Validation of the Clinical Use of GIScar, an Academic-developed Genomic Instability Score Predicting Sensitivity to Maintenance Olaparib for Ovarian Cancer
Authors: Leman Raphaël , Muller Etienne , Legros Angelina , Goardon Nicolas , Chentli Imène , Atkinson Alexandre , Tranchant Aurore , Castera Laurent , Krieger Sophie , Ricou Agathe , Boulouard Flavie , Joly Florence , Boucly Romain , Dumont Aurélie , Basset Noémie , Coulet Florence , Chevalier Louise-Marie , Rouleau Etienne , Leitner Katharina , González-Martin Antonio , Gargiulo Piera , Lück Hans-Joachim , Genestie Catherine ,   the PAOLA-1 investigators, Bogner Gerhard , Marth Christian , Petru Edgar , Reinthaller Alexander , Schauer Christian , Sevelda Paul , D'Hondt Lionel , Vergote Ignace , Vuylsteke Peter , Hietanen Sakari , Lindahl Gabriel , Mäenpää Johanna , Nøttrup Trine Jakobi , Puistola Ulla , Abadie-Lacourtoisie Sophie , Alexandre Jérôme , Boissier Emilie , Bourgeois Hugues , Chevalier-Place Annick , Combe Pierre , Costan Cristina , Dauba Jérôme , De Cock Laure , Desauw Christophe , Despax Raymond , Dohollou Nadine , Dubot Coraline , Fabbro Michel , Favier Laure , Floquet Anne , Follana Philippe , Tixidre Claire Garnier , Garnier Georges , Gladieff Laurence , Grenier Julien , Guillemet Cécile , Hardy-Bessard Anne-Claire , Joly Florence , Kalbacher Elsa , Kaminsky Marie-Christine , Kurtz Jean-Emmanuel , Largillier Rémy , Lefeuvre-Plesse Claudia , Lesoin Anne , Levache Charles-Briac , L'Haridon Tifenn , Lortholary Alain , Lotz Jean-Pierre , Meunier Jérôme , Mousseau Mirerille , Mouret-Reynier Marie-Ange , Pautier Patricia , Petit Thierry , Provansal Magali , Pujade-Lauraine Eric , Raban Nadia , Ray-Coquard Isabelle , Rodrigues Manuel , Selle Frédéric , Sverdlin Robert , Tazi Youssef , You Benoît , Aktas Bahriye , Bauerschlag Dirk Olaf , Beck Thomas , Belau Antje , Bronger Holger , Buchholz Stefan , Buderath Paul , Burges Alexander , Canzler Ulrich , de Gregorio Nikolaus , Denschlag Dominik , Dieterich Max , Eichbaum Michael , El-Balat Ahmed , Emons Günter , Fasching Peter , Feisel-Schwickardi Gabriele , Frank Matthias , Friedrich Michael , Grischke Eva-Maria , Gropp-Meier Martina , Hanker Lars , Hannig Carla , Harter Philipp , Hasenburg Annette , Hellriegel Martin , Herwig Uwe , Heubner Martin , Hulde Joachim , Jackisch Christian , Kögel Matthias , Krieger Peter , Kühn Thorsten , Liebrich Clemens , Lück Hans-Joachim , Mallmann Peter , Marmé Frederik , Meier Werner , Möbus Voker , Mohamed Omar Farag , Nestle-Krämling Carolin , Neunhöffer Tanja , Oskay-Özcelik Gülten , Park-Simon Tjoung-Won , Rautenberg Beate , Rein Daniel , Ruhwedel Wencke , Runnebaum Ingo , Sagasser Jacqueline , Schmalfeldt Barbara , Schneeweiss Andreas , Schnelzer Andreas , Scholz Heinz , Sehouli Jalid , Sperfeld Antje , Steckkönig Annette , Strauß Hans-Georg , Tomé Oliver , Treustedt Jörn , Voß Hermann , Wischnik Arthur , Witteler Ralf , Wöckel Achim , Woeltjen Hans-Heinrich , Zorr Andreas , Bologna Alessandra , Colombo Nicoletta , Tognon Germana , Cinieri Saverio , Lorusso Domenica , Mosconi Anna Maria , Pignata Sandro , Savarese Antonella , Scambia Giovanni , Sorio Roberto , Zamagni Claudio , Fujiwara Keiichi , Fujiwara Hiroyuki , Kobayashi Hiroaki , Matsumoto Takashi , Nagao Shoji , Satoh Toyomi , Yonemori Kan , Yoshida Hiroyuki , Bratos Raquel , Caballero Cristina , Garica Yolanda , González-Martín Antonio , Alia Eva Maria Guerra , Hernando Susana , Herrero Ana , Lainez Nuria , Manso Luis , Martin Cristina , Murata Eleonor , Ortega Eugenia , Palacio Isabel , Poveda Andres , Romero Ignacio , Rubio Maria Jesús , Ray-Coquard Isabelle , Pujade-Lauraine Eric , Vaur Dominique 
Published: September 2023

Abstract

Purpose:
The optimal application of maintenance PARP inhibitor therapy for ovarian cancer requires accessible, robust, and rapid testing of homologous recombination deficiency (HRD). However, in many countries, access to HRD testing is problematic and the failure rate is high. We developed an academic HRD test to support treatment decision-making.

Experimental Design:
Genomic Instability Scar (GIScar) was developed through targeted sequencing of a 127-gene panel to determine HRD status. GIScar was trained from a noninterventional study with 250 prospectively collected ovarian tumor samples. GIScar was validated on 469 DNA tumor samples from the PAOLA-1 trial evaluating maintenance olaparib for newly diagnosed ovarian cancer, and its predictive value was compared with Myriad Genetics MyChoice (MGMC).

Results:
GIScar showed significant correlation with MGMC HRD classification (kappa statistics: 0.780). From PAOLA-1 samples, more HRD-positive tumors were identified by GIScar (258) than MGMC (242), with a lower proportion of inconclusive results (1% vs. 9%, respectively). The HRs for progression-free survival (PFS) with olaparib versus placebo were 0.45 [95% confidence interval (CI), 0.33–0.62] in GIScar-identified HRD-positive BRCA-mutated tumors, 0.50 (95% CI, 0.31–0.80) in HRD-positive BRCA-wild-type tumors, and 1.02 (95% CI, 0.74–1.40) in HRD-negative tumors. Tumors identified as HRD positive by GIScar but HRD negative by MGMC had better PFS with olaparib (HR, 0.23; 95% CI, 0.07–0.72).

Conclusions:
GIScar is a valuable diagnostic tool, reliably detecting HRD and predicting sensitivity to olaparib for ovarian cancer. GIScar showed high analytic concordance with MGMC test and fewer inconclusive results. GIScar is easily implemented into diagnostic laboratories with a rapid turnaround.