The avoiding late diagnosis of ovarian cancer (ALDO) project; a pilot national surveillance programme for women with pathogenic germline variants inBRCA1andBRCA2

Abstract

BackgroundOur study aimed to establish ‘real-world’ performance and cost-effectiveness of ovarian cancer (OC) surveillance in women with pathogenic germlineBRCA1/2variants who defer risk-reducing bilateral salpingo-oophorectomy (RRSO).MethodsOur study recruited 875 femaleBRCA1/2-heterozygotes at 13 UK centres and via an online media campaign, with 767 undergoing at least one 4-monthly surveillance test with the Risk of Ovarian Cancer Algorithm (ROCA) test. Surveillance performance was calculated with modelling of occult cancers detected at RRSO. The incremental cost-effectiveness ratio (ICER) was calculated using Markov population cohort simulation.ResultsOur study identified 8 OCs during 1277 women screen years: 2 occult OCs at RRSO (both stage 1a), and 6 screen-detected; 3 of 6 (50%) were ≤stage 3a and 5 of 6 (83%) were completely surgically cytoreduced. Modelled sensitivity, specificity, Positive Predictive Value (PPV) and Negative Predictive Value (NPV) for OC were 87.5% (95% CI, 47.3 to 99.7), 99.9% (99.9–100), 75% (34.9–96.8) and 99.9% (99.9–100), respectively. The predicted number of quality-adjusted life years (QALY) gained by surveillance was 0.179 with an ICER cost-saving of -£102,496/QALY.ConclusionOC surveillance for women deferring RRSO in a ‘real-world’ setting is feasible and demonstrates similar performance to research trials; it down-stages OC, leading to a high complete cytoreduction rate and is cost-saving in the UK National Health Service (NHS) setting. While RRSO remains recommended management, ROCA-based surveillance may be considered for femaleBRCA-heterozygotes who are deferring such surgery.

UK consensus recommendations for clinical management of cancer risk for women with germline pathogenic variants in cancer predisposition genes:RAD51C,RAD51D,BRIP1andPALB2

“…However, it remains unknown whether this surveillance would improve survival in screened high-risk patients 39. The recently published Avoiding Late Diagnosis of Ovarian Cancer (ALDO) project, evaluated the utility of ROCA in BRCA1 and BRCA2 carriers (not available at the time of the consensus meeting), confirmed previous research that although this approach cannot prevent ovarian cancer, in women who defer RRSO, it may facilitate detection of ovarian cancer at earlier stages, resulting in less complex surgery and reduced need for pre-op chemotherapy 40. Recent guidelines on the management of individuals with PALB2 GPV did not recommend OC surveillance 11.…”

Screening and prevention of ovarian cancer

“…29,30 The UK ALDO pilot study evaluated ROCA-based surveillance every four months in 767 BRCA1 and BRCA2 carriers across 12 centres in the UK. 31 ALDO demonstrated similar performance characteristics (sensitivity, specificity, negative predictive value, positive predictive value) of a Ca125 ROCA-based screening strategy in a real-world clinical setting to UKFOCSS phase 2, although the sample size and number of cancers detected were much smaller. Downstaging can lead to less radical surgery, with lesser morbidity and cost savings of poly (ADP-ribose) polymerase (PARP)-inhibitor treatment costs.…”

“…These trials include the UK Familial Ovarian Cancer Screening Study (UKFOCSS phase 1 27 and phase 2 28 ), the United States Cancer Genetics Network (CGN) and the Gynaecological Oncology Group (GOG) studies, 29,30 and the Avoiding Late Diagnosis of Ovarian Cancer (ALDO) pilot trial. 31 All these studies used a Ca125-based multimodal screening strategy, interpreted using the longitudinal Ca125 algorithm ROCA along with transvaginal ultrasound as a second line test. Annual screening using absolute serum Ca125 (single cutoff) and transvaginal ultrasound is not effective in women at high risk of ovarian cancer and is not recommended.…”

“…The evidence from key trials in ovarian cancer screening for average and high risk populations is summarised in Box 2. 3,21,22,[27][28][29]31,32 Data on ovarian cancer screening for women with Lynch syndrome are limited, as the aforementioned trials mainly recruited BRCA1 and BRCA2 carriers. In addition, Lynch syndrome-related ovarian cancer is biologically different to BRCA-related HGSOC, being less aggressive and predominantly early stage at clinical diagnosis.…”

“…Most of the evidence comes from prospective single‐arm interventional trials in women who have a lifetime risk of ovarian cancer of 10% or more, and included predominantly BRCA1 and BRCA2 carriers, but also women with a strong family history of ovarian cancer. These trials include the UK Familial Ovarian Cancer Screening Study (UKFOCSS phase 1 27 and phase 2 28 ), the United States Cancer Genetics Network (CGN) and the Gynaecological Oncology Group (GOG) studies, 29,30 and the Avoiding Late Diagnosis of Ovarian Cancer (ALDO) pilot trial 31 …”