BACKGROUND:Breast cancer is etiologically heterogeneous, but which risk factors differ in their associations across tumor subtypes remains unclear. We conducted a large, pooled analysis to evaluate independent, dose-response associations between breast cancer risk factors and quantitative tumor features. METHODS:Analyses of 15,731 invasive breast cancers from 24 studies evaluated associations (p-trend) between reproductive and hormonal factors, body mass index (BMI), alcohol, smoking, and family history in relation to quantitative immunohistochemistry measures on tissue microarrays (ER, PR, HER2, KI67, TP53) and tumor grade. Analyses in a subset of 10 population-based studies estimated subtype-specific odds ratios (ORs) comparing cases to controls. A Bayesian False Discovery Probability (BFDP) <0.2 was used to identify associations with strong statistical evidence. RESULTS:Nulliparity and later age at menopause were associated with higher ER-positivity (p-trend=0.021 and 0.001, respectively), with corresponding OR[ER+] (95% CI) = 1.49 (1.16-1.90) for nulliparous vs. parous and 1.07 (1.03-1.11) per 5 years. Current combined menopausal hormone therapy (MHT) use was associated with lower grade (p-trend<0.001), with OR [grade1] = 3.37 (2.69-4.21) for current vs. never users. Higher BMI was associated with lower ER-positivity and higher grade in premenopausal women (p-trend<0.001 and <0.001), with OR[ER+] = 0.80 (0.74-0.87) and OR[grade1] = 0.75 (0.63-0.88) per 5 units, and with higher PR-positivity and higher grade in postmenopausal women (p-trend<0.001 and <0.001), with OR[PR+] = 1.08 (1.03-1.14) and OR[grade 3] = 1.10 (1.04-1.17) per 5 units. CONCLUSION:This pooled analysis of 15,731 cases showed that nulliparity, age at menopause, MHT, and BMI have independent, dose-response associations with ER, PR, and grade, clarifying patterns of etiologic heterogeneity. Associations with HER2, KI67 and TP53, or other risk factors did not meet our threshold for strong evidence.

Background: Hypofractionated radiotherapy has become standard of care for adjuvant breast cancer treatment in the UK. The impact of hypofractionation on late effects, such as second cancers, is not yet known. We evaluated the risk of second cancers in or near the radiation field after hypofractionated radiotherapy of 40Gy in 15 fractions (40Gy15F) compared with 50Gy in 25 fractions (50Gy25F) for breast cancer. Methods: We used the National Cancer Registration Dataset to emulate a target trial within a retrospective cohort study of 278,051 five-year female breast cancer survivors diagnosed in England between 1995-2017. Dose fractionation was ascertained through linkage with the national Radiotherapy Dataset. We evaluated second invasive cancers in or near the radiotherapy field (including lung, oesophageal, and soft tissue sarcomas). Relative risks (RR) of second cancers by fractionation were estimated using multivariable Poisson regression adjusted for age at breast cancer, endocrine therapy, chemotherapy, breast cancer surgery, and stage. Ten-year cumulative risks were estimated for the total incidence of second cancers by fractionation group. Findings: The cohort comprised 278,051 women, including 137,614 (49·5%) treated with 50Gy25F and 140,437 (50·1%) treated with 40Gy15F. Over a median follow-up of 11·0 years (IQR:7·5-15·0 years) 3,671 (1·3%) women developed a second cancer in or near the radiotherapy field. Second cancer risks were similar for 40Gy15F compared to 50Gy25F for lung cancer (RR=1·04, 95%CI:0·96–1·13), oesophageal cancer (RR=0·91, 95%CI:0·71–1·16), and soft tissue sarcomas (RR=0·99, 95%CI:0·80–1·22). The ten-year cumulative risks for second cancers in or near the radiotherapy field were 1·95% (95%CI:1·80–2·10) for 40Gy15F and 1·98% (95%CI:1·90–2·06) for 50Gy25F. Interpretation: In this large-scale national cohort second cancer risks in or near the radiation field were similar for women treated with 50Gy25F and 40Gy15F for breast cancer. These findings provide reassurance about the long-term safety of hypofractionated radiotherapy.

