Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches
Abstract
:1. Homologous Recombination Deficiency (HRD)
2. HRD in Ovarian Cancer
Trial | Drug | Efficacy Data | Ref. |
---|---|---|---|
ARIEL2 | Rucaparib | Response rates: 69% for BRCA-mutated tumors, 39% for BRCA wild-type and high LOH tumors, and 11% for BRCA wild-type and low LOH tumors (p < 0.0001). | [42,43] |
ARIEL3 | Rucaparib | Improved PFS compared with placebo in both patients with mutated BRCA (16.6 versus 5 months, HR = 0.23, 95% CI = 0.16–0.34) and those with HRD (13.6 versus 5.4 months, HR = 0.32, 95% CI = 0.24–0.42), and in the whole population (10.8 versus 5.4 months, HR = 0.36, 95% CI = 0.30–0.45) including LOH negative patients. | [44] |
NOVA | Niraparib | Niraparib was associated with better median PFS in all subgroups, with a more substantial benefit in the gBRCA cohort (21.0 versus 5.5 months, HR = 0.27; 95% CI = 0.17–0.41) than in the non-gBRCA cohort with HRD (12.9 versus 3.8 months, HR = 0.38; 95% CI = 0.24–0.59) and the entire non-gBRCA cohort (9.3 versus 3.9 months, HR = 0.45; 95% CI = 0.34). | [45] |
Study19 | Olaparib | Improvement in OS in patients with BRCA-mutated recurrent ovarian cancer who received olaparib maintenance therapy following platinum-based chemotherapy (29.8 versus 27.8 months, HR = 0.73; 95% CI = 0.55–0.95). This occurrence represents a secondary endpoint of the trial. The results support previously reported benefits of olaparib in PFS compared to placebo, which is the primary trial endpoint (8.4 versus 4.8 months, HR = 0.35; 95% CI = 0.25–0.49). | [46,47] |
SOLO-1 | Olaparib | The SOLO-1 trial demonstrated a long-term PFS advantage for olaparib versus placebo in the first-line maintenance treatment of patients with HGSOC with a germline or somatic mutation in BRCA1/2 who had a complete or partial response after platinum-based chemotherapy. Data revealed olaparib reduced the risk of disease progression or death by 67% (based on an HR of 0.33; 95% CI = 0.25–0.43) and increased PFS to a median of 56.0 months compared with 13.8 months of placebo. | [48,49] |
SOLO-2 | Olaparib | Results from the phase III SOLO-2 trial demonstrate an improvement in PFS in patients with platinum-sensitive relapsed ovarian cancer and gBRCA mutations treated with olaparib compared to placebo in the maintenance setting: PFS (19.1 versus 5.5 months, HR = 0.30; 95% CI = 0.22–0.41). Although there was no statistically significant difference in OS, the results supported the use of olaparib for maintenance in these patients. | [50,51,52] |
PRIMA | Niraparib | In the HRD population, maintenance therapy with niraparib led to a reduction in the risk of progression or death by 57% (HR = 0.43; 95% CI 0.31–0.59), whereas in the intention-to-treat population, the risk reduction was 38% (HR = 0.62; 95% CI 0.5–0.76). In the HR-proficient subgroup maintenance therapy with niraparib led to 32% reduction in the risk of progression or death (HR = 0.68; 95% CI, 0.49–0.94). | [20,49] |
VELIA | Veliparib | Across all patient subgroups, PFS for the combined induction and maintenance phases in the veliparib arm was 23.5 months versus 17.3 months in the placebo arm (HR = 0.68; 95% CI 0.56–0.83). The benefit was most evident for those with BRCA mutations. In this group, the median PFS was 34.7 months, compared with 22.0 months for veliparib and placebo, respectively (HR 0.44; 95% CI 0.28–0.68), whereas in the HRD cohort, PFS was 31.9 versus. 20.5 months (HR = 0.57; 95% CI: 0.43–0.76). Unfortunately, veliparib is not FDA-approved. | [53] |
PAOLA-1 | Olaparib | Results showed that olaparib in combination with bevacizumab reduced the risk of disease progression or death by 41% and improved PFS in the intention-to-treat population with a median of 22.1 months compared with 16.6 months in patients treated with bevacizumab monotherapy (HR = 0.59; 95% CI 0.49–0.72). Subgroup analysis also highlighted an essential synergistic effect of the combination in patients with BRCA mutation and HRD, with a mean PFS of 37.2 months and an HR of 0.31 (95% CI 0.20–0.47) and 0.33 (95% CI 0.25–0.45), respectively. However, adding olaparib to bevacizumab showed almost no effect in the HRD-negative or unknown HRD status subgroup, where the median PFS was 16.9 months in the experimental arm versus 16 months in the control arm. These data support the hypothesis of the synergistic effect of olaparib and bevacizumab in BRCA mutant and HRD patients, underscoring the importance of HRD status as a novel prognostic factor and predictor of response to PARP inhibitors. | [49,54] |
3. HRD Assays
3.1. Mutations of Genes in the HRR Pathway
3.2. Genomic Scars or Mutational Markers Showing Profiles of Genomic Instability
3.3. Functional Assays of HRD
4. Outsourcing of HRD Analysis
5. HRD in a Laboratory Routine
6. Current HRD Assay Limitations
6.1. FFPE Material
6.2. Representative Tumour Area Selection
6.3. Tumour Evolution Events
6.4. Intratumor Heterogenicity
6.5. Alterations of Uncertain Significance (VUS)
7. Conclusions
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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ARID1A | EMSY | MSH2 |
ATM | FANCA | NBN |
ATR | FANCC | PALB2 |
BRCA1/2 | FANCE | PTEN |
BARD1 | FANCF | RAD50 |
BAP1 | FANCD2 | RAD51 |
BRIP1 | FANCG | RAD51B |
BLM | FANCI | RAD51C |
CDK12 | FANCL | RAD51D |
CHEK1 | H2AX | RAD54L |
CHEK2 | MRE11 | TP53 |
Genomic scar | Description |
---|---|
Loss of heterozygosity (LOH) | One of the two alleles for a gene is lost, resulting in a homozygous cell. Failure of the remaining allele could result in the growth of malignant cells. |
Telomeric allelic imbalance (TAI) | The proportion of alleles at the end of the chromosome (telomere) in a pair does not correspond, indicating that one chromosome has more alleles than the other. |
Large-scale transitions (LSTs) | Breakpoints between regions of the chromosome cause discrepancies within the chromosome pair. |
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Mangogna, A.; Munari, G.; Pepe, F.; Maffii, E.; Giampaolino, P.; Ricci, G.; Fassan, M.; Malapelle, U.; Biffi, S. Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches. J. Pers. Med. 2023, 13, 284. https://doi.org/10.3390/jpm13020284
Mangogna A, Munari G, Pepe F, Maffii E, Giampaolino P, Ricci G, Fassan M, Malapelle U, Biffi S. Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches. Journal of Personalized Medicine. 2023; 13(2):284. https://doi.org/10.3390/jpm13020284
Chicago/Turabian StyleMangogna, Alessandro, Giada Munari, Francesco Pepe, Edoardo Maffii, Pierluigi Giampaolino, Giuseppe Ricci, Matteo Fassan, Umberto Malapelle, and Stefania Biffi. 2023. "Homologous Recombination Deficiency in Ovarian Cancer: from the Biological Rationale to Current Diagnostic Approaches" Journal of Personalized Medicine 13, no. 2: 284. https://doi.org/10.3390/jpm13020284