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1.
Artigo em Inglês | MEDLINE | ID: mdl-33500318

RESUMO

BACKGROUND: It is not known if modifiable lifestyle factors that predict survival after invasive breast cancer differ by subtype. METHODS: We analyzed data for 121,435 women diagnosed with breast cancer from 67 studies in the Breast Cancer Association Consortium with 16,890 deaths (8,554 breast cancer-specific) over 10 years. Cox regression was used to estimate associations between risk factors and 10-year all-cause mortality and breast cancer-specific mortality overall, by estrogen receptor (ER) status, and by intrinsic-like subtype. RESULTS: There was no evidence of heterogeneous associations between risk factors and mortality by subtype (adjusted p>0.30). The strongest associations were between all-cause mortality and BMI {greater than or equal to}30 vs 18.5-25 kg/m2 (HR (95%CI): 1.19 (1.06,1.34)); current vs never smoking (1.37 (1.27,1.47)), high vs low physical activity (0.43 (0.21,0.86)), age {greater than or equal to}30 years vs <20 years at first pregnancy (0.79 (0.72,0.86)); >0 to <5 years vs {greater than or equal to}10 years since last full term birth (1.31 (1.11,1.55)); ever vs never use of oral contraceptives (0.91 (0.87,0.96)); ever vs never use of menopausal hormone therapy, including current estrogen-progestin therapy (0.61 (0.54,0.69)). Similar associations with breast cancer mortality were weaker; e.g. 1.11 (1.02,1.21) for current vs never smoking. CONCLUSIONS: We confirm associations between modifiable lifestyle factors and 10-year all-cause mortality. There was no strong evidence that associations differed by ER status or intrinsic-like subtype. IMPACT: Given the large dataset and lack of evidence that associations between modifiable risk factors and 10-year mortality differed by subtype, these associations could be cautiously used in prognostication models to inform patient-centered care.

2.
Int J Cancer ; 148(2): 307-319, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-32851660

RESUMO

Blood lipids have been associated with the development of a range of cancers, including breast, lung and colorectal cancer. For endometrial cancer, observational studies have reported inconsistent associations between blood lipids and cancer risk. To reduce biases from unmeasured confounding, we performed a bidirectional, two-sample Mendelian randomization analysis to investigate the relationship between levels of three blood lipids (low-density lipoprotein [LDL] and high-density lipoprotein [HDL] cholesterol, and triglycerides) and endometrial cancer risk. Genetic variants associated with each of these blood lipid levels (P < 5 × 10-8 ) were identified as instrumental variables, and assessed using genome-wide association study data from the Endometrial Cancer Association Consortium (12 906 cases and 108 979 controls) and the Global Lipids Genetic Consortium (n = 188 578). Mendelian randomization analyses found genetically raised LDL cholesterol levels to be associated with lower risks of endometrial cancer of all histologies combined, and of endometrioid and non-endometrioid subtypes. Conversely, higher genetically predicted HDL cholesterol levels were associated with increased risk of non-endometrioid endometrial cancer. After accounting for the potential confounding role of obesity (as measured by genetic variants associated with body mass index), the association between genetically predicted increased LDL cholesterol levels and lower endometrial cancer risk remained significant, especially for non-endometrioid endometrial cancer. There was no evidence to support a role for triglycerides in endometrial cancer development. Our study supports a role for LDL and HDL cholesterol in the development of non-endometrioid endometrial cancer. Further studies are required to understand the mechanisms underlying these findings.

