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

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 6–12 monthly CA125>35U/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 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% vs. 90% (p=0.0001), and PPV was 4.6% vs. 10% (p>0.10). Eighteen of 19 malignant ovarian neoplasms (prevalent=4, incident=6, RRSO=9) were detected via screening or risk-reducing salpingo-oophorectomy (RRSO). Amongst incident cases (which best reflect long-term screening performance), 3/6 invasive cancers were early-stage (I/II) (50% versus 10% historical BRCA1 controls; p=0.016). Six of 9 RRSO-related cases were stage I. ROCA flagged 3/6 (50%) incident cases before CA125 exceeded 35U/mL. Eight of 9 stages 0/I/II ovarian cancer patients 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.

Factors associated with deciding between risk-reducing salpingo-oophorectomy and ovarian cancer screening among high-risk women enrolled in GOG-0199: An NRG Oncology/Gynecologic Oncology Group study

“…Participants were at least 30 years of age, had no prior history of ovarian/fallopian tube/ peritoneal cancer, and had at least one intact ovary. At enrollment, participants chose either RRSO or OCS with the ROCA algorithm [20]. …”

“…Furthermore, OCS is associated with frequent false-positive screening test results and anxiety [17, 18]. More recently, the Risk of Ovarian Cancer Algorithm (ROCA), a novel screening strategy consisting of longitudinal CA-125 measurements analyzed by Bayesian modeling, followed by secondary screening with TVUS if indicated, has shown promise among average-risk [19], and high-risk women [20], with no clinically significant psychological morbidity among average-risk women undergoing repeat testing following abnormal screening tests [21]. At the time this study was carried out, the performance characteristics and psychological impact of this investigational screening strategy among increased risk women were not known.…”

Epithelial ovarian cancer: Evolution of management in the era of precision medicine

“…In some cases, for example Ashkenazi populations, susceptibility can readily be identified using screening for 3 founder mutations. In addition, efforts are ongoing to improve genomic screening strategy . Potential biomarkers, such as human epididymis protein 4 (HE4) (a glycoprotein secreted by Mullerian epithelia of the female reproductive tract), have been tested in combination with CA 125; a risk of ovarian cancer algorithm has been developed, and transvaginal sonography has been assessed as a biomarker test, but larger confirmatory studies are required.…”

Recommendations for biomarker testing in epithelial ovarian cancer: a National Consensus Statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology

“…The results were compared against CA125 screening of the general population every 6-12 months and historical controls. ROCA screening every 3 months showed greater sensitivity (92%) with high specificity in this high-risk population [24]. The UK Familial Ovarian Cancer Screening Study was performed in women with a familial estimated high risk (lifetime risk [10%).…”