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. 2016 Sep 15;22(18):4664-75.
doi: 10.1158/1078-0432.CCR-16-0316. Epub 2016 Apr 8.

A Prospective Evaluation of Early Detection Biomarkers for Ovarian Cancer in the European EPIC Cohort

Kathryn L Terry  1 , Helena Schock  2 , Renée T Fortner  2 , Anika Hüsing  2 , Raina N Fichorova  3 , Hidemi S Yamamoto  3 , Allison F Vitonis  4 , Theron Johnson  2 , Kim Overvad  5 , Anne Tjønneland  6 , Marie-Christine Boutron-Ruault  7 , Sylvie Mesrine  7 , Gianluca Severi  8 , Laure Dossus  9 , Sabina Rinaldi  9 , Heiner Boeing  10 , Vassiliki Benetou  11 , Pagona Lagiou  11 , Antonia Trichopoulou  11 , Vittorio Krogh  12 , Elisabetta Kuhn  13 , Salvatore Panico  14 , H Bas Bueno-de-Mesquita  15 , N Charlotte Onland-Moret  16 , Petra H Peeters  16 , Inger Torhild Gram  17 , Elisabete Weiderpass  18 , Eric J Duell  19 , Maria-Jose Sanchez  20 , Eva Ardanaz  21 , Nerea Etxezarreta  22 , Carmen Navarro  23 , Annika Idahl  24 , Eva Lundin  25 , Karin Jirström  26 , Jonas Manjer  26 , Nicholas J Wareham  27 , Kay-Tee Khaw  28 , Karl Smith Byrne  29 , Ruth C Travis  29 , Marc J Gunter  30 , Melissa A Merritt  30 , Elio Riboli  30 , Daniel W Cramer  4 , Rudolf Kaaks  31
Affiliations

A Prospective Evaluation of Early Detection Biomarkers for Ovarian Cancer in the European EPIC Cohort

Kathryn L Terry et al. Clin Cancer Res. .

Abstract

Purpose: About 60% of ovarian cancers are diagnosed at late stage, when 5-year survival is less than 30% in contrast to 90% for local disease. This has prompted search for early detection biomarkers. For initial testing, specimens taken months or years before ovarian cancer diagnosis are the best source of information to evaluate early detection biomarkers. Here we evaluate the most promising ovarian cancer screening biomarkers in prospectively collected samples from the European Prospective Investigation into Cancer and Nutrition study.

Experimental design: We measured CA125, HE4, CA72.4, and CA15.3 in 810 invasive epithelial ovarian cancer cases and 1,939 controls. We calculated the sensitivity at 95% and 98% specificity as well as area under the receiver operator curve (C-statistic) for each marker individually and in combination. In addition, we evaluated marker performance by stage at diagnosis and time between blood draw and diagnosis.

Results: We observed the best discrimination between cases and controls within 6 months of diagnosis for CA125 (C-statistic = 0.92), then HE4 (0.84), CA72.4 (0.77), and CA15.3 (0.73). Marker performance declined with longer time between blood draw and diagnosis and for earlier staged disease. However, assessment of discriminatory ability at early stage was limited by small numbers. Combinations of markers performed modestly, but significantly better than any single marker.

Conclusions: CA125 remains the single best marker for the early detection of invasive epithelial ovarian cancer, but can be slightly improved by combining with other markers. Identifying novel markers for ovarian cancer will require studies including larger numbers of early-stage cases. Clin Cancer Res; 22(18); 4664-75. ©2016 AACRSee related commentary by Skates, p. 4542.

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Figures

Figure 1
Figure 1
Locally estimated scatterplot smoothing (Loess) curves over time prior to diagnosis. The blue line represents controls, the green line stage I cases, the yellow line stage II cases, and the red line stage III/IV cases. For CA125 and CA15.3 data are shown only for lag-times between blood donation and cancer diagnosis up to 6 years.
Figure 2
Figure 2
ROC curves and C-statistics for diagnosis ≤6 months, ≤12 months, 1-2 years and 2-3 years after blood collection
See this image and copyright information in PMC

References

    1. American Cancer Society . Cancer Facts & Figuress. American Cancer Society; Atlanta, GA: 2015.
    1. Terry KL, Sluss PM, Skates SJ, Mok SC, Ye B, Vitonis AF, et al. Blood and urine markers for ovarian cancer: a comprehensive review. Disease markers. 2004;20:53–70. - PMC - PubMed
    1. Pepe MS, Etzioni R, Feng Z, Potter JD, Thompson ML, Thornquist M, et al. Phases of biomarker development for early detection of cancer. J Natl Cancer Inst. 2001;93:1054–61. - PubMed
    1. FDA. SUBSTANTIAL EQUIVALENCE DETERMINATION DECISION SUMMARY. 510(k) Available from: http://www.accessdata.fda.gov/cdrh_docs/reviews/K081754.pdf.
    1. FDA HE4 EIA. Available from: http://www.fda.gov/ohrms/dockets/ac/08/briefing/220028-4403.b1-02-Propos....

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