Authors: J. Millstein, T. Budden, E.L. Goode, M.S. Anglesio, A. Talhouk, M.P. Intermaggio, H.S. Leong, S. Chen, W. Elatre, B. Gilks, T. Nazeran, M. Volchek, R.C. Bentley, C. Wang, D.S. Chiu, S. Kommoss, S.C.Y. Leung, J. Senz, A. Lum, V. Chow, H. Sudderuddin, R. Mackenzie, J. George, S. Fereday, J. Hendley, N. Traficante, H. Steed, J.M. Koziak, M. Köbel, I.A. McNeish, T. Goranova, D. Ennis, G. Macintyre, D. Silva De Silva, T. Ramón y Cajal, J. García-Donas, S. Hernando Polo, G.C. Rodriguez, K.L. Cushing-Haugen, H.R. Harris, C.S. Greene, R.A. Zelaya, S. Behrens, R.T. Fortner, P. Sinn, E. Herpel, J. Lester, J. Lubiński, O. Oszurek, A. Tołoczko, C. Cybulski, J. Menkiszak, C.L. Pearce, M.C. Pike, C. Tseng, J. Alsop, V. Rhenius, H. Song, M. Jimenez-Linan, A.M. Piskorz, A. Gentry-Maharaj, C. Karpinskyj, M. Widschwendter, N. Singh, C.J. Kennedy, R. Sharma, P.R. Harnett, B. Gao, S.E. Johnatty, R. Sayer, J. Boros, S.J. Winham, G.L. Keeney, S.H. Kaufmann, M.C. Larson, H. Luk, B.Y. Hernandez, P.J. Thompson, L.R. Wilkens, M.E. Carney, B. Trabert, J. Lissowska, L. Brinton, M.E. Sherman, C. Bodelon, S. Hinsley, L.A. Lewsley, R. Glasspool, S.N. Banerjee, E.A. Stronach, P. Haluska, I. Ray-Coquard, S. Mahner, B. Winterhoff, D. Slamon, D.A. Levine, L.E. Kelemen, J. Benitez, J. Chang-Claude, J. Gronwald, A.H. Wu, U. Menon, M.T. Goodman, J.M. Schildkraut, N. Wentzensen, R. Brown, A. Berchuck, G. Chenevix-Trench, A. deFazio, S.A. Gayther, M.J. García, M.J. Henderson, M.A. Rossing, A. Beeghly-Fadiel, P.A. Fasching, S. Orsulic, B.Y. Karlan, G.E. Konecny, D.G. Huntsman, D.D. Bowtell, J.D. Brenton, J.A. Doherty, P.D.P. Pharoah, S.J. Ramus
Summary: Background: Median overall survival (OS) for women with high-grade serous ovarian cancer (HGSOC) is ∼4 years, yet survival varies widely between patients. There are no well-established, gene expression signatures associated with prognosis. The aim of this study was to develop a robust prognostic signature for OS in patients with HGSOC.
Patients and methods: Expression of 513 genes, selected from a meta-analysis of 1455 tumours and other candidates, was measured using NanoString technology from formalin-fixed paraffin-embedded tumour tissue collected from 3769 women with HGSOC from multiple studies. Elastic net regularization for survival analysis was applied to develop a prognostic model for 5-year OS, trained on 2702 tumours from 15 studies and evaluated on an independent set of 1067 tumours from six studies.
Results: Expression levels of 276 genes were associated with OS (false discovery rate < 0.05) in covariate-adjusted single-gene analyses. The top five genes were TAP1, ZFHX4, CXCL9, FBN1 and PTGER3 (P < 0.001). The best performing prognostic signature included 101 genes enriched in pathways with treatment implications. Each gain of one standard deviation in the gene expression score conferred a greater than twofold increase in risk of death [hazard ratio (HR) 2.35, 95% confidence interval (CI) 2.02–2.71; P < 0.001]. Median survival [HR (95% CI)] by gene expression score quintile was 9.5 (8.3 to –), 5.4 (4.6–7.0), 3.8 (3.3–4.6), 3.2 (2.9–3.7) and 2.3 (2.1–2.6) years.
Conclusion: The OTTA-SPOT (Ovarian Tumor Tissue Analysis consortium - Stratified Prognosis of Ovarian Tumours) gene expression signature may improve risk stratification in clinical trials by identifying patients who are least likely to achieve 5-year survival. The identified novel genes associated with the outcome may also yield opportunities for the development of targeted therapeutic approaches.
Source: Annals of Oncology, 2020