BRCA wild-type

To evaluate the efficacy and safety of biomarker-driven combinatorial therapies of pamiparib, tislelizumab, bevacizumab, and nab-paclitaxel in platinum-resistant, recurrent ovarian cancer. Recruitment is estimated to be completed by 2024 and results may be published by 2027. ClinicalTrials.gov: NCT05044871.

Consequently, the combination of CLK2 and poly ADP-ribose polymerase inhibitors achieved synergistic lethal effect to overcome platinum resistance in patient-derived xenografts, especially those with wild-type BRCA1. These findings provide evidence for a potential strategy to overcome platinum resistance in OC patients by targeting CLK2.

Furthermore, TS-24 demonstrated the additional effect of inhibiting cell migration. Our study suggests that employing CTSS inhibitors for the functional restoration of BRCA1 to enhance RT-induced apoptosis may provide a novel therapeutic opportunity for TNBC patients harboring wild-type BRCA1.

Patients with HER2-overexpressing OC exhibited distinct histological, IHC, and genomic profiles. HER2-targeting agents are potential options for BRCA-wildtype patients, particularly as later lines of treatment.

Two CDK-inhibitors (CDKi), the broad range dinaciclib and the CDK12-specific SR-4835, strongly reduced the expression of key HR genes and impaired HR functionality, as illustrated by BRCA1 and RAD51 nuclear foci obliteration. However, no olaparib response improvement was observed in vivo with SR-4835. These data support that the implementation of CDK-inhibitors could be effective to sensitize TNBC to olaparib as well as possibly to cisplatin or gemcitabine.

Subsequent preclinical experiments demonstrated significant cytotoxicity of POLA1 silencing in combination with CHK1i in platinum-resistant HGSOC cell line models. Therefore, POLA1 expression may be predictive for CHK1i resistance, and the concurrent POLA1 inhibition may improve the efficacy of CHK1i monotherapy in this hard-to-treat population, deserving further investigation.

Furthermore, VDX-111 inhibited tumor growth in patient-derived xenograft and syngeneic murine models. In conclusion, the cytotoxic effects of VDX-111 seen in vitro and in vivo appear to occur in a necroptosis-dependent manner and may promote an antitumor immune response.

Many are searching for reliable biomarkers of immune response to increase efficacy of ICI therapy involving ovarian cancer. In this review, we examine the evidence supporting the combination of PARPi and ICIs in ovarian cancer, which is still lacking.

Changes in some family relationships were observed, and an improvement in communication was noted following the GT process. These findings can assist healthcare professionals considering a personalized approaches in clinical practice.

We examined human TNBC cell lines harboring wild-type and mutant BRCA1 and found that WWOX expression promoted NHEJ repair in cells with wild-type BRCA1. Our findings suggest that WWOX and BRCA1 play an important role in DSB repair pathway choice in mammary epithelial cells, underscoring their functional interaction and significance in breast carcinogenesis.

This retrospective study suggests that BRCA status can help to offer an individualized, systematic treatment after optimal primary surgery for advanced ovarian cancer, but is limited by the small sample size. Prospective trials are essential to confirm these results.

The SeqOne assay offers a clinically validated approach to detect HRD.

No differences in survival outcomes were observed among patients with different BRCA statuses. Furthermore, for patients who had undergone two or more lines of chemotherapy before PARP inhibitor maintenance therapy, no negative effects of PARP inhibitors on subsequent treatment were found, regardless of BRCA status.

Findings highlight the value of paired Bxs to identify predictive biomarkers of PARPi + immune checkpoint inhibitor sensitivity. The striking predictive value of the BLIA/BLIS signature warrants evaluation in a larger trial. Emerging resistance mechanisms justify AMTEC trial expansion to include PARPi + MEKi or PARPi + AKTi in biomarker selected patients, which is now in progress.

Furthermore, the downregulation of KLF5 expression promotes the DNA damage induced by olaparib and significantly reduces the IC 50 of the RARP inhibitor in pancreatic cancer cells...Our results indicate that inhibition of KLF5 may induce BRCAness in a larger pancreatic cancer subset with proficient BRCA. The combination of KLF5 inhibitors and PARP inhibitors provides a novel treatment strategy to enhance the sensitivity of BRCA1-proficient pancreatic cancer to PARP inhibitors.

PARPis are an effective therapeutic option for newly-diagnosed and recurrent ovarian cancer. Despite a minor increase in the frequency of serious adverse effects, they are generally well tolerated.

Tuvusertib demonstrated manageable safety and exposure-related target engagement. Further clinical evaluation of tuvusertib is ongoing.

Subtype-specific survival in young women with breast cancer needs to be evaluated in interaction with the gBRCA status. For TNBC, gBRCAm is of favorable prognostic value for overall survival, while patients with gBRCAwt TNBC need to be considered to have the highest risk for adverse survival outcomes.

BRCA mutation is one cause of HRD and appears that SET morphology associated with HGSC is unique to BRCA-mutation and not under the umbrella of other causes and effects of HRD. HRD in HGSC may produce its own molecular surrogate that is yet to be discovered. Definitive determination of which platform is superior for clinical validation of HRD assessment as a surrogate to Myriad MyChoiceDX gold standard requires matched analysis against Myriad and patient's progression free survival.

Our study failed to show significant associations between PD-L1 IHC and HRD parameters. TMB score was positively associated with LOH-high, but not HRR gene mutation. Independently evaluating these markers needs to be considered to select patients for targeting therapies.

