Annual screening strategies in BRCA1 and BRCA2 gene mutation carriers: a comparative effectiveness analysis

Abstract

Background: Although breast cancer screening with mammography and magnetic resonance imaging (MRI) is recommended for breast cancer-susceptibility gene (BRCA) mutation carriers, there is no current consensus on the optimal screening regimen.

Methods: The authors used a computer simulation model to compare 6 annual screening strategies (film mammography [FM], digital mammography [DM], FM and magnetic resonance imaging [MRI] or DM and MRI contemporaneously, and alternating FM/MRI or DM/MRI at 6-month intervals) beginning at ages 25 years, 30 years, 35 years, and 40 years, and 2 strategies of annual MRI with delayed alternating DM/FM versus clinical surveillance alone. Strategies were evaluated without and with mammography-induced breast cancer risk using 2 models of excess relative risk. Input parameters were obtained from the medical literature, publicly available databases, and calibration.

Results: Without radiation risk effects, alternating DM/MRI starting at age 25 years provided the highest life expectancy (BRCA1, 72.52 years, BRCA2, 77.63 years). When radiation risk was included, a small proportion of diagnosed cancers was attributable to radiation exposure (BRCA1, <2%; BRCA2, <4%). With radiation risk, alternating DM/MRI at age 25 years or annual MRI at age 25 years/delayed alternating DM at age 30 years was the most effective, depending on the radiation risk model used. Alternating DM/MRI starting at age 25 years also produced the highest number of false-positive screens per woman (BRCA1, 4.5 BRCA2, 8.1).

Conclusions: Annual MRI at age 25 years/delayed alternating DM at age 30 years is probably the most effective screening strategy in BRCA mutation carriers. Screening benefits, associated risks, and personal acceptance of false-positive results should be considered in choosing the optimal screening strategy for individual women.

Figure 1

A–1B. Projected life expectancy for annual screening strategies in BRCA1 (1A) and BRCA2 (1B) mutation carriers in the absence of radiation risk. For both populations, alternating DM with MRI produced the highest life expectancy at all ages of screening initiation, and the highest LE was achieved with alternating DM with MRI starting at age 25.

Figure 2

Cumulative incidence of breast cancer (BC) in the alternating DM with MRI strategy starting at age 25. When compared to no screening, the cumulative incidence of BRCA1 cancers increased from 66.1% (without radiation risk, top dashed line) to 71.2% (light blue line). BRCA2 cancers increased from 54.0% (without radiation risk, bottom dashed line) to 57.0% (green line). When radiation effects were included, <2% of diagnosed cancers can be attributed to radiation exposure, using both Attained-Age (AA, pink and brown lines) and Age-At-Exposure (AE) models (navy and yellow lines).

Figures 3

A–D. Efficiency frontiers for BRCA1 AA (3A) and AE (3B) models, and for BRCA2 AA (3C) and AE (3D) models. The strategies that maximized LE for a given level of FP screens are considered efficient and connected by the solid line. Open circles indicate dominated strategies. Strategies are notated as modality (age at first screen). Ann = Annual, Alt = Alternating at six month intervals, DM = Digital Mammography.

Figures 3

A–D. Efficiency frontiers for BRCA1 AA (3A) and AE (3B) models, and for BRCA2 AA (3C) and AE (3D) models. The strategies that maximized LE for a given level of FP screens are considered efficient and connected by the solid line. Open circles indicate dominated strategies. Strategies are notated as modality (age at first screen). Ann = Annual, Alt = Alternating at six month intervals, DM = Digital Mammography.

Figures 3

A–D. Efficiency frontiers for BRCA1 AA (3A) and AE (3B) models, and for BRCA2 AA (3C) and AE (3D) models. The strategies that maximized LE for a given level of FP screens are considered efficient and connected by the solid line. Open circles indicate dominated strategies. Strategies are notated as modality (age at first screen). Ann = Annual, Alt = Alternating at six month intervals, DM = Digital Mammography.

Figures 3

A–D. Efficiency frontiers for BRCA1 AA (3A) and AE (3B) models, and for BRCA2 AA (3C) and AE (3D) models. The strategies that maximized LE for a given level of FP screens are considered efficient and connected by the solid line. Open circles indicate dominated strategies. Strategies are notated as modality (age at first screen). Ann = Annual, Alt = Alternating at six month intervals, DM = Digital Mammography.

Figure 4

A–4B. Influential parameters and effect on life expectancy (LE) gain, alternating DM/MRI at age 25 vs. annual DM alone at age 25. Results are presented in decreasing order of LE gain variation, with lifetime breast cancer risk estimates being the most influential factor in estimating LE gains from multimodality screening in both BRCA1 and BRCA2 carriers. Vertical axes represent the LE gain in the base case (BRCA1 = 0.49 years, BRCA2 = 0.26 years). DM = Digital Mammography, ERR = Excess Relative Risk.

Figure 4

A–4B. Influential parameters and effect on life expectancy (LE) gain, alternating DM/MRI at age 25 vs. annual DM alone at age 25. Results are presented in decreasing order of LE gain variation, with lifetime breast cancer risk estimates being the most influential factor in estimating LE gains from multimodality screening in both BRCA1 and BRCA2 carriers. Vertical axes represent the LE gain in the base case (BRCA1 = 0.49 years, BRCA2 = 0.26 years). DM = Digital Mammography, ERR = Excess Relative Risk.