br Methods br Results Changes in life

2. Methods
3. Results Changes in life expectancy associated with the two screening strategies (one-time and annual screening) across all study cohorts Digoxigenin-11-dUTP included in Table 2. One-time screening at age 50 for the primary cohort resulted in a LE gain of 3.9days. One-time screening in cohorts with affected FDRs had greater returns: 5.8days of life gained for BRCA2 carriers with one FDR, 9.1days with two FDRs, and 31.5days with three or more FDRs. Annual screening from ages 50–80 resulted in a LE loss of 12.9days for the primary cohort as well as a loss of 1.3days for BRCA2 carriers with one affected FDR. However, annual screening resulted in LE gains of 20.6days with two FDRs and 260.0days with three or more FDRs. Sensitivity analysis shows changes in LE gains when varying starting age for screening, over a range of 30–70, for each strategy. For the primary cohort, LE gains persisted for starting ages above 32 and peaked when applying a strategy of one-time screening at age 49 (Fig. 1). For cohorts with affected FDRs, the results are as follows: With one affected FDR, LE gains persisted for all starting ages and peaked with one-time screening at age 48 (Fig. 2a). With two FDRs, LE gains peaked with annual screening starting at age 52 (Fig. 2b). With three or more FDRs, LE gains peaked with annual screening starting at age 37 (Fig. 2c). Results were also sensitive to changes in MRI sensitivity. For the primary cohort, the values tested ranged from 25 to 100% (Fig. 3a, 50–100% graphed). The threshold value where one-time screening was no longer effective (i.e. resulted in LE loss) was when sensitivity was less than 27.7%. The threshold value where one-time screening was no longer superior to annual screening was when sensitivity was greater than 94.0%. For cohorts with affected FDRs, thresholds at which point one-time screening at age 50 was no longer effective were: 23.2%, 18.8%, and 15.8% for one, two, and three or more FDRs, respectively. Thresholds where one-time screening was no longer superior to annual screening were: 67.2%, 43.6%, and 16.4% for one, two, and three or more FDRs, respectively. Results were also sensitive to changes in MRI specificity. For the primary cohort, the values tested ranged from 50 to 100% (Fig. 3b, 90–100% graphed). The threshold value where one-time screening was no longer effective was when specificity was less than 93.6%. The threshold value where one-time screening was no longer superior to annual screening was when specificity was greater than 98.2%. For the cohorts with affected FDRs, thresholds at which point one-time screening at age 50 was no longer effective were: 91.8%, 88.6%, and 53.0% for one, two, and three or more FDRs, respectively. Thresholds where one-time screening was no longer superior to annual screening were: 97.6%, 96.6%, and 78.2% for one, two, and three or more FDRs, respectively. Results were also sensitive to changes in surgical mortality. For the primary cohort, the values tested ranged from to 10% (Fig. 3c, 0.0–2.5% graphed). One-time screening was no longer effective was when surgical mortality rates were greater than 2.3%. The threshold value for when one-time screening was no longer superior to annual screening was when surgical mortality was below 0.6%. For the cohorts with affected FDRs, thresholds at which point one-time screening at age 50 was no longer effective were: 3.0% and 4.2% for one and two FDRs, respectively, and the threshold was above 10% for three or more FDRs. Thresholds where one-time screening was no longer superior to annual screening were: 0.8%, 1.2%, and 8.1% for one, two and three or more FDRs, respectively.
4. Discussion We found that one-time screening of BRCA2 mutation carriers can increase life expectancy. Despite heightened PAC risk in this cohort, more aggressive screening at regular intervals may result in diminished life expectancy. This finding can be attributed to a phenomenon that is increasingly recognized in cancer screening initiatives: an increased number of false-positive results, which can occur when healthy patients are screened repeatedly, can lead to more harm than benefit. This is particularly important in the setting of PAC, given the relatively high morbidity and mortality risks of pancreatic surgery. When we evaluated subsets of BRCA2 mutation carriers with varying numbers of FDRs, we found that only those with multiple FDRs (two or more) would benefit from annual screening. Conversely, high-risk BRCA2 mutation carriers with three or more FDRs might benefit from an even earlier starting age for screening. In this setting, PAC risk is high enough that the benefits of increased screening frequency outweigh the harms. In addition to the burden of false-positive results, the benefit of screening is significantly limited, even in high risk individuals, by the poor efficacy of PAC treatment, an area of medicine in dire need of improvement. Five year survival for patients with PAC diagnosed at an early stage and who undergo successful resection with clear surgical margins (R0 resection) remains low at <20% (Wagner et al., 2004). Even within this select group, over 80% of PAC tumors recur with metastatic disease, as many of these patients already have micrometastases at diagnosis that are not detectable by current imaging modalities (Garrido-Laguna and Hidalgo, 2015). Promising new adjuvant and neoadjuvant therapeutic regimens may improve survival for early stage PAC patients(Neoptolemos et al., 2010; Oettle et al., 2007) and could significantly alter the calculus for screening benefit in the near future.