Validation of the Clinical Use of GIScar, an Academic-developed Genomic Instability Score Predicting Sensitivity to Maintenance Olaparib for Ovarian Cancer
Raphaël Leman, Etienne Müller, Angélina Legros, Nicolas Goardon, Imène Chentli, Alexandre Atkinson, Aurore Tranchant, Laurent Castéra, Sophie Krieger, Agathe Ricou, Flavie Boulouard, Florence Joly, Romain Boucly, Aurélie Dumont, Noémie Basset, Florence Coulet, Louise-Marie Chevalier, Étienne Rouleau, Katharina Leitner, Antonio González-Martı́n, Piera Gargiulo, Hans‐Joachim Lück, Catherine Genestie, the PAOLA-1 investigators, Gerhard Bogner, Christian Marth, Edgar Petru, Alexander Reinthaller, Christian Schauer, P. Sevelda, Lionel D’Hondt, Ignace Vergote, Peter Vuylsteke, Sakari Hietanen, Gabriel Lindahl, Johanna Mäenpää, Trine Jakobi Nøttrup, Ulla Puistola, Sophie Abadie‐Lacourtoisie, Jérôme Alexandre, Émilie Boissier, Hugues Bourgeois, Annick Chevalier-Place, Pierre Combe, Cristina Costan, Jérôme Dauba, Laure De Cock, Christophe Desauw, Raymond Despax, Nadine Dohollou, Coraline Dubot, Michel Fabbro, Laure Favier, Anne Floquet, Philippe Follana, Claire Garnier Tixidre, Georges Garnier, Laurence Gladieff, Julien Grenier, Cécile Guillemet, Anne‐Claire Hardy‐Bessard, Florence Joly, Elsa Kalbacher, Marie‐Christine Kaminsky, Jean‐Emmanuel Kurtz, Rémy Largillier, Claudia Lefeuvre‐Plesse, Anne Lesoin, Charles-Briac Levaché, Tifenn L’Haridon, Alain Lortholary, Jean‐Pierre Lotz, Jérôme Meunier, M Mousseau, Marie‐Ange Mouret‐Reynier, Patricia Pautier, Thierry Petit, Magali Provansal, Éric Pujade-Lauraine, Nadia Raban, Isabelle Ray‐Coquard, Manuel Rodrigues, Frédèric Selle, Robert Sverdlin, Youssef Tazi, Benoît You, Bahriye Aktas, Dirk Bauerschlag, Thomas Beck, Antje Belau, Holger Bronger, Stefan Buchholz, Paul Buderath, Alexander Burges, Ulrich Canzler, Nikolaus de Gregorio, Dominik Denschlag, Max Dieterich, Michael Eichbaum, Ayşe Balat
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.