The BRCA Gene in Epithelial Ovarian Cancer
Abstract
:Simple Summary
Abstract
1. BRCA Gene as Therapeutic Target
1.1. DNA Damage Repair (DDR) and BRCA Function
1.2. Challenges of BRCA Testing: Germline vs. Somatic vs. Both
2. BRCA Gene and Hereditary Ovarian Cancer Syndrome
3. BRCA Gene in the Clinic
3.1. Prognostic Implication
3.2. Predictive Factor of PARPi Sensitivity
4. Clinical Data with PARPi in BRCA-Mutated OC Patients
4.1. Maintenance Therapy
4.2. PARPi Single Agent as Treatment
4.3. Challenges and Future Approaches
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
References
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Germline HR Testing | Somatic HR Testing | |
---|---|---|
Sample | Blood (EDTA anticoagulated) or derivative fractions | Fresh or FFPE tissue, cytological samples |
Processing is not very good | Important fixation, paraffination, decalcification conditions | |
Rapid sample processing to avoid RNA degradation | Sample selection for at least 30% tumor cells (>50% ideally) | |
Analytical considerations | Only germline variants are detected | Both germline and somatic variants are detected |
Expected VAF, around 50% | Expected VAF from 5% | |
Read depth 50× to 200× | Recommended read depth 500× to 2000× | |
No variants due to technical issues | Potential false positives due to fixation | |
More straightforward and validated NGS and pipeline analyses | Complex and difficult to implement NGS and pipelines | |
10% of patients with indication will be missed (somatic only) | All patients with indication will be detected | |
Other considerations | False negative results at homopolymeric traits with mutations | |
Significant number if VUS identified | ||
Need for accurate detection of large genomic rearrangements and CNVs |
Study | Phase | Population | Study Arm | Control Arm | Results |
---|---|---|---|---|---|
Study-19 NCT00753545 | II | Recurrent HG (G2 or 3) OC/FP/PPC ≥2 platinum-based chemotherapy With an objective response to the platinum regimen | Olaparib 400 mg BID | Placebo | gBRCAm PFS 11.2 vs. 4.3 m HR 0.18 (95% CI, 0.10–0.31) |
SOLO-2 NCT01874353 | III | Recurrent OC/FP/PPC ≥2 platinum-based chemotherapy With an objective response to the platinum regimen BRCAm | Olaparib 300 mg BID | Placebo | PFS 19.1 vs. 5.5 m HR 0.30 (95% CI, 0.22–0.41) |
NOVA NCT01847274 | III | Recurrent HGSOC/FP/PPC ≥2 platinum-based chemotherapy Platinum sensitive (>6 months) | Niraparib 300 mg daily | Placebo | gBRCAm PFS: 21.0 vs. 5.5 m HR 0.27 (95% CI, 0.17–0.41) Non-gBRCA PFS 9.3 vs. 3.9 m HR 0.45 (95% CI, 0.34–0.61) |
ARIEL-3 NCT01968213 | III | Recurrent HGSOC/endometrioid (or FP/PPC) ≥2 platinum-based chemotherapy Platinum sensitive (>6 months) ≤1 non-platinum chemotherapy CR/PR platinum-based chemotherapy | Rucaparib 600 mg BID | Placebo | ITT PFS 10.8 m vs. 5.4 m HR 0.37 (95% CI, 0.30–0.45) BRCAm PFS 16.6 m vs. 5.4 m HR 0.23 (95% CI, 0.16–0.34) |
Study | Phase | Population | Study Arm | Control Arm | Results |
---|---|---|---|---|---|
