The 2026 Congress of the European Society for Medical Oncology (ESMO) was held in Madrid, Spain, from October 23 to 27. As one of the world's most important annual meetings in clinical oncology, ESMO presents major research advances across multiple fields each year, including gynecologic oncology. PARP inhibitor maintenance therapy has significantly improved outcomes in patients with BRCA-mutated ovarian cancer. In clinical practice, however, eligibility for treatment is commonly determined using a binary classification based on the presence or absence of pathogenic BRCA mutations.Two poster studies presented at this year’s ESMO Congress (1348eP and 1349eP) independently focused on the specific genomic locations and protein functional domains of BRCA1/2 mutations. Through systematic reviews and meta-analysis, both studies demonstrated that not all BRCA mutations confer the same degree of benefit from PARP inhibitors, and that the functional domain in which a mutation occurs is a key factor influencing treatment efficacy.
Together, these studies challenge the current simplistic binary classification approach and suggest that future clinical practice should move beyond asking whether a mutation is present to examining where the mutation occurs. This more refined approach may provide new insights into the individualized selection of PARP inhibitor therapy for ovarian cancer.
Oncology Frontier invited Professor Tao Zhu from Zhejiang Cancer Hospital to comment on these two studies. The research findings and his expert insights are presented below.
Research Overview
1. Association Between BRCA1/BRCA2 Mutation Sites and the Benefit of PARP Inhibitor Maintenance Therapy in Ovarian Cancer: A Systematic Review
Abstract No.: 1348eP
Background
PARP inhibitor maintenance therapy has significantly improved outcomes in patients with epithelial ovarian cancer. However, some studies have suggested that only patients carrying germline pathogenic BRCA1/2 variants benefit from PARP inhibitor maintenance therapy. This study aimed to analyze differences in treatment benefit according to the genomic locations of BRCA1/2 mutations.
Methods
A systematic review was conducted in accordance with PRISMA guidelines. PubMed, Embase, and Scopus were searched for studies published between January 2015 and March 2026. Studies involving patients with epithelial ovarian cancer who received PARP inhibitors and for whom BRCA mutation sites were reported were included. Survival outcomes were analyzed according to the type of pathogenic or likely pathogenic BRCA1/2 variant (LP/PV) and mutation location, including exon and protein functional domain.
Results
A total of 12 studies involving 3,349 patients were included. Among them, 2,430 patients (72.5%) carried pathogenic or likely pathogenic BRCA1/2 variants, and 1,326 (54.6%) of these BRCA mutation carriers received PARP inhibitor treatment. The most common mutation types were frameshift mutations (51.5%), nonsense mutations (23.7%), and missense mutations (15.0%).
Analysis by protein functional domain showed that BRCA1 mutations were primarily concentrated in the BRCT domain (22.4%) and DNA-binding domain (DBD, 19.0%). BRCA2 mutations were most frequently found in the RAD51-binding domain (40.9%) and the DNA-binding domain (DBD, 19.4%).
Survival analyses indicated that the benefit of PARP inhibitors varied according to mutation location. Patients with BRCA1 mutations in the DNA-binding domain (DBD) experienced a significant progression-free survival (PFS) benefit. Patients with BRCA1 RING domain mutations and BRCA2 RAD51-binding domain mutations also benefited from PARP inhibitor treatment.
At the mutation-type level, frameshift and nonsense mutations were associated with clinical benefit from PARP inhibitors, whereas no significant benefit was observed for splice-site mutations. With regard to specific exons, patients with mutations outside exon 11 appeared to derive greater benefit from olaparib than those with exon 11 mutations, although the evidence was not entirely consistent across studies.
Conclusions
The clinical benefit of PARP inhibitor treatment in patients with ovarian cancer is not uniform across all BRCA1/2 mutations. The specific genomic location of a mutation can significantly influence treatment efficacy. Incorporating protein functional domain information into clinical decision-making may help identify patients most likely to benefit from PARP inhibitor therapy.
2. BRCA Functional Domain Mutations as Predictive Biomarkers of PARP Inhibitor Benefit in Ovarian Cancer: A Systematic Review and Meta-Analysis
Abstract No.: 1349eP
Background
In clinical practice, BRCA-mutated high-grade serous ovarian cancer (HGSOC) is often treated as a single disease category. However, substantial heterogeneity exists in patient prognosis and response to PARP inhibitors, suggesting that not all BRCA mutations disrupt homologous recombination repair to the same extent or produce a uniform synthetic lethality effect. This study investigated whether specific BRCA mutation domains could differentially predict the benefit of PARP inhibitor treatment.
Methods
PubMed, Embase, and the Cochrane Library were searched for studies published up to April 2026. Eligible studies reported survival outcomes in patients with BRCA-mutated HGSOC receiving PARP inhibitors versus a control group, with results stratified by mutation functional domain. A random-effects model was used to pool hazard ratios (HRs) in R software (version 4.5.2), and heterogeneity was assessed using I².
PROSPERO registration number: CRD420261378729.
Results
Five studies met the inclusion criteria, comprising four retrospective cohort studies and one phase III clinical trial, with a total of 1,659 patients. The PFS benefit associated with PARP inhibitors varied according to the functional domain affected by the mutation:
- BRCA1 DNA-binding domain (DBD) mutations: HR = 0.37; 95% CI: 0.24–0.55; P < 0.01; I² = 0%. Significant PFS benefit was observed.
- BRCA1 RING domain mutations: HR = 0.31; 95% CI: 0.12–0.30; P = 0.02; I² = 35%. Significant PFS benefit was observed.
- BRCA1 BRCT domain mutations: HR = 0.58; 95% CI: 0.30–1.11; P = 0.9; I² = 55%. No statistically significant PFS benefit was observed.
