Background An increasing number of breast cancer (BC) survivors are at risk of developing contralateral breast cancer (CBC). We aimed to investigate the influence of various adjuvant systemic regimens on, subtype-specific, risk of CBC. Methods This population-based cohort study included female patients diagnosed with first invasive BC between 2003 and 2010; follow-up was complete until 2016. Clinico-pathological data were obtained from the Netherlands Cancer Registry and additional data on receptor status through linkage with PALGA: the Dutch Pathology Registry. Cumulative incidences (death and distant metastases as competing risk) and hazard ratios (HRs) were estimated for all invasive metachronous CBC and CBC subtypes. Results Of 83 144 BC patients, 2816 developed a CBC; the 10-year cumulative incidence was 3.8% (95% confidence interval [CI] = 3.7% to 4.0%). Overall, adjuvant chemotherapy (HR = 0.70, 95% CI = 0.62 to 0.80), endocrine therapy (HR = 0.46, 95% CI = 0.41 to 0.52), and trastuzumab with chemotherapy (HR = 0.57, 95% CI = 0.45 to 0.73) were strongly associated with a reduced CBC risk. Specifically, taxane-containing chemotherapy (HR = 0.48, 95% CI = 0.36 to 0.62) and aromatase inhibitors (HR = 0.32, 95% CI = 0.23 to 0.44) were associated with a large CBC risk reduction. More detailed analyses showed that endocrine therapy statistically significantly decreased the risk of estrogen receptor (ER)-positive CBC (HR = 0.41, 95% CI = 0.36 to 0.47) but not ER-negative CBC (HR = 1.32, 95% CI = 0.90 to 1.93) compared with no endocrine therapy. Patients receiving chemotherapy for ER-negative first BC had a higher risk of ER-negative CBC from 5 years of follow-up (HR = 2.84, 95% CI = 1.62 to 4.99) compared with patients not receiving chemotherapy for ER-negative first BC. Conclusion Endocrine therapy, chemotherapy, as well as trastuzumab with chemotherapy reduce CBC risk. However, each adjuvant therapy regimen had a different impact on the CBC subtype distribution. Taxane-containing chemotherapy and aromatase inhibitors were associated with the largest CBC risk reduction.

BackgroundBreast cancer survivors are at risk for contralateral breast cancer (CBC), with the consequent burden of further treatment and potentially less favorable prognosis. We aimed to develop and validate a CBC risk prediction model and evaluate its applicability for clinical decision-making.MethodsWe included data of 132,756 invasive non-metastatic breast cancer patients from 20 studies with 4682 CBC events and a median follow-up of 8.8 years. We developed a multivariable Fine and Gray prediction model (PredictCBC-1A) including patient, primary tumor, and treatment characteristics and BRCA1/2 germline mutation status, accounting for the competing risks of death and distant metastasis. We also developed a model without BRCA1/2 mutation status (PredictCBC-1B) since this information was available for only 6% of patients and is routinely unavailable in the general breast cancer population. Prediction performance was evaluated using calibration and discrimination, calculated by a time-dependent area under the curve (AUC) at 5 and 10 years after diagnosis of primary breast cancer, and an internal-external cross-validation procedure. Decision curve analysis was performed to evaluate the net benefit of the model to quantify clinical utility.ResultsIn the multivariable model, BRCA1/2 germline mutation status, family history, and systemic adjuvant treatment showed the strongest associations with CBC risk. The AUC of PredictCBC-1A was 0.63 (95% prediction interval (PI) at 5 years, 0.52–0.74; at 10 years, 0.53–0.72). Calibration-in-the-large was -0.13 (95% PI: -1.62–1.37), and the calibration slope was 0.90 (95% PI: 0.73–1.08). The AUC of Predict-1B at 10 years was 0.59 (95% PI: 0.52–0.66); calibration was slightly lower. Decision curve analysis for preventive contralateral mastectomy showed potential clinical utility of PredictCBC-1A between thresholds of 4–10% 10-year CBC risk for BRCA1/2 mutation carriers and non-carriers.ConclusionsWe developed a reasonably calibrated model to predict the risk of CBC in women of European-descent; however, prediction accuracy was moderate. Our model shows potential for improved risk counseling, but decision-making regarding contralateral preventive mastectomy, especially in the general breast cancer population where limited information of the mutation status in BRCA1/2 is available, remains challenging.

