HRD + BRCA1 mutation

We developed a novel method to determine genomic instability for characterizing the consequences of HRD using OCA Plus, which was developed using CGP of cancer FFPE samples to aid research into precision oncology. By combining genomic instability assessment with DNA repair pathway analysis such as mutations in BRCA1/2 and other genes in HRR pathway, OCA Plus will support research into the mechanisms underlying HRD.

We found that in cell lines, HRD was associated with sensitivity to PARP inhibition in breast cancer, but not at a pan-cancer level. By generating large-scale, pan-cancer datasets on HRD predictions in cell lines, we aim to facilitate efforts to improve our understanding of HRD and its utility as a biomarker.

In the case of the strong implication of BRCA PV/LPV with a negative result with one genetic test, different platforms could be considered in limited cases. Careful interpretation and further studies for the cross-validation of gene analysis platforms are needed.

A positive response to chemotherapy at the time of interval tumor reductive surgery defined by the chemotherapy response score was associated with homologous recombination status and the likelihood of achieving a complete gross resection.

Overall, our study provides novel insights into the molecular determinants of PARPi resistance and highlights LY6E as a promising prognostic biomarker in the management of HRD ovarian cancer. Future studies are needed to fully elucidate the molecular mechanisms underlying the role of LY6E in PARPi resistance.

P2, N=64, Active, not recruiting, SWOG Cancer Research Network | Trial completion date: Jul 2024 --> Jan 2025

Our data supports considering ascitic cytology samples suitable for HRD testing and BRCA1 and BRCA2 mutation analysis. Further studies are needed to validate the practice of using ascitic cytology as a diagnostic specimen for HRD testing when tissue is not accessible, as it could prove crucial to provide ovarian cancer patients with essential information in an early stage of the diagnostic process.

Our findings uncover an alternative mechanism by which PARP inhibitors efficiently suppress tumours, thereby pointing to a potential new therapeutic strategy for centrosome error-related tumours.

P2, N=123, Active, not recruiting, National Cancer Institute (NCI)

Although the related literature is often controversial, recently published case reports and/or randomized studies demonstrated the effectiveness of PARPi in treating patients with somatic BRCA mutations. The aim of this review is to summarize the predictive role of somatic BRCA mutations and to provide further assistance for clinicians with the identification of patients who could potentially benefit from PARPi.

sWGS and targeted sequencing identified therapeutic opportunities in 75% of p53abn EC patients. Further research is needed to determine the efficacy of treatments targeting these identified pathways within p53abn ECs.

Using a robust measure to detect HRD scars from MSK-IMPACT panel data, we demonstrate evidence for BRCA-mediated tumorigenesis in an expanded spectrum of cancers with potential therapeutic relevance.

We also present a case demonstrating a favorable response to the dual therapy of olaparib and osimertinib in NSCLC harboring EGFR, RAD50, and ARID1A mutations that progressed on osimertinib. There were 2298 patients in the NSCLC cohort (MSKCC database). HRD aberrations are uncommon in EGFR mutated lung cancer patients. Further investigation on the role of PARP inhibitor in EGFR mutated lung cancer is warranted.

Comprehensive genomic profiling using liquid biopsy can rapidly identify potential candidates for targeted therapy in cervical cancer patients, regardless of histopathology. Clinical studies of precision medicines in Asia are encouraged for such patients.

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.

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.

This study demonstrates that cases identified as having HRD based on tumor tissue analysis prior to chemotherapy can be identified as not having HRD when tumor tissue collected at the time of IDS is examined. When testing for HRD, it should be recognized that this may change during the course of treatment.

The incidence of ST response to maintenance olaparib is high and appears to be modulated by maintenance sequence (primary vs recurrent therapy). Response to most recent chemotherapy could be incorporated into prospective data as a surrogate for predicting response to PARP inhibitors. Efforts to increase utilization of PARP inhibitor therapy in the primary maintenance setting are warranted.

Comparison between the Illumina and Myriad assays showed that overall HRD status, the individual components of BRCA analysis, and HRD GIS detection results were highly concordant (>93%), suggesting the TSO 500 HRD assay will approach the analytical accuracy of the FDA-approved Myriad assay.

HER2 testing by immunohistochemistry and in situ hybridisation is applicable to endometrial serous carcinomas to assess trastuzumab eligibility...Awareness of the variety and pitfalls of expression patterns for p16 and p53 in vulvar carcinomas is crucial for accurate designation. It is hoped that collaborative efforts in standardising and optimising biomarker testing for gynaecological tumours will contribute to evidence-based therapeutic decisions.

Taken together, the present study proves the feasibility of a new HRD gene panel with reliable panel performance and offers the possibility to easily screen for resistance mutations acquired over treatment time.Mutations in HR-associated genes, besides BRCA1/2, might represent promising potential targets for synthetic lethality approaches. Thus, a substantial number of patients may benefit from expanding the scope of therapeutic agents like PARPi.

The majority of patients from this real-world dataset underwent FoundationOneCDx testing after initiation of first-line treatment. Testing appeared to influence treatment patterns, with a higher proportion of patients with BRCAm, HRRm, and HRD-positive disease receiving PARP inhibitors.

P2, N=30, Recruiting, West Cancer Center | Not yet recruiting --> Recruiting

P2, N=64, Active, not recruiting, SWOG Cancer Research Network | Trial completion date: Jan 2024 --> May 2024

Across a diverse integrated healthcare system of Veterans, mutations associated with HRD were found to be common, however, not prognostic in OS across a diverse patient population of CCA. Further work is needed to clarify exposure to platinum containing chemotherapy. TP53 MT CCA remains a critical unmet need that drives worsened outcomes including here in patients with mutations in HRD.

