Cost-Effectiveness of Gene-Specific Prevention Strategies for Ovarian and Breast Cancer.

Importance: Pathogenic variants (PVs) in BRCA1, BRCA2, PALB2, RAD51C, RAD51D, and BRIP1 cancer susceptibility genes (CSGs) confer an increased ovarian cancer (OC) risk, with BRCA1, BRCA2, PALB2, RAD51C, and RAD51D PVs also conferring an elevated breast cancer (BC) risk. Risk-reducing surgery, medical prevention, and BC surveillance offer the opportunity to prevent cancers and deaths, but their cost-effectiveness for individual CSGs remains poorly addressed. Objective: To estimate the cost-effectiveness of prevention strategies for OC and BC among individuals carrying PVs in the previously listed CSGs. Design, Setting, and Participants: In this economic evaluation, a decision-analytic Markov model evaluated the cost-effectiveness of risk-reducing salpingo-oophorectomy (RRSO) and, where relevant, risk-reducing mastectomy (RRM) compared with nonsurgical interventions (including BC surveillance and medical prevention for increased BC risk) from December 1, 2022, to August 31, 2023. The analysis took a UK payer perspective with a lifetime horizon. The simulated cohort consisted of women aged 30 years who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. Appropriate sensitivity and scenario analyses were performed. Exposures: CSG-specific interventions, including RRSO at age 35 to 50 years with or without BC surveillance and medical prevention (ie, tamoxifen or anastrozole) from age 30 or 40 years, RRM at age 30 to 40 years, both RRSO and RRM, BC surveillance and medical prevention, or no intervention. Main Outcomes and Measures: The incremental cost-effectiveness ratio (ICER) was calculated as incremental cost per quality-adjusted life-year (QALY) gained. OC and BC cases and deaths were estimated. Results: In the simulated cohort of women aged 30 years with no cancer, undergoing both RRSO and RRM was most cost-effective for individuals carrying BRCA1 (RRM at age 30 years; RRSO at age 35 years), BRCA2 (RRM at age 35 years; RRSO at age 40 years), and PALB2 (RRM at age 40 years; RRSO at age 45 years) PVs. The corresponding ICERs were -£1942/QALY (-$2680/QALY), -£89/QALY (-$123/QALY), and £2381/QALY ($3286/QALY), respectively. RRSO at age 45 years was cost-effective for RAD51C, RAD51D, and BRIP1 PV carriers compared with nonsurgical strategies. The corresponding ICERs were £962/QALY ($1328/QALY), £771/QALY ($1064/QALY), and £2355/QALY ($3250/QALY), respectively. The most cost-effective preventive strategy per 1000 PV carriers could prevent 923 OC and BC cases and 302 deaths among those carrying BRCA1; 686 OC and BC cases and 170 deaths for BRCA2; 464 OC and BC cases and 130 deaths for PALB2; 102 OC cases and 64 deaths for RAD51C; 118 OC cases and 76 deaths for RAD51D; and 55 OC cases and 37 deaths for BRIP1. Probabilistic sensitivity analysis indicated both RRSO and RRM were most cost-effective in 96.5%, 89.2%, and 84.8% of simulations for BRCA1, BRCA2, and PALB2 PVs, respectively, while RRSO was cost-effective in approximately 100% of simulations for RAD51C, RAD51D, and BRIP1 PVs. Conclusions and Relevance: In this cost-effectiveness study, RRSO with or without RRM at varying optimal ages was cost-effective compared with nonsurgical strategies for individuals who carried BRCA1, BRCA2, PALB2, RAD51C, RAD51D, or BRIP1 PVs. These findings support personalizing risk-reducing surgery and guideline recommendations for individual CSG-specific OC and BC risk management.

Diagnostic Accuracy in Assessment of Depth of Myometrial Invasion in Low-grade Endometrioid Carcinoma: A 2 Center Comparative Study by MRI and Intraoperative Assessment.

The role of lymphadenectomy in endometrial carcinomas is controversial, especially in low-grade endometrioid carcinomas. In many institutions, lymphadenectomy in the latter neoplasms is undertaken only when there is deep myometrial invasion, defined as invasion involving 50% or more of the myometrium (FIGO stage IB). There has been considerable debate as to the best modality to detect deep myometrial invasion. In Europe, preoperative magnetic resonance imaging (MRI) is the most commonly used modality while in North America, intraoperative assessment (IOA) is undertaken in most, but not all, institutions. The aim of this study was to compare the diagnostic accuracy of these 2 modalities in identifying deep myometrial invasion in low-grade endometrioid carcinomas. Two patient cohorts were studied from Belfast, UK (n=253) and Boston, USA (n=276). With respect to detecting deep myometrial invasion, MRI had a sensitivity of 72.84%, positive predictive value of 75.64% and a positive likelihood ratio of 6.59 (95% confidence interval; 4.23-10.28). IOA had a sensitivity of 78.26%, positive predictive value of 80% and a positive likelihood ratio of 20.00 (95% confidence interval; 10.35-38.63). The superior positive likelihood ratio suggests that IOA is better than MRI in determining deep myometrial invasion and the nonoverlapping 95% confidence intervals suggest this is a significant finding. However, there are significant resource implications associated with IOA and preoperative MRI carries other advantages that are discussed herein.