Compared to wild-type, gBRCA carriers with locally advanced TNBC treated with neoadjuvant chemotherapy containing carboplatin had a higher pCR rate and better outcomes. These results strengthen the contention that gBRCA status should be considered when tailoring treatment decisions in women with locally advanced TNBC.

Circulating tumour DNA (ctDNA) recapitulated most tissue-derived stem-clonal and subclonal mutations while detecting some additional subclonal mutations. RNA-Seq revealed a stable basal-like pattern, with most highly expressed variants belonging to stem clone.

In patients with advanced ovarian cancer who are BRCA WT, HRD does not seem to predict cytoreductive surgical outcome or pre-treatment disease volume, although patients with HRI were less likely to be offered PCS. Larger, prospective cohort with HR status on all comers with HGSOC, will help to determine the significance of HR status when deciding on PCS or ICS.

There is a paucity of data to suggest superiority of one germline or somatic assay; therefore, selection should optimize turnaround time, cost to patients, preferred result format, and logistical burden. Each clinic should implement a standard testing strategy for all ovarian cancer patients that ensures HRD status is known at the time of upfront chemotherapy completion to facilitate comprehensive counseling about anticipated maintenance PARPi benefit.

Chemotherapy-free doublet and triplet therapy demonstrated encouraging activity, including among patients who had BRCA wild-type, HRDsig-positive or HRDsig-negative PSROC harboring NF1 or MKNK1 mutations.

Data from this large real-life dataset suggested that maintenance with niraparib in the real-life setting of platinum sensitive OC recurrence is effective and well tolerated.

Breast cancer patients who are at high risk of hereditary breast cancer but with wild-type BRCA 1/2 genes (BRCAx) have increased risk of developing contralateral breast cancer when compared to the low-risk patients. More careful surveillance and follow-up can be offered to these patients especially when they have family history of breast cancer.

Furthermore, increased conformational flexibility in the Arg866Cys variant was observed by principal component analysis. This work aims to comprehend the inherently disordered region of BRCA1 as well as the impact of missense mutations on folding patterns and binding to DNA for functional aspects.

PFS was longer than expected with both regimens. A patient subset with wild-type BRCA platinum-sensitive aTNBC had durable disease control with chemotherapy-free maintenance.

Conclusion In our cohort, BRCA1/2-mutated pts and HRD showed a trend towards a better response to NACT as opposed to BRCA-WT and HR proficient pts, according to CRS, although statistical significance is not reached due to the limited number of patients. Further research is guaranteed.

P2, N=136, Recruiting, AGO Research GmbH | Trial completion date: Dec 2023 --> Dec 2026 | Trial primary completion date: Dec 2023 --> Dec 2025

Similar results were obtained in ex vivo patient-derived primary breast cancer cells. Thus, the present study revealed that RES + OLA treatment inhibited PARP1 activity in the chromatin, and blocked TIP60-mediated chromatin relaxation, which, in turn, affected PARP1-dependent TIP60-BRCA1 association, resulting in deregulation of HR pathway in breast cancer cells.

P1/2; Trial completion date: May 2025 --> Nov 2026 | Trial primary completion date: May 2025 --> Nov 2026

Applied to a BRCA wild-type enriched subgroup of 195 PAOLA-1 clinical trial patients, GIInger identified HRD-positive patients who experienced significantly extended progression-free survival when treated with PARPi. GIInger is, therefore, a cost-effective and easy-to-implement method for accurately stratifying patients with ovarian cancer for first-line PARPi treatment.

Brain metastases in ovarian cancer are rare and complex for diagnosis and management. This case focuses both on diagnosis and treatment, emphasizing the importance of a multimodal approach in a multidisciplinary team.

Testing positive for a BRCA PV is associated with a higher risk of relapse and death in patients with BC in the Portuguese population. Risk-reducing mastectomy and salpingo-oophorectomy were associated with lower incidence of relapse and longer median iDFS and OS, respectively.

Low endogenous KAT2B expression, which we identify in a subset of cultured BRCA2-expressing CRC cells, leads to an accumulation of γH2AX (more DNA damage), resulting in low PARPi resistance in BRCA-expressing cells. Our results reveal KAT2B and histone acetylation as regulators of BRCA2 expression and PARPi responses in BRCA2-expressing CRC cells, providing further insights into molecular prerequisites for targeting BRCA-functional tumors.

P2; Trial completion date: Jul 2024 --> Dec 2022 | Active, not recruiting --> Terminated; This study has been terminated due to Lack of Accrual.

In patients with newly diagnosed advanced EOC, PARPi maintenance therapy was significantly more effective in terms of survival than no PARPi treatment. However, the risk of serious adverse events was higher for patients who received PARPi maintenance therapy.

The study was terminated due to the observed ORR at the interim futility analysis. This highlights a need for effective therapies in treating patients with recurrent BRCAwt PROC.

Cancers with wild-type BRCA, homologous recombination proficiency, or de novo or acquired resistance to PARP inhibition represent a growing population of patients who may benefit from combinatorial PARP inhibitor strategies. We review targeted inhibitors of angiogenesis, epigenetic regulators, and PI3K, MAPK, and other cellular signaling pathways as inducers of homologous recombination deficiency, providing support for the use of PARP inhibitors in contexts not previously considered susceptible to PARP inhibition.

This large, real-world study found no association between OS and either BRCA or HRR status but identified a possible linkage between HRD positivity and shorter median OS in patients with advanced solid tumors who did not receive PARPi or immunotherapy.