- BRCA2 DNA-binding domain (DBD) mutations: HR = 0.28; 95% CI: 0.12–0.66; P < 0.01; I² = 0%. Significant PFS benefit was observed.
- BRCA2 RAD51-binding domain mutations: HR = 0.29; 95% CI: 0.18–0.47; P < 0.01; I² = 0%. Significant PFS benefit was observed.
- BRCA2 exon 10/11 mutations: HR = 0.42; 95% CI: 0.31–0.59; P < 0.01; I² = 0%. Significant PFS benefit was observed.
Conclusions
In HGSOC, the efficacy of PARP inhibitors varies according to the functional domain affected by BRCA mutations. These findings suggest that clinical decision-making should move beyond the simple binary determination of whether a BRCA mutation is present and toward functional domain-based stratification. Prospective validation is needed, along with standardized reporting of mutation-site information in clinical trials, to optimize patient selection for PARP inhibitor maintenance therapy.
Expert Commentary
Professor Tao Zhu:
The two systematic reviews and meta-analyses presented at this year’s ESMO Congress, abstracts 1348eP and 1349eP, focused on the relationship between BRCA1/2 mutation functional domains and the benefit of PARP inhibitors in ovarian cancer. Both challenge the current clinical practice of binary stratification based on the presence or absence of pathogenic BRCA mutations and offer important insights into individualized PARP inhibitor treatment for ovarian cancer.
For a long time, the presence of pathogenic or likely pathogenic BRCA1/2 variants has served as the central criterion for identifying patients likely to benefit from PARP inhibitor maintenance therapy. This approach assumes that all pathogenic BRCA variants confer a similar synthetic lethality effect and, consequently, comparable treatment benefit. In real-world practice, however, ovarian cancer patients carrying the same BRCA mutation can experience substantial individual differences in the duration of disease control and risk of recurrence after receiving PARP inhibitors.
These two studies help explain the source of this heterogeneity by examining BRCA mutations from the perspective of protein functional domains. The functional domain in which a BRCA mutation occurs directly determines the extent to which homologous recombination repair is impaired, thereby influencing the efficacy of PARP inhibitors.
The systematic review in abstract 1348eP showed that BRCA1 and BRCA2 mutations have distinct patterns of distribution across functional domains. BRCA1 mutations are concentrated in the BRCT and DBD domains, whereas BRCA2 mutations occur more frequently in the RAD51-binding and DBD domains. Mutation type also provides clinically relevant information: patients with frameshift or nonsense mutations appear more likely to benefit from PARP inhibitors, while no significant benefit was observed among those with splice-site mutations. Some data also suggest that exon location may influence the efficacy of olaparib. However, the evidence remains inconsistent and requires further validation.
The meta-analysis in abstract 1349eP provides additional quantitative evidence, demonstrating substantial differences in PFS benefit across patient populations with mutations in different functional domains. Patients with BRCA1 DBD or RING domain mutations clearly benefited from PARP inhibitors. In contrast, BRCA1 BRCT domain mutations were not associated with a statistically significant improvement in PFS. This is a finding of considerable clinical relevance, suggesting that even among patients with pathogenic BRCA1 mutations, those with BRCT domain mutations may derive limited benefit from PARP inhibitor maintenance therapy.
For BRCA2, however, significant PFS benefits from PARP inhibitor treatment were observed across mutations in the DBD, RAD51-binding domain, and exons 10/11. Most subgroups in this meta-analysis had an I² value of 0%, indicating low between-study heterogeneity and lending greater confidence to the findings. Nevertheless, it is important to note that the included studies were predominantly retrospective cohort studies, with only one phase III clinical trial. The overall level of evidence therefore remains limited.
Taken together, these two studies prompt us to reconsider how genetic testing reports are currently interpreted in clinical practice. Most genetic testing reports simply indicate whether a pathogenic BRCA mutation has been detected, with relatively little in-depth interpretation of the protein functional domain in which the mutation occurs. In the future, clinical interpretation of BRCA reports should go beyond determining whether a variant is pathogenic and also consider the specific functional domain affected.
For patients with ovarian cancer harboring BRCA1 BRCT domain mutations, the expected benefit of PARP inhibitor maintenance therapy should be carefully weighed against treatment costs and the risk of adverse events. By contrast, patients with BRCA1 DBD or RING domain mutations, as well as those with BRCA2 mutations in the functional domains associated with benefit, represent populations with a greater likelihood of benefiting from PARP inhibitor maintenance therapy.
Of course, these studies also have several limitations. First, both are systematic reviews and meta-analyses that synthesize existing evidence rather than prospective clinical trials. They therefore cannot fully eliminate selection bias in the original studies. Second, germline and somatic BRCA mutations were not adequately analyzed in separate strata, and the predictive value of functional domains in the context of somatic mutations remains unclear. Third, some subgroups had limited sample sizes, and efficacy data remain scarce for less common mutation types, such as splice-site and missense mutations. Fourth, the studies primarily focused on HGSOC, and it remains uncertain whether these findings can be extrapolated to other histological subtypes of epithelial ovarian cancer.
Looking ahead to clinical practice, these two studies point to a particularly valuable direction: incorporating protein functional domain annotations into BRCA genetic testing reports. In ovarian cancer clinical trials, mutation information should also be collected and reported in a standardized manner, including the specific mutation site, exon, and functional domain. Prospective cohort studies are needed to validate the predictive value of functional domain-based stratification.
We look forward to larger prospective studies that will further refine efficacy prediction models based on BRCA functional domains. Ultimately, this may enable more precise and individualized patient selection for PARP inhibitor treatment in ovarian cancer, ensuring that patients who are most likely to benefit receive appropriately targeted therapy while helping avoid overtreatment in those whose expected benefit may be limited.
Professor Tao Zhu
