Association of the CHEK2 c.1100delC variant, radiotherapy, and systemic treatment with contralateral breast cancer risk and breast cancer-specific survival

Background Breast cancer (BC) patients with a germline CHEK2 c.1100delC variant have an increased risk of contralateral BC (CBC) and worse BC-specific survival (BCSS) compared to non-carriers. Aim To assessed the associations of CHEK2 c.1100delC, radiotherapy, and systemic treatment with CBC risk and BCSS. Methods Analyses were based on 82,701 women diagnosed with a first primary invasive BC including 963 CHEK2 c.1100delC carriers; median follow-up was 9.1 years. Differential associations with treatment by CHEK2 c.1100delC status were tested by including interaction terms in a multivariable Cox regression model. A multi-state model was used for further insight into the relation between CHEK2 c.1100delC status, treatment, CBC risk and death. Results There was no evidence for differential associations of therapy with CBC risk by CHEK2 c.1100delC status. The strongest association with reduced CBC risk was observed for the combination of chemotherapy and endocrine therapy [HR (95% CI): 0.66 (0.55–0.78)]. No association was observed with radiotherapy. Results from the multi-state model showed shorter BCSS for CHEK2 c.1100delC carriers versus non-carriers also after accounting for CBC occurrence [HR (95% CI): 1.30 (1.09–1.56)]. Conclusion Systemic therapy was associated with reduced CBC risk irrespective of CHEK2 c.1100delC status. Moreover, CHEK2 c.1100delC carriers had shorter BCSS, which appears not to be fully explained by their CBC risk

A genome-wide gene-environment interaction study of breast cancer risk for women of European ancestry

Background Genome-wide studies of gene–environment interactions (G×E) may identify variants associated with disease risk in conjunction with lifestyle/environmental exposures. We conducted a genome-wide G×E analysis of ~ 7.6 million common variants and seven lifestyle/environmental risk factors for breast cancer risk overall and for estrogen receptor positive (ER +) breast cancer. Methods Analyses were conducted using 72,285 breast cancer cases and 80,354 controls of European ancestry from the Breast Cancer Association Consortium. Gene–environment interactions were evaluated using standard unconditional logistic regression models and likelihood ratio tests for breast cancer risk overall and for ER + breast cancer. Bayesian False Discovery Probability was employed to assess the noteworthiness of each SNP-risk factor pairs. Results Assuming a 1 × 10–5 prior probability of a true association for each SNP-risk factor pairs and a Bayesian False Discovery Probability < 15%, we identified two independent SNP-risk factor pairs: rs80018847(9p13)-LINGO2 and adult height in association with overall breast cancer risk (ORint = 0.94, 95% CI 0.92–0.96), and rs4770552(13q12)-SPATA13 and age at menarche for ER + breast cancer risk (ORint = 0.91, 95% CI 0.88–0.94). Conclusions Overall, the contribution of G×E interactions to the heritability of breast cancer is very small. At the population level, multiplicative G×E interactions do not make an important contribution to risk prediction in breast cancer

Physical activity, sedentary time and breast cancer risk: a Mendelian randomisation study

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

A case-only study to identify genetic modifiers of breast cancer risk for BRCA1/BRCA2 mutation carriers

Breast cancer (BC) risk for BRCA1 and BRCA2 mutation carriers varies by genetic and familial factors. About 50 common variants have been shown to modify BC risk for mutation carriers. All but three, were identified in general population studies. Other mutation carrier-specific susceptibility variants may exist but studies of mutation carriers have so far been underpowered. We conduct a novel case-only genome-wide association study comparing genotype frequencies between 60,212 general population BC cases and 13,007 cases with BRCA1 or BRCA2 mutations. We identify robust novel associations for 2 variants with BC for BRCA1 and 3 for BRCA2 mutation carriers, P < 10−8, at 5 loci, which are not associated with risk in the general population. They include rs60882887 at 11p11.2 where MADD, SP11 and EIF1, genes previously implicated in BC biology, are predicted as potential targets. These findings will contribute towards customising BC polygenic risk scores for BRCA1 and BRCA2 mutation carriers

