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PLCO Ovarian Phase III Validation Study

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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
Case/control
UNKNOWN
Breast and Gynecologic Cancers Research
3

The obvious appeal of a strategy for the early detection of ovarian cancer is based upon the tendency for the disease to present at advanced stages associated with poor survival. If the diagnosis could be largely shifted to stages I or II associated with survival close to 90%, then the overall mortality for this disease could be dramatically altered without any advances in therapy. While approaches to ovarian cancer screening might include pelvic examination or sonography, a vast amount of information exists on potential blood markers for the disease. The precision of sensitivity and specificity estimates will be greater for larger versus smaller study populations; but the effect produced by differences in the populations studied cannot as easily be predicted. Most of the studies relied on phase II validation (i.e. case vs. control differences); but case groups may differ by disease stage and histology that may affect overall estimates of sensitivity. Many studies have limited case specimens to those collected pre-operatively, but not all were explicit in this regard. Few studies have used pre-diagnostic sera months or years before diagnosis, so-called Phase III studies. Similarly, the nature of the control group will also affect specificity estimates. Inclusion of surgical controls that have benign gynecological conditions such as fibroids, endometriosis, or benign ovarian tumors may elevate marker levels and lower specificity. One strategy, besides combining markers, to improve the sensitivity and/or specificity would be to use marker history in the context of serial testing. Elevated but declining marker levels would indicate a transient condition associated with marker production. Elevated but stable levels might indicate chronic but benign conditions associated with marker production, while elevated and increasing levels are more likely indicative of cancer. Our hypothesis is that a panel of biomarkers will have better performance characteristics as a screening test for pre-clinical ovarian cancer than any single marker, and yield a longer lead time than CA125 alone.

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

Announcement 11/20/2014

New Round of EDRN FOAs

The RFAs for EDRN have been released:
- Biomarker Developmental Laboratories (U01),
- Clinical Validation Centers (U01),
- Biomarker Reference Laboratories (U24),
- Data Management and Coordinating Center (U24).

EDRN Renewal flyer NOTE-New receipt deadline for applications submitted for all EDRN FOAs is January 20, 2015, by 5:00 PM local time of applicant organization.

There will be a Pre-Application webinar to discuss each of the four individual EDRN FOAs on Tuesday, December 2nd, 2014, from 1pm-5pm (Eastern). Potential applicants interested in participating in the webinar should send a message to Dr. Sharmistha Ghosh (ghoshjanjigias@mail.nih.gov) no later than 5:00 p.m. (EST) November 21, 2014. Please mention the FOA of interest in the subject line.

Announcement 10/07/2014

EDRN Patient Advocates will host an EDRN Advocacy Educational Webinar, Biomarkers for Prostate Cancer Detection and Monitoring, on Monday, January 12th, 2015, at 1 p.m. EDT / 10 a.m. PDT. Registration is not required for this. Please click for more information.