Geertruida H. de Bock

High-Grade Serous Carcinoma at Risk-Reducing Salpingo-Oophorectomy in Asymptomatic Carriers of BRCA1/2 Pathogenic Variants: Prevalence and Clinical Factors

PURPOSE To investigate the prevalence of and clinical factors associated with high-grade serous carcinoma (HGSC) at risk-reducing salpingo-oophorectomy (RRSO) in asymptomatic BRCA1/2-pathogenic variant (PV) carriers. PATIENTS AND METHODS We included BRCA1/2-PV carriers who underwent RRSO between 1995 and 2018 from the Hereditary Breast and Ovarian cancer in the Netherlands study. All pathology reports were screened, and histopathology reviews were performed for RRSO specimens with epithelial abnormalities or where HGSC developed after normal RRSO. We then compared clinical characteristics, including parity and oral contraceptive pill (OCP) use, for women with and without HGSC at RRSO. RESULTS Of the 2,557 included women, 1,624 had BRCA1, 930 had BRCA2, and three had both BRCA1/2-PV. The median age at RRSO was 43.0 years (range: 25.3-73.8) for BRCA1-PV and 46.8 years (27.6-77.9) for BRCA2-PV carriers. Histopathologic review confirmed 28 of 29 HGSCs and two further HGSCs from among 20 apparently normal RRSO specimens. Thus, 24 (1.5%) BRCA1-PV and 6 (0.6%) BRCA2-PV carriers had HGSC at RRSO, with the fallopian tube identified as the primary site in 73%. The prevalence of HGSC in women who underwent RRSO at the recommended age was 0.4%. Among BRCA1/2-PV carriers, older age at RRSO increased the risk of HGSC and long-term OCP use was protective. CONCLUSION We detected HGSC in 1.5% ( BRCA1-PV) and 0.6% ( BRCA2-PV) of RRSO specimens from asymptomatic BRCA1/2-PV carriers. Consistent with the fallopian tube hypothesis, we found most lesions in the fallopian tube. Our results highlight the importance of timely RRSO with total removal and assessment of the fallopian tubes and show the protective effects of long-term OCP.

High-grade serous carcinoma occurring after risk-reducing salpingo-oophorectomy in BRCA1/2 germline pathogenic variant carriers

Abstract Background Risk-reducing salpingo-oophorectomy (RRSO) effectively prevents high-grade serous carcinoma (HGSC) in BRCA1/2 germline pathogenic variant (GPV) carriers. Still, some women develop HGSC after RRSO without pathological findings. This study assessed long-term incidence and risk factors for developing HGSC after RRSO without pathological findings. Methods BRCA1/2 GPV carriers were selected from the Hereditary Breast and Ovarian cancer in the Netherlands (HEBON) cohort. Follow-up data for HGSC after RRSO were obtained from the Dutch Nationwide Pathology Databank (PALGA) and confirmed by histopathological review. Cumulative incidence rates of HGSC were calculated using Kaplan-Meier analyses. A Cox proportional hazards model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) for factors associated with an increased risk of HGSC after RRSO without pathological findings. Results A total of 2519 women were included, with a median follow-up of 13.4 years (range: 0.0-27.6 years). The 20-year cumulative incidence rate of HGSC was 1.5% (95% CI = 0.0 to 2.1) for BRCA1 and 0.2% (95% CI = 0.0 to 1.4) for BRCA2 GPV carriers. All women who developed HGSC underwent RRSO after the recommended age. Incomplete embedding of the RRSO specimen (HR = 4.2, 95% CI = 1.4 to 12.6), higher age at RRSO (HR per year = 1.1, 95% CI = 1.0 to 1.1), and carrying a BRCA1 GPV (HR = 12.1, 95% CI = 1.6 to 91.2) were associated with increased risk of HGSC. Conclusions In BRCA1/2 GPV carriers, long-term incidence of HGSC after RRSO without pathological findings was low. Strict adherence to guidelines regarding timely RRSO followed by complete specimen embedding can further reduce the risk of HGSC in the years after RRSO.

High-risk human papillomavirus testing for underscreened populations: cost-effectiveness and affordability in three country settings

The high-risk human papillomavirus (hrHPV)-based screening recommended by the World Health Organization is expected to lead to worldwide reduction of the cervical cancer burden, but the countries burdened most by cervical cancer also struggle with the costs of transitioning to this approach. Country-specific evaluations are needed to inform policymakers on implementation of hrHPV-based screening for their setting. Following initial implementation in Uganda, Bangladesh and Slovakia focused on underscreened women in the PRESCRIP-TEC project, we investigated the potential cost-effectiveness and affordability of hrHPV-based screening strategies. Country-specific model-based cost-effectiveness and budget impact analyses were conducted for the three countries, comparing the PRESCRIP-TEC strategy with the existing screening strategy in each setting. Data from initial project implementation informed the relevant model parameters. The PRESCRIP-TEC strategy resulted in disability-adjusted life year (DALY) gains in all three countries. The cervical cancer incidence rate was reduced by a third for Uganda, 15% for Bangladesh and 11% for Slovakia. The incremental cost-effectiveness ratios were UGX 0.56 million per DALY for Uganda (I$ 475), BDT 76 thousand per DALY for Bangladesh (I$ 1698) and EUR 1782 (I$ 3637) per DALY for Slovakia. Substantial additional funding will be required to enable implementation, particularly in relation to the initial start-up costs. The provided estimates can serve to inform policymakers and researchers in the context of implementing hrHPV-based screening in diverse settings.

