 unique proteins in plasma from 598 women selected from the Karolinska Mammography Project to explore the association between protein levels, clinical characteristics, and gene variants, and to identify proteins with a causal role in breast cancer. We present 812 cis-acting protein quantitative trait loci for 737 proteins which are used as instruments in Mendelian randomisation analyses of breast cancer risk. Of those, we present five proteins (CD160, DNPH1, LAYN, LRRC37A2 and TLR1) that show a potential causal role in breast cancer risk with confirmatory results in independent cohorts. Our study suggests that these proteins should be further explored as biomarkers and potential drug targets in breast cancer.
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| 3. |
- Shu, Xiang, et al.
(författare)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Tidskriftsartikel (refereegranskat)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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| 4. |
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| 5. |
- Byström, Sanna, et al.
(författare)
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Affinity proteomic profiling of plasma for proteins associated to area-based mammographic breast density
- 2018
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Ingår i: Breast Cancer Research. - : BIOMED CENTRAL LTD. - 1465-5411 .- 1465-542X. ; 20
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Tidskriftsartikel (refereegranskat)abstract
- Background: Mammographic breast density is one of the strongest risk factors for breast cancer, but molecular understanding of how breast density relates to cancer risk is less complete. Studies of proteins in blood plasma, possibly associated with mammographic density, are well-suited as these allow large-scale analyses and might shed light on the association between breast cancer and breast density. Methods: Plasma samples from 1329 women in the Swedish KARMA project, without prior history of breast cancer, were profiled with antibody suspension bead array (SBA) assays. Two sample sets comprising 729 and 600 women were screened by two different SBAs targeting a total number of 357 proteins. Protein targets were selected through searching the literature, for either being related to breast cancer or for being linked to the extracellular matrix. Association between proteins and absolute area-based breast density (AD) was assessed by quantile regression, adjusting for age and body mass index (BMI). Results: Plasma profiling revealed linear association between 20 proteins and AD, concordant in the two sets of samples (p < 0.05). Plasma levels of seven proteins were positively associated and 13 proteins negatively associated with AD. For eleven of these proteins evidence for gene expression in breast tissue existed. Among these, ABCC11, TNFRSF10D, F11R and ERRF were positively associated with AD, and SHC1, CFLAR, ACOX2, ITGB6, RASSF1, FANCD2 and IRX5 were negatively associated with AD. Conclusions: Screening proteins in plasma indicates associations between breast density and processes of tissue homeostasis, DNA repair, cancer development and/or progression in breast cancer. Further validation and follow-up studies of the shortlisted protein candidates in independent cohorts will be needed to infer their role in breast density and its progression in premenopausal and postmenopausal women.
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| 6. |
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| 7. |
- Dixon-Suen, Suzanne C, et al.
(författare)
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Physical activity, sedentary time and breast cancer risk : a Mendelian randomisation study
- 2022
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Ingår i: British Journal of Sports Medicine. - : BMJ Publishing Group Ltd. - 0306-3674 .- 1473-0480. ; 56:20, s. 1157-1170
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Physical inactivity and sedentary behaviour are associated with higher breast cancer risk in observational studies, but ascribing causality is difficult. Mendelian randomisation (MR) assesses causality by simulating randomised trial groups using genotype. We assessed whether lifelong physical activity or sedentary time, assessed using genotype, may be causally associated with breast cancer risk overall, pre/post-menopause, and by case-groups defined by tumour characteristics.METHODS: We performed two-sample inverse-variance-weighted MR using individual-level Breast Cancer Association Consortium case-control data from 130 957 European-ancestry women (69 838 invasive cases), and published UK Biobank data (n=91 105-377 234). Genetic instruments were single nucleotide polymorphisms (SNPs) associated in UK Biobank with wrist-worn accelerometer-measured overall physical activity (nsnps=5) or sedentary time (nsnps=6), or accelerometer-measured (nsnps=1) or self-reported (nsnps=5) vigorous physical activity.RESULTS: Greater genetically-predicted overall activity was associated with lower breast cancer overall risk (OR=0.59; 95% confidence interval (CI) 0.42 to 0.83 per-standard deviation (SD;~8 milligravities acceleration)) and for most case-groups. Genetically-predicted vigorous activity was associated with lower risk of pre/perimenopausal breast cancer (OR=0.62; 95% CI 0.45 to 0.87,≥3 vs. 0 self-reported days/week), with consistent estimates for most case-groups. Greater genetically-predicted sedentary time was associated with higher hormone-receptor-negative tumour risk (OR=1.77; 95% CI 1.07 to 2.92 per-SD (~7% time spent sedentary)), with elevated estimates for most case-groups. Results were robust to sensitivity analyses examining pleiotropy (including weighted-median-MR, MR-Egger).CONCLUSION: Our study provides strong evidence that greater overall physical activity, greater vigorous activity, and lower sedentary time are likely to reduce breast cancer risk. More widespread adoption of active lifestyles may reduce the burden from the most common cancer in women.