This is a repository copy of Breast cancer polygenic risk score and contralateral breast cancer risk.

Our study aimed to provide a comprehensive overview of trends in incidence, survival, mortality and treatment of first primary invasive breast cancer (BC), according to age, stage and receptor subtype in the Netherlands between 1989 and 2017. Data from all women diagnosed with first primary stage I to IV BC (N = 320 249) were obtained from the Netherlands Cancer Registry. BC mortality and general population data were retrieved from Statistics Netherlands. Age‐standardised incidence and mortality rates were calculated with annual percentage change (APC) and average annual percentage change (AAPC) statistics. The relative survival (RS) was used as estimator for disease‐specific survival. The BC incidence for all BC patients combined significantly increased until 2013 from 126 to 158 per 100 000 person‐years, after which a declining trend was observed. Surgery became less extensive, but (neo‐)adjuvant systemic treatments and their combinations were given more frequently. The RS improved for all age groups and for most stages and receptor subtypes, but remained stable for all subtypes since 2012 to 2013 and since 2000 to 2009 for Stage IV BC at 15 years of follow‐up. Overall, the 5‐ and 10‐year RS increased from 76.8% (95% confidence interval [CI]: 76.1, 77.4) and 55.9% (95% CI: 54.7, 57.1) in 1989 to 1999 to 91.0% (95% CI: 90.5, 91.5) and 82.9% (95% CI: 82.2, 83.5), respectively, in 2010 to 2016. BC mortality improved regardless of age and overall decreased from 57 to 35 per 100 000 person‐years between 1989 and 2017. In conclusion, the BC incidence in the Netherlands has steadily increased since 1989, but the latest trends show promising declines. Survival improved markedly for most patients and the mortality decreased regardless of age.

Background Three tools are currently available to predict the risk of contralateral breast cancer (CBC). We aimed to compare the performance of the Manchester formula, CBCrisk, and PredictCBC in patients with invasive breast cancer (BC). Methods We analyzed data of 132,756 patients (4682 CBC) from 20 international studies with a median follow-up of 8.8 years. Prediction performance included discrimination, quantified as a time-dependent Area-Under-the-Curve (AUC) at 5 and 10 years after diagnosis of primary BC, and calibration, quantified as the expected-observed (E/O) ratio at 5 and 10 years and the calibration slope. Results The AUC at 10 years was: 0.58 (95% confidence intervals [CI] 0.57-0.59) for CBCrisk; 0.60 (95% CI 0.59-0.61) for the Manchester formula; 0.63 (95% CI 0.59-0.66) and 0.59 (95% CI 0.56-0.62) for PredictCBC-1A (for settings where BRCA1/2 mutation status is available) and PredictCBC-1B (for the general population), respectively. The E/O at 10 years: 0.82 (95% CI 0.51-1.32) for CBCrisk; 1.53 (95% CI 0.63-3.73) for the Manchester formula; 1.28 (95% CI 0.63-2.58) for PredictCBC-1A and 1.35 (95% CI 0.65-2.77) for PredictCBC-1B. The calibration slope was 1.26 (95% CI 1.01-1.50) for CBCrisk; 0.90 (95% CI 0.79-1.02) for PredictCBC-1A; 0.81 (95% CI 0.63-0.99) for PredictCBC-1B, and 0.39 (95% CI 0.34-0.43) for the Manchester formula. Conclusions Current CBC risk prediction tools provide only moderate discrimination and the Manchester formula was poorly calibrated. Better predictors and re-calibration are needed to improve CBC prediction and to identify low-and high-CBC risk patients for clinical decision-making.

