Prediction and clinical utility of a contralateral breast cancer risk model

Abstract

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.

Prediction of contralateral breast cancer: external validation of risk calculators in 20 international cohorts

“…Of these, 16 non-familial BC BCAC studies including invasive non-metastatic European-descent female patients with first primary invasive BC diagnosed from 1990 onwards, and with at least 10 CBC events, were included in the analyses [14]. Details about studies and patient selection, and data imputation were described previously [5].…”

“…The predictors included in the CBC risk estimation in the Manchester formula, CBCrisk and PredictCBC models are provided in Table 1. Predictors that were sporadically missing were multiply imputed as described elsewhere [5].…”

“…A rising number of women with breast cancer (BC) are at risk to develop a new primary tumor in the contralateral breast (CBC) with consequently another cancer treatment and potentially less favorable prognosis [1]. Although CBC incidence is low (~ 0.4% per year) in the general BC population, contralateral preventive mastectomy (CPM) is increasing, also among women with low-CBC risk [2][3][4][5].…”

“…Third, PredictCBC was developed, cross-validated and evaluated using data from 132,756 patients with first BC and 4672 CBC events, as part of an international collaboration [5]. PredictCBC predicts CBC risk as a function of family history (first degree) of primary BC, and information of primary BC diagnosis: age, nodal status, size, grade, morphology, ER status, human epidermal growth factor receptor 2 (HER2) status, administration of adjuvant or neoadjuvant chemotherapy, adjuvant endocrine therapy, adjuvant trastuzumab therapy, and radiotherapy.…”

“…PredictCBC predicts CBC risk as a function of family history (first degree) of primary BC, and information of primary BC diagnosis: age, nodal status, size, grade, morphology, ER status, human epidermal growth factor receptor 2 (HER2) status, administration of adjuvant or neoadjuvant chemotherapy, adjuvant endocrine therapy, adjuvant trastuzumab therapy, and radiotherapy. Two versions were developed: PredictCBC version 1A includes presence or absence of a mutation in the BRCA1 or BRCA2 genes, an important determinant of CBC [5,11,12], while PredictCBC version 1B was developed for untested patients.…”