3.
Cancer Causes Control ; 32(3): 251-260, 2021 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-33377172

RESUMO

PURPOSE: Personalized cancer treatment requires predictive biomarkers, including image-based biomarkers. Breast cancer (BC) patients receiving neoadjuvant chemotherapy (NACT) are in a clinically vulnerable situation with the tumor present. This study investigated whether mammographic density (MD), assessed pre-NACT, is predictive of pathological complete response (pCR). METHODS: A total of 495 BC patients receiving NACT in Sweden 2005-2019 were included, merged from two different cohorts. Cohort 1 was retrospectively collected (n = 295) and cohort 2 was prospectively collected (n = 200). Mammograms were scored for MD pre-NACT according to the Breast Imaging-Reporting and Data System (BI-RADS), 5th Edition. The association between MD and accomplishing pCR post-NACT was analyzed using logistic regression models-for the whole cohort, stratified by menopausal status, and in different St. Gallen surrogate subtypes. RESULTS: In comparison to patients with low MD (BI-RADS a), the multivariable-adjusted odds ratio (OR) of accomplishing pCR following NACT was on a descending scale: 0.62 (95% confidence interval (CI) 0.24-1.57), 0.38 (95% CI 0.14-1.02), and 0.32 (95% CI 0.09-1.08) for BI-RADS b, c, and d, respectively. For premenopausal patients selectively, the corresponding point estimates were lower, although wider CIs: 0.31 (95% CI 0.06-1.62), 0.24 (95% CI 0.04-1.27), and 0.13 (95% CI 0.02-0.88). Subgroup analyses based on BC subtypes resulted in imprecise estimates, i.e., wide CIs. CONCLUSIONS: It seemed as though patients with higher MD at baseline were less likely to reach pCR after NACT-a finding more pronounced in premenopausal women. Larger multicenter studies are needed to enable analyses and interpretation for different BC subtypes.

4.
Elife ; 92020 11 23.
Artigo em Inglês | MEDLINE | ID: mdl-33226344

RESUMO

Sense of coherence (SoC) is the origin of health according to Antonovsky. The link between SoC and risk of cancer has however rarely been assessed. We performed a cohort study of 46,436 women from the Karolinska Mammography Project for Risk Prediction of Breast Cancer (Karma). Participants answered a SoC-13 questionnaire at recruitment to Karma and were subsequently followed up for incident breast cancer. Multivariate Cox models were used to assess the hazard ratios (HRs) of breast cancer in relation to SoC. We identified 771 incident cases of breast cancer during follow-up (median time: 5.2 years). No association was found between SoC, either as a categorical (strong vs. weak SoC, HR: 1.08, 95% CI: 0.90-1.29) or continuous (HR: 1.08; 95% CI: 1.00-1.17 per standard deviation increase of SoC) variable, and risk of breast cancer. In summary, we found little evidence to support an association between SoC and risk of breast cancer.

5.
BMC Med ; 18(1): 238, 2020 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-32900363

RESUMO

BACKGROUND: Cancer patients have a highly increased risk of psychiatric disorders following diagnosis, compared with cancer-free individuals. Inflammation is involved in the development of both cancer and psychiatric disorders. The role of non-steroidal anti-inflammatory drugs (NSAIDs) in the subsequent risk of psychiatric disorders after cancer diagnosis is however unknown. METHODS: We performed a cohort study of all patients diagnosed with a first primary malignancy between July 2006 and December 2013 in Sweden. Cox proportional hazards models were used to assess the association of NSAID use during the year before cancer diagnosis with the risk of depression, anxiety, and stress-related disorders during the first year after cancer diagnosis. RESULTS: Among 316,904 patients identified, 5613 patients received a diagnosis of depression, anxiety, or stress-related disorders during the year after cancer diagnosis. Compared with no use of NSAIDs, the use of aspirin alone was associated with a lower rate of depression, anxiety, and stress-related disorders (hazard ratio [HR], 0.88; 95% confidence interval [CI], 0.81 to 0.97), whereas the use of non-aspirin NSAIDs alone was associated with a higher rate (HR, 1.24; 95% CI, 1.15 to 1.32), after adjustment for sociodemographic factors, comorbidity, indications for NSAID use, and cancer characteristics. The association of aspirin with reduced rate of depression, anxiety, and stress-related disorders was strongest for current use (HR, 0.84; 95% CI, 0.75 to 0.93), low-dose use (HR, 0.88; 95% CI, 0.80 to 0.98), long-term use (HR, 0.84; 95% CI, 0.76 to 0.94), and among patients with cardiovascular disease (HR, 0.81; 95% CI, 0.68 to 0.95) or breast cancer (HR, 0.74; 95% CI, 0.56 to 0.98). CONCLUSION: Pre-diagnostic use of aspirin was associated with a decreased risk of depression, anxiety, and stress-related disorders during the first year following cancer diagnosis.

