HRD

Analysis of somatic mutations by whole exome sequencing showed that counter-intuitively, the cluster of HR + /HER2- samples exhibiting higher immune scores was associated with lower tumour mutational burden, lower homologous recombination deficiency scores, and fewer copy number aberrations, implicating the involvement of non-canonical tumour immune pathways. Further investigations are warranted to determine the underlying mechanisms of these pathways, with the potential to develop innovative immunotherapeutic approaches tailored to this specific patient population.

In this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor-positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly [adenosine diphosphate-ribose] polymerase) inhibitors.

P2, N=100, Recruiting, Vall d'Hebron Institute of Oncology

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.

Here, we analyzed 423 serial whole blood and plasma samples from 103 patients with relapsed high-grade ovarian cancer receiving carboplatin, poly(ADP-ribose) polymerase inhibitor (PARPi) and heat shock protein 90 inhibitor (HSP90i) treatment within the phase II EUDARIO trial using error-corrected sequencing of 72 genes...Together, these results provide unique insights into the architecture and the preferential selection of DDR-mutated hematopoietic clones under intense DNA-damaging treatment. Specifically, PARPi and HSP90i therapies pose an independent risk for the expansion of DDR-CH in a dose-dependent manner.

These preclinical findings illustrate the potential of LP-184 as a pan-HRD cancer therapeutic. Taken together, our results support continued clinical evaluation of LP-184 in a large subset of HRD solid tumors.

Several agnostic drug-target matches have already been approved for clinical use, e.g., immune therapy for tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB), NTRK1-3 and RET inhibitors for cancers carrying rearrangements in these kinases, and dabrafenib plus trametinib for BRAF V600E mutated malignancies. The existing format of data dissemination may not be optimal for agnostic cancer medicine, as conventional scientific journals are understandably biased towards the publication of positive findings and usually discourage the submission of case reports. Despite all the limitations and concerns, histology-independent drug-target matching is certainly feasible and, therefore, will be increasingly utilized in the future.

The primary end point is an investigator-assessed objective response rate in each cohort. Clinical Trial Registration: jRCT2011200023 (ClinicalTrials.gov).

PBRM1 and RAD51 dual-loss ccRCC indicates superior responses to immunotherapy. Dual-loss ccRCC harbors an immune-desert microenvironment but enriched with M1 macrophages. Dual-loss ccRCC is susceptible to defective homologous recombination but possesses high chromosomal stability.

In this secondary analysis of the PAOLA-1 randomized clinical trial, patients with a BRCA-like tumor, but not those with a non-BRCA-like tumor, had a significantly longer survival after olaparib plus bevacizumab treatment than placebo plus bevacizumab treatment. Thus, the BRCA1-like classifier could be used as a biomarker for olaparib plus bevacizumab as a maintenance treatment.

Inflammation-related blood data, such as neutrophil count, obtained at the initial pre-treatment visit might serve as potential predictors for prolonged olaparib treatment. While this study offers valuable insights into potential indicators for prolonged olaparib treatment, it underscores the need for more expansive research to strengthen our understanding of PARP inhibitors and optimize treatment strategies in ovarian cancer.

The anoikis-related prognostic model developed in this study could be a useful tool for clinical decision-making. This study may provide a new perspective for the treatment of anoikis-related PCa.

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

Significant differences in GA and immune biomarkers are noted between IDH1/2+ and IDHwt iCCA. IDH1-/2-mutated tumors appear immunologically cold without gLOH. These immunogenomic data provide insight for precision targeting of iCCA with IDH alterations.

P3, N=174, Active, not recruiting, The Netherlands Cancer Institute | Trial completion date: Dec 2029 --> Dec 2033 | Trial primary completion date: Apr 2024 --> Oct 2024

High MKi67 gene expression identified highly proliferative HCC with aggressive biology involving classical pathways in cell cycle regulation and DNA repair, as well as poor overall oncologic outcomes. This suggests potential for personalized treatment strategies, but validation and refinement of these observations require further research to elucidate the underlying mechanisms and validate therapeutic targeting of these pathways in MKi67-high HCC tumors.

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.

Homologous recombination proficiency in patients with breast cancer despite germline PALB2/RAD51C pathogenic variants.

Assays for GI assessment not only show a high concordance with each other but also in correlation with Myriad myChoice. Thus, almost all of the assays included here can be used effectively to assess HRD-associated GI in the clinical setting. This is important as PARPi treatment on the basis of these tests is compliant with European Medicines Agency approvals, which are methodologically not test-bound.

Consequently, there is urgent need for the development of increasingly reliable HRD tests, overcoming present limitations, as they play a key role in the diagnostic and therapeutic process as well as have a prognostic and predictive value. In this review we offer an overview of the state of the art regarding the actual knowledge about BRCA and HRD mutational status, the rationale of PARPi use and HRD testing (current and in development assays) and their implications in clinical practice and in the treatment decision process, in order to optimize and choose the best tailored therapy in patients with ovarian cancer.

