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. 2024 Dec 1;4(12):3190-3200.
doi: 10.1158/2767-9764.CRC-24-0294.

Beyond HRD Status: Unraveling Genetic Variants Impacting PARP Inhibitor Sensitivity in Advanced Ovarian Cancer

Maj K Kjeldsen  1   2   3 , Morten Jørgensen  1 , Dina Sofie B Grønseth  2 , Martin Schønemann-Lund  4 , Gitte-Bettina Nyvang  3   5 , Charlotte Aaquist Haslund  3   6 , Anja Oer Knudsen  3   5 , Anne Krejbjerg Motavaf  6 , Susanne Malander  3   7   8 , Maarit Anttila  3   9 , Gabriel Lindahl  3   10   11 , Johanna Mäenpää  3   12 , Maria Dimoula  3   13 , Theresa L Werner  14 , Trine Zeeberg Iversen  3   15 , Sakari Hietanen  3   16 , Lars Fokdal  3   17 , Hanna Dahlstrand  3   18 , Line Bjørge  3   19   20 , Michael J Birrer  21 , Mansoor R Mirza #  1   3 , Maria Rossing #  2   22
Affiliations

Beyond HRD Status: Unraveling Genetic Variants Impacting PARP Inhibitor Sensitivity in Advanced Ovarian Cancer

Maj K Kjeldsen et al. Cancer Res Commun. .

Abstract

Abstract: The management of advanced epithelial ovarian cancer (AOC) has undergone significant advancements with the emergence of molecular diagnostics, particularly in predicting responses to PARP inhibitors (PARPi) based on homologous recombination deficiency (HRD) status. However, understanding sensitivity and resistance beyond HRD status remains elusive. This study aims to explore molecular factors that may elucidate why HRD status does not consistently predict PARPi sensitivity. Therefore, we conducted a post hoc translational analysis of formalin-fixed paraffin-embedded tumor samples from the ENGOT-ov24/NSGO-AVANOVA part 1 and 2 trial (NCT02354131), focusing on alterations pertaining radiologic response and progression-free survival (PFS). DNA sequencing was performed using the TruSight Oncology 500 HT gene panel, with variants classified according to recent guidelines. HRD status had been assessed by Myriad MyChoice CDx. We identified, among 92 patients in the ENGOT-ov24/NSGO-AVANOVA part 1 and 2 trial, 151 pathogenic or likely pathogenic variants across 81 samples. PARPi-sensitizing variants were found in two out of 10 HRD-negative samples from patients with clinical benefit (PFS ≥12 months), whereas three out of 10 HRD-positive samples from patients having no benefit (PFS ≤6 months) harbored variants associated with PARPi resistance. Additionally, analysis of BRCA1 variants revealed that truncating variants in exon 11 correlated with clinical benefit when niraparib was combined with bevacizumab. Conclusively, our findings highlight the complexity of PARPi response in AOC and underscore the importance of exploring somatic variants beyond HRD status. Further investigation into exon 11 variants of BRCA1 and the potential of combination treatment is warranted.

Significance: The irregular response to PARPi in HRD-positive and -negative tumors highlights the need for identifying additional biomarkers. This study explores the mutational landscape beyond HRD status in AOC, ultimately advancing precision oncology in future clinical practice.

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Conflict of interest statement

M.K. Kjeldsen reports grants from GSK during the conduct of the study, as well as grants from OvaCure and Knud Højgaards Fond outside the submitted work. C.A. Haslund reports personal fees from GSK, Bristol Myers Squibb, and AstraZeneca outside the submitted work. J. Mäenpää reports personal fees from Eisai outside the submitted work. T.L. Werner reports other from Repare, Blueprint, Clovis, Tesaro, and Mersana outside the submitted work. S. Hietanen reports personal fees from AstraZeneca, GSK, and Eisai outside the submitted work. H. Dahlstrand reports personal fees from Educational Sessions for AstraZeneca, Roche, and GSK outside the submitted work. L. Bjørge reports grants from AstraZeneca and other from GSK, MSD, and GSK outside the submitted work. M.R. Mirza reports grants from GSK during the conduct of the study. M. Rossing reports grants from AstraZeneca and personal fees from AstraZeneca and MSD outside the submitted work. No disclosures were reported by the other authors.

