Ruth Etzioni

Estimating the Opportunity for Early Detection of Ovarian Cancer Using Individual-Patient Data from a Large Randomized Controlled Trial

Abstract Background: The UK Collaborative Trial of Ovarian Cancer Screening did not detect a reduction in ovarian cancer mortality with either multimodal screening (MMS) or transvaginal ultrasound screening (USS) compared with no screening. The trial data provide an invaluable resource to quantify the opportunity for interception in ovarian cancer. Methods: We used Bayesian inference to estimate ovarian cancer natural history based on individual screening and cancer diagnosis records from the UK Collaborative Trial of Ovarian Cancer Screening, a randomized controlled ovarian cancer screening trial conducted in England, Wales, and Northern Ireland. The trial included 202,638 women ages 50 to 74 years with no family history of ovarian cancer, randomized in a 1:1:2 ratio to annual MMS (serum CA125 interpreted using the risk of ovarian cancer algorithm), annual USS, or no screening. The current analysis included 199,499 women, with 674,806 screens and 2,025 cancer diagnoses. Results: Among high-grade serous cancers (HGSC), the estimated preclinical detectable phase was 1.7 years (95% credible interval, 1.3–2.2), compared with 7.8 years (95% credible interval, 5.7–10.6) for non-HGSCs. The preclinical detectable phase depended on screening modality: for HGSCs, it was longer in the MMS arm (2.2 years) compared with the USS arm (0.8 years), whereas for non-HGSCs, it was shorter in the MMS arm (2.7 years) compared with the USS arm (8.2 years). Conclusions: The interception opportunity for ovarian cancer strongly depends on histologic subtype and screening modality. Impact: Achieving a clinically significant benefit of ovarian cancer early detection will require prolonging the interception window through judicious combination of first- and second-line tests.

Prediagnostic evaluation of multicancer detection tests: design and analysis considerations

Abstract There is growing interest in multicancer detection tests, which identify molecular signals in the blood that indicate a potential preclinical cancer. A key stage in evaluating these tests is a prediagnostic performance study, in which investigators store specimens from asymptomatic individuals and later test stored specimens from patients with cancer and a random sample of controls to determine predictive performance. Performance metrics include rates of cancer-specific true-positive and false-positive findings and a cancer-specific positive predictive value, with the latter compared with a decision-analytic threshold. The sample size trade-off method, which trades imprecise targeting of the true-positive rate for precise targeting of a zero-false-positive rate can substantially reduce sample size while increasing the lower bound of the positive predictive value. For a 1-year follow-up, with ovarian cancer as the rarest cancer considered, the sample size trade-off method yields a sample size of 163 000 compared with a sample size of 720 000, based on standard calculations. These design and analysis recommendations should be considered in planning a specimen repository and in the prediagnostic evaluation of multicancer detection tests.

Estimating stage-specific sensitivity for cancer screening tests

Objectives When evaluating potential new cancer screening modalities, estimating sensitivity, especially for early-stage cases, is critical. There are methods to approximate stage-specific sensitivity in asymptomatic populations, both in the prospective (active screening) and retrospective (stored specimens) scenarios. We explored their validity via a simulation study. Methods We fit natural history models to lung and ovarian cancer screening data that permitted estimation of stage-specific (early/late) true sensitivity, defined as the probability subjects screened in the given stage had positive tests. We then ran simulations, using the fitted models, of the prospective and retrospective scenarios. Prospective sensitivity by stage was estimated as screen-detected divided by screen-plus interval-detected cancers, where stage is defined as stage at detection. Retrospective sensitivity by stage was estimated based on cancers detected within specified windows before clinical diagnosis with stage defined as stage at clinical diagnosis. Results Stage-specific true sensitivities estimated by the lung cancer natural history model were 47% (early) and 63% (late). Simulation results for the prospective setting gave estimated sensitivities of 81% (early) versus 62% (late). In the retrospective scenario, early/late sensitivity estimates were 35%/57% (1-year window) and 27%/49% (2-year window). In the prospective scenario, most subjects with negative early-stage screens presented as other than early-stage interval cases. Results were similar for ovarian cancer, with estimated prospective sensitivity much greater than true sensitivity for early stage, 84% versus 25%. Conclusions Existing methods for approximating stage-specific sensitivity in both prospective and retrospective scenarios are unsatisfactory; improvements are needed before they can be considered to be reliable.

Short-term Endpoints for Cancer Screening Trials: Does Tumor Subtype Matter?

Abstract Multicancer early detection tests are precipitating a reexamination of potential short-term endpoints for cancer screening trials. A reduction in advanced stage incidence is a prime candidate, and stage-shift models that substitute early-stage for late-stage survival have been used to predict mortality reduction due to screening. However, standard stage-shift models often ignore prognostic subtypes, effectively implying that cancers detected early also have an associated subtype shift. To illustrate the differences between mortality predictions from stage-shift models that ignore versus preserve prognostic subtype, we use ovarian cancer partitioned by histologic subtype and prostate cancer partitioned by grade. We infer general conditions under which stage-shift models that preserve prognostic subtype are likely to predict mortality reductions that differ from those that ignore subtype and examine the implications for short-term endpoints based on stage in cancer screening trials.

Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society

Abstract The American Cancer Society (ACS) recommends that individuals with a cervix initiate cervical cancer screening at age 25 years and undergo primary human papillomavirus (HPV) testing every 5 years through age 65 years (preferred); if primary HPV testing is not available, then individuals aged 25 to 65 years should be screened with cotesting (HPV testing in combination with cytology) every 5 years or cytology alone every 3 years (acceptable) ( strong recommendation ). The ACS recommends that individuals aged >65 years who have no history of cervical intraepithelial neoplasia grade 2 or more severe disease within the past 25 years, and who have documented adequate negative prior screening in the prior 10 years, discontinue all cervical cancer screening ( qualified recommendation ). These new screening recommendations differ in 4 important respects compared with the 2012 recommendations: 1) The preferred screening strategy is primary HPV testing every 5 years, with cotesting and cytology alone acceptable where access to US Food and Drug Administration‐approved primary HPV testing is not yet available; 2) the recommended age to start screening is 25 years rather than 21 years; 3) primary HPV testing, as well as cotesting or cytology alone when primary testing is not available, is recommended starting at age 25 years rather than age 30 years; and 4) the guideline is transitional, ie, options for screening with cotesting or cytology alone are provided but should be phased out once full access to primary HPV testing for cervical cancer screening is available without barriers. Evidence related to other relevant issues was reviewed, and no changes were made to recommendations for screening intervals, age or criteria for screening cessation, screening based on vaccination status, or screening after hysterectomy. Follow‐up for individuals who screen positive for HPV and/or cytology should be in accordance with the 2019 American Society for Colposcopy and Cervical Pathology risk‐based management consensus guidelines for abnormal cervical cancer screening tests and cancer precursors.