Prediction and clinical utility of a contralateral breast cancer risk model

TY - JOUR

T1 - Prediction and clinical utility of a contralateral breast cancer risk model

AU - Giardiello, Daniele

AU - Steyerberg, Ewout W

AU - Hauptmann, Michael

AU - Adank, Muriel A

AU - Akdeniz, Delal

AU - Blomqvist, Carl

AU - Bojesen, Stig E

AU - Bolla, Manjeet K

AU - Brinkhuis, Mariël

AU - Chang-Claude, Jenny

AU - Czene, Kamila

AU - Devilee, Peter

AU - Dunning, Alison M

AU - Easton, Douglas F

AU - Eccles, Diana M

AU - Fasching, Peter A

AU - Figueroa, Jonine

AU - Flyger, Henrik

AU - García-Closas, Montserrat

AU - Haeberle, Lothar

AU - Haiman, Christopher A

AU - Hall, Per

AU - Hamann, Ute

AU - Hopper, John L

AU - Jager, Agnes

AU - Jakubowska, Anna

AU - Jung, Audrey

AU - Keeman, Renske

AU - Kramer, Iris

AU - Lambrechts, Diether

AU - Le Marchand, Loic

AU - Lindblom, Annika

AU - Lubiński, Jan

AU - Manoochehri, Mehdi

AU - Mariani, Luigi

AU - Nevanlinna, Heli

AU - Oldenburg, Hester S A

AU - Pelders, Saskia

AU - Pharoah, Paul D P

AU - Shah, Mitul

AU - Siesling, Sabine

AU - Smit, Vincent T H B M

AU - Southey, Melissa C

AU - Tapper, William J

AU - Tollenaar, Rob A E M

AU - van den Broek, Alexandra J

AU - van Deurzen, Carolien H M

AU - van Leeuwen, Flora E

AU - van Ongeval, Chantal

AU - Van't Veer, Laura J

AU - Wang, Qin

AU - Wendt, Camilla

AU - Westenend, Pieter J

AU - Hooning, Maartje J

AU - Schmidt, Marjanka K

PY - 2019/12/17

Y1 - 2019/12/17

N2 - 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.

AB - 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.

KW - Area Under Curve

KW - BRCA1 Protein/genetics

KW - BRCA2 Protein/genetics

KW - Breast Neoplasms/epidemiology

KW - Clinical Decision-Making

KW - Disease Management

KW - Disease Susceptibility

KW - Female

KW - Germ-Line Mutation

KW - Humans

KW - Neoplasms, Second Primary/epidemiology

KW - Netherlands/epidemiology

KW - Prognosis

KW - Proportional Hazards Models

KW - Risk Assessment

KW - Risk Factors

U2 - 10.1186/s13058-019-1221-1

DO - 10.1186/s13058-019-1221-1

M3 - SCORING: Journal article

C2 - 31847907

VL - 21

SP - 144

JO - BREAST CANCER RES

JF - BREAST CANCER RES

SN - 1465-5411

IS - 1

ER -