6.
Breast Cancer Res ; 22(1): 101, 2020 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-32993747

RESUMO

BACKGROUND: A decrease in breast density due to tamoxifen preventive therapy might indicate greater benefit from the drug. It is not known whether mammographic density continues to decline after 1 year of therapy, or whether measures of breast density change are sufficiently stable for personalised recommendations. METHODS: Mammographic density was measured annually over up to 5 years in premenopausal women with no previous diagnosis of breast cancer but at increased risk of breast cancer attending a family-history clinic in Manchester, UK (baseline 2010-2013). Tamoxifen (20 mg/day) for prevention was prescribed for up to 5 years in one group; the other group did not receive tamoxifen and were matched by age. Fully automatic methods were used on mammograms over the 5-year follow-up: three area-based measures (NN-VAS, Stratus, Densitas) and one volumetric (Volpara). Additionally, percentage breast density at baseline and first follow-up mammograms was measured visually. The size of density declines at the first follow-up mammogram and thereafter was estimated using a linear mixed model adjusted for age and body mass index. The stability of density change at 1 year was assessed by evaluating mean squared error loss from predictions based on individual or mean density change at 1 year. RESULTS: Analysis used mammograms from 126 healthy premenopausal women before and as they received tamoxifen for prevention (median age 42 years) and 172 matched controls (median age 41 years), with median 3 years follow-up. There was a strong correlation between percentage density measures used on the same mammogram in both the tamoxifen and no tamoxifen groups (all correlation coeficients > 0.8). Tamoxifen reduced mean breast density in year 1 by approximately 17-25% of the inter-quartile range of four automated percentage density measures at baseline, and from year 2, it decreased further by approximately 2-7% per year. Predicting change at 2 years using individual change at 1 year was approximately 60-300% worse than using mean change at 1year. CONCLUSIONS: All measures showed a consistent and large average tamoxifen-induced change in density over the first year, and a continued decline thereafter. However, these measures of density change at 1 year were not stable on an individual basis.

7.
Int J Cancer ; 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32976625

RESUMO

Current breast cancer risk models identify mostly less aggressive tumors, although only women developing fatal breast cancer will greatly benefit from early identification. Here, we evaluated the use of mammography features (microcalcification clusters, computer-generated Breast Imaging Reporting and Data System [cBIRADS] density and lack of breast density reduction) as early markers of aggressive subtypes and tumor characteristics. Mammograms were retrieved from a population-based cohort of women that were diagnosed with breast cancer from 2001 to 2008 in Stockholm-Gotland County, Sweden. Tumor and patient characteristics were obtained from Stockholm Breast Cancer Quality Register and the Swedish Cancer Registry. Multinomial logistic regression was used to individually model each mammographic feature as a function of molecular subtypes, tumor characteristics and detection mode. A total of 4546 women with invasive breast cancer were included in the study. Women with microcalcification clusters in the affected breast were more likely to have human epidermal growth factor receptor 2 subtype (odds ratio [OR] 1.78; 95% confidence interval [CI] 1.24-2.54) and potentially less likely to have basal subtype (OR 0.54; 0.30-0.96) compared to Luminal A subtype. High mammographic cBIRADS showed association with larger tumor size and interval vs screen-detected cancers. Lack of density reduction was associated with interval vs screen-detected cancers (OR 1.43; 1.11-1.83) and potentially of Luminal B subtype vs Luminal A subtype (OR 1.76; 1.04-2.99). In conclusion, microcalcification clusters, cBIRADS density and lack of breast density reduction could serve as early markers of particular subtypes and tumor characteristics of breast cancer. This information has the potential to be integrated into risk models to identify women at risk for developing aggressive breast cancer in need of supplemental screening.

