PALB2 (Partner and localizer of BRCA2)

The mutational patterns affecting homologous recombination repair differ across gynecologic and breast cancers. Further research into cancer-specific HRD mechanisms is warranted.

Tumor sequencing of 42 high-priority variants identified 11 (26.2%) with wild-type allele loss and high homologous recombination deficiency. Functional CRISPR/Cas9 knock-in assays in MCF10A cells confirmed that two deep intronic variants created aberrant splice sites, disrupted splicing and impacted transcript expression.

Germline mutations constitute a minority of NSCLC cases but carry important prognostic, predictive, and preventive implications. Systematic germline testing in selected patients, particularly those with early-onset disease, strong family history, or tumor sequencing suggestive of hereditary variants, could guide precision oncology, enable targeted treatments, and facilitate familial risk management.

This phase II trial evaluated the efficacy and safety of combining niraparib with the PD-1 inhibitor HX008 in patients with metastatic breast cancer who had germline DNA damage response (DDR) mutations. Somatic TP53 mutations significantly correlated with shorter PFS, while ASXL1 mutations correlated with longer PFS. This chemotherapy-free regimen demonstrates promising efficacy and a tolerable safety profile in patients with metastatic breast cancer and germline DDR mutations, providing a novel therapeutic option for this patient population, even those with brain metastases.

Taken together, this study identifies ATM c.7374_7375insAlu as a novel FC founder PV that contributes to PC and BC predisposition. Improving carrier detection may identify at-risk relatives who may benefit from cancer-directed surveillance.

P=N/A, N=6000, Recruiting, Queen Mary University of London

These data suggest that a subset of HRD PC may derive prolonged benefit from PARP-ICB maintenance and support further development of biomarker-guided precision immunotherapy strategies in PC. ClinicalTrials.gov identifier: NCT04666740 .

PRS assessment identified four PRSs with good discriminatory power (AUC > 0.690), with PGS003738 showing the highest performance (AUC = 0.702, top decile OR = 3.57). These findings highlight the need for population-specific genetic studies to improve breast cancer risk stratification in Arab populations.

Most PARPi responders had alterations in HRR genes, particularly BRCA2, although some responders lacked known biomarkers associated with PARPi response. Our findings in this real-world data set support HRR gene testing for PARPi use in mCRPC and highlight the need for novel genome-wide biomarkers for patient selection.

P=N/A, N=70, Recruiting, AstraZeneca | Trial completion date: Dec 2025 --> Dec 2027 | Trial primary completion date: Dec 2025 --> Dec 2027

Altogether, GRIDSS implementation increased diagnostic yield while maintaining feasibility for diagnostic workflows. Comprehensive workflow scheme for germline structural variant detection and results in our diagnostic setting.

P2, N=65, Completed, SOLTI Breast Cancer Research Group | Recruiting --> Completed