Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib
Abstract Background The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors represented a paradigm shift in the treatment of ovarian cancer. Genomic data from patients with high-grade ovarian cancer in six phase II/III trials involving the PARP inhibitor olaparib were analyzed to better un...
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2024-12-01
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| Series: | Genome Medicine |
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| Online Access: | https://doi.org/10.1186/s13073-024-01413-5 |
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| author | Alan Barnicle Isabelle Ray-Coquard Etienne Rouleau Karen Cadoo Fiona Simpkins Carol Aghajanian Alexandra Leary Andrés Poveda Stephanie Lheureux Eric Pujade-Lauraine Benoit You Jonathan Ledermann Ursula Matulonis Charlie Gourley Kirsten M. Timms Zhongwu Lai Darren R. Hodgson Cathy E. Elks Simon Dearden Coumaran Egile Pierre Lao-Sirieix Elizabeth A. Harrington Jessica S. Brown |
| author_facet | Alan Barnicle Isabelle Ray-Coquard Etienne Rouleau Karen Cadoo Fiona Simpkins Carol Aghajanian Alexandra Leary Andrés Poveda Stephanie Lheureux Eric Pujade-Lauraine Benoit You Jonathan Ledermann Ursula Matulonis Charlie Gourley Kirsten M. Timms Zhongwu Lai Darren R. Hodgson Cathy E. Elks Simon Dearden Coumaran Egile Pierre Lao-Sirieix Elizabeth A. Harrington Jessica S. Brown |
| author_sort | Alan Barnicle |
| collection | DOAJ |
| description | Abstract Background The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors represented a paradigm shift in the treatment of ovarian cancer. Genomic data from patients with high-grade ovarian cancer in six phase II/III trials involving the PARP inhibitor olaparib were analyzed to better understand patterns and potential causes of genomic instability. Patients and methods Homologous recombination deficiency (HRD) was assessed in 2147 tumor samples from SOLO1, PAOLA-1, Study 19, SOLO2, OPINION, and LIGHT using next-generation sequencing technology. Genomic instability scores (GIS) were assessed in BRCA1 and/or BRCA2 (BRCA)-mutated (BRCAm), non-BRCA homologous recombination repair-mutated (non-BRCA HRRm), and non-HRRm tumors. Results BRCAm was identified in 1021/2147 (47.6%) tumors. BRCAm tumors had significantly higher GIS than non-BRCAm tumors (P < 0.001) and high biallelic loss (815/838; 97.3%) regardless of germline (658/672; 97.9%) or somatic (101/108; 93.5%) BRCAm status. In non-BRCA HRRm tumors (n = 121) a similar proportion were HRD-positive (GIS ≥ 42: 55/121; 45.5%) relative to HRD-negative (GIS < 42: 52/121; 43.0%). GIS was highly variable in non-BRCA HRRm (median 42 [interquartile range (IQR) 29–58]) and non-HRRm (n = 1005; median 32 [IQR 20–55]) tumors. Gene mutations with high GIS included HRR genes BRIP1 (median 46 [IQR 41–58]), RAD51C (median 58 [IQR 48–66]), RAD51D (median 62 [IQR 54–69]), and PALB2 (median 64 [IQR 58–74]), and non-HRR genes NF1 (median 49 [IQR 25–60]) and RB1 (median 55 [IQR 30–71]). CCNE1-amplified and PIK3CA-mutated tumors had low GIS (CCNE1-amplified: median 24 [IQR 18–29]; PIK3CA-mutated: median 32 [IQR 14–52]) and were predominantly non-BRCAm. Conclusions These analyses provide valuable insight into patterns of genomic instability and potential drivers of HRD, besides BRCAm, in ovarian cancer and will help guide future research into the potential clinical effectiveness of anti-cancer treatments in ovarian cancer, including PARP inhibitors as well as other precision oncology agents. Trial registration The SOLO1 trial was registered at ClinicalTrials.gov (NCT01844986) on April 30, 2013; the PAOLA-1 trial was registered at ClinicalTrials.gov (NCT02477644) on June 18, 2015 (retrospectively registered); Study 19 was registered at ClinicalTrials.gov (NCT00753545) on September 12, 2008 (retrospectively registered); the SOLO2 trial was registered at ClinicalTrials.gov (NCT01874353) on June 7, 2013; the OPINION trial was registered at ClinicalTrials.gov (NCT03402841) on January 3, 2018; the LIGHT trial was registered at ClinicalTrials.gov (NCT02983799) on November 4, 2016. |
| format | Article |
| id | doaj-art-2cc22ceb55de4044a920709aead2f670 |
| institution | Kabale University |
| issn | 1756-994X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | BMC |
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| series | Genome Medicine |
| spelling | doaj-art-2cc22ceb55de4044a920709aead2f6702024-12-22T12:39:19ZengBMCGenome Medicine1756-994X2024-12-0116111610.1186/s13073-024-01413-5Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparibAlan Barnicle0Isabelle Ray-Coquard1Etienne Rouleau2Karen Cadoo3Fiona Simpkins4Carol Aghajanian5Alexandra Leary6Andrés Poveda7Stephanie Lheureux8Eric Pujade-Lauraine9Benoit You10Jonathan Ledermann11Ursula Matulonis12Charlie Gourley13Kirsten M. Timms14Zhongwu Lai15Darren R. Hodgson16Cathy E. Elks17Simon Dearden18Coumaran Egile19Pierre Lao-Sirieix20Elizabeth A. Harrington21Jessica S. Brown22Translational Medicine, Oncology R&D, AstraZeneca, Cambridge Biomedical CampusMedical Oncology Department, Centre Léon Bérard and University Claude Bernard Lyon, and Groupe d’Investigateurs Nationaux pour l’Etude des Cancers Ovariens (GINECO)Department of Medical Biology and Pathology, Gustave Roussy, Cancer Genetics Laboratory, Gustave RoussyMemorial Sloan Kettering Cancer CenterDepartment of Obstetrics and Gynecology, Jordan Center for Gynecologic Oncology at the Abramson Cancer Center, University of PennsylvaniaMemorial Sloan Kettering Cancer CenterInstitut Gustave Roussy, and GINECOInitia Oncology, Hospital QuironsaludDepartment of Medical Oncology, Princess Margaret HospitalAssociation de Recherche Cancers Gynécologiques (ARCAGY)-GINECO, and GINECOMedical Oncology, IC-HCL, EPSILYONUCL Cancer Institute, University College London and UCL HospitalsDana-Farber Cancer InstituteCancer Research UK Scotland Centre, University of EdinburghMyriad GeneticsTranslational Medicine, Oncology R&D, Research and Early Development, AstraZenecaTranslational Medicine, Oncology R&D, Research and Early Development, AstraZenecaPrecision Medicine and Biosamples, Oncology R&D, AstraZenecaPrecision Medicine and Biosamples, Oncology R&D, AstraZenecaPrecision Medicine and Biosamples, Oncology R&D, AstraZenecaPrecision Medicine and Biosamples, Oncology R&D, AstraZenecaTranslational Medicine, Oncology R&D, AstraZeneca, Cambridge Biomedical CampusTranslational Medicine, Oncology R&D, AstraZeneca, Cambridge Biomedical CampusAbstract Background The introduction of poly(ADP-ribose) polymerase (PARP) inhibitors represented a paradigm shift in the treatment of ovarian cancer. Genomic data from patients with high-grade ovarian cancer in six phase II/III trials involving the PARP inhibitor olaparib were analyzed to better understand patterns and potential causes of genomic instability. Patients and methods Homologous recombination deficiency (HRD) was assessed in 2147 tumor samples from SOLO1, PAOLA-1, Study 19, SOLO2, OPINION, and LIGHT using next-generation sequencing technology. Genomic instability scores (GIS) were assessed in BRCA1 and/or BRCA2 (BRCA)-mutated (BRCAm), non-BRCA homologous recombination repair-mutated (non-BRCA HRRm), and non-HRRm tumors. Results BRCAm was identified in 1021/2147 (47.6%) tumors. BRCAm tumors had significantly higher GIS than non-BRCAm tumors (P < 0.001) and high biallelic loss (815/838; 97.3%) regardless of germline (658/672; 97.9%) or somatic (101/108; 93.5%) BRCAm status. In non-BRCA HRRm tumors (n = 121) a similar proportion were HRD-positive (GIS ≥ 42: 55/121; 45.5%) relative to HRD-negative (GIS < 42: 52/121; 43.0%). GIS was highly variable in non-BRCA HRRm (median 42 [interquartile range (IQR) 29–58]) and non-HRRm (n = 1005; median 32 [IQR 20–55]) tumors. Gene mutations with high GIS included HRR genes BRIP1 (median 46 [IQR 41–58]), RAD51C (median 58 [IQR 48–66]), RAD51D (median 62 [IQR 54–69]), and PALB2 (median 64 [IQR 58–74]), and non-HRR genes NF1 (median 49 [IQR 25–60]) and RB1 (median 55 [IQR 30–71]). CCNE1-amplified and PIK3CA-mutated tumors had low GIS (CCNE1-amplified: median 24 [IQR 18–29]; PIK3CA-mutated: median 32 [IQR 14–52]) and were predominantly non-BRCAm. Conclusions These analyses provide valuable insight into patterns of genomic instability and potential drivers of HRD, besides BRCAm, in ovarian cancer and will help guide future research into the potential clinical effectiveness of anti-cancer treatments in ovarian cancer, including PARP inhibitors as well as other precision oncology agents. Trial registration The SOLO1 trial was registered at ClinicalTrials.gov (NCT01844986) on April 30, 2013; the PAOLA-1 trial was registered at ClinicalTrials.gov (NCT02477644) on June 18, 2015 (retrospectively registered); Study 19 was registered at ClinicalTrials.gov (NCT00753545) on September 12, 2008 (retrospectively registered); the SOLO2 trial was registered at ClinicalTrials.gov (NCT01874353) on June 7, 2013; the OPINION trial was registered at ClinicalTrials.gov (NCT03402841) on January 3, 2018; the LIGHT trial was registered at ClinicalTrials.gov (NCT02983799) on November 4, 2016.https://doi.org/10.1186/s13073-024-01413-5Ovarian cancerGenomic instabilityTranslational researchOlaparib |
| spellingShingle | Alan Barnicle Isabelle Ray-Coquard Etienne Rouleau Karen Cadoo Fiona Simpkins Carol Aghajanian Alexandra Leary Andrés Poveda Stephanie Lheureux Eric Pujade-Lauraine Benoit You Jonathan Ledermann Ursula Matulonis Charlie Gourley Kirsten M. Timms Zhongwu Lai Darren R. Hodgson Cathy E. Elks Simon Dearden Coumaran Egile Pierre Lao-Sirieix Elizabeth A. Harrington Jessica S. Brown Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib Genome Medicine Ovarian cancer Genomic instability Translational research Olaparib |
| title | Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib |
| title_full | Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib |
| title_fullStr | Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib |
| title_full_unstemmed | Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib |
| title_short | Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib |
| title_sort | patterns of genomic instability in 2000 patients with ovarian cancer across six clinical trials evaluating olaparib |
| topic | Ovarian cancer Genomic instability Translational research Olaparib |
| url | https://doi.org/10.1186/s13073-024-01413-5 |
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