8.
Int J Cancer ; 2020 Sep 25.
Artigo em Inglês | MEDLINE | ID: mdl-32976626

RESUMO

Alcohol consumption is correlated positively with risk for breast cancer in observational studies, but observational studies are subject to reverse causation and confounding. The association with epithelial ovarian cancer (EOC) is unclear. We performed both observational Cox regression and two-sample Mendelian randomization (MR) analyses using data from various European cohort studies (observational) and publicly available cancer consortia (MR). These estimates were compared to World Cancer Research Fund (WCRF) findings. In our observational analyses, the multivariable-adjusted hazard ratios (HR) for a one standard drink/day increase was 1.06 (95% confidence interval [CI]; 1.04, 1.08) for breast cancer and 1.00 (0.92, 1.08) for EOC, both of which were consistent with previous WCRF findings. MR ORs per genetically predicted one standard drink/day increase estimated via 34 SNPs using MR-PRESSO were 1.00 (0.93, 1.08) for breast cancer and 0.95 (0.85, 1.06) for EOC. Stratification by EOC subtype or estrogen receptor status in breast cancers made no meaningful difference to the results. For breast cancer, the CIs for the genetically derived estimates include the point-estimate from observational studies so are not inconsistent with a small increase in risk. Our data provide additional evidence that alcohol intake is unlikely to have anything other than a very small effect on risk of EOC.

9.
Radiology ; 297(2): 327-333, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32897160

RESUMO

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. © RSNA, 2020 Online supplemental material is available for this article.

10.
Int J Cancer ; 2020 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-32949149

RESUMO

We examined the association between established risk factors for breast cancer and microcalcification clusters and their asymmetry. A cohort study of 53 273 Swedish women aged 30 to 80 years, with comprehensive information on breast cancer risk factors and mammograms, was conducted. Total number of microcalcification clusters and the average mammographic density area were measured using a Computer Aided Detection system and the STRATUS method, respectively. A polygenic risk score for breast cancer, including 313 single nucleotide polymorphisms, was calculated for those women genotyped (N = 7387). Odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for potential confounders, were estimated. Age was strongly associated with microcalcification clusters. Both high mammographic density (>40 cm2 ), and high polygenic risk score (80-100 percentile) were associated with microcalcification clusters, OR = 2.08 (95% CI = 1.93-2.25) and OR = 1.22 (95% CI = 1.06-1.48), respectively. Among reproductive risk factors, life-time breastfeeding duration >1 year was associated with microcalcification clusters OR = 1.22 (95% CI = 1.03-1.46). The association was confined to postmenopausal women. Among lifestyle risk factors, women with a body mass index ≥30 kg/m2 had the lowest risk of microcalcification clusters OR = 0.79 (95% CI = 0.73-0.85) and the association was stronger among premenopausal women. Our results suggest that age, mammographic density, genetic predictors of breast cancer, having more than two children, longer duration of breast-feeding are significantly associated with increased risk of microcalcification clusters. However, most lifestyle risk factors for breast cancer seem to protect against presence of microcalcification clusters. More research is needed to study biological mechanisms behind microcalcifications formation.

11.
Life Sci Alliance ; 3(10)2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32737166

RESUMO

Despite recognizing aging as a common risk factor of many human diseases, little is known about its molecular traits. To identify age-associated proteins circulating in human blood, we screened 156 individuals aged 50-92 using exploratory and multiplexed affinity proteomics assays. Profiling eight additional study sets (N = 3,987), performing antibody validation, and conducting a meta-analysis revealed a consistent age association (P = 6.61 × 10-6) for circulating histidine-rich glycoprotein (HRG). Sequence variants of HRG influenced how the protein was recognized in the immunoassays. Indeed, only the HRG profiles affected by rs9898 were associated with age and predicted the risk of mortality (HR = 1.25 per SD; 95% CI = 1.12-1.39; P = 6.45 × 10-5) during a follow-up period of 8.5 yr after blood sampling (IQR = 7.7-9.3 yr). Our affinity proteomics analysis found associations between the particular molecular traits of circulating HRG with age and all-cause mortality. The distinct profiles of this multipurpose protein could serve as an accessible and informative indicator of the physiological processes related to biological aging.

