Summary
In a genome-wide scan, we show that 30 variants in 25 genomic regions are associated with risk of TN breast cancer. Women carrying many of the risk variants may have 4-fold increased risk ...relative to women with few variants.
Triple-negative (TN) breast cancer is an aggressive subtype of breast cancer associated with a unique set of epidemiologic and genetic risk factors. We conducted a two-stage genome-wide association study of TN breast cancer (stage 1: 1529 TN cases, 3399 controls; stage 2: 2148 cases, 1309 controls) to identify loci that influence TN breast cancer risk. Variants in the 19p13.1 and PTHLH loci showed genome-wide significant associations (P < 5 × 10−
8) in stage 1 and 2 combined. Results also suggested a substantial enrichment of significantly associated variants among the single nucleotide polymorphisms (SNPs) analyzed in stage 2. Variants from 25 of 74 known breast cancer susceptibility loci were also associated with risk of TN breast cancer (P < 0.05). Associations with TN breast cancer were confirmed for 10 loci (LGR6, MDM4, CASP8, 2q35, 2p24.1, TERT-rs10069690, ESR1, TOX3, 19p13.1, RALY), and we identified associations with TN breast cancer for 15 additional breast cancer loci (P < 0.05: PEX14, 2q24.1, 2q31.1, ADAM29, EBF1, TCF7L2, 11q13.1, 11q24.3, 12p13.1, PTHLH, NTN4, 12q24, BRCA2, RAD51L1-rs2588809, MKL1). Further, two SNPs independent of previously reported signals in ESR1 rs12525163 odds ratio (OR) = 1.15, P = 4.9 × 10−
4 and 19p13.1 (rs1864112 OR = 0.84, P = 1.8 × 10−
9) were associated with TN breast cancer. A polygenic risk score (PRS) for TN breast cancer based on known breast cancer risk variants showed a 4-fold difference in risk between the highest and lowest PRS quintiles (OR = 4.03, 95% confidence interval 3.46–4.70, P = 4.8 × 10−
69). This translates to an absolute risk for TN breast cancer ranging from 0.8% to 3.4%, suggesting that genetic variation may be used for TN breast cancer risk prediction.
Predict Breast (www.predict.nhs.uk) is an online prognostication and treatment benefit tool for early invasive breast cancer. The aim of this study was to incorporate the prognostic effect of ...progesterone receptor (PR) status into a new version of PREDICT and to compare its performance to the current version (2.2).
The prognostic effect of PR status was based on the analysis of data from 45,088 European patients with breast cancer from 49 studies in the Breast Cancer Association Consortium. Cox proportional hazard models were used to estimate the hazard ratio for PR status. Data from a New Zealand study of 11,365 patients with early invasive breast cancer were used for external validation. Model calibration and discrimination were used to test the model performance.
Having a PR-positive tumour was associated with a 23% and 28% lower risk of dying from breast cancer for women with oestrogen receptor (ER)-negative and ER-positive breast cancer, respectively. The area under the ROC curve increased with the addition of PR status from 0.807 to 0.809 for patients with ER-negative tumours (p = 0.023) and from 0.898 to 0.902 for patients with ER-positive tumours (p = 2.3 × 10−6) in the New Zealand cohort. Model calibration was modest with 940 observed deaths compared to 1151 predicted.
The inclusion of the prognostic effect of PR status to PREDICT Breast has led to an improvement of model performance and more accurate absolute treatment benefit predictions for individual patients. Further studies should determine whether the baseline hazard function requires recalibration.
•PR) status is associated with a better prognosis after adjusting for other factors.•PREDICT with the inclusion of PR was assessed by calibration and discrimination.•addition of PR status improved model performance in terms of discrimination.•Calibration in an external dataset showed over-estimation of breast cancer mortality.
The presence of isolated tumor cells in the bone marrow (ITC-BM) of breast cancer patients is an independent prognostic parameter, indicating hematogenous tumor cell dissemination. While the HER2 ...status of breast cancer tissue has predictive value for the efficacy of different therapies, its prognostic relevance is controversial. To investigate the relationship between HER2 and ITC-BM, we retrospectively analyzed tumor tissues of 327 patients who underwent bone marrow aspiration at primary diagnosis or during the disease-free interval. Screening for ITC-BM was performed immunocytochemically, using the anti-cytokeratin antibody A45 B/B3. HER2 was determined by immunohistochemistry (IHC) with the antibody CB 11 (n = 277) and by fluorescence in situ hybridization (FISH, PathVision, Vysis, n = 206). ITC-BM were found in 83 of 327 patients (25.4%), with a median of 2.0 per 2 x 10(6 ) mononuclear cells. HER2 positivity (2+ /3+ ) was demonstrated in 18.8% of the tumors, amplification by FISH in 56 of 206 cases (27.2%). Established pathological parameters,tiviathological parameters, such as tumor size (p = 0.15), lymph node status (p = 0.93) and HER2 did not predict the presence of ITC-BM. After a median follow-up of 49 months (1-255), the presence of ITC-BM was a significant prognostic factor for distant disease free and overall survival, as well in univariate (log-rank-test, p = 0.024) as in multivariate analysis (cox-regression, p = 0.033 ). This also was confirmed in subgroups of patients by aease free survival (p = 0.013) and local recurrence (p = 0.003). The detection of ITC-BM is superior in predicting overall survival, compared to the HER2 status of the primary tumor. The direct identification of HER2 on ITC-BM is the aim of ongoing research, potentially synergizing the prognostic relevance of ITC-BM and the predictive value of the HER2 status.
Polygenic risk score (PRS), calculated based on genome-wide association studies (GWASs), can improve breast cancer (BC) risk assessment. To date, most BC GWASs have been performed in individuals of ...European (EUR) ancestry, and the generalisation of EUR-based PRS to other populations is a major challenge. In this study, we examined the performance of EUR-based BC PRS models in Ashkenazi Jewish (AJ) women.
We generated PRSs based on data on EUR women from the Breast Cancer Association Consortium (BCAC). We tested the performance of the PRSs in a cohort of 2161 AJ women from Israel (1437 cases and 724 controls) from BCAC (BCAC cohort from Israel (BCAC-IL)). In addition, we tested the performance of these EUR-based BC PRSs, as well as the established 313-SNP EUR BC PRS, in an independent cohort of 181 AJ women from Hadassah Medical Center (HMC) in Israel.
In the BCAC-IL cohort, the highest OR per 1 SD was 1.56 (±0.09). The OR for AJ women at the top 10% of the PRS distribution compared with the middle quintile was 2.10 (±0.24). In the HMC cohort, the OR per 1 SD of the EUR-based PRS that performed best in the BCAC-IL cohort was 1.58±0.27. The OR per 1 SD of the commonly used 313-SNP BC PRS was 1.64 (±0.28).
Extant EUR GWAS data can be used for generating PRSs that identify AJ women with markedly elevated risk of BC and therefore hold promise for improving BC risk assessment in AJ women.
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