Furthermore, our findings confirmed a positive correlation between COTL1 expression, CD8, and PD-L1 in LGG, as well as an association of high COTL1 expression with decreased patient survival in LGG. Based on these compelling findings, COTL1 may hold significant clinical implications for the development of novel cancer therapies and serve as a potential target for tumors associated with immunotherapy in the future.

As a control, commercially available HRD standards were also sequenced and the HRDest scores obtained from the OTR reads were well within the HRD reference range provided by the manufacturer. In conclusion, we showed that OTR reads of tumor-only panel sequencing can be used to determine genome-wide CNV profiles and to approximate HRD scores.

Furthermore, functional experiments demonstrated that silencing CARD11 and GATA2 impairs HR repair efficiency and enhances the sensitivity of tumor cells to olaparib treatment. In summary, in the absence of mutations in the HR genes, the sensitivity of tumor cells to PARP inhibitors and platinum-based chemotherapy may be enhanced in a subset of breast cancer patients with LNGC somatic mutations.

The myChoice® CDx Nordic core facility has been well received among the Nordic countries and provides new insights on the influence of national guidelines on HRD testing. Overall, we experienced an efficient turnaround time and a high fraction of conclusive results. Interestingly, prior somatic BRCA testing is redundant when assessing HRD status through myChoice® CDx test since somatic BRCA screening is already a significant component of the myChoice® CDx test. Thus, it should be considered to omit prior somatic BRCA testing to ensure a rationalised HRD diagnostic flow optimised for clinical use.

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

In DLBCLs with germline PTVs of ATM, deletion and insertion in CD58 were further revealed. Thus, in lymphoma-cancer families, we identified germline defects of both DNA repair and immune genes in lymphoma patients.

In summary, DeepHRD exhibits consistent hazard ratios ranging from 0.45 to 0.49 across the three clinical cohorts and captures 1.8- to 3.1-fold more HRD-positive breast and ovarian cancer patients. DeepHRD-positive breast cancer patients that received platinum exhibited better complete response and PFS. Similarly, DeepHRD-positive platinum-treated ovarian cancer patients had a better OS.

All performance metrics passed the validation criteria. In conclusion, the OncoDEEP kit can be used for reliable diagnostic comprehensive profiling of solid tumors, but currently, extensive fusion analysis requires an additional screening method.

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.

WGD was detected in 41% of samples with greater than 10% tumor fraction in cell-free DNA across three cancer types. While this represents a substantial percentage of advanced cancers, more research needs to be done regarding the impact of these events on clinical outcomes and treatment response. Additionally, co-occurrence of these events with other advanced cancer biomarkers such as microsatellite instability or homologous recombination deficiency was not reported.

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.

The robust concordance between the open standard LDT and the CDx, especially the correlation with PFS, warrants future validation and implementation of the open standard LDT for HRD testing in diagnostic settings.

In this review, we outline the current understanding of the role of HRD in genomic instability leading to breast tumorigenesis and delineate outcomes from various clinical trials. Furthermore, we discuss potential strategies for combining HRD-targeted therapy with immunotherapy to achieve the best healthcare outcomes in breast cancer patients.

Furthermore, GSscan can accurately predict HRD status using only 1 ng of input DNA and a minimum sequencing coverage of 0.02 × , providing a reliable, accessible, and cost-effective approach. In summary, GSscan effectively and accurately detected HRD status, and provide a broadly applicable framework for disease diagnosis and selecting appropriate disease treatment.

Risk of prior authorization was increased for patients with BRCA, despite greater clinical benefit. Prior authorization contributes to delays in care, and reform is needed.

P2, N=0, Withdrawn, European Organisation for Research and Treatment of Cancer - EORTC | N=152 --> 0 | Trial completion date: Feb 2030 --> Jul 2030 | Not yet recruiting --> Withdrawn | Trial primary completion date: Sep 2027 --> Sep 2028

P=N/A, N=2000, Active, not recruiting, University of Washington | Recruiting --> Active, not recruiting

Our results demonstrate unique genetic markers and potential treatment targets in MaBC, thereby underlining the necessity of tailoring treatment strategies for this under-studied patient population. These WGS-based findings add to the growing knowledge of MaBC genomics and highlight the need to expand research on this type of cancer.

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.

ehCCA subtypes feature characteristic GA profiles that have potential to influence therapy selection with significantly lower frequencies of FGFR2 and IDH1 when compared with iCCA. In contrast, targetable GA in ERBB2 and KRAS G12C are more frequent in ehCCA than iCCA, and highest in gbCCA and cbdCCA respectively. GA in IO drug response associated biomarker frequencies (MSI, TMB level and PD-L1 expression) are similar in all 3 ehCCA subgroups.