PLCO Ovarian Phase III Validation Study

Feng, ZidingFred Hutchinson Cancer Research Center
APO B2M B7-H4 CA125 CA15.3 CA19.9 CA72.4 CTAP-III EGFR Eotaxin HE4 HEPC IGF2 IGFBP2 ITIH4 KLK6 Leptin Mesothelin MIF MMP3 MMP7 OPN Prolactin SLPI Spondin-2 sV CAM Transferrin Transthyretin
No design specified.
Breast and Gynecologic Cancers Research Group

Our preliminary data indicate that the performance of CA 125 as a screening test for ovarian cancer can be improved upon by additional biomarkers. With completion of one additional validation step, we will be ready to test the performance of a consensus marker panel in a phase III validation study. Given the original aims of the PLCO trial, we believe that the PLCO represents an ideal longitudinal cohort offering specimens for phase III validation of ovarian cancer biomarkers.

1). Using 1 ml of sera from the PLCO subjects, apply the panel of markers identified through the phase II study to all prediagnostic specimens from all PLCO participants who subsequently developed ovarian cancer and from all longitudinal specimens from 10 matched controls who did not develop ovarian cancer for each case. 2). Using any residual sera, apply high end mass spectrometry and other discovery techniques to seek new markers especially in pre-clinical cases who were false negative or controls who were false positive by the panels.
Based upon comprehensive reviews of ovarian cancer biomarkers and preliminary studies in which multiple biomarkers have been compared simultaneously, investigators representing Ovarian Cancer SPORES, EDRN and the PLCO trial are working towards defining a consensus panel of biomarkers appropriate for ovarian cancer screening. Towards this goal, SPORE and EDRN investigators proposed to assemble a new set of phase II specimens (160 ovarian cancer cases with pre-operative bloods over-sampled for early-stage disease, 160 benign disease controls, 480 general population controls, and serial samples collected one year apart from 40 healthy women). The top 5 markers identified in preliminary work by Boston-NW and FHCRC investigators, plus an expanded panel of Luminex markers, were evaluated to identify a final consensus panel of 5 to 15 biomarkers. CA125 and the top 5 new markers were measured by standard ELISA using an automated platform, or kit, at BWH. CA125 and the top 5 new markers, as well as additional candidate markers unique to each institution, were measured using Luminex at FHCRC and Pittsburgh. Results from ELISA were compared to results obtained from Luminex to evaluate the consistency of CA125 and the top 5 new markers across platforms and institutions. Markers were selected for inclusion in the panel based on their individual performance, their contribution to a panel, and their stability over time, where the last predicts the improvement in performance expected from their use in a longitudinal algorithm. For markers that could be measured adequately on Luminex, to preserve specimen volume, the Luminex platform was used to evaluate the final consensus panel in the requested PLCO specimens; standard ELISA were used only if necessary due to inadequate measurement by Luminex. The phase III PLCO set included pre-clinical specimens from all women who developed ovarian cancer during PLCO follow up (estimated to be about 100) and 1000 controls who did not develop ovarian cancer matched by age of subject and age of specimen. The analysis of pre-clinical specimens from cases was phased, beginning with the serum sample collected closest to date of diagnosis. If the panel performed well, additional pre-clinical samples were analyzed to assess its use in a longitudinal algorithm and to estimate lead time of the panel and the individual markers. Sensitivity and specificity for detecting pre-clinical disease 1, 2 and 3 years prior to clinical diagnosis were determined and the feasibility of applying the panel for general population screening was estimated. Characteristics of cases who were and were not able to be detected by the panel were examined. One ml of serum was requested for each PLCO subject included in the set, which allowed for measurement of the standard ELISAs and Luminex panels as well as any re-testing that may be necessary. Any residual sera, especially from case subjects who were falsely negative and controls who were falsely

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