Search

Evidence linking coding germline variants in breast cancer (BC)-susceptibility genes other than BRCA1, BRCA2, and CHEK2 with contralateral breast cancer (CBC) risk and breast cancer-specific survival (BCSS) is scarce. The aim of this study was to assess the association of protein-truncating variants (PTVs) and rare missense variants (MSVs) in nine known (ATM, BARD1, BRCA1, BRCA2, CHEK2, PALB2, RAD51C, RAD51D, and TP53) and 25 suspected BC-susceptibility genes with CBC risk and BCSS. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated with Cox regression models. Analyses included 34,401 women of European ancestry diagnosed with BC, including 676 CBCs and 3,449 BC deaths; the median follow-up was 10.9 years. Subtype analyses were based on estrogen receptor (ER) status of the first BC. Combined PTVs and pathