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
{"title":"在6个评估奥拉帕尼的临床试验中，bbb2000例卵巢癌患者的基因组不稳定性模式","authors":"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","doi":"10.1186/s13073-024-01413-5","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>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.</p><p><strong>Patients and methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>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.</p>","PeriodicalId":12645,"journal":{"name":"Genome Medicine","volume":"16 1","pages":"145"},"PeriodicalIF":10.4000,"publicationDate":"2024-12-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657106/pdf/","citationCount":"0","resultStr":"{\"title\":\"Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib.\",\"authors\":\"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\",\"doi\":\"10.1186/s13073-024-01413-5\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>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.</p><p><strong>Patients and methods: </strong>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.</p><p><strong>Results: </strong>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.</p><p><strong>Conclusions: </strong>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.</p><p><strong>Trial registration: </strong>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.</p>\",\"PeriodicalId\":12645,\"journal\":{\"name\":\"Genome Medicine\",\"volume\":\"16 1\",\"pages\":\"145\"},\"PeriodicalIF\":10.4000,\"publicationDate\":\"2024-12-18\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11657106/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Genome Medicine\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1186/s13073-024-01413-5\",\"RegionNum\":1,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Genome Medicine","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s13073-024-01413-5","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib.
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.
期刊介绍：
Genome Medicine is an open access journal that publishes outstanding research applying genetics, genomics, and multi-omics to understand, diagnose, and treat disease. Bridging basic science and clinical research, it covers areas such as cancer genomics, immuno-oncology, immunogenomics, infectious disease, microbiome, neurogenomics, systems medicine, clinical genomics, gene therapies, precision medicine, and clinical trials. The journal publishes original research, methods, software, and reviews to serve authors and promote broad interest and importance in the field.
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