A total of 14,311 women without BC, born between 1920 and 2003 (median: 1966), had their risk of BC assessed (Figure 1). Age at entry ranged from 16-81 years (median=39.9; IQR=33.9-46.9). Detailed study population characteristics are described (Table-1) according to final known genetic status. Seven-hundred-and-thirty-six women (5.1%) have been identified as BRCA PV carriers (BRCA1=364, BRCA2=372)–Table 1. Two-hundred-and-seventy-two (37.0%) of these were referred into the FHRPC as known PV carriers unaffected by BC. The remainder were identified after clinic entry (Figure-1). As such 298/14,311 (2.1%) were identified as BRCA PV carriers with no known PV in the family at clinic entry. Overall BRCA testing in the individual woman or affected family member has completed in 4168(29.1%) clinic attenders. Of 649 women with BC, 539-(83.1%) had known BRCA status.
There have been 129,119.5 women-years follow up with 649 BCs (588 post-prevalent), resulting in annual incidence of 4.55/1,000. This excluded 45 prevalent asymptomatic screen detected cancers (0.31%) and a further sixteen women who developed symptomatic BC between referral and clinic attendance. Therefore, there were 61 total prevalent cancers (0.43%-61/14311). Within the enhanced screening programme there were 63972.4 years follow up, 349 (2.4%) women developed BC following prevalence screen (incidence=5.46/1000). Four-hundred-and-fifty-five women (455/14311-3.2%) have undergone pre-symptomatic BRRM with seven occult BCs (1.5%) diagnosed at surgery. The remaining 239 cancers occurred after clinic discharge making a total of 255 (including 16 pre-prevalent scan) off programme. Breast cancer incidence by risk group is shown in table 2. Incidence post prevalence in BRCA1 was 1.73% and in BRCA2 1.55% annually from date of mutation report. The low rate in untested women reflects those at 25% risk and very young women prior to testing. Carriers of known PVs in other genes were included in the lifetime risk category known at entry due to low numbers.
The age and known PV carrier status of the women with BCs are shown in table-3. Cancer pathology on the FHRPC enhanced screening programme is shown in table-4. BRCA1-related BCs were more likely grade 3 and oestrogen receptor negative (ER-) than cases in the high-risk BRCA negative cohort as expected (p<0.0001 for both). Tumours from women who tested BRCA PV negative in the high-risk cohort were more likely to be grade 1 than both BRCA1 (p<0.001) and BRCA2 (p=0.04) tumours. Only 36/394 (9%) women with cancers in the enhanced screening programme had no genetic testing compared with 84/255 (32.9%) of those off programme. Of the cancers in the enhanced screening programme 70 (17.9%) were carcinoma in situ (CIS) with a higher proportion seen on prevalent screen (33.3%- supplementary-table-1). The majority of invasive cancers were LN negative (72.9%), small (≤20mm-73.2%) and stage-1 (61.4%). BRCA1/BRCA2 PV associated cancers were smaller overall with 75.0% and 85.4% being ≤20mm respectively, potentially reflecting MRI screening in these groups. Overall deaths were lower in women screened on the enhanced-programme (13.8%) compared with off-programme (20.8%)-(Table-3), although off-programme women were older. Of the deaths with BRCA1/2 PVs, 7/16 were unrelated to BC; BRCA1-4/8 (ovarian(n=2), carcinosarcoma uterus(n=1),pancreatic(n=1)) BRCA2-3/8 (ovarian,lung cancer,old-age). Only one each BRCA1 and BRCA2 deaths in carriers were BC related in women on MRI screening (2/38). In total 34/54(63%) of deaths in women with cancers detected in the enhanced screening programme were BC related.
BC deaths, as expected, were more frequent in women with symptomatic interval cancers (supplementary-table-1,Figure 2a). Incident screen detected 10-year survival was 91.9%-(95% CI=86.7–95.1) vs interval 80.2% (95%CI=68.6–87.9) (p<0.001); prevalence screen survival 94.5%-(95%CI=79.8–98.6) vs incidence screen (p=0.052). The pathologies with the highest proportion of BC deaths were lobular (23.3%,10-year survival=85.9%(95%CI=66.7–94.5)) triple negative (14.3%;10-year-survival=83.5% (95%CI=72.7–90.3)) and high-grade ER+HER2- cancers (13.0%;10-year-survival=88.5%(95%CI=74.3–95.1)) although numbers in each group were relatively small limiting statistical comparison. As expected, the lowest proportion of BC specific deaths was noted in those with grade-1 tumours (2.4%; 10-year-survival=95.5%(95%CI=70.7–99.3)) and CIS (2.8%;10-year-survival=98.2%(95%CI=87.6–99.7)), although BC specific survival was also excellent in grade-2 ER+HER2- BC (10-year-survival=95.1%(95%CI=85.3–98.4). Nearly all triple negative BC deaths occurred in the first 5-years-(Figure 2b).
Although overall survival was worse in those diagnosed >50 years (10-year=83.5%-≤40 years-10-year=93.5%,p=0.04; 41-50 years-10-year=88.8%,p=0.025-Supplementary figure-1), BC specific survival was virtually identical for all age groups, with 10-year ≤40years survival 93.8% (95%CI=84.2–97.6-supplementary-table-1; Figure-2c). For the ≤40years group with invasive BC (n=58), 5, 10 and 20-year overall survival was 92.2% (80.5-97.0), 92.2% (80.5-97.0) and 79.9% (59.9-90.6). Survival was not significantly different between BRCA1, BRCA2 and non-BRCA carriers on enhanced screening (Figure-2d) with 20-year BC specific survival particularly good in 60 BRCA1 carriers at 91.5%-(78.5–96.8) compared to 59 BRCA2 at 85.1%-(64.1–94.3) and 275 non-BRCA 84.7%-(76.5–90.3). The BRCA2 survival curve crossed over BRCA1 after 10 years. Only 51 BRCA carriers were aware of their status at BC diagnosis. Kaplan-Meier curves comparing BRCA PV carriers who knew their status at diagnosis versus those who did not and BRCA carriers who had MRI versus those who only had mammography are shown in Supplementary Figures 2&3. Survival in the known carriers and MRI screened (90.6%, 95%CI=80.3-95.7%) and 90.1% (95%CI=62.6– 97.7%) 10-year survival respectively), but this was not significantly better than the controls who did not know their status (94.8%; 95%CI=68.0-93.2%) and those not undergoing MRI (87.0%: 95%CI=80.6–94.8%). We also carried out a time dependency analysis and this did not show any advantage to knowing the BRCA status (Supplementary-Figure-4)
Five and 10-year BC specific survival in those with BC detected on programme vs off programme screening was:5-year 94.1%-(95%CI=91.0–96.1) vs 94.3%-(95%CI=90.5-96.6) and 10-year 91.0%-(95%CI=87.2–93.7) vs 90.4%-(95%CI=85.7–93.4) respectively.