12.
BMC Med ; 18(1): 225, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32838791

RESUMO

BACKGROUND: Despite the biological link between thyroid hormones and breast cancer cell proliferation shown in experimental studies, little is known about the association between hyperthyroidism and breast cancer, as well as its association with the most common mammographic and genetic risk predictors for breast cancer. METHODS: This study estimates the incidence rate ratios (IRRs) of breast cancer among women diagnosed with hyperthyroidism, compared to those who are not, using two cohorts: a Swedish national cohort of the general female population (n = 3,793,492, 2002-2011) and the Karolinska Mammography Project for Risk Prediction of Breast Cancer (KARMA, n = 69,598, 2002-2017). We used logistic regression to estimate the odds ratios (ORs) of hyperthyroidism according to the mammographic and genetic risk predictors for breast cancer. RESULTS: An increased risk of breast cancer was observed in patients in the national cohort with hyperthyroidism (IRR = 1.23, 95% CI = 1.12-1.36), particularly for toxic nodular goiter (IRR = 1.38, 95% CI = 1.16-1.63). Hyperthyroidism was associated with higher body mass index, early age at first birth, and lower breastfeeding duration. Higher mammographic density was observed in women with toxic nodular goiter, compared to women without hyperthyroidism. Additionally, among genotyped women without breast cancer in the KARMA cohort (N = 11,991), hyperthyroidism was associated with a high polygenic risk score (PRS) for breast cancer overall (OR = 1.98, 95% CI = 1.09-3.60) and for estrogen receptor-positive specific PRS (OR = 1.90, 95% CI = 1.04-3.43). CONCLUSION: Hyperthyroidism is associated with an increased risk of breast cancer, particularly for patients with toxic nodular goiter. The association could be explained by higher mammographic density among these women, as well as pleiotropic genetic variants determining shared hormonal/endocrine factors leading to the pathology of both diseases.

13.
Int J Cancer ; 2020 Aug 28.
Artigo em Inglês | MEDLINE | ID: mdl-32856720

RESUMO

The association between breast cancer risk defined by the Tyrer-Cuzick score (TC) and disease prognosis is not well established. Here, we investigated the relationship between 5-year TC and disease aggressiveness and then characterized underlying molecular processes. In a case-only study (n = 2474), we studied the association of TC with molecular subtypes and tumor characteristics. In a subset of patients (n = 672), we correlated gene expression to TC and computed a low-risk TC gene expression (TC-Gx) profile, that is, a profile expected to be negatively associated with risk, which we used to test for association with disease aggressiveness. We performed enrichment analysis to pinpoint molecular processes likely to be altered in low-risk tumors. A higher TC was found to be inversely associated with more aggressive surrogate molecular subtypes and tumor characteristics (P < .05) including Ki-67 proliferation status (P < 5 × 10-07 ). Our low-risk TC-Gx, based on the weighted sum of 37 expression values of genes strongly correlated with TC, was associated with basal-like (P < 5 × 10-13 ), HER2-enriched subtype (P < 5 × 10-07 ) and worse 10-year breast cancer-specific survival (log-rank P < 5 × 10-04 ). Associations between low-risk TC-Gx and more aggressive molecular subtypes were replicated in an independent cohort from The Cancer Genome Atlas database (n = 975). Gene expression that correlated with low TC was enriched in proliferation and oncogenic signaling pathways (FDR < 0.05). Moreover, higher proliferation was a key factor explaining the association with worse survival. Women who developed breast cancer despite having a low risk were diagnosed with more aggressive tumors and had a worse prognosis, most likely driven by increased proliferation. Our findings imply the need to establish risk factors associated with more aggressive breast cancer subtypes.