Understanding how modifiable cancer risk factors change across the life course is crucial for evidence-based prevention. However, surveillance of lifestyle factors often relies on cross-sectional studies, unable to capture within-person patterns across the life course. Longitudinal studies assessing long-term exposure patterns are scarce. Within the Generations Study, a prospective cohort of > 113,700 UK women (median recruitment age: 48.4 years; range: 16–102) recruited between 2003 and 2009, we explored life course trajectories of modifiable cancer risk factors, leveraging up to six self-reported exposure measurements collected retrospectively and prospectively. Linear mixed-effects models with natural cubic splines for age were fitted for alcohol consumption, smoking, physical activity and body mass index (BMI). Mean velocity curves were derived from differentiated spline curves. Interactions between age and birth cohort assessed generational differences. Each risk factor showed distinct, nonlinear patterns in the level and rate of change across the life course. Alcohol consumption, smoking and physical activity peaked in late adolescence, whilst BMI increased with age, peaking in the late 60s. Younger cohorts (born 1960–2003) exhibited progressively higher BMI trajectories and earlier peaks in alcohol consumption and smoking intensity compared to older cohorts (born 1908–1959). Modifiable cancer risk factor exposure varied throughout life, highlighting the importance of repeated exposure measurements to capture these patterns. Our findings revealed key life stages for behavioural transitions. This insight can guide targeted prevention and intervention efforts.

Abstract BRCA-associated homologous recombination deficiency (HRD) is present in ~50% of high-grade serous carcinomas (HGSC) and predicts sensitivity to platinum-based therapy. However, there is little understanding of why some patients with BRCA-deficient tumors experience poor outcomes. In a large HGSC cohort (n = 1389) including 282 individuals with pathogenic germline BRCA variants (gBRCApv), residual disease after primary surgery has limited prognostic effect in gBRCApv-carriers compared to non-carriers, and prognostic outcomes differ based on the mutation location within functional domains of the BRCA genes. Multi-omic profiling is performed on 154 tumors, enriched for patients with BRCA-deficient tumors that experienced short overall survival ( ≤ 3 years, n = 42). Patients with BRCA2-deficient HGSC and loss of NF1 survive twice as long as those without NF1 loss, whereas PIK3CA, RAD21 and MYC amplification define BRCA2-deficient HGSC with exceptionally short survival. Patients with BRCA1-deficient HGSC and a more elevated HRD score survive significantly longer. BRCA1-deficient tumors in short survivors have evidence of immunosuppressive c-kit signaling and EMT. Our findings confirm that outcome is not determined by BRCA status alone, but rather a combination of co-occurring genomic alterations, the extent of DNA repair deficiency, and the tumor-immune microenvironment.

BACKGROUND:Among premenopausal women, higher body mass index (BMI) is associated with lower breast cancer risk, although the underlying mechanisms are unclear. Investigating adiposity distribution may help clarify impacts on breast cancer risk. This study was initiated to investigate associations of central and peripheral adiposity with premenopausal breast cancer risk overall and by other risk factors and breast cancer characteristics. METHODS:We used individual-level data from 14 prospective cohort studies to estimate hazard ratios (HRs) for premenopausal breast cancer using Cox proportional hazards regression. Analyses included 440,179 women followed for a median of 7.5 years (interquartile range: 4.0-11.3) between 1976 and 2017, with 6,779 incident premenopausal breast cancers. RESULTS:All central adiposity measures were inversely associated with breast cancer risk overall when not controlling for BMI (e.g. for waist circumference, HR per 10 cm increase: 0.92, 95% confidence interval (CI): 0.90-0.94) whereas in models adjusting for BMI, these measures were no longer associated with risk (e.g. for waist circumference: HR 0.99, 95% CI: 0.95-1.03). This finding was consistent across age categories, with some evidence that BMI-adjusted associations differed by breast cancer subtype. Inverse associations for in situ breast cancer were observed with waist-to-height and waist-to-hip ratios and a positive association was observed for oestrogen-receptor-positive breast cancer with hip circumference (HR per 10 cm increase: 1.08, 95% CI: 1.10-1.14). For luminal B, HER2-positive breast cancer, we observed an inverse association with hip circumference (HR per 10 cm: 0.84, 95% CI: 0.71-0.98), but positive associations with waist circumference (HR per 10 cm: 1.18, 95% CI: 1.03-1.36), waist-to-hip ratio (HR per 0.1 units: 1.29, 95% CI: 1.15-1.45) and waist-to height ratio (HR per 0.1 units: 1.46, 95% CI: 1.17-1.84). CONCLUSIONS:Our analyses did not support an association between central adiposity and overall premenopausal breast cancer risk after adjustment for BMI. However, our findings suggest associations might differ by breast cancer hormone receptor and intrinsic subtypes.