Clinicopathological Characteristics of Ovarian and Breast Cancer in PALB2, RAD51C, and RAD51D Germline Pathogenic Variant Carriers

Background/Objectives: Germline pathogenic variants (GPVs) in PALB2, RAD51C, and RAD51D increase breast cancer (BC) and ovarian cancer (OC) risk. Limited data on clinicopathological characteristics of BC and OC in women with these GPVs hamper guideline development. Therefore, this study aims to describe these characteristics in a consecutive series of female PALB2, RAD51C, and RAD51D GPV carriers. Methods: Women with a PALB2, RAD51C, or RAD51D GPV determined before July 2023 at the University Medical Center Groningen were included. Cancer diagnoses were obtained through linkage with the Dutch Nationwide Pathology Databank (Palga). Median onset age and histopathological subtypes were compared to the data of The Netherlands Cancer Registry (NCR). Results: Among 164 GPV carriers (125 PALB2, 30 RAD51C, and 9 RAD51D), 54 BC and 6 OC cases were identified. The median BC onset age was 52 (n = 50), 71 (n = 3), and 43 years (n = 1) for PALB2, RAD51C, and RAD51D, respectively, compared with 62 years in the NCR. No BC histological subtype differences were observed in PALB2 carriers. The populations of RAD51C and RAD51D carriers were too small to compare to NCR data. No OC cases occurred in PALB2 carriers. The median OC onset age was 66 (n = 4) and 56 years (n = 2) for RAD51C and RAD51D carriers, respectively, versus 67 years in the NCR. All RAD51D carriers had high-grade serous carcinoma, compared to 51.5% in the NCR. Conclusions: Differences in onset age and histological subtypes were observed between GPV carriers and national data. Further research on cancer characteristics is needed to optimize counseling and cancer prevention in these women.

Evaluation of BRCA1/2 testing rates in epithelial ovarian cancer patients: lessons learned from real-world clinical data

Abstract Identification of somatic and germline BRCA1/2 pathogenic variants in epithelial ovarian cancer (EOC) patients is essential for determining poly-(ADP-ribose)-polymerase (PARP) inhibitor sensitivity and genetic predisposition. In the Netherlands, BRCA1/2 testing changed to a tumor-first approach to efficiently identify both somatic and germline pathogenic variants in all patients. Here, we performed an in-depth evaluation of the first four years of the tumor-first test-pathway. Data of consecutive series of patients diagnosed with EOC in two regions were obtained from the Netherlands Cancer Registry. Tumor and/or germline test data were retrieved from hospital databases. The primary outcome was the percentage of patients completing the BRCA1/2 test-pathway, defined as having a negative tumor test or a referral for a germline test in case of a positive tumor test or no tumor test. Factors associated with test-pathway completion were identified through multivariable logistic regression analysis. In total, 69.8% (757/1085) completed the test-pathway. This was 74.4% in the most recent year. Younger patients, patients diagnosed in year three or four, patients with high-grade serous/high-grade endometrioid carcinoma, advanced stage disease, middle or high socioeconomic status, and patients who underwent surgery or chemotherapy, were more likely to complete the test-pathway. We report inequalities in genetic testing access in EOC patients, which highlight the need for better guideline adherence, particularly in older patients, those with low socioeconomic status, low-grade histotypes, early-stage disease and those without surgery or chemotherapy. Additionally, timely testing of patients, and testing relatives if patients cannot be tested, are crucial to increase test uptake.

High-risk human papillomavirus testing for cervical cancer screening in Uganda: Considering potential harms and benefits in a low-resource setting

Objectives The World Health Organization supports both the screen-and-treat (ST) approach and the screen, triage and treat (STT) approach to cervical cancer screening using high-risk human papillomavirus (hrHPV) testing. For Uganda, the sequence of hrHPV-ST and hrHPV-STT could be similar, with visual inspection with acetic acid (VIA) after positive hrHPV tests in both. To consider potential tradeoffs (overtreatment in ST versus missed cancer cases in STT), we compared hrHPV-STT with VIA triage (STT-VIA), and STT with HPV 16/18 genotyping risk stratification, to hrHPV-ST for Uganda, in terms of overtreatment, cervical cancer incidence, and life years, for the general female population of Uganda. Methods A microsimulation model of cervical cancer was adapted. Incremental benefit-harm ratios of STT were calculated as ratios of prevented overtreatment to reduced life years, and to increased cancer cases. Additional scenarios with 20% difference in intra- and inter-screening follow-up between ST and STT were modeled. Results Both STT strategies resulted in life year losses on average compared to ST. STT-VIA prevented more overtreatment but led to increased cervical cancer incidence and life year losses. STT-G-VIA resulted in better harm-benefit ratios and additional costs. With better follow-up, STT prevented overtreatment and improved outcomes. Discussion For Uganda, the STT approach appears preferrable, if the screening sequences of hrHPV-based ST and STT are similar in practice. While VIA triage alone would reduce overtreatment the most, it could also result in more cancer cases. Risk stratification via genotyping could improve STT. Potential follow-up differences and resource availability should be considered by decision-makers when planning Uganda’s hrHPV-based screening strategy.