Development and Validation of the Gene Expression Predictor of High-grade Serous Ovarian Carcinoma Molecular SubTYPE (PrOTYPE).

Authors:
Aline Talhouk Joshy George Chen Wang Timothy Budden Tuan Zea Tan Derek S Chiu Stefan Kommoss Huei San Leong Stephanie Chen Maria P Intermaggio Blake Gilks Tayyebeh M Nazeran Mila Volchek Wafaa Elatre Rex C Bentley Janine Senz Amy Lum Veronica Chow Hanwei Sudderuddin Robertson Mackenzie Samuel C Y Leong Geyi Liu Dustin Johnson Billy Chen Aocs Group Jennifer Alsop Susana N Banerjee Sabine Behrens Clara Bodelon Alison H Brand Louise Brinton Michael E Carney Yoke-Eng Chiew Kara L Cushing-Haugen Cezary Cybulski Darren Ennis Sian Fereday Renée T Fortner Jesús García-Donas Aleksandra Gentry-Maharaj Rosalind Glasspool Teodora Goranova Casey S Greene Paul Haluska Holly R Harris Joy Hendley Brenda Y Hernandez Esther Herpel Mercedes Jimenez-Linan Chloe Karpinskyj Scott H Kaufmann Gary L Keeney Catherine J Kennedy Martin Köbel Jennifer M Koziak Melissa C Larson Jenny Lester Liz-Anne Lewsley Jolanta Lissowska Jan Lubiński Hugh Luk Geoff Macintyre Sven Mahner Iain A McNeish Janusz Menkiszak Nikilyn Nevins Ana Osorio Oleg Oszurek José Palacios Samantha Hinsley Celeste L Pearce Malcolm C Pike Anna M Piskorz Isabelle Ray-Coquard Valerie Rhenius Cristina Rodriguez-Antona Raghwa Sharma Mark E Sherman Dilrini De Silva Naveena Singh Peter Sinn Dennis Slamon Honglin Song Helen Steed Euan A Stronach Pamela J Thompson Aleksandra Tołoczko Britton Trabert Nadia Traficante Chiu-Chen Tseng Martin Widschwendter Lynne R Wilkens Stacey J Winham Boris Winterhoff Alicia Beeghly-Fadiel Javier Benitez Andrew Berchuck James D Brenton Robert Brown Jenny Chang-Claude Georgia Chenevix-Trench Anna deFazio Peter A Fasching María J García Simon A Gayther Marc T Goodman Jacek Gronwald Michelle J Henderson Beth Y Karlan Linda E Kelemen Usha Menon Sandra Orsulic Paul D P Pharoah Nicolas Wentzensen Anna H Wu Joellen M Schildkraut Mary Anne Rossing Gottfried E Konecny David G Huntsman Ruby Yun-Ju Huang Ellen L Goode Susan J Ramus Jennifer A Doherty David D Bowtell Michael S Anglesio

Clin Cancer Res 2020 Oct 17;26(20):5411-5423. Epub 2020 Jun 17.

British Columbia's Gynecological Cancer Research Program (OVCARE), BC Cancer, Vancouver General Hospital, and University of British Columbia, Vancouver, British Columbia, Canada.

Purpose: Gene expression-based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of individual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features.

Experimental Design: Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting.

Results: Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with >95% accuracy that was maintained in all analytic and biological validations.

Conclusions: We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications..

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Source
http://dx.doi.org/10.1158/1078-0432.CCR-20-0103DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572656PMC
October 2020
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