Abstract / Description of output
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.
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.
Original language | English |
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Journal | Genome Medicine |
Publication status | Published - 18 Dec 2024 |
Keywords / Materials (for Non-textual outputs)
- ovarian cancer
- genomic instability
- translational research
- olaparib