Background Breast cancer patients are at significant risk of a second contralateral, breast cancer (CBC). Identification of women at high or low CBC risk could improve patient management decisions. Previous research has shown that breast cancer-associated single nucleotide polymorphisms (SNPs) summarized in a polygenic risk score (PRS) predict the risk of a first breast cancer with an odds ratio (OR) per 1 SD of 1.55 (95% confidence interval (95%CI)=1.52-1.58) (77-SNP PRS). The aim of this study was to evaluate the association between a recently developed PRS and CBC risk. Methods We identified 19 studies from the Breast Cancer Association Consortium (BCAC) with follow-up information on participating patients and at least 10 patients diagnosed with CBC. This included 38,228 females of European ancestry diagnosed with first invasive breast cancer since 1990. Genotyping was done using the iCOGS array or OncoArray, with genotypes for SNPs not on the arrays estimated by imputation. We used a 313-SNP PRS, optimized for prediction of overall (first) breast cancer in the BCAC dataset. Metachronous CBC risk by PRS was quantified using univariable and multivariable Cox regression analyses stratified by country and adjusted for multiple patient, tumor, and treatment characteristics. We assessed PRS interaction with age, family history, adjuvant systemic therapy, and ER-status. Results Median time to develop a CBC (N=1,046) after a first breast cancer was 5.8 years (range 0.3-21.9). Higher PRS was associated with increased CBC risk: hazard ratio (HR) per 1 SD=1.31 (95%CI=1.23-1.39). Patients in the highest and lowest 5% of the PRS had 1.95 fold and 0.67 fold risks of CBC, respectively, compared with patients in the middle quintile. Adjustments for age, year of diagnosis, family history, tumor size, nodal status, ER-status, or treatment (chemotherapy, endocrine therapy, radiotherapy) did not substantially alter these results. We found an interaction with age at first breast cancer diagnosis (Pinteraction=.002); the PRS was associated with an increased CBC risk for patients aged ≥40 years (HR=1.37, 95%CI=1.28-1.47), but not for patients <40 years (HR=1.06, 95%CI=0.93-1.21). Conclusion The PRS is predictive for the development of CBC in patients ≥40 years at first breast cancer diagnosis. For this group, the PRS could be incorporated in CBC risk prediction models to help define high and low risk patients, and hence optimize screening and treatment strategies. Citation Format: Kramer I, Hooning MJ, Breast Cancer Association Consortium (BCAC), Mavaddat N, Canisius S, Keeman R, van den Broek AJ, Steyerberg E, Hauptmann M, Pharoah PD, Easton DF, Hall P, Schmidt MK. Association between a breast cancer polygenic risk score and contralateral breast cancer risk [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-09-04.
Introduction Over the last 2 decades, an increasing number of primary breast cancer (PBC) patients opted for a risk reducing contralateral mastectomy, to minimize risk of subsequent contralateral breast cancer (CBC). Therefore, accurate risk estimates of CBC are important for patient tailored counseling and decision making regarding treatment. Currently, CBC risk estimates are determined by BRCA1/2 mutation status, age at PBC diagnosis and family history. For other risk factors, results are inconclusive. We therefore aimed to quantify the association with CBC risk for patient, tumor and treatment related factors as reported in the literature. Methods Medline was searched for publications on CBC risk by one reviewer (DA). We focused on associations between CBC risk and BRCA1/2 and CHEK2*1100delC mutations, SNPs, risk-reducing salpingo-oophorectomy and various factors at PBC diagnosis: family history of breast cancer (BC), age, BMI, menopausal status, mammographic density, TNM-stage, receptor status, morphology, administered radiotherapy and adjuvant systemic treatment. Eligible papers were published in English between 01-01-1990 and 01-04-2015, investigated female patients with invasive early BC and reported relative risk (RR) estimates (i.e., hazard ratios, relative risks or odds ratios). We combined RR estimates using a random effects model. Heterogeneity was assessed using the I2 statistic. Forest plots for crude and adjusted estimates were generated stratifying for mutation status (i.e., BRCA1, BRCA2, CHEK2*1100delC), non-carriers and unselected patients (i.e., population/hospital based cohorts). Results After screening of 1,423 papers for title and abstract, 173 eligible papers were fully read, and 96 papers fulfilled the inclusion criteria. Both in the unselected group and in the BRCA1 and BRCA2 groups, administration of adjuvant endocrine therapy (vs. not), was associated with decreased CBC risk (RR, 0.62 (95% CI 0.55-0.69), 0.55 (95% CI 0.39-0.77), and 0.62 (95% CI 0.40-0.95), respectively). Adjuvant chemotherapy was associated with reduced CBC risk in unselected patients (RR 0.73; 95% CI 0.62-0.86). CBC risk was increased in unselected patients who received radiotherapy at age<40 years (vs. not) (RR 1.33; 95% CI 1.18-1.49), had a lobular (vs. ductal) PBC (RR 1.70; 95% CI 1.33-2.16), had a T2/T3 (vs. T1) PBC (RR 1.15; 95%CI 1.01-1.30), with BMI >30 (vs. <25) at PBC (RR 1.50; 95% CI 1.27-1.76) or had a positive family history for BC (vs. not) (RR 1.82; 95% CI 1.35-2.46). For the other factors of interest we did not observe any effects on CBC risk. For CHEK2*1100delC mutation carriers and non-carriers, information on factors affecting CBC risk was scarce. In non-carriers, the RR for adjuvant chemotherapy was 0.60 (95% CI 0.53-0.68). Conclusions In unselected patients, adjuvant systemic treatment for PBC decreases CBC risk while a lobular morphology of PBC, high BMI, and a family history of BC increase the risk of CBC. Data is scarce for carriers of a BRCA1/2 or CHEK2*1100delC mutation and non-carriers. This review identifies prognostic factors to consider for individualized CBC risk estimation which may support medical decision making in BC patients. Citation Format: Akdeniz D, Schmidt MK, McCool D, van den Broek AJ, Hauptmann M, Seynaeve CM, Steyerberg EW, Hooning MJ. Risk of metachronous contralateral breast cancer: Systematic review and meta-analysis [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-07-05.
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