14.
Breast Cancer Res ; 22(1): 95, 2020 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-32847607

RESUMO

BACKGROUND: Mammographic density (MD) is a strong risk factor for breast cancer. We examined how endogenous plasma hormones are associated with average MD area (cm2) and annual MD change (cm2/year). METHODS: This study within the prospective KARMA cohort included analyses of plasma hormones of 1040 women. Hormones from the progestogen (n = 3), androgen (n = 7), oestrogen (n = 2) and corticoid (n = 5) pathways were analysed by ultra-performance supercritical fluid chromatography-tandem mass spectrometry (UPSFC-MS/MS), as well as peptide hormones and proteins (n = 2). MD was measured as a dense area using the STRATUS method (mean over the left and right breasts) and mean annual MD change over time. RESULTS: Greater baseline mean MD was associated with overall higher concentrations of progesterone (average + 1.29 cm2 per doubling of hormone concentration), 17OH-progesterone (+ 1.09 cm2), oesterone sulphate (+ 1.42 cm2), prolactin (+ 2.11 cm2) and SHBG (+ 4.18 cm2), and inversely associated with 11-deoxycortisol (- 1.33 cm2). The association between MD and progesterone was confined to the premenopausal women only. The overall annual MD change was - 0.8 cm2. Hormones from the androgen pathway were statistically significantly associated with MD change. The annual MD change was - 0.96 cm2 and - 1.16 cm2 lesser, for women in the highest quartile concentrations of testosterone and free testosterone, respectively, compared to those with the lowest concentrations. CONCLUSIONS: Our results suggest that, whereas hormones from the progestogen, oestrogen and corticoid pathways drive baseline MD, MD change over time is mainly driven by androgens. This study emphasises the complexity of risk factors for breast cancer and their mechanisms of action.

15.
Br J Clin Pharmacol ; 2020 Jul 26.
Artigo em Inglês | MEDLINE | ID: mdl-32713032

RESUMO

AIMS: Tamoxifen is bioactivated to endoxifen by polymorphic CYP2D6-dependent metabolism. Here, endoxifen levels were compared to CYP2D6 diplotypes, tentative target concentrations and side effects. METHODS: 118 Swedish premenopausal breast cancer patients diagnosed 2006-2014, with on-going postoperative tamoxifen treatment January 2017, were included. Biobanked DNA from peripheral blood was used for CYP2D6 genotyping by TaqMan real-time PCR (CYP2D6*1, *3, *4, *5, *6, *9, *10, *41, *1xN). Plasma levels of tamoxifen and three major metabolites were quantified by LC-MS/MS. Clinical information on treatment and side effects was retrospectively obtained from medical records. RESULTS: In the final analysis of 114 patients, a clear relationship between CYP2D6 genotype and plasma endoxifen levels was evident. Low endoxifen (1.6 - 5.2 ng/mL), i.e. below the suggested threshold for clinical efficacy, was found in all patients with two reduced-function alleles, two null-alleles, or a null/reduced-function combination. CYP2D6*41 was the most common reduced-function allele (82%) and 17 of 21 CYP2D6*41-carriers exhibited a lower CYP2D6-activity than predicted from published guidelines. No difference in endoxifen levels was observed between carriers of two null-alleles versus patients homozygous for CYP2D6*41 or the corresponding heterozygous combination (p=0.338). In patients with endoxifen levels below 5.9 ng/mL (36/114), side effects were either mild or absent. At higher endoxifen levels moderate-to-severe side effects were reported in a concentration-dependent manner. CONCLUSION: Significantly reduced endoxifen levels were observed not only in all homozygous carriers of CYP2D6 null-alleles, but also in carriers of two reduced-function alleles. This finding may be highly relevant for future, genotype-based dose considerations.

17.
Nat Commun ; 11(1): 3353, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620889

RESUMO

Genome-wide association studies (GWAS) have led to the identification of hundreds of susceptibility loci across cancers, but the impact of further studies remains uncertain. Here we analyse summary-level data from GWAS of European ancestry across fourteen cancer sites to estimate the number of common susceptibility variants (polygenicity) and underlying effect-size distribution. All cancers show a high degree of polygenicity, involving at a minimum of thousands of loci. We project that sample sizes required to explain 80% of GWAS heritability vary from 60,000 cases for testicular to over 1,000,000 cases for lung cancer. The maximum relative risk achievable for subjects at the 99th risk percentile of underlying polygenic risk scores (PRS), compared to average risk, ranges from 12 for testicular to 2.5 for ovarian cancer. We show that PRS have potential for risk stratification for cancers of breast, colon and prostate, but less so for others because of modest heritability and lower incidence.