SOLO-1 NCT01844986 | III | HGSOC/endometrioid (or FP/PPC) FIGO III–IV BRCAm CR/PR platinum-based chemotherapy | Olaparib 300 mg BID | Placebo | PFS NR vs. 13.8 m HR 0.30 (95% CI 0.23–0.41) |
PRIMA NCT02655016 | III | HGSOC/endometrioid (or FP/PPC) FIGO III–IV Regardless of BRCA status CR/PR platinum-based chemotherapy | Niraparib 300 mg daily | Placebo | ITT PFS 13.8 vs. 8.2 m HR 0.62 (95% CI 0.50–0.76) HRD PFS 21.9 vs. 10.4 m HR 0.43 (95% CI 0.31–0.59) BRCAmut 0.40 (95% CI, 0.27–0.62) |
PAOLA-1 NCT02477644 | III | HGSOC/endometrioid/other epithelial non-mucinous (or FP/PPC) FIGO IIIB, IIIC or IV gBRCAm/BRCAwt if HGS CR/PR platinum-based chemotherapy | Olaparib 300 mg BID + bevacizumab 15 mg/kg/3 wks | Placebo + Bevacizumab 15 mg/kg/3 wks | ITT PFS 22.1 vs. 16.6 m HR 0.59 (95% CI 0.49–0.72) BRCAmut HR 0.31 (95% CI 0.20–0.47) |
VELIA NCT02470585 | III | HGSOC OC (or FP/PPC) FIGO III–IV | Paclitaxel-carboplatin-veliparib (150 mg BID-2 weeks 400 mg BID) → veliparib | Paclitaxel-carboplatin-placebo → placebo | ITT PFS: 23.5 vs. 17.3 m HR 0.68 (95% CI 0.56–0.83) BRCAmut PFS: 34.7 vs. 22 m HR 0.44 (95% CI 0.28–0.68) |
Study | Phase | Population | Study Arm | Control Arm | Results |
---|---|---|---|---|---|
SOLO-3 NCT02282020 | III | Recurrent HGSOC/endometrioid (or FP/PPC) ≥2 platinum-based chemotherapy Platinum sensitive (>6 months) BRCAm | Olaparib 300 mg BID | Chemotherapy | PFS 13.4 vs. 9.2 m HR 0.62 (95% CI 0.43–0.91) |
Study-10 NCT01482715 | I/II | Recurrent HG OC/FP/PPC ≥3 platinum-based chemotherapy BRCAm | Rucaparib 600 mg BID | No comparator arm | ORR 59.5% mDOR 7.8 m (95% CI 5.6–10.5) |
ARIEL-2 NCT01891344 | II | Recurrent HGSOC (G2 or G3)/endometrioid (or FP/PPC) Prior platinum-based chemotherapy Platinum sensitive (>6 months) (R: 8 weeks from the last cycle) | Rucaparib 600 mg BID | No comparator arm | PFS BRCAm: 12.8 m LOH low: 5.2 m LOH high: 5.7 m HR 0.27 (95% CI 0.16–0.44) |
ARIEL-4 NCT02855944 | III | Recurrent HG OC/FP/PPC ≥2 chemotherapy regimens g/s BRCAm | Rucaparib 600 mg BID | Chemotherapy | PFS 7.4 m vs. 5.7 m HR 0.64 (95% CI 0.49–0.84) |
QUADRA NCT02354586 | II | Recurrent HGSOC (or FP/PPC) ≥3–4 previous chemotherapy regimens Platinum sensitive (>6 months) HRD/gBRCA testing | Niraparib 300 mg daily | No comparator arm | PFS 5.5 m (95% CI 3.5–8.2) |
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Sánchez-Lorenzo, L.; Salas-Benito, D.; Villamayor, J.; Patiño-García, A.; González-Martín, A. The BRCA Gene in Epithelial Ovarian Cancer. Cancers 2022, 14, 1235. https://doi.org/10.3390/cancers14051235
Sánchez-Lorenzo L, Salas-Benito D, Villamayor J, Patiño-García A, González-Martín A. The BRCA Gene in Epithelial Ovarian Cancer. Cancers. 2022; 14(5):1235. https://doi.org/10.3390/cancers14051235
Chicago/Turabian StyleSánchez-Lorenzo, Luisa, Diego Salas-Benito, Julia Villamayor, Ana Patiño-García, and Antonio González-Martín. 2022. "The BRCA Gene in Epithelial Ovarian Cancer" Cancers 14, no. 5: 1235. https://doi.org/10.3390/cancers14051235