Reproducibility of lymphovascular space invasion (LVSI) assessment in endometrial cancer.

AIMS: Lymphovascular space invasion (LVSI) in endometrial cancer (EC) is an important prognostic variable impacting on a patient's individual recurrence risk and adjuvant treatment recommendations. Recent work has shown that grading the extent of LVSI further improves its prognostic strength in patients with stage I endometrioid EC. Despite this, there is little information on the reproducibility of LVSI assessment in EC. Therefore, we designed a study to evaluate interobserver agreement in discriminating true LVSI from LVSI mimics (Phase I) and reproducibility of grading extent of LVSI (Phase II). METHODS AND RESULTS: Scanned haematoxylin and eosin (H&E) slides of endometrioid EC (EEC) with a predefined possible LVSI focus were hosted on a website and assessed by a panel of six European gynaecological pathologists. In Phase I, 48 H&E slides were included for LVSI assessment and in Phase II, 42 H&E slides for LVSI grading. Each observer was instructed to apply the criteria for LVSI used in daily practice. The degree of agreement was measured using the two-way absolute agreement average-measures intraclass correlation coefficient (ICC). Reproducibility of LVSI assessment (ICC = 0.64, P < 0.001) and LVSI grading (ICC = 0.62, P < 0.001) in EEC was substantial among the observers. CONCLUSIONS: Given the good reproducibility of LVSI, this study further supports the important role of LVSI in decision algorithms for adjuvant treatment.

Assessment of a new system for primary site assignment in high-grade serous carcinoma of the fallopian tube, ovary, and peritoneum.

AIMS: The available evidence indicates that most non-uterine high-grade serous carcinomas (HGSCs) arise from the fallopian tube (FT), but approaches to primary site assignment have not evolved to reflect this. The aim of this study was to assess the application of recently proposed criteria for site assignment. METHODS AND RESULTS: One hundred and fifty-one HGSCs from four centres were reviewed retrospectively. Sixty-three of 80 (79%) chemonaive (CN) and 45 of 71 (68%) post-neoadjuvant chemotherapy (NACT) cases were assigned as FT primaries with the new criteria, whereas 58 of 80 (73%) and 45 of 71 (63%) were assigned as ovarian primaries with traditional criteria (P < 0.0001). Of 111 prospectively collected HGSCs, with consistent detailed fimbrial examination, 44 of 53 (83%) CN and 44 of 58 (76%) NACT cases were assigned as FT primaries. The reproducibility of site assignment was tested in a subset of 50 cases: all four reviewing pathologists agreed on the primary site in 48 of 50 (96%) cases, and three of four agreed in 49 of 50 (98%) cases. Of the 53 prospectively studied CN cases, bilateral ovarian involvement (62%) was significantly more frequent than bilateral tubal involvement (12%, P < 0.0001), further supporting a tubal origin and ovarian metastasis in most cases. CONCLUSIONS: With currently accepted protocols, the proposed guidelines are easy to apply and result in consistent site assignment in non-uterine HGSCs. Most cases of non-uterine HGSC were considered to be primary FT neoplasms.

Significant variation in the assessment of cervical involvement in endometrial carcinoma: an interobserver variation study.

The histologic assessment of cervical involvement in endometrial carcinoma may be problematic for a number of reasons, but an accurate evaluation of this is important for correct staging, dictating the need for adjuvant therapy, and prognostication. In this study, we assessed interobserver variation in the evaluation of cervical involvement in hysterectomy specimens of endometrial carcinoma among 6 specialist gynecologic pathologists. Seventy-six cases of endometrial carcinoma enriched for cases exhibiting some perceived issue in the assessment of cervical involvement were used. In all the cases, a single slide of the primary tumor in the uterine corpus and a single slide of the cervix were circulated among the 6 participants who filled in a proforma. On the basis of the responses, the tumors were staged according to the 1988 International Federation of Gynecology and Obstetrics (FIGO) staging system (I, IIA, IIB) and the 2009 FIGO staging system (I, II). Using the 1988 FIGO staging system, the unweighted and weighted κ values between individual observers ranged from 0.3115 to 0.6139 (average 0.4675) and from 0.3492 to 0.6533 (average 0.5065), respectively. The κ values between observers for the 2009 FIGO staging system ranged from 0.3481 to 0.6862 (average 0.4908). Although enriched for problematic cases, our study shows that there is at most a fair-to-good agreement among specialist gynecologic pathologists in the assessment of cervical involvement in endometrial carcinoma. Problematic factors include determination of the junction between the lower uterine segment and upper endocervix, the distinction between "floaters" and true cervical glandular involvement, the distinction between cervical glandular involvement and stromal involvement, and the distinction between cervical glandular involvement and reactive non-neoplastic lesions of the endocervical glands. There is a need for specialist pathology groups dealing with gynecologic cancers to develop and disseminate recommendations regarding the assessment of cervical involvement in endometrial carcinoma.