Assuntos
Predisposição Genética para Doença , Modelos Genéticos , Herança Multifatorial , Neoplasias/epidemiologia , Animais , Feminino , Estudo de Associação Genômica Ampla , Humanos , Incidência , Masculino , Neoplasias/genética , Polimorfismo de Nucleotídeo Único , Medição de Risco/métodos , Fatores de Risco
18.
Nat Rev Clin Oncol ; 17(11): 687-705, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32555420

RESUMO

The European Collaborative on Personalized Early Detection and Prevention of Breast Cancer (ENVISION) brings together several international research consortia working on different aspects of the personalized early detection and prevention of breast cancer. In a consensus conference held in 2019, the members of this network identified research areas requiring development to enable evidence-based personalized interventions that might improve the benefits and reduce the harms of existing breast cancer screening and prevention programmes. The priority areas identified were: 1) breast cancer subtype-specific risk assessment tools applicable to women of all ancestries; 2) intermediate surrogate markers of response to preventive measures; 3) novel non-surgical preventive measures to reduce the incidence of breast cancer of poor prognosis; and 4) hybrid effectiveness-implementation research combined with modelling studies to evaluate the long-term population outcomes of risk-based early detection strategies. The implementation of such programmes would require health-care systems to be open to learning and adapting, the engagement of a diverse range of stakeholders and tailoring to societal norms and values, while also addressing the ethical and legal issues. In this Consensus Statement, we discuss the current state of breast cancer risk prediction, risk-stratified prevention and early detection strategies, and their implementation. Throughout, we highlight priorities for advancing each of these areas.

19.
Breast ; 53: 33-41, 2020 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-32563178

RESUMO

OBJECTIVES: To assess if mammographic density (MD) changes during neoadjuvant breast cancer treatment and is predictive of a pathological complete response (pCR). METHODS: We prospectively included 200 breast cancer patients assigned to neoadjuvant chemotherapy (NACT) in the NeoDense study (2014-2019). Raw data mammograms were used to assess MD with a fully automated volumetric method and radiologists categorized MD using the Breast Imaging-Reporting and Data System (BI-RADS), 5th Edition. Logistic regression was used to calculate odds ratios (OR) for pCR comparing BI-RADS categories c vs. a, b, and d as well as with a 0.5% change in percent dense volume adjusting for baseline characteristics. RESULTS: The overall median age was 53.1 years, and 48% of study participants were premenopausal pre-NACT. A total of 23% (N = 45) of the patients accomplished pCR following NACT. Patients with very dense breasts (BI-RADS d) were more likely to have a positive axillary lymph node status at diagnosis: 89% of the patients with very dense breasts compared to 72% in the entire cohort. A total of 74% of patients decreased their absolute dense volume during NACT. The likelihood of accomplishing pCR following NACT was independent of volumetric MD at diagnosis and change in volumetric MD during treatment. No trend was observed between decreasing density according to BI-RADS and the likelihood of accomplishing pCR following NACT. CONCLUSIONS: The majority of patients decreased their MD during NACT. We found no evidence of MD as a predictive marker of pCR in the neoadjuvant setting.

20.
Mar Pollut Bull ; 155: 110962, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32469791

RESUMO

The aim of the study was to assess the effect of seaweed cultivation on the coastal environment. We analysed a multitude of environmental parameters using an asymmetrical before after control impact (BACI) design, comparing the seaweed farm (impact) with multiple unaffected locations (controls). The seaweed farm had a significant positive effect on benthic infauna (p<0.05) and was found to attract 17 mobile faunal and 7 other seaweed species, indicating that the farmed crop may provide habitat to mobile faunal species. A light attenuation of approximately 40% at 5m depth was noted at the peak of the seaweed biomass just before harvest. No changes were observed in benthic oxygen flux, dissolved nutrient concentrations, and benthic mobile fauna between farm and control sites. These results show that seaweed aquaculture has limited environmental effects, especially compared to other forms of aquaculture such as fish and bivalve farming.


Assuntos
Kelp , Feófitas , Alga Marinha , Animais , Aquicultura , Meio Ambiente
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