Patterns of genomic instability in > 2000 patients with ovarian cancer across six clinical trials evaluating olaparib

被引：1

作者：

Barnicle, Alan ^{[1
]}

Ray-Coquard, Isabelle ^{[2
,3
,4
]}

Rouleau, Etienne ^{[5
]}

Cadoo, Karen ^{[6
]}

Simpkins, Fiona ^{[7
]}

Aghajanian, Carol ^{[6
]}

Leary, Alexandra ^{[8
]}

Poveda, Andres ^{[9
]}

Lheureux, Stephanie ^{[10
]}

Pujade-Lauraine, Eric ^{[11
]}

You, Benoit ^{[12
,13
]}

Ledermann, Jonathan

Matulonis, Ursula

Gourley, Charlie ^{[14
]}

Timms, Kirsten M. ^{[15
]}

Lai, Zhongwu ^{[16
]}

Hodgson, Darren R. ^{[16
]}

Elks, Cathy E. ^{[17
]}

Dearden, Simon ^{[17
]}

Egile, Coumaran ^{[17
]}

Lao-Sirieix, Pierre ^{[17
]}

Harrington, Elizabeth A. ^{[1
]}

Brown, Jessica S. ^{[1
]}

机构：

[1] AstraZeneca, Translat Med, Oncol R&D, Cambridge Biomed Campus,1 Francis Crick Ave, Cambridge CB2 0AA, England

[2] Ctr Leon Berard, Med Oncol Dept, Lyon, France

[3] Univ Claude Bernard Lyon, Lyon, France

[4] Grp Invest Nat Etud Canc Ovariens GINECO, Lyon, France

[5] Gustave Roussy, Dept Med Biol & Pathol, Canc Genet Lab, Villejuif, France

[6] Mem Sloan Kettering Canc Ctr, New York, NY USA

[7] Univ Penn, Jordan Ctr Gynecol Oncol, Dept Obstet & Gynecol, Abramson Canc Ctr, Philadelphia, PA USA

[8] Inst Gustave Roussy, GINECO, Villejuif, France

[9] Hosp Quironsalud, Initia Oncol, Valencia, Spain

[10] Princess Margaret Hosp, Dept Med Oncol, Toronto, ON, Canada

[11] Assoc Rech Canc Gynecol ARCAGY, GINECO, Paris, France

[12] Univ Lyon 1, Med Oncol, IC HCL, EPSILYON, Lyon, France

[13] GINECO, Lyon, France

[14] Univ Edinburgh, Canc Res UK Scotland Ctr, Edinburgh, Scotland

[15] Myriad Genet, Salt Lake City, UT USA

[16] AstraZeneca, Translat Med, Oncol R&D, Res & Early Dev, Boston, MA USA

[17] AstraZeneca, Precis Med & Biosamples, Oncol R&D, Cambridge, England

来源：

GENOME MEDICINE | 2024年 / 16卷 / 01期

关键词：

Ovarian cancer; Genomic instability; Translational research; Olaparib; HOMOLOGOUS RECOMBINATION DEFICIENCY; MAINTENANCE THERAPY; PATIENTS PTS; PSR OC; PLUS BEVACIZUMAB; DNA-REPAIR; SURVIVAL; MUTATION; CHEMOTHERAPY; MONOTHERAPY;

D O I：

10.1186/s13073-024-01413-5

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：16

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