P2; The prevalence of HRD in non-TNBC suggests that therapy targeting HRD should be evaluated in a wider breast cancer patient population. Strict HRD criteria should be implemented to increase diagnostic precision with respect to functional HRD.

Responses were observed in patients without germline or somatic BRCA1/2 mutations, including patients with mutations in other homologous recombination repair genes and tumours with functional homologous recombination deficiency by RAD51 foci. Conclusion The response rate to olaparib and ceralasertib did not meet pre-specified criteria for activity in the overall evaluable population, but responses were observed in patients who would not be expected to respond to Olaparib monotherapy.

Disease course data were obtained for all patients with reversion events: four patients acquired mutations after PARP-inhibitor treatment failure, two showed somatic reversion mutations after disease progression, following Pt-based treatment, five showed mutations after both treatments, one patient with pancreatic cancer and BRCA1 reversion mutations had no history of either treatment. Although reversion mutations commonly occur in BRCA-associated cancers, our findings suggest that reversion mutations due to Pt-chemotherapy might be correlated with BRCA1/2-mediated tumorigenesis even in non-BRCA-associated histologies.

P1/2, N=18, Active, not recruiting, Academic and Community Cancer Research United | Phase classification: P2 --> P1/2 | Trial primary completion date: Jan 2020 --> Feb 2024

Patients with sBRCA and gPALB2 derive similar benefit from PARPi as those with gBRCA alterations. In combination, HRDsig+, sBRCA, and gPALB2 represent an additional 19% of mBC that can potentially benefit from PARPi. Randomized trials exploring a more inclusive biomarker such as HRDsig are warranted.

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.

P2, N=14, Completed, MedSIR | Terminated --> Completed | Trial completion date: Dec 2022 --> Nov 2023

Consistently detecting clinically significant the HRD status in PDAC has remained challenging with current commercially available platforms. Multiple novel HRD-targeted therapies for PDAC are currently in development and clinical trials, offering new opportunities for these patients.

Overall, our study suggests that HRD exists in a fraction of pHGG samples, but is driven by inactivation of genes other than BRCA1/2, resulting in a different set of genomic scars compared to those in BCs. Functional analysis of sensitivity to PARP inhibitor and related DNA damage inhibitors is ongoing to evaluate potential therapeutic relevance of these genomic scars.

Contrary to our initial hypothesis, we did not find any significant association between BRCA1 gene expression and survival outcomes in breast cancer patients. Based on the results of our study, we speculate that the interplay between enhanced cancer cell proliferation and aggressive tumor characteristics may counterbalance the effect of high BRCA1 expression in breast cancer.

Tumour sequencing identified three times as many cases that might be eligible for HR repair defect targeted therapy than germline testing alone (16% versus 5.2%). Unlike a previous study (Ann Oncol., 2019 30:1071-1079), the majority of the BRCA-like BCs were ER+ with no evidence of a VUS in a known HBC gene suggesting these are driven by novel germline or somatic mutations in genes involved in DNA HR repair.

Patients were treated with a variety of PARPi including Olaparib (n=48), Talazoparib (n=33), Rucaparib (n = 13) and Niraparib (n = 6.) Of the 418 patients, 45 individuals harbored an HRD germline mutation...The percentage of Trp53 R172H cells in the blood was measured by flow cytometry at baseline (6 weeks after transplantation) and after treatment with vehicle alone, Talazoparib or Olaparib daily, or cisplatin weekly, for 4 weeks...Indeed, our data suggest the opposite, with the fitness advantage of DDR gene-mutated HSPCs lost in cells with a heterozygous Brca1-mutations. These data suggest that PARPi therapy may have less of an impact on leukemia risk compared to carboplatin and in fact may show synergistic effects with HRD in blocking the competitive advantage of DDR CH during genotoxic stress.

A total of 456 stage I/II patients were included. 22/456 (4.8%) had a germline or somatic BRCA1 mutation 46/456 (10.0%) had a BRCA2 mutation; These 68/456(14.9%) patients comprised the HRD group. The remaining cases were confirmed homologous recombination proficient (HRP, 388/ 456, 85.1%).

Altogether, these findings support an unveiled link between BRCA2 inactivation, HR deficiency and increased expression of immune checkpoints in TNBC. This clinical case highlights the importance of screening TNBC patients for genetic mutations and TMB biomarkers in order to predict the potential efficacy of immunotherapy.

"GIS was positive in 40% of the BRCA1/2-negative cases. The RediScore bioinformatics algorithm developed for GIS calculation in combination with NGS BRCA1/2 analysis is a viable and effective approach for HRD calculation in patients with ovarian cancer, offering a positive prediction for PARP inhibitor responsiveness in 55% of the patients."

Conclusions HRD positive, defined as GIS score >9, may be an appropriate threshold to predict the likelihood of response to PARPi in prostate cancer. Prospective, and large sample clinical trials will be needed to confirm our findings.

Conclusions This pioneering real-world study reports HRD prevalence in a large cohort of pts, ranging from 52.0% - 58.5% across the three study regions. Our results highlight the unmet need for capturing biomarker testing data and the utility of different HRD testing kits in real-world in resource-limited settings to inform treatment decisions.