Background:Studies have reported higher lung cancer incidence among groups with lower socioeconomic position (SEP). However, it is not known how this difference in lung cancer incidence between SEP groups varies across different geographical settings. Furthermore, most prior studies that assessed the association between SEP and lung cancer incidence were conducted without detailed adjustment for smoking. Therefore, we aimed to assess this relationship across world regions. Methods:In this international prospective cohort consortium study, we used data from the Lung Cancer Cohort Consortium (LC3), which includes 20 prospective population cohorts from 16 countries in North America, Europe, Asia, and Australia. Participants were enrolled between 1985 and 2010 and followed for cancer outcomes using registry linkages and/or active follow-up. We estimated hazard ratios (HRs) for the association between educational level (our primary measure of SEP, in 4 categories) and incident lung cancer using Cox proportional hazards models separately for participants with and without a smoking history. The models were adjusted for age, sex, cohort (when multiple cohorts were included), smoking duration, cigarettes per day, and time since cessation. Findings:Among 2,487,511 participants, 53,830 developed lung cancer during a 13.5-year median follow-up (IQR = 6.5-15.0 years). Among participants with a smoking history, higher education was associated with decreased lung cancer incidence in nearly every cohort after detailed smoking adjustment. By world region, this association was observed in North America (HR per one-category increase in education [HRtrend] = 0.88, 95% CI = 0.87-0.89), Europe (HRtrend = 0.89, 95% CI = 0.88-0.91), and Asia (HRtrend = 0.91, 95% CI = 0.86-0.96), but not in the Australian study (HRtrend = 1.02, 95% CI = 0.95-1.09). By histological subtype, education associated most strongly with squamous cell carcinoma and more weakly with adenocarcinoma (p-heterogeneity < 0.0001). Among participants who never smoked, there was no association between education and lung cancer incidence in any cohort (all p-trend > 0.05), except the USA Southern Community Cohort Study (HRtrend = 0.75, 95% CI = 0.62-0.90). Interpretation:Based on longitudinal data from 2.5 million participants from 16 countries, our findings suggest that higher educational attainment was associated with lower lung cancer risk among participants with a smoking history, but not among participants who never smoked. Limitations of our study include that cohort participants cannot fully represent the general populations of the geographical regions included, and education was the only measure of SEP consistently available across our consortium. Funding:This study was supported in part by the National Cancer Institute (NCI), the Lung Cancer Research Foundation (LCRF), and the World Cancer Research Fund (WCRF).

Incidence of premenopausal breast cancer (BC) has risen in recent years, though most existing BC prediction models are not generalizable to young women due to underrepresentation of this age group in model development. Using questionnaire-based data from 19 prospective studies harmonized within the Premenopausal Breast Cancer Collaborative Group (PBCCG), representing 783,830 women, we developed a premenopausal BC risk prediction model. The data were split into training (2/3) and validation (1/3) datasets with equal distribution of cohorts in each. In the training dataset variables were chosen from known and hypothesized risk factors: age, age at menarche, age at first birth, parity, breastfeeding, height, BMI, young adulthood BMI, recent weight change, alcohol consumption, first-degree family history of BC, and personal history of benign breast disease (BBD). Hazard ratios (HR) and 95

BACKGROUND:Alcohol is a known carcinogen, yet the evidence for an association with pancreatic cancer risk is considered as limited or inconclusive by international expert panels. We examined the association between alcohol intake and pancreatic cancer risk in a large consortium of prospective studies. METHODS AND FINDINGS:Population-based individual-level data was pooled from 30 cohorts across four continents, including Asia, Australia, Europe, and North America. A total of 2,494,432 participants without cancer at baseline (62% women, 84% European ancestries, 70% alcohol drinkers [alcohol intake ≥ 0.1 g/day], 47% never smokers) were recruited between 1980 and 2013 at the median age of 57 years and 10,067 incident pancreatic cancer cases were recorded. In age- and sex-stratified Cox proportional hazards models adjusted for smoking history, diabetes status, body mass index, height, education, race and ethnicity, and physical activity, pancreatic cancer hazard ratios (HR) and 95% confidence intervals (CI) were estimated for categories of alcohol intake and in continuous for a 10 g/day increase. Potential heterogeneity by sex, smoking status, geographic regions, and type of alcoholic beverage was investigated. Alcohol intake was positively associated with pancreatic cancer risk, with HR30-to-<60 g/day and HR≥60 g/day equal to 1.12 (95% CI [1.03,1.21]) and 1.32 (95% CI [1.18,1.47]), respectively, compared to intake of 0.1 to <5 g/day. A 10 g/day increment of alcohol intake was associated with a 3% increased pancreatic cancer risk overall (HR: 1.03; 95% CI [1.02,1.04]; pvalue < 0.001) and among never smokers (HR: 1.03; 95% CI [1.01,1.06]; pvalue = 0.006), with no evidence of heterogeneity by sex (pheterogeneity = 0.274) or smoking status (pheterogeneity = 0.624). Associations were consistent in Europe-Australia (HR10 g/day = 1.03, 95% CI [1.00,1.05]; pvalue = 0.042) and North America (HR10 g/day = 1.03, 95% CI [1.02,1.05]; pvalue < 0.001), while no association was observed in cohorts from Asia (HR10 g/day = 1.00, 95% CI [0.96,1.03]; pvalue = 0.800; pheterogeneity = 0.003). Positive associations with pancreatic cancer risk were found for alcohol intake from beer (HR10 g/day = 1.02, 95% CI [1.00,1.04]; pvalue = 0.015) and spirits/liquor (HR10 g/day = 1.04, 95% CI [1.03,1.06]; pvalue < 0.001), but not wine (HR10 g/day = 1.00, 95% CI [0.98,1.03]; pvalue = 0.827). The differential associations across geographic regions and types of alcoholic beverages might reflect differences in drinking habits and deserve more investigations. CONCLUSIONS:Findings from this large-scale pooled analysis support a modest positive association between alcohol intake and pancreatic cancer risk, irrespective of sex and smoking status. Associations were particularly evident for baseline alcohol intake of at least 15 g/day in women and 30 g/day in men.