Tobacco Smoking and Risk of Second Primary Lung Cancer

Introduction: Lung cancer survivors are at high risk of developing a second primary lung cancer (SPLC). However, SPLC risk factors have not been established and the impact of tobacco smoking remains controversial. We examined the risk factors for SPLC across multiple epidemiologic cohorts and evaluated the impact of smoking cessation on reducing SPLC risk. Methods: We analyzed data from 7059 participants in the Multiethnic Cohort (MEC) diagnosed with an initial primary lung cancer (IPLC) between 1993 and 2017. Cause-specific proportional hazards models estimated SPLC risk. We conducted validation studies using the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 3423 IPLC cases) and European Prospective Investigation into Cancer and Nutrition (N = 4731 IPLC cases) cohorts and pooled the SPLC risk estimates using random effects meta-analysis. Results: Overall, 163 MEC cases (2.3%) developed SPLC. Smoking pack-years (hazard ratio [HR] = 1.18 per 10 pack-years, p < 0.001) and smoking intensity (HR = 1.30 per 10 cigarettes per day, p < 0.001) were significantly associated with increased SPLC risk. Individuals who met the 2013 U.S. Preventive Services Task Force's screening criteria at IPLC diagnosis also had an increased SPLC risk (HR = 1.92; p < 0.001). Validation studies with the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and European Prospective Investigation into Cancer and Nutrition revealed consistent results. Meta-analysis yielded pooled HRs of 1.16 per 10 pack-years (pmeta < 0.001), 1.25 per 10 cigarettes per day (pmeta < 0.001), and 1.99 (pmeta < 0.001) for meeting the U.S. Preventive Services Task Force's criteria. In MEC, smoking cessation after IPLC diagnosis was associated with an 83% reduction in SPLC risk (HR = 0.17; p < 0.001). Conclusions: Tobacco smoking is a risk factor for SPLC. Smoking cessation may reduce the risk of SPLC. Additional strategies for SPLC surveillance and screening are warranted

Tobacco Smoking and Risk of Second Primary Lung Cancer

Introduction: Lung cancer survivors are at high risk of developing a second primary lung cancer (SPLC). However, SPLC risk factors have not been established and the impact of tobacco smoking remains controversial. We examined the risk factors for SPLC across multiple epidemiologic cohorts and evaluated the impact of smoking cessation on reducing SPLC risk. Methods: We analyzed data from 7059 participants in the Multiethnic Cohort (MEC) diagnosed with an initial primary lung cancer (IPLC) between 1993 and 2017. Cause-specific proportional hazards models estimated SPLC risk. We conducted validation studies using the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (N = 3423 IPLC cases) and European Prospective Investigation into Cancer and Nutrition (N = 4731 IPLC cases) cohorts and pooled the SPLC risk estimates using random effects meta-analysis. Results: Overall, 163 MEC cases (2.3%) developed SPLC. Smoking pack-years (hazard ratio [HR] = 1.18 per 10 pack-years, p < 0.001) and smoking intensity (HR = 1.30 per 10 cigarettes per day, p < 0.001) were significantly associated with increased SPLC risk. Individuals who met the 2013 U.S. Preventive Services Task Force's screening criteria at IPLC diagnosis also had an increased SPLC risk (HR = 1.92; p < 0.001). Validation studies with the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial and European Prospective Investigation into Cancer and Nutrition revealed consistent results. Meta-analysis yielded pooled HRs of 1.16 per 10 pack-years (pmeta < 0.001), 1.25 per 10 cigarettes per day (pmeta < 0.001), and 1.99 (pmeta < 0.001) for meeting the U.S. Preventive Services Task Force's criteria. In MEC, smoking cessation after IPLC diagnosis was associated with an 83% reduction in SPLC risk (HR = 0.17; p < 0.001). Conclusions: Tobacco smoking is a risk factor for SPLC. Smoking cessation may reduce the risk of SPLC. Additional strategies for SPLC surveillance and screening are warranted

Rare germline copy number variants (CNVs) and breast cancer risk

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.Dennis et al. investigate potential breast cancer associations with rare germline copy number variants (CNVs) by conducting a genome-wide analysis in a large breast cancer case-control dataset. The authors detected associations with exonic deletions in established breast cancer susceptibility genes and suggestive associations for a number of non-coding CNVs.Genome Instability and Cance

Breast Cancer Polygenic Risk Score and Contralateral Breast Cancer Risk

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies.Surgical oncolog