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. 2023 Jun:7:e2200555.
doi: 10.1200/PO.22.00555.

Normalized LST Is an Efficient Biomarker for Homologous Recombination Deficiency and Olaparib Response in Ovarian Carcinoma

Yann Christinat  1 , Liza Ho  1 , Sophie Clément  2 , Catherine Genestie  3 , Jalid Sehouli  4 , Saverio Cinieri  5 , Antonio Gonzalez Martin  5 , Ursula Denison  6 , Keiichi Fujiwara  7 , Ignace Vergote  8 , Germana Tognon  9 , Sakari Hietanen  10 , Isabelle Ray-Coquard  11 , Eric Pujade-Lauraine  12 , Thomas A McKee  1
Affiliations

Normalized LST Is an Efficient Biomarker for Homologous Recombination Deficiency and Olaparib Response in Ovarian Carcinoma

Yann Christinat et al. JCO Precis Oncol. 2023 Jun.

Erratum in

Abstract

Purpose: The efficiency of the Myriad Homologous Recombination Deficiency (HRD) test to guide the use of poly (ADP-ribose) polymerase (PARP) inhibitors has been demonstrated in several phase III trials. However, a need exists for alternative clinically validated tests.

Methods: A novel biomarker for HRD was developed using The Cancer Genome Atlas database and, as part of the ENGOT HRD European Initiative, applied to 469 samples from the PAOLA-1/ENGOT-ov25 trial. Results were compared with the Myriad myChoice Genomic Instability Score (GIS) with respect to the progression-free survival in the olaparib + bevacizumab and placebo + bevacizumab arms.

Results: Analysis of the TCGA cohort revealed that a normalization of the number of large-scale state transitions by the number of whole-genome doubling events allows a better separation and classification of HRD samples than the GIS. Analysis of the PAOLA-1 samples, using the Geneva test (OncoScan + nLST), yielded a lower failure rate (27 of 469 v 59 of 469) and a hazard ratio of 0.40 (95% CI, 0.28 to 0.57) compared with 0.37 for Myriad myChoice (BRCAm or GIS+) in the nLST-positive samples. In patients with BRCAwt, the Geneva test identified a novel subpopulation of patients, with a favorable 1-year PFS (85%) but a poor 2-year PFS (30%) on olaparib + bevacizumab treatment.

Conclusion: The proposed test efficiently separates HRD-positive from HRD-negative patients, predicts response to PARP inhibition, and can be easily deployed in a clinical laboratory for routine practice. The performance is similar to the available commercial test, but its lower failure rate allows an increase in the number of patients who will receive a conclusive laboratory result.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Figures

FIG 1.
FIG 1.
Distribution of (A) LST, (B) TAI, and (C) LOH scores and (D) their sum for The Cancer Genome Atlas cohort with respect to the number of WGD events as obtained using the ABSOLUTE software. LOH, loss of heterozygosity events; LST, large-scale state transitions; TAI, telomeric allelic imbalance events; WGD, whole genome doubling.
FIG 2.
FIG 2.
Evaluation of different methods on The Cancer Genome Atlas cohort: (A) results at different cutoffs and (B) results at the recommended cutoffs. BCSS, between-clusters sum of squares; CN, copy number; LOH, loss of heterozygosity events; LST, large-scale state transitions; TAI, telomeric allelic imbalance events; nLST, normalized LST; WGD, whole-genome doubling.
FIG 3.
FIG 3.
Hazard ratio for the Myriad test (GIS + BRCA mutation status) and the Geneva HRD test: (A) full EHEI cohort (469 patients) and (B) BRCA wild-type patients (according to the Myriad myChoice test; 311 patients). GIS, Genomic Instability Score; HRD, homologous recombination deficiency.
FIG 4.
FIG 4.
Kaplan-Meier plot of a three-way classification of the nLST score in the olaparib + bevacizumab arm: (A) BRCA wild-type subpopulation and (B) BRCA-mutated subpopulation. nLST, normalized LST.
See this image and copyright information in PMC

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