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Background: Individuals with germline pathogenic variants in BRCA1 or BRCA2 are at a high risk of breast and ovarian carcinomas with BRCA1/2 deficiency and homologous recombination deficiency that can be detected by analysis of genome-wide genomic instability features such as large-scale state transitions, telomeric allelic imbalances, and genomic loss of heterozygosity. Malignancies with homologous recombination deficiency are more sensitive to platinum-based therapies and poly(ADP-ribose) polymerase inhibitors. We investigated the fraction of non-breast or ovarian malignancies that have BRCA1/2 deficiency and genomic instability features., Methods: The full tumor history of a large, historical, clinic-based, consecutive cohort of 2965 individuals with germline pathogenic variants in BRCA1/2 was retrieved from the Dutch nationwide pathology databank (Palga). In total, 169 non-breast or ovarian malignancies were collected and analyzed using targeted next-generation sequencing and shallow whole-genome sequencing to determine somatic second-hit alterations and genomic instabilities indicative of homologous recombination deficiency, respectively., Results: BRCA1/2 deficiency was detected in 27% (21/79) and 23% (21/90) of 20 different types of non-breast or ovarian malignancies in individuals with germline pathogenic variants in BRCA1 and BRCA2, respectively. These malignancies had a higher genomic instability score than BRCA1- or BRCA2-proficient malignancies (P < .001 and P < .001, respectively)., Conclusions: BRCA1/2 deficiency and genomic instability features were found in 27% and 23% of a broad spectrum of non-breast or ovarian malignancies in individuals with germline pathogenic variants in BRCA1 and BRCA2, respectively. Evaluation of the effectiveness of poly(ADP-ribose) polymerase inhibitors in these individuals should be focused on tumors with a confirmed absence of a wild-type allele., (© The Author(s) 2024. Published by Oxford University Press.)

Rationale: PSMA-targeting radioligand therapy (PSMA-RLT) has shown promise in metastatic castration-resistant prostate cancer (mCRPC), particularly in PSMA-avid tumours. However, predicting response remains challenging. Preclinical data suggests aberrant p53-signalling as a predictor of poor response. Methods: The patient population of this pre-planned retrospective cohort study consists of 96 patients with mCRPC who underwent treatment with PSMA-RLT and were molecularly profiled by whole-genome sequencing and or targeted next-generation sequencing. Response to PSMA-RLT was assessed per molecular subtype, including TP53 -mutational status. Results: Patients with TP53 loss-of-function alterations had a shorter median progression-free survival (3.7 versus 6.2 months, P <0.001), a lower median PSA change (-55% vs. -75%, P =0.012) and shorter overall survival from initiation of PMSA-RLT (7.6 vs. 13.9 months, P =0.003) compared to TP53 -wildtype patients. Pathogenic alterations in AR , MYC , BRCA1 , or BRCA2 as well as in genes linked to the PI3K or MAPK pathways or genes involved in homologous recombination repair, were not associated with response. Only lactate dehydrogenase was, alongside TP53 -status, significantly associated with response. Transcriptome analysis of 21 patients, identified six p53 signalling genes whose low expression was associated to a shorter progression-free survival ( P <0.05). Conclusion: TP53 loss-of-function may serve as a prognostic factor for PSMA-RLT outcomes in patients with mCRPC., Competing Interests: Competing Interests: Maarten J. van der Doelen: Research support: 'Bayer, Janssen-Cilag'. Travel support: 'Astellas'. James Nagarajah: Research support: 'ABX, Novartis'. Advisory role: 'ITM, POINT biopharma, CURIUM, Novartis, Bayer'. Inge M. van Oort: Advisory role: 'Bayer, Astellas, Janssen, MSD/AstraZeneca'. Research support: 'Astellas, Janssen, Bayer'. Jack. A. Schalken: Speaker honorarium: 'Astellas, Bayer'. Niven Mehra: Advisory role: 'Roche, MSD, BMS, Bayer, Astellas, Janssen'. Research support: 'Astellas, Janssen, Pfizer, Roche and Sanofi' Genzyme'. Travel support: 'Astellas, MSD'. The remaining authors declare no conflict of interest., (© The author(s).)

