Early detection of ovarian cancer using the risk of ovarian cancer algorithm with frequent CA125 testing in women at increased familial risk – Combined results from two screening trials

• Type of Material: Article
• Authors: Steven J. Skates, Massachusetts General Hospital; Mark H. Greene, National Cancer Institute; Saundra S. Buys, University of Utah; Phuong L. Mai, National Cancer Institute; Powel Brown, University of Texas; Marion Piedmonte, Roswell Park Cancer Institute; Gustavo Rodriguez, NorthShore University HealthSystem; John O. Schorge, Massachusetts General Hospital; Mark Sherman, National Cancer Institute; Mary B. Daly, Fox Chase Cancer Center; Thomas Rutherford, Western CT Health Network; Wendy R. Brewster, The University of North Carolina; David M. O'Malley, Ohio State University; Edward Partridge, University of Alabama; John Boggess, Rex Cancer Center; Charles W. Drescher, Fred Hutchinson Cancer Research Center; Claudine Isaacs, Georgetown University; Andrew Berchuck, Duke University; Susan Domchek, University of Pennsylvania; Susan A. Davidson, Denver Health Medical Center; Robert Edwards, Magee-Womens Hospital; Steven A. Elg, The Iowa Clinic; Katie Wakeley, South Shore Hospital; Kelly-Anne Phillips, Peter Maccallum Cancer Centre; Deborah Armstrong, Johns Hopkins University; Ira R Horowitz, Emory University; Carol J. Fabian, University of Kansas; Joan Walker, University of Oklahoma; Patrick M. Sluss, Massachusetts General Hospital; William Welch, Brigham and Women's Hospital
• Language: English
• Date: 2017-07-15
• Publisher: American Association for Cancer Research
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: ©2017 AACR.
• Final Published Version (URL): http://dx.doi.org/10.1158/1078-0432.CCR-15-2750
• Title of Journal or Parent Work: Clinical Cancer Research
• ISSN: 1078-0432
• Volume: 23
• Issue: 14
• Start Page: 3628
• End Page: 3637
• Grant/Funding Information: Drs. P. Mai and M. Greene were supported by the Intramural Research Program, NCI/NIH.; The ROCA study was supported mainly by research grants/contracts from NCI to sites in the Cancer Genetics Network, the Ovarian SPORE program, and the Early Detection Research Network (CA078284 D. Finkelstein, CA078134 H. Anton-Culver, CA078164 D. Bowen, CA078156 S. Domchek, CA078148 C. Griffin, CA078146 C. Isaacs, CA078174 G. Mineau, CA078157 J. Schildkraut, CA078142 L. Strong, HHSN2612007440000C D. Finkelstein, CA083638 R. Ozols, CA083591 E. Partridge, CA086389 H. Lynch, CA180858 C. Eng); Fujirebio Diagnostics Inc supported the CGN study for one year after NCI funding ended.; The Gynecologic Oncology Group’s study (GOG-0199) was supported by intramural research funds from the Clinical Genetics Branch, and National Cancer Institute grants to the Gynecologic Oncology Group (GOG) Administrative Office and Tissue Bank (CA027469 P. Di Saia), the GOG Statistical and Data Center (CA037517 J. Blessing), and by NCI’s Community Clinical Oncology Program (CCOP) grant (CA101165 P. Di Saia).
• Keywords: Risk Factors; Breast Neoplasms; Female; Neoplasm Staging; Middle Aged; Membrane Proteins; Early Detection of Cancer; Adult; Ovarian Neoplasms; Humans; Algorithms; Aged; CA-125 Antigen
• Research Categories: Health Sciences, Oncology

Abstract

Purpose: Women at familial/genetic ovarian cancer risk often undergo screening despite unproven efficacy. Research suggests each woman has her own CA125 baseline; significant increases above this level may identify cancers earlier than standard 6- to 12-monthly CA125 > 35 U/mL. Experimental Design: Data from prospective Cancer Genetics Network and Gynecologic Oncology Group trials, which screened 3,692 women (13,080 woman-screening years) with a strong breast/ovarian cancer family history or BRCA1/2 mutations, were combined to assess a novel screening strategy. Specifically, serum CA125 q3 months, evaluated using a risk of ovarian cancer algorithm (ROCA), detected significant increases above each subject's baseline, which triggered transvaginal ultrasound. Specificity and positive predictive value (PPV) were compared with levels derived from general population screening (specificity 90%, PPV 10%), and stage-at-detection was compared with historical high-risk controls. Results: Specificity for ultrasound referral was 92% versus 90% (P = 0.0001), and PPV was 4.6% versus 10% (P > 0.10). Eighteen of 19 malignant ovarian neoplasms [prevalent ¼ 4, incident = 6, risk-reducing salpingo-oophorectomy (RRSO) = 9] were detected via screening or RRSO. Among incident cases (which best reflect long-term screening performance), three of six invasive cancers were early-stage (I/II; 50% vs. 10% historical BRCA1 controls; P = 0.016). Six of nine RRSO-related cases were stage I. ROCA flagged three of six (50%) incident cases before CA125 exceeded 35 U/mL. Eight of nine patients with stages 0/I/II ovarian cancer were alive at last follow-up (median 6 years). Conclusions: For screened women at familial/genetic ovarian cancer risk, ROCA q3 months had better early-stage sensitivity at high specificity, and low yet possibly acceptable PPV compared with CA125 > 35 U/mL q6/q12 months, warranting further larger cohort evaluation.