Journal Article

Prediction and clinical utility of a contralateral breast cancer risk model

van den Broek, Alexandra J., Manoochehri, Mehdi, Hopper, John L., van Ongeval, Chantal, Blomqvist, Carl, Giardiello, Daniele, Jung, Audrey, Easton, Douglas F., Figueroa, Jonine, Jager, Agnes, Haeberle, Lothar, Brinkhuis, Mariël, Siesling, Sabine, van Deurzen, Carolien H. M., Wendt, Camilla, Hall, Per, Lindblom, Annika, Tapper, William J., van Leeuwen, Flora E., Fasching, Peter A., Jakubowska, Anna, Kramer, Iris, Schmidt, Marjanka K., Adank, Muriel A., Wang, Qin, García-Closas, Montserrat, Dunning, Alison M., Oldenburg, Hester S. A., Pharoah, Paul D. P., Smit, Vincent T. H. B. M., Hauptmann, Michael, Eccles, Diana M., Lubiński, Jan, Bojesen, Stig E., Tollenaar, Rob A. E. M., Akdeniz, Delal, Chang-Claude, Jenny, Nevanlinna, Heli, Lambrechts, Diether, Steyerberg, Ewout W., Hooning, Maartje J., Czene, Kamila, Haiman, Christopher A., Pelders, Saskia, Devilee, Peter, Le Marchand, Loic, Flyger, Henrik, Bolla, Manjeet K., Van’t Veer, Laura J., Mariani, Luigi, Southey, Melissa C., Hamann, Ute, Keeman, Renske, Westenend, Pieter J., Shah, Mitul

2019

Overview

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 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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Accounting / Area Under Curve / Biomedical and Life Sciences / Biomedicine / BRCA mutation carriers / BRCA1 protein / BRCA1 Protein - genetics / BRCA2 Protein - genetics / Breast cancer / Breast Neoplasms - epidemiology / Breast Neoplasms - etiology / Breast Neoplasms - pathology / Breast Neoplasms - therapy / Calibration / Cancer metastasis / Cancer patients / Cancer Research / Cancer survivors / Cancer therapies / Care and treatment / Chemotherapy / Clinical Decision-Making / Clinical medicine / Contralateral breast cancer / Death / Decision making / Disease Management / Disease Susceptibility / Endocrine therapy / Family medical history / Female / Gene mutation / Germ-Line Mutation / Health aspects / Humans / Invasiveness / Mammography / Medical prognosis / Medical research / Metastases / Metastasis / Mutation / Neoplasms, Second Primary - epidemiology / Neoplasms, Second Primary - etiology / Neoplasms, Second Primary - pathology / Neoplasms, Second Primary - prevention & control / Netherlands - epidemiology / Oncology / Parameter estimation / Patients / Prediction models / Prognosis / Proportional Hazards Models / Research Article / Risk Assessment / Risk Factors / Risk prediction model / Skin cancer / Studies / Surgery / Surgical Oncology / Tumors