Homologous recombination repair deficiency (HRD) is observed in 10% of patients with castrate-resistant prostate cancer (PCa). Preliminary data suggest that HRD-PCa might be more responsive to immune checkpoint inhibitors (ICIs). In this study, we compare the tumor immune landscape and peripheral T cell receptor (TCR) repertoire of patients with and without HRD-PCa to gain further insight into the immunogenicity of HRD-PCa. Immunohistochemistry was performed on tumor tissue of 81 patients, including 15 patients with HRD-PCa. Peripheral TCR sequencing was performed in a partially overlapping cohort of 48 patients, including 16 patients with HRD-PCa. HRD patients more frequently had intratumoral CD3 + , CD3 + CD8 - FoxP3 - or Foxp3 + TILs above median compared to patients without DNA damage repair alterations (DDRwt; CD3 + and Foxp3 + : 77% vs 35%, p = .013; CD3 + CD8 - FoxP3 - : 80% vs 44%, p = .031). No significant difference in CD8 + TILs or PD-L1 expression was observed. In peripheral blood, HRD patients displayed a more diverse TCR repertoire compared to DDRwt patients (p = .014). Additionally, HRD patients shared TCR clusters with low generation probability, suggesting patient-overlapping T cell responses. A pooled analysis of clinical data from 227 patients with molecularly characterized PCa suggested increased efficacy of ICIs in HRD-PCa. In conclusion, patients with HRD-PCa display increased TIL density and an altered peripheral TCR repertoire. Further research into the efficacy of ICIs and the presence of shared neoantigens in HRD-PCa is warranted., Competing Interests: The authors report there are no competing interest to declare, (© 2022 Radboud University Medical Center. Published with license by Taylor & Francis Group, LLC.)

Clonality analysis in classic Hodgkin lymphoma (cHL) is of added value for correctly diagnosing patients with atypical presentation or histology reminiscent of T cell lymphoma, and for establishing the clonal relationship in patients with recurrent disease. However, such analysis has been hampered by the sparsity of malignant Hodgkin and Reed-Sternberg (HRS) cells in a background of reactive immune cells. Recently, the EuroClonality-NGS Working Group developed a novel next-generation sequencing (NGS)-based assay and bioinformatics platform (ARResT/Interrogate) to detect immunoglobulin (IG) gene rearrangements for clonality testing in B-cell lymphoproliferations. Here, we demonstrate the improved performance of IG-NGS compared to conventional BIOMED-2/EuroClonality analysis to detect clonal gene rearrangements in 16 well-characterized primary cHL cases within the IG heavy chain (IGH) and kappa light chain (IGK) loci. This was most obvious in formalin-fixed paraffin-embedded (FFPE) tissue specimens, where three times more clonal cases were detected with IG-NGS (9 cases) compared to BIOMED-2 (3 cases). In total, almost four times more clonal rearrangements were detected in FFPE with IG-NGS (N = 23) as compared to BIOMED-2/EuroClonality (N = 6) as judged on identical IGH and IGK targets. The same clonal rearrangements were also identified in paired fresh frozen cHL samples. To validate the neoplastic origin of the detected clonotypes, IG-NGS clonality analysis was performed on isolated HRS cells, demonstrating identical clonotypes as detected in cHL whole-tissue specimens. Interestingly, IG-NGS and HRS single-cell analysis after DEPArray™ digital sorting revealed rearrangement patterns and copy number variation profiles indicating clonal diversity and intratumoral heterogeneity in cHL. Our data demonstrate improved performance of NGS-based detection of IG gene rearrangements in cHL whole-tissue specimens, providing a sensitive molecular diagnostic assay for clonality assessment in Hodgkin lymphoma., (© 2021. The Author(s).)