TY - JOUR
T1 - Beyond HRD status: Unraveling Genetic Variants Impacting PARP Inhibitor Sensitivity in Advanced Ovarian Cancer
AU - Kjeldsen, Maj K.
AU - Jørgensen, Morten
AU - Grønseth, Dina Sofie B.
AU - Schønemann-Lund, Martin
AU - Nyvang, Gitte-Bettina
AU - Haslund, Charlotte Aaquist
AU - Knudsen, Anja Oer
AU - Motavaf, Anne Krejbjerg
AU - Malander, Susanne
AU - Anttila, Maarit
AU - Lindahl, Gabriel
AU - Mäenpää, Johanna
AU - Dimoula, Maria
AU - Werner, Theresa L.
AU - Iversen, Trine Zeeberg
AU - Hietanen, Sakari
AU - Fokdal, Lars
AU - Dahlstrand, Hanna
AU - Bjørge, Line
AU - Birrer, Michael J.
AU - Mirza, Mansoor R.
AU - Rossing, Maria
N1 - ©2024 The Authors; Published by the American Association for Cancer Research.
PY - 2024/12
Y1 - 2024/12
N2 - The management of advanced ovarian cancer (AOC) has undergone significant advancements with the emergence of molecular diagnostics, particularly in predicting responses to poly(ADP-ribose) polymerase 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 (AVANOVA1&2; NCT02354131), focusing on alterations pertaining radiological 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 AVANOVA1&2 trial, 151 pathogenic or likely pathogenic variants across 81 samples. PARPi sensitizing variants were found in two out of ten HRDneg samples from patients with clinical benefit (PFS ≥ 12 months), while three out of ten HRDpos 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.
AB - The management of advanced ovarian cancer (AOC) has undergone significant advancements with the emergence of molecular diagnostics, particularly in predicting responses to poly(ADP-ribose) polymerase 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 (AVANOVA1&2; NCT02354131), focusing on alterations pertaining radiological 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 AVANOVA1&2 trial, 151 pathogenic or likely pathogenic variants across 81 samples. PARPi sensitizing variants were found in two out of ten HRDneg samples from patients with clinical benefit (PFS ≥ 12 months), while three out of ten HRDpos 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.
KW - Adult
KW - Aged
KW - BRCA1 Protein/genetics
KW - BRCA2 Protein/genetics
KW - Biomarkers, Tumor/genetics
KW - Drug Resistance, Neoplasm/genetics
KW - Female
KW - Humans
KW - Middle Aged
KW - Mutation
KW - Ovarian Neoplasms/genetics
KW - Poly(ADP-ribose) Polymerase Inhibitors/therapeutic use
U2 - 10.1158/2767-9764.CRC-24-0294
DO - 10.1158/2767-9764.CRC-24-0294
M3 - Journal article
C2 - 39591206
SN - 2767-9764
VL - 4
SP - 3190
EP - 3200
JO - Cancer Research Communications
JF - Cancer Research Communications
IS - 12
ER -