BACKGROUND:Oestrogen plus progestin hormone therapy is an established risk factor for breast cancer in postmenopausal women. We examined the less well-studied association between exogenous hormones and breast cancer in young women, who might use hormone therapy after gynaecological surgery or to relieve perimenopausal symptoms. METHODS:In this pooled cohort analysis, we investigated the relationship between exogenous hormones and breast cancer in young women using data from 10-13 prospective cohorts from North America, Europe, Asia, and Australia. The participating cohorts followed up women for incident breast cancer until age 55 years. We used cohort-stratified, multivariable-adjusted Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% CI for associations of hormone therapy with incident young-onset breast cancer. We also estimated risk differences based on cumulative risk until age 55 years. FINDINGS:We included 459 476 women aged 16-54 years (mean 42·0 years [IQR 35·5-49·2]), of whom 8455 (2%) developed young-onset breast cancer (diagnosed before age 55 years; median follow-up 7·8 years [5·2-11·2]). Overall, 15% of participants reported using hormone therapy, with oestrogen plus progestin hormone therapy (6%) and unopposed oestrogen (5%) being the most common types. Cumulative risk of young-onset breast cancer was 4·1% in non-users. Hormone therapy of any type was not associated with incident young-onset breast cancer (HR 0·96 [95% CI 0·88 to 1·04]), but ever oestrogen hormone therapy use was inversely associated (0·86 [0·75 to 0·98]; risk difference -0·5% [-1·0 to -0·0]). The HR for ever oestrogen plus progestin hormone therapy and young-onset breast cancer was 1·10 (0·98 to 1·24), with positive associations observed for long-term use (1·18 [1·01 to 1·38] for >2 years) and use among women without hysterectomy or bilateral oophorectomy (1·15 [1·02 to 1·31]). Oestrogen hormone therapy and young-onset breast cancer association was similar for all breast cancer subtypes, but oestrogen plus progestin hormone therapy was more strongly associated with oestrogen receptor negative (1·44 [1·11 to 1·88]) and triple-negative disease (1·50 [1·02 to 2·20]) than with other subtypes. INTERPRETATION:Oestrogen hormone therapy use was inversely associated with young-onset breast cancer, and oestrogen plus progestin hormone therapy was associated with higher young-onset breast cancer incidence among women with intact uterus and ovaries. These findings largely parallel results from studies of hormone use and later-onset breast cancer and provide novel evidence for establishing clinical recommendations among younger women. FUNDING:NIH Intramural Research Program.

