Ann Lab Med.  2023 Jan;43(1):64-72. 10.3343/alm.2023.43.1.64.

Comparison of Homologous Recombination Repair Gene Next-Generation Sequencing Analysis in Patients With Metastatic Castration-Resistant Prostate Cancer Between Local and Central Laboratories in Korea

• Kim Y
• Park I
• Kim B
• Choi YJ
• Oh SC
• Lee KA

• KMID: 2551587
• DOI: http://doi.org/10.3343/alm.2023.43.1.64

Abstract

Background
Following success of the phase III PROfound trial, the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib was approved by the US Food and Drug Administration in May 2020 for adult patients with deleterious homologous recombination repair (HRR) gene-mutated metastatic castration-resistant prostate cancer (mCRPC). As locally adopted multigene panel next-generation sequencing (NGS) assays for selecting PARP inhibitor candidates have not been thoroughly evaluated, we compared the analytical performance of the FoundationOne CDx (Foundation Medicine, Inc., Cambridge, MA, USA) (central laboratory) and other NGS assays (local laboratory) with samples from the PROfound trial in Korea.
Methods
One hundred PROfound samples (60 HRR mutation [HRRm] cases and 40 non-HRRm cases) were analyzed. The results of HRR gene mutation analysis were compared between the FoundationOne CDx and two other NGS assays [SureSelect Custom Design assay (Agilent Technologies, Inc., Santa Clara, CA, USA) and Oncomine Comprehensive assay (Thermo Fisher Scientific, Inc., Waltham, MA, USA)].
Results
The positive percent agreement for single nucleotide variants (SNVs) and insertion/deletions (indels) between the central laboratory and local laboratory was 98.7%–100.0%. The negative percent agreement and overall percent agreement (OPA) for SNVs and indels between central and local laboratories were both 100%. Compared with that of the FoundationOne CDx assay, the OPA for copy number variations of the Oncomine Comprehensive and SureSelect Custom assays reached 99.8%–100%. Most mCRPC patients harboring a deleterious genetic variant were successfully identified with both local laboratory assays.
Conclusions
The NGS approach at a local laboratory showed comparable analytical performance for identifying HRRm status to the FoundationOne CDx assay used at the central laboratory.

Keyword

Recombinational DNA repair; Poly (ADP-ribose) polymerase inhibitors; Prostatic neoplasms; Castration-resistant; High-throughput nucleotide sequencing; Ion Torrent sequencing; Illumina sequencing

Figure

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  Fig. 1 Study flow chart. Abbreviations: FFPE, formalin-fixed, paraffin-embedded; HRR, homologous recombination repair; HRRm, homologous recombination repair mutation; mCRPC, metastatic castration-resistant prostate cancer; NGS, next-generation sequencing.

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  Fig. 2 Summary of quality metrics in 100 PROfound samples. Abbreviations: HRRm, homologous recombination repair mutation.

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  Fig. 3 A false-negative pathogenic variant in the central laboratory with the FoundationOne CDx assay. The pathogenic variant c.2250G>A, p.(Lys750=) at the splicing junction in ATM had been rejected in the central laboratory with the FoundationOne CDx assay. However, both the Oncomine Comprehensive assay (A) and SureSelect Custom assay (B) in the local laboratory successfully detected the variant.

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