Figures

Figure 1
Figure 1
Flowchart showing patients included in final gene panel analysis. * Formalin-fixed paraffin-embedded. ** TSO500 gene panel by Illumina.
Figure 2
Figure 2
Oncoplot showing pathogenic gene alterations. The plot is split into groups by cellular pathways affected by the alteration on the vertical axis and clinical outcome (clinical benefit: PFS ≥12 months, no benefit: PFS ≤6 months) on the horizontal axis. Each column represents one patient. In total, 81 patient samples. See color guide reflecting specific alterations below the plot. # = Reason of “end of treatment” other than progressive disease. Integer “HRD-status and GIS” = the exact GIS reported by MyChoice.
Figure 3
Figure 3
Best response in target lesions from baseline (RECIST 1.1-criteria). Dashed lines at +20% and −30% change from baseline equals stable disease. See guide in plot for color explanations.
Figure 4
Figure 4
PFS in months colored by HRD status. Dashed lines at 6 and 12 months illustrate cutoff for “no benefit” and “clinical benefit”. X-axis indicates the number of patients. Reason for end of treatment other than progression: # = toxicity, $ = partial withdrawal of consent (study assessments continued), ¤ = investigator decision, and “…” = no progression at study closure. See guide in plot for color explanations.
Figure 5
Figure 5
BRCA1 (top) and BRCA2 (bottom) with variants found in AVANOVA1&2 colored by treatment response (see legend). BRCA1: Transcript NM_007294.4. In total, 1,863 aa. RING domain (aa 2–101), PALB2-binding domain (also called coiled-coil domain; aa 1,391–1,424), BRCT repeats (aa 1,650–1857), and exon 11 (aa 224–1,366). BRCA2: Transcript NM_000059.4. In total, 3,418 aa. PALB2-binding domain (aa 10–40), DNA-binding domain (aa 2,481–3,186), and exons 10 and 11 (aa 266–2,281).
See this image and copyright information in PMC

References

    1. Christinat Y, Ho L, Clément S, Genestie C, Sehouli J, Cinieri S, et al. . Normalized LST is an efficient biomarker for homologous recombination deficiency and olaparib response in ovarian carcinoma. JCO Precis Oncol 2023;7:e2200555. - PMC - PubMed
    1. Loverix L, Vergote I, Busschaert P, Vanderstichele A, Venken T, Boeckx B, et al. . PARP inhibitor predictive value of the Leuven HRD test compared with Myriad MyChoice CDx PLUS HRD on 468 ovarian cancer patients from the PAOLA-1/ENGOT-ov25 trial. Eur J Cancer 2023;188:131–9. - PubMed
    1. Willing EM, Vollbrecht C, Vössing C, Weist P, Schallenberg S, Herbst JM, et al. . Development of the NOGGO GIS v1 assay, a comprehensive hybrid-capture-based NGS assay for therapeutic stratification of homologous repair deficiency driven tumors and clinical validation. Cancers (Basel) 2023;15:3445. - PMC - PubMed
    1. Callens C, Rodrigues M, Briaux A, Frouin E, Eeckhoutte A, Pujade-Lauraine E, et al. . Shallow whole genome sequencing approach to detect homologous recombination deficiency in the PAOLA-1/ENGOT-OV25 phase-III trial. Oncogene 2023;42:3556–63. - PMC - PubMed
    1. Leman R, Muller E, Legros A, Goardon N, Chentli I, Atkinson A, et al. . Validation of the clinical use of GIScar, an academic-developed genomic instability score predicting sensitivity to maintenance olaparib for ovarian cancer. Clin Cancer Res 2023;29:4419–29. - PMC - PubMed

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