Purpose To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2... Show morePurpose To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes. Methods We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk. Results For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS313 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively. Conclusion The PRS313 can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS313 needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making. Show less
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... Show moreBackground 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. Show less
Background: Breast 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... Show moreBackground: Breast 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.Methods: We 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.Results: In 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.Conclusions: We 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. Show less
Peripheral blood mononuclear cells (MNC) enhance cardiac recovery and repair after myocardial infarction (MI). The SDF-1α/CXCR4 axis plays a major role in cell homing to infarcted myocardium and is... Show morePeripheral blood mononuclear cells (MNC) enhance cardiac recovery and repair after myocardial infarction (MI). The SDF-1α/CXCR4 axis plays a major role in cell homing to infarcted myocardium and is negatively regulated by CD26. Therefore, we studied the expression of CD26 during MI and its effects on cardiac function. Blood samples from forty-two patients who underwent a primary percutaneous coronary intervention (PCI) for a first ST-elevated MI were collected during primary PCI, 1 week and 3 months after MI. Soluble CD26 (sCD26) and membrane bound CD26 expression on MNCs (mncCD26) were determined. Left ventricular function and infarct size were measured within 1 day, 1 week and 3 months follow up by magnetic resonance imaging. One week post MI, sCD26 was down regulated compared to baseline, while mncCD26 was higher at baseline and 1 week compared to 3 months. Increased mncCD26 expression at 1 week after MI was associated with decreased overall recovery of left ventricular function as measured by left ventricular end systolic volume index. Furthermore, the in vitro migration capacity of MNCs to SDF-1α was decreased 1 week post MI and the migration capacity to SDF-1α was negatively correlated with mncCD26 expression. CD26 inhibition with sitagliptin - a drug currently used in diabetic patients - resulted in improved in vitro migration capacities of MNCs. In conclusion, our preliminary results suggest that high cellular CD26 expression decreases the migration of MNCs towards SDF-1α and high cellular CD26 expression negatively influences cardiac function post MI. Treating patients shortly post MI with sitagliptin to inhibit CD26 may therefore increase MNC homing to the infarct area and could improve cardiac recovery and repair. Show less
Post, S.; Smits, A.M.; Broek, A.J. van den; Sluijter, J.P.G.; Hoefer, I.E.; Janssen, B.J.; ... ; Goumans, M.J. 2010
Aims Mononuclear cells (MNCs) from patients with hereditary haemorrhagic telangiectasia type 1 (HHT1), a genetic disorder caused by mutations in endoglin, show a reduced ability to home to... Show moreAims Mononuclear cells (MNCs) from patients with hereditary haemorrhagic telangiectasia type 1 (HHT1), a genetic disorder caused by mutations in endoglin, show a reduced ability to home to infarcted mouse myocardium. Stromal cell-derived factor-1a (SDF-1 alpha) and the chemokine receptor CXCR4 are crucial for homing and negatively influenced by CD26. The aim of this study was to gain insight into the impaired homing of HHT1-MNCs. Methods and results CXCR4 and CD26 expression on MNCs was determined by flow cytometry. Transwell migration to SDF-1 alpha was used to analyse in vitro migration. Experimentally induced myocardial infarction in mice, followed by tail vein injection of MNCs, was applied to study homing in vivo. HHT1-MNCs expressed elevated levels of CXCR4, but this was counterbalanced by high levels of CD26, resulting in decreased migration towards an SDF-1 alpha gradient in vitro. Migration was enhanced by inhibiting CD26 with Diprotin-A. While MNCs from healthy controls responded to transforming growth factor-beta stimulation by increasing CXCR4 and lowering CD26 expression levels, HHT1-MNCs did not react as efficiently: in particular, CD26 expression remained high. Inhibiting CD26 on MNCs increased the homing of human cells into the infarcted mouse heart. Interestingly, the defect in homing of HHT1-MNCs was restored by pre-incubating the HHT1-MNCs with Diprotin-A before injection into the tail vein. Conclusion We show that a decreased homing of HHT1-MNCs is caused by an impaired ability of the cells to respond to SDF-1 alpha. Our results suggest that modulating CD26 levels using inhibitors like Diprotin-A can restore homing in cases where increased expression of CD26 contributes to the underlying pathological mechanism. Show less