AS282 - Evaluation of serum markers for use in multi-stage ovarian cancer screening

Investigator Names and Contact Information

Nicole Urban, Sc.D

Introduction/Intent

Serum markers CA125, HE4, MSLN, MMP7 and SLPI provide early signal for ovarian cancer in preclinical samples from various trials. In Aim 1 we will use nanotechnology to optimize and validate assays for these markers. In Aim 2, using the WHI OS samples as a development set, we will optimize three decision rules using these serum markers. One rule will identify women who are likely to benefit from surveillance for ovarian cancer, a second will identify women likely to benefit from pelvic imaging, and a third will identify women likely to benefit from surgical consult regarding laparoscopic biopsy. In Aim 3, using the WHI CT samples as a validation set, we will test these decision rules retrospectively to predict their performance in screening. Outcomes include sensitivity measured by proportion of cases detected by the decision rule; positive predictive value (PPV) measured by surgical procedures per cancer detected by the decision rule; and average lead time measured by the difference between time (age) at diagnosis and time (age) at detection by the decision rule. WHI CT serum samples are requested from approximately 160 cases and 640 controls; WHI OS samples for 240 cases and 480 controls have already been provided.

Specific Aims

Epithelial malignancy of the ovary and/or fallopian tube is usually lethal. Strategies for early detection are challenged by the need for a high positive predictive value (PPV), which is difficult to achieve in a rare disease. A strategy is needed to identify from among the general population of women over the age of 50 those at high-risk (HR) for a diagnosis of ovarian/fallopian tube cancer (OC) so that they can be referred for appropriate surveillance, imaging or surgical consult. Several promising new serum markers have been identified in recent years. Our goal is to understand how best to introduce them in clinical practice. Tools to identify high-risk women will be investigated including serum markers CA125, HE4, MSLN, MMP7 and SLPI and epidemiologic risk factors. To explore the translational potential of serum markers that we have validated in clinical and pre-clinical samples, we will optimize decision rules and conduct a simulated prospective validation using stored serum samples from the Women’s Health Initiative (WHI Observational Study (OS) and Clinical Trial (CT). Decision rules to select women for ovarian cancer screening will be investigated as well as decision rules for use in ovarian cancer screening.

The Specific Aims of the proposed study are to optimize and validate ovarian cancer screening decision rules using serum markers, and evaluate the contribution of epidemiologic risk factors to these rules.

Aim 1. Identify the best assays for use in measuring HE4, MSLN, MMP7 and SLPI by evaluating candidate assays in clinical samples available from the Pacific Ovarian Cancer Research Consortium (POCRC) parent grant and in preclinical samples available from the Carotene and Retinol Efficacy Trial (CARET) repository. Assays that employ nanotechnology show superior performance in preliminary work to date.

Aim 2. Using 240 cases and 480 matched controls from the WHI OS, define and optimize decision rules to identify women for referral to 1) surveillance using serum markers (up to 20% annually), 2) imaging using transvaginal sonography (up to 10% annually), and 3) surgical consult (up to 1% annually).

Aim 3. Using approximately 160 cases and 640 matched controls from the WHI CT, test the decision rules developed in Aim 2. Using predefined thresholds for positivity, evaluate for each decision rule its 1) sensitivity measured by proportion of cases detected, 2) specificity measured by positive tests in women without ovarian cancer, and 3) average lead time measured by time between detection and diagnosis.