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| 8. |
- Eriksson, Mikael, et al.
(författare)
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Identification of Women at High Risk of Breast Cancer Who Need Supplemental Screening
- 2020
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Ingår i: Radiology. - : Radiological Society of North America (RSNA). - 1527-1315 .- 0033-8419. ; 297:2, s. 327-333
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Tidskriftsartikel (refereegranskat)abstract
- Background Mammography screening reduces breast cancer mortality, but a proportion of breast cancers are missed and are detected at later stages or develop during between-screening intervals. Purpose To develop a risk model based on negative mammograms that identifies women likely to be diagnosed with breast cancer before or at the next screening examination. Materials and Methods This study was based on the prospective screening cohort Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA), 2011-2017. An image-based risk model was developed by using the Stratus method and computer-aided detection mammographic features (density, masses, microcalcifications), differences in the left and right breasts, and age. The lifestyle extended model included menopausal status, family history of breast cancer, body mass index, hormone replacement therapy, and use of tobacco and alcohol. The genetic extended model included a polygenic risk score with 313 single nucleotide polymorphisms. Age-adjusted relative risks and tumor subtype specific risks were estimated by using logistic regression, and absolute risks were calculated. Results Of 70 877 participants in the KARMA cohort, 974 incident cancers were sampled from 9376 healthy women (mean age, 54 years ± 10 [standard deviation]). The area under the receiver operating characteristic curve (AUC) for the image-based model was 0.73 (95% confidence interval [CI]: 0.71, 0.74). The AUCs for the lifestyle and genetic extended models were 0.74 (95% CI: 0.72, 0.75) and 0.77 (95% CI: 0.75, 0.79), respectively. There was a relative eightfold difference in risk between women at high risk and those at general risk. High-risk women were more likely to be diagnosed with stage II cancers and with tumors 20 mm or larger and were less likely to have stage I and estrogen receptor-positive tumors. The image-based model was validated in three external cohorts. Conclusion By combining three mammographic features, differences in the left and right breasts, and optionally lifestyle factors and family history and a polygenic risk score, the model identified women at high likelihood of being diagnosed with breast cancer within 2 years of a negative screening examination and in possible need of supplemental screening.
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| 9. |
- Eriksson, Mikael, et al.
(författare)
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Low-Dose Tamoxifen for Mammographic Density Reduction : A Randomized Controlled Trial
- 2021
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Ingår i: Journal of Clinical Oncology. - 0732-183X. ; 39:17, s. 1899-
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE: Tamoxifen prevents breast cancer in high-risk women and reduces mortality in the adjuvant setting. Mammographic density change is a proxy for tamoxifen therapy response. We tested whether lower doses of tamoxifen were noninferior to reduce mammographic density and associated with fewer symptoms.PATIENTS AND METHODS: Women, 40-74 years of age, participating in the Swedish mammography screening program were invited to the 6-month double-blind six-arm randomized placebo-controlled noninferiority dose-determination KARISMA phase II trial stratified by menopausal status (EudraCT 2016-000882-22). In all, 1,439 women were accrued with 1,230 participants accessible for intention-to-treat analysis. The primary outcome was proportion of women treated with placebo, 1, 2.5, 5, and 10 mg whose mammographic density decreased at least as much as the median reduction in the 20 mg arm. The noninferior margin was 17%. Secondary outcome was reduction of symptoms. Post hoc analyses were performed by menopausal status. Per-protocol population and full population were analyzed in sensitivity analysis.RESULTS: The 1,439 participants, 566 and 873 pre- and postmenopausal women, respectively, were recruited between October 1, 2016, and September 30, 2019. The participants had noninferior mammographic density reduction following 2.5, 5, and 10 mg tamoxifen compared with the median 10.1% decrease observed in the 20 mg group, a reduction confined to premenopausal women. Severe vasomotor symptoms (hot flashes, cold sweats, and night sweats) were reduced by approximately 50% in the 2.5, 5, and 10 mg groups compared with the 20 mg group.CONCLUSION: Premenopausal women showed noninferior magnitude of breast density decrease at 2.5 mg of tamoxifen, but fewer side effects compared with the standard dose of 20 mg. Future studies should test whether 2.5 mg of tamoxifen reduces the risk of primary breast cancer.
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