Search Results (3)

Background/Objectives: PARP inhibitors (PARPis) currently play frontline roles in the management of prostate, pancreatic, ovarian and breast cancers, but their roles in colorectal cancer (CRC) management have yet to be clarified. Importantly, the specific predictive biomarkers for PARPis in CRC are still matters of investigations. The aim of this study is to identify the potential predictive biomarkers of PARP inhibition in CRC. Methods: Gene set enrichment analyses (GSEAs) and drug ontology enrichment analyses (DOEAs) of PARPi response gene sets were applied as the surrogates of PARPi response to two CRC cohorts in order to compare the predictive capacities of TP53 mutation status, MSI status, as well as PARP1 and PARP2 expression for PARP inhibition to those of a homologous repair deficiency surrogate, and large-scale state transition (LST). Differential enrichment score (ES) and ontology enrichment (OE) analyses were used to interrogate the differential correlation of the predictive biomarkers with PARPi response, relative to LST. Results: The results demonstrated that LST-low, rather than LST-high, CRC subsets exhibited an enrichment of the PARPi response, in contrast to what has been established for other cancers. Furthermore, CRC subsets with wild-type TP53, positive MSI, as well as high PARP1 and PARP2 expression exhibited an enrichment of the PARPi response gene sets. Moreover, there was no differential enrichment of the PARPi response between LST and each of the MSI statuses, PARP1 expression and PARP2 expression. Furthermore, the preliminary differential enrichment observed between the LST-based and TP53 mutation status-based PARPi responses could not be validated with further testing. Conclusions: MSI status, TP53 mutation status as well as PARP1 and PARP2 expression may be substitutes for low LST as predictive biomarkers of PARPi response in CRC. Full article

Background: HRD is a key biomarker in ovarian cancer, predicting response to PARP inhibitors. However, it remains unclear whether HRD-positive patients differ from HRD-negative patients in terms of clinical characteristics in PARP inhibitor-naïve populations. This study aims to evaluate platinum-sensitive PARP-inhibitor naïve ovarian cancer patients’ clinical characteristics and survival outcomes based on HRD status. Secondly, to investigate whether platinum-resistant patients with homologous recombination repair (HRR) gene mutations are HRD-positive. Methods: Two distinct HRD algorithms—an in-house genomic instability score (GIS) and the normalized large-scale state transitions score (nLST)—were used to stratify patients as HRD-positive or HRD-negative. Clinical data and survival in PARP inhibitor-naïve, platinum-sensitive HGSC patients were analyzed. Results: A total of 71 platinum-sensitive PARP-inhibitor naïve patients were analyzed. By in-house GIS, 37 patients (52%) were classified as HRD-positive and 34 (48%) as HRD-negative. Using nLST, 43 (61%) were HRD-positive and 28 (39%) were HRD-negative. Our analysis revealed no significant differences in clinical parameters or survival between HRD-positive and HRD-negative platinum-sensitive patients. The only observed difference was that somatic BRCA1/2-mutated patients were younger. In the subgroup of six platinum-resistant patients harboring HRR gene mutations, four patients (67%) were classified as HRD positive. Conclusions: Our findings suggest that HRD status does not significantly influence clinical characteristics or survival outcomes in platinum-sensitive, PARP inhibitor-naïve HGSC patients. As some platinum-resistant patients with HRR gene mutations were HRD positive; this subgroup may benefit from further investigation into the potential effect of PARP inhibitors. Full article

The Homologous Recombination Deficiency (HRD) Score, determined by evaluating genomic instability through the assessment of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale state transitions (LST), serves as a crucial biomarker for identifying patients who might benefit from targeted therapies, such as PARP inhibitors (PARPi). This study aimed to investigate the efficacy of HRD testing in high-grade serous ovarian carcinoma, tubal, and peritoneal cancer patients who are negative for somatic BRCA1 and BRCA2 mutations and to evaluate the impact of HRD status on Bevacizumab and PARPi therapy response. A cohort of 100 Romanian female patients, aged 42–77, was initially selected. Among them, 30 patients had unsuitable samples for HRD testing due to insufficient tumor content or DNA integrity. Using the OncoScan C.N.V. platform, HRD testing was successfully performed on the remaining 70 patients, with 20 testing negative and 50 testing positive for HRD. Among the HRD-positive patients, 35 were eligible for and benefited from PARPi maintenance therapy, resulting in a median progression-free survival (PFS) increase from 4 months to 8.2 months. Our findings support the importance of HRD testing in ovarian cancer patients, demonstrating the potential therapeutic advantage of PARPi therapy in HRD-positive patients without somatic BRCA1/2 mutations. Full article