We aimed to assess contralateral breast cancer (CBC) risk in patients with ductal carcinoma in situ (DCIS) compared with invasive breast cancer (BC). Women diagnosed with DCIS (N = 28,003) or stage I–III BC (N = 275,836) between 1989 and 2017 were identified from the nationwide Netherlands Cancer Registry. Cumulative incidences were estimated, accounting for competing risks, and hazard ratios (HRs) for metachronous invasive CBC. To evaluate effects of adjuvant systemic therapy and screening, separate analyses were performed for stage I BC without adjuvant systemic therapy and by mode of first BC detection. Multivariable models including clinico-pathological and treatment data were created to assess CBC risk prediction performance in DCIS patients. The 10-year cumulative incidence of invasive CBC was 4.8% for DCIS patients (CBC = 1334). Invasive CBC risk was higher in DCIS patients compared with invasive BC overall (HR = 1.10, 95% confidence interval (CI) = 1.04–1.17), and lower compared with stage I BC without adjuvant systemic therapy (HR = 0.87; 95% CI = 0.82–0.92). In patients diagnosed ≥2011, the HR for invasive CBC was 1.38 (95% CI = 1.35–1.68) after screen-detected DCIS compared with screen-detected invasive BC, and was 2.14 (95% CI = 1.46–3.13) when not screen-detected. The C-index was 0.52 (95% CI = 0.50–0.54) for invasive CBC prediction in DCIS patients. In conclusion, CBC risks are low overall. DCIS patients had a slightly higher risk of invasive CBC compared with invasive BC, likely explained by the risk-reducing effect of (neo)adjuvant systemic therapy among BC patients. For support of clinical decision making more information is needed to differentiate CBC risks among DCIS patients.

BACKGROUND: Hodgkin lymphoma (HL) survivors treated with chest radiotherapy have an increased risk of breast cancer (BC). Prior HL treatment and associated cardiovascular disease (CVD) risk may limit BC treatment options. It is unknown how treatment adaptations affect BC and CVD outcomes. METHODS: The authors compared 195 BC patients treated with chest/axillary radiotherapy for HL (BC-HL) with 5988 age-and calendar year-matched patients with first primary BC (BC-1). Analyses included cumulative incidence functions and Cox regression models, accounting for tumor characteristics and BC treatment. RESULTS: Compared to BC-1 patients, BC-HL patients received anthracycline-containing chemotherapy (23.7% vs. 43.8%, p < .001) and breast-conserving surgery followed by radiotherapy (7.1% vs. 57.7%, p < .001) less often. BC treatment considerations were reported for 71% of BC-HL patients. BC-HL patients had a significantly higher risk of 15-year overall mortality than BC-1 patients (61% vs. 23%). Furthermore, risks of BC-specific mortality and nonfatal BC events were significantly increased among BC-HL patients, also when accounting for tumor and treatment characteristics (2.2-to 4.5-fold). BC-HL patients with a screen-d etected BC had a significantly reduced (61%) BC-s pecific mortality. One-third of BC-H L patients had CVD at BCdiagnosis, compared to < 0.1% of BC-1 patients. Fifteen-year CVD-specific mortality and CVD incidence were significantly higher in BC-HL patients than in BC-1 patients (15.2% vs. 0.4% and 40.4% vs. 6.8%, respectively), which was due to HL treatment rather than BC treatment. CONCLUSIONS: BC-HL patients experience a higher burden of CVD and worse BC outcomes than BC-1 patients. Clinicians should be aware of increased CVD risk when selecting BC treatment for HL survivors.

Lobular primary breast cancer (PBC) histology has been proposed as a risk factor for contralateral breast cancer (CBC), but results have been inconsistent. We investigated CBC risk and the impact of systemic therapy in lobular versus ductal PBC. Further, CBC characteristics following these histologic subtypes were explored. We selected 74,373 women diagnosed between 2003 and 2010 with stage I‐III invasive PBC from the nationwide Netherlands Cancer Registry. We assessed absolute risk of CBC taking into account competing risks among those with lobular ( n = 8903), lobular mixed with other types ( n = 3512), versus ductal ( n = 62,230) histology. Hazard ratios (HR) for CBC were estimated in a cause‐specific Cox model, adjusting for age at PBC diagnosis, radiotherapy, chemotherapy and/or endocrine therapy. Multivariable HRs for CBC were 1.18 (95% CI: 1.04–1.33) for lobular and 1.37 (95% CI: 1.16–1.63) for lobular mixed versus ductal PBC. Ten‐year cumulative CBC incidences in patients with lobular, lobular mixed versus ductal PBC were 3.2%, 3.6% versus 2.8% when treated with systemic therapy and 6.6%, 7.7% versus 5.6% in patients without systemic therapy, respectively. Metachronous CBCs were diagnosed in a less favourable stage in 19%, 26% and 23% and less favourable differentiation grade in 22%, 33% and 27% than the PBCs of patients with lobular, lobular mixed and ductal PBC, respectively. In conclusion, lobular and lobular mixed PBC histology are associated with modestly increased CBC risk. Personalised CBC risk assessment needs to consider PBC histology, including systemic treatment administration. The impact on prognosis of CBCs with unfavourable characteristics warrants further evaluation.