Materials and Methods

The data from 2 independent but related national clinical trials (clinical utility study and intended-use validation study) conducted between 2007 and 2012 on the use of the MIA for triaging patients with an adnexal mass were merged and analyzed retrospectively. A total of 1110 subjects were prospectively enrolled at 44 sites across the United States, including primary care women’s health clinics, general obstetrics and gynecology group practices, gynecologic oncology practices, community and university-based hospitals, and health maintenance organizations. Institutional review board approval was obtained from each site. From the combined clinical trial populations, the subset of patients enrolled by nongynecologic oncologist providers was selected for further study. All clinicians initially enrolling patients in the current analysis were from nongynecologic oncology specialty practices, although patients may ultimately have had consultation with or undergone surgery by a gynecologic oncologist.

Both trials had identical inclusion and exclusion criteria: consented females aged ≥18 years, agreeable to phlebotomy, with an adnexal mass documented by imaging (computed tomography, ultrasonography, or magnetic resonance imaging) and planned for surgery within 3 months of imaging. Exclusion criteria included a diagnosed malignancy within the past 5 years, with the exception of nonmelanoma skin cancer, declined phlebotomy or did not conduct the surgery within 3 months as planned. Menopause was defined as the absence of menses for ≥12 months, or age ≥50 years. All data were collected on standardized case report forms.

The methods for blood collection and specimen handling have been previously reported. Biomarker measurements were performed according to the MIA Instructions for Use at Quest Diagnostics, Inc (Chantilly, VA) or the Division of Clinical Chemistry, Department of Pathology, Johns Hopkins Medical Institutions. The MIA is a FDA-cleared, assay that incorporates CA125 (CA125-II), transferrin, transthyretin (prealbumin), apolipoprotein A1, and beta-2-microglobulin. These biomarker results were transformed by the OvaCalc software (Vermillion, Inc., Austin, TX) using a proprietary multivariate algorithm to generate an ovarian malignancy risk score as described previously. The algorithm renders a single risk score from 0.0 to 10.0, and subjects were stratified as high risk with MIA scores ≥5.0 (premenopausal) or ≥4.4 (postmenopausal). For CA125 measurement, the same value used for MIA calculation was used for individual analysis, and compared with clinical cutoff values in accordance with published ACOG referral criteria of ≥200 units/mL for premenopausal women or >35 units/mL for postmenopausal women.

To establish a benchmark for clinical accuracy in predicting ovarian malignancy before surgery, clinicians were required to document their assessment according to previously reported methods. Clinical assessment methods always included physical examination, family history, imaging, and laboratory tests (including CA125 results, if used) but not MIA results. Clinical prediction of malignancy was recorded, as was the specialty of the surgeon who performed surgery (nongynecologic oncologist or gynecologic oncologist). The postoperative pathology diagnosis was recorded at each enrolling site, and independently reviewed.

The Dearking modified-ACOG guidelines for consultation with a gynecologic oncologist were used for patients meeting 1 or more of the following criteria :

Premenopausal women

• 1.
  

  Very elevated CA125 (>67 units/mL)

  
  
• 2.
  

  Ascites

  
  
• 3.
  

  Evidence of abdominal or distant metastasis

Postmenopausal women

• 1.
  

  Elevated CA125 (>35 units/mL)

  
  
• 2.
  

  Nodular or fixed pelvic mass

  
  
• 3.
  

  Ascites

  
  
• 4.
  

  Evidence of abdominal or distant metastasis

Case report forms, biomarker values and MIA scores were sent to Applied Clinical Intelligence for statistical analysis. Results were statistically stratified based on specialty of clinician who performed the surgery, the subject’s menopausal status, stage of malignancy, and surgical pathology. Clinical diagnostic performance criteria (sensitivity, specificity, PPV, and negative predictive value) were calculated for clinical assessment, CA125, modified ACOG guidelines, and MIA. Ninety-five percent confidence intervals were constructed where appropriate, and differences in sensitivity and specificity were tested for statistical significance using McNemar’s test. Statistical analysis was performed with SAS 9.2 (SAS Institute Inc., Cary, NC). Descriptive statistics were compiled for the expected and actual gynecologic oncologist referral rates for clinical assessment, CA125, and modified-ACOG guidelines based on surgeon of record.

Results

A total of 770 patients (clinical utility study, n = 276; intended-use validation study, n = 494) were enrolled by nongynecologic oncologist providers and were evaluable for CA125, MIA, and modified-ACOG guidelines, and 763 patients were evaluable for clinical assessment of the likelihood of ovarian cancer ( Table 1 ). The overall prevalence of malignancy was 21.3%. A primary invasive malignancy arising in the ovary or ovaries was present in 14.9% of cases (n = 115), whereas, invasive epithelial ovarian cancer was the pathological diagnosis in 13.5% of cases. Of the invasive ovarian malignancies, 52.1% of cases had International Federation of Gynecology and Obstetrics (FIGO) stage I or stage II disease.

Test performance for detection of malignancy is shown in Table 2 . MIA demonstrated statistically significantly higher sensitivity (90.2%, 95% confidence interval [CI], 84.7–93.9) compared with clinical assessment (73.2%, 95% CI, 65.9–79.4), CA125 (68.3%, 95% CI, 60.8–74.9), and modified ACOG guidelines (79.3%, 95% CI, 72.4–84.8) ( P < .0001). MIA showed statistically significant deterioration in specificity compared with clinical assessment, CA125, and modified-ACOG criteria ( P < .0001). Test performance for detection of malignancy stratified by menopausal status is shown in Tables 3 and 4 .

Table 3

Test performance in predicting any malignancy among premenopausal patients with an adnexal mass (n = 57)

Variable	Clinical assessment	CA125 a	Modified ACOG guidelines	MIA
	(n = 421)	(n = 424)	(n = 424)	(n = 424)
Sensitivity	70.2	52.6	82.5	87.7
n/N	40/57	30/57	47/57	50/57
95% CI	57.3–80.5	39.9–65.0	70.6–90.2	88.1–99.0
Specificity	90.1	96.2	75.5	60.5
n/N	328/364	353/367	277/367	222/367
95% CI	86.6–92.8	93.7–97.7	70.8–79.6	55.4–65.4
PPV	52.6	68.2	34.3	25.6
n/N	40/76	30/44	47/137	50/195
95% CI	41.6–63.5	53.4–80.0	26.9–42.6	20.0–32.2
NPV	95.1	92.9	96.5	96.9
n/N	328/345	353/380	277/287	222/229
95% CI	92.3–96.9	89.9–95.1	93.7–98.1	93.8–98.5

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