TY - JOUR
T1 - 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
AU - Skates, Steven J.
AU - Greene, Mark H.
AU - Buys, Saundra S.
AU - Mai, Phuong L.
AU - Brown, Powel
AU - Piedmonte, Marion
AU - Rodriguez, Gustavo
AU - Schorge, John O.
AU - Sherman, Mark
AU - Daly, Mary B.
AU - Rutherford, Thomas
AU - Brewster, Wendy R.
AU - O'Malley, David M.
AU - Partridge, Edward
AU - Boggess, John
AU - Drescher, Charles W.
AU - Isaacs, Claudine
AU - Berchuck, Andrew
AU - Domchek, Susan
AU - Davidson, Susan A.
AU - Edwards, Robert
AU - Elg, Steven A.
AU - Wakeley, Katie
AU - Phillips, Kelly Anne
AU - Armstrong, Deborah
AU - Horowitz, Ira
AU - Fabian, Carol J.
AU - Walker, Joan
AU - Sluss, Patrick M.
AU - Welch, William
AU - Minasian, Lori
AU - Horick, Nora K.
AU - Kasten, Carol H.
AU - Nayfield, Susan
AU - Alberts, David
AU - Finkelstein, Dianne M.
AU - Lu, Karen H.
N1 - Funding Information:
In addition to the clinical site principal investigators who enrolled more than 50 patients in ROCA and are listed as authors, the following clinical sites and PI's contributed significant numbers of patients to the study and are gratefully acknowledged: Holly Gallion MD (Magee-Women's Hospital), Alex Miller MD (University of Texas Health Sciences Center San Antonio, San Antonio, TX), Paula Ryan MD PhD (Massachusetts General Hospital), Judy Garber MD PhD (Dana-Farber Cancer Institute), Henry Lynch MD (Creighton University, Omaha, NE), James Evans MD PhD (University of North Carolina), Henry Lynch MD (EDRN High Risk Registry), Lee-may Chen MD (University of California San Francisco, San Francisco, CA), Olufunmilayo Olopade MD (University of Chicago, Chicago, IL), and Thomas Caputo MD (Cornell University, Ithaca, NY). The ROCA study was conducted under the auspices of the Cancer Genetics Network (CGN) with the support of the CGN PI's, which is gratefully acknowledged: Deborah Bowen PhD (Fred Hutchinson Cancer Research Center), Claudine Isaacs MD (Georgetown University), Constance Griffin MD (Johns Hopkins University), Geraldine Mineau PhD (Huntsman Cancer Institute), Joellen Schildkraut PhD (Duke University), Louise Strong MD (MD Anderson Cancer Center), Susan Domchek MD (University of Pennsylvania), Gail Tomlinson MD PhD (University of Texas Southwestern Medical Center), Dennis Ahnen MD (University of Colorado), Hoda Anton-Culver PhD (University of California Irvine, Irvine, CA), Sharon Plon MD PhD (Baylor College of Medicine, Houston, TX), James Evans MD PhD (University of North Carolina), William Wood MD (Emory University), Alex Miller MD (University of Texas Health Sciences Center at San Antonio), Dianne M. Finkelstein PhD (CGN Coordinating Center, Massachusetts General Hospital), and Perry Miller PhD MD (CGN Medical Informatics, Yale Medical School). In addition, two ovarian SPORE sites and an EDRN site participated with the support of the PI's Edward Partridge MD (University of Alabama at Birmingham), Robert Ozols MD (Fox Chase Cancer Center), and Henry Lynch MD (Creighton University). The Study Coordinators and Research Assistants throughout the CGN, the two ovarian SPORE sites, the EDRN site, and five other sites were crucial to the successful completion of the ROCA study and their tireless efforts are gratefully acknowledged. The success of GOG-0199 was due to the enormous investment in time and effort made by GOG senior leadership, GOG's Cancer Prevention and Control Committee, the Principal Investigators, Study Managers and Research Assistants from the 150 GOG sites which activated this complex protocol both in the US and Australia, and multiple staff members from the Clinical Genetics Branch, CTEP and CCOP programs at NCI. Most importantly, the CGN study and GOG-0199 study would not have been possible without the selfless contributions of the 2,359 (CGN) and 2,605 (GOG) women at increased risk who enrolled in these time-intensive studies. 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 to D.M. Finkelstein, CA078134 to H. Anton-Culver, CA078164 to D. Bowen, CA078156 to S. Domchek, CA078148 to C. Griffin, CA078146 to C. Isaacs, CA078174 to G. Mineau, CA078157 to J. Schildkraut, CA078142 to L. Strong, HHSN2612007440000C to D.M. Finkelstein, CA083638 to R. Ozols, CA083591 to E. Partridge, CA086389 to H. Lynch). Fujirebio Diagnostics Inc supported the CGN study for one year after NCI funding ended. P.L. Mai and M. H. Greene were supported by the Intramural Research Program, NCI/NIH. 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 to P. Di Saia), the GOG Statistical and Data Center (CA037517 to J. Blessing), and by NCI's Community Clinical Oncology Program (CCOP) grant (CA101165 to P. Di Saia). Participation by the investigators of the Australia and New Zealand Gynaecological Oncology Group (ANZGOG) is gratefully acknowledged. K.-A. Phillips is an Australian National Breast Cancer Foundation Fellow. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2017 AACR.
PY - 2017/7/15
Y1 - 2017/7/15
N2 - 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.
AB - 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.
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U2 - 10.1158/1078-0432.CCR-15-2750
DO - 10.1158/1078-0432.CCR-15-2750
M3 - Article
C2 - 28143870
AN - SCOPUS:85014912406
SN - 1078-0432
VL - 23
SP - 3628
EP - 3637
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 14
ER -