Tens of millions of people worldwide have inherited chromosomally integrated human herpesvirus 6 (iciHHV-6), yet we know little about the consequences. iciHHV-6-positive individuals inherit the genome of HHV-6A or HHV-6B in the germline, and viral genomes are therefore present in every nucleated cell. To investigate the epidemiology of iciHHV-6 in the UK, almost 32,000 individuals were screened from two volunteer research studies: the family-based Generation Scotland: Scottish Family Health Study (GS:SFHS) and the Breakthrough Generations Study (BGS). iciHHV-6 prevalence in GS:SFHS was, to our knowledge, higher than that in other large studies at 2.74% (647/23,637), with an iciHHV-6B prevalence of 2.55%. Scottish participants were more likely to be iciHHV-6B-positive than English (P < 0.001), and the BGS results suggested a north-south gradient of iciHHV-6B prevalence in mainland Britain. Disease association analysis confirmed the previously reported association with angina, with an odds ratio of 1.91 (95% confidence interval, 1.29, 2.82) following adjustment for known risk factors, providing compelling evidence that iciHHV-6 contributes to the risk of a common symptom. De novo integrations were not detected within GS:SFHS pedigrees; rather, our findings indicated that three viral lineages accounted for over 95% of iciHHV-6A-positive samples, and six viral lineages accounted for 90% of iciHHV-6B-positive samples in GS:SFHS. This study demonstrates that iciHHV-6 is common in the UK, shows significant regional heterogeneity in prevalence, is not entirely harmless, and is largely derived from a relatively small number of ancestral viral lineages.IMPORTANCEHuman herpesvirus 6 (HHV-6) has the unusual ability to integrate into the host chromosome telomeres. Most of the world's population is infected by HHV-6 in early childhood, but around 1% inherit the virus as a chromosomally integrated viral genome-referred to as inherited chromosomally integrated HHV-6 (iciHHV-6). Little is known about the consequences of iciHHV-6, which has the potential to cause disease through various mechanisms. Here, we have used large cohorts to study iciHHV-6 prevalence, lineages, and phenotypic associations. We replicate a previously reported association between iciHHV-6 and angina, suggesting that iciHHV-6 is not entirely benign. We show significant variation in iciHHV-6 prevalence within the UK with almost 3% of Scottish people carrying iciHHV-6. In the first detailed analysis of viral lineages at the population level, we show that 90% of iciHHV-6 is explained by nine ancestral viral lineages. These results have important implications for future disease association analyses.

Supplementary Table S5. Summary of cell lines used in this study.

Supplementary Table S10. Number of patients by study and histotype.

Supplementary Table S4. Differential gene expression analysis comparing transcriptomes of tumors based on BRCA and RB1 alteration status.

Supplementary Table S15. Clinical characteristics of patients with HGSC according to RB1 and BRCA status.

Multivariate analysis of molecular alterations and OS in patients with HGSC and ENOC.

Background: Identifying affecting and predictive factors of steroid-sensitive nephrotic syndrome’s (SSNS's) outcome may greatly benefit the proper management of SSNS patients. Objectives: The current systematic review comprehensively reviews all available evidence on the risk factors of SSNS relapse in children and adolescents. Methods: An extensive search was conducted on the electronic databases of Medline, Embase, Web of Science, and Scopus until February 18, 2024. Studies investigating the risk factors of relapse were included in this systematic review. Results: A total of 11 articles were included. Age, gender, and laboratory variables, such as serum creatinine and serum protein are not risk factors for relapse in these studies. Possible associations were reported for risk factors, such as the number of relapses and response time. Overall, the studies reported conflicting results on the value of relapse risk factors. Conclusions: Although factors, such as hematuria, hypertension, time from treatment to response, and number of relapses have been proposed as possible risk factors for relapse, no conclusion can be reached due to the heterogeneity of studies. Future studies should have more conforming designs to make comparisons more reliable.

Supplementary Table S13. Clinical and molecular characteristics of ENOC.

Sensitivity to therapeutic agents in BRCA1-altered cell lines with RB1 knockout. A,RB1 was knocked out using CRISPR/Cas9 in three patient-derived Australian Ovarian Cancer Study (AOCS) HGSC cell lines with either wild-type or altered BRCA1 (BRCA1 var) background. Representative Western Blots show protein levels of RB1 and phosphorylated RB1 (pRB1) compared with GAPDH loading control in single-cell cloned, homozygous RB1 wild-type (WT) and knockout (KO) colonies in comparison with heterogeneous populations with a scramble single guide RNA (sgRNA). Independent blots were used for RB1 and pRB1. B, Cell viability was compared between RB1 WT and KO clones following treatment with cisplatin (72 h), paclitaxel (72 h), or olaparib (120 h). Nonlinear regression drug curves are shown; P values are shown in Supplementary Table S18 (n = 3). Error bars indicate ± SEM; for some values, error bars are shorter than the symbols and thus are not visible. C, Proportion of surviving colonies following 16 days of treatment with cisplatin, paclitaxel, or a combination of both (Cis/Pac; with half of the IC50 determined per drug and cell line respectively) relative to DMF vehicle control (n = 3 replicates). Data are presented as mean ± SEM. Mean values were compared by Student’s t test (ns, not significant; *, P < 0.05; **, P < 0.01). Representative scans of the fixed cell colonies stained with crystal violet are shown for each condition.

Supplementary Table S7. Sequences of single guide RNAs used for CRISPR-mediated gene knockout.

Clinicopathologic characteristics and RB1 expression patterns across histotypes.