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Effectiveness of 6 monthly MRI screening for breast cancer in women with a BRCA mutation – a numerical simulation.1VU University Medical Center, Amsterdam, Netherlands, 2ZGT Hengelo, Hengelo, Netherlands, 3University Medical Center Groningen, Groningen, Netherlands, 4Radboud University Medical Center, Nijmegen, Netherlands
Synopsis
Currently, MRI screening for breast cancer in women with a BRCA mutation is annually. However, studies on tumour doubling times indicate that some tumours grow faster. To assess the value of more frequent screening we numerically simulated annual and 6 monthly screening based on reported tumour doubling times in women with the BRCA mutation. For annual screening, the simulation predicted 14% of cancers with poor prognosis (diameter > 2 cm), in line with clinical studies. For 6 monthly screening the simulation predicted 3% with poor prognosis. Therefore, 6 monthly screening should yield a substantial reduction in tumours with a poor prognoses .
Introduction
The current practice in screening women at high risk for breast cancer, including women with a BRCA mutation, is annual MRI and, in women over 30, mammography [KuhlCK2005, LeacHMO2005, WarnerE2008, KuhlCK2010, BoetesC2011, SardanelliF2011, WarnerE2011, BergWA2012, PassaperumaK2012, ChiarelliAM2014, ObdeijnIM2014]. No clinical studies with more frequent MRI screening have been published. However, a study found that tumour volume doubling times in women with the BRCA mutation may be as fast as one month [TilanusLinthorstMM2007]. Studies with 6 monthly ultrasound have had limited success as these cancers are difficult to detect with ultrasound [BosseK2014, RiedlCC2015, ZelstJCM2017]. A numerical simulation based on reported tumour doubling times for the BRCA mutation is used to predict the reduction in tumours with poor prognosis (diameter > 2 cm ) by increasing the MRI screening frequency from annually to 6 monthly.Methods
The simulation is based only on two pieces of information: 1) the doubling times of typical BRCA related cancers taken from Tilanus-Linthorst et al. 2007 and 2) that cancers smaller than 0.5 cm diameter cannot be reliably detected on MRI [LibermanL2006]. Tilanus-Linthorst et al. presented tumour volume doubling times in 58 patients with BRCA mutation, shown in Figure 1. For MRI detectability diameter doubling times are relevant, which is equivalent to 3 volume-doubling times. As the cancers below 0.5 cm in diameter cannot be detected reliably with MRI, the starting point of growth in the simulation for each cancer was 0.5 cm. It was assumed that all cancers above 0.5 cm in size can always be detected by MRI. This assumption is reasonable as the large cancers that yield a poor prognosis are easily detected with MRI.
The equation used in the simulation for the diameter (D) of a tumour at detection is
D = 0.5*2^( GT/(3*DT) )
where DT is the volume doubling time and GT is the growth time. The GT is a random variable with a uniform distribution with a range of (0, 0.5) for 6 monthly screening and (0, 1.0) for yearly screening. The units are years.
The simulation was run 10,001 times for the set of the 58 doubling times for each of 6 monthly and annual screening. The Java code for the simulation is listed in Figure 1 including the numerical values of the 58 doubling times.
Results
A histogram of the volume doubling time used in the simulation is shown in Figure 2. The most common volume doubling time is centred around 0.15 years, which doubles the diameter of a malignancy about every 6 months. A few of the cancers quadruple their diameter in 6 months.
The output of the numerical simulation is provided in Table 1 including the 95% confidence intervals. The occurrence for tumours found at a screening instant with a diameter greater than 2 cm, dropped from 14% (95% CI: 7% to 21%) for annual screening to 3% (95% CI: 0% to 7%) for 6 monthly MRI screening.
Discussion
A BRCA gene mutation has been inherited by 1-4% of women. The risk of developing breast cancer is estimated to be 27% to 80% up to 70 years of age [BroekAJ2015].
Table 1 shows that the clinical and simulation results for annual screening match reasonably well especially for diameters greater than 2 cm. The slightly poorer match for diameters less than 1 cm may be due to the limited sensitivity of MRI for smaller tumours.
While doubling the screening frequency could be expected to double the cost, this is probably not the case. Recent developments in abbreviated MRI screening protocols [KuhlCK2014, HeacockL2016, MachidaY2016, MangoVL2016, MoschettaM2016], including standalone ultrafast sequences [BoetesC1994, SardanelliF2000, SaranathanM2012, LeY2012, MannRM2014, PlatelB2014, AbeH2016, MusRD2017], promise to at least half the cost of each MRI screen for breast cancer. Therefore, the annual costs of future 6 monthly screenings using an abbreviated protocol should be no more than current annual screening.
Conclusion
Increasing the MRI screening of women with the BRCA mutation from annually to every 6 months will reduce the frequency of cancer detection with a poor prognosis (diameter > 2 cm) from 14% to 3%.Acknowledgements
Funded by Cancer Center Amsterdam.References
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