The Scarface Score: Deciphering Response to DNA Damage Agents in High-Grade Serous Ovarian Cancer—A GEICO Study

Abstract

Genomic Instability (GI) is a transversal phenomenon shared by several tumor types that provide both prognostic and predictive information. In the context of high-grade serous ovarian cancer (HGSOC), response to DNA-damaging agents such as platinum-based and poly(ADP-ribose) polymerase inhibitors (PARPi) has been closely linked to deficiencies in the DNA repair machinery by homologous recombination repair (HRR) and GI. In this study, we have developed the Scarface score, an integrative algorithm based on genomic and transcriptomic data obtained from the NGS analysis of a prospective GEICO cohort of 190 formalin-fixed paraffin-embedded (FFPE) tumor samples from patients diagnosed with HGSOC with a median follow up of 31.03 months (5.87–159.27 months). In the first step, three single-source models, including the SNP-based model (accuracy = 0.8077), analyzing 8 SNPs distributed along the genome; the GI-based model (accuracy = 0.9038) interrogating 28 parameters of GI; and the HTG-based model (accuracy = 0.8077), evaluating the expression of 7 genes related with tumor biology; were proved to predict response. Then, an ensemble model called the Scarface score was found to predict response to DNA-damaging agents with an accuracy of 0.9615 and a kappa index of 0.9128 (p < 0.0001). The Scarface Score approaches the routine establishment of GI in the clinical setting, enabling its incorporation as a predictive and prognostic tool in the management of HGSOC.

Stratification of Homologous Recombination Deficiency-Negative High-Grade Ovarian Cancer by the Type of Peritoneal Spread into Two Groups with Distinct Survival Outcomes

“…The identification of the HRD status of HGOC patients as being a reliable predictor of a high response to neoadjuvant platinum-based therapy and PARPi has led to the large-scale development of HRD testing. This was implemented either on a commercial basis (e.g., Myriad MyChoice, Foundation Medicine), as integrated kits for in-house testing (e.g., Illumina TruSight Oncology 500 DNA Kit, SOPHiA DDM™ Homologous Recombination Deficiency (HRD) Solution) or as local multi-factorial analysis for research and diagnostic purposes (e.g., the Leuven HRD test [ 28 ] or the Scarface Score [ 23 ]). The tests differ in cost, accessibility, and time of return; nonetheless, they are an integral part of tumor profiling for gynecological tumors.…”

“…HRD testing for prediction of the therapy response can focus on pathogenic variants in genes of the HRR pathway and/or the presence of characteristic genomic scar patterns [ 16 ]. Such scar patterns independently predict the response to the drugs mentioned above and to prognosis in ovarian cancer patients [ 16 , 23 , 24 , 25 ].…”

Stratification of Homologous Recombination Deficiency-Negative High-Grade Ovarian Cancer by the Type of Peritoneal Spread into Two Groups with Distinct Survival Outcome

“…Illumina TruSight Oncology 500 DNA Kit, SOPHiA DDM™ Homologous Recombination Deficiency (HRD) Solution), or as local multi-factorial analysis for research and diagnostic purposes (e.g. the Leuven HRD test [25], or the Scarface Score [21]). The tests differ in cost, accessibility, and time of return; nonetheless, they are an integral part of tumor profiling for gynecological tumors.…”

“…HRD testing for the prediction of therapy response can focus on pathogenic variants in genes of the HRR pathway and/or the presence of characteristic genomic scar patterns [13]. Such scar patterns independently predict response to the drugs mentioned above and to prognosis in ovarian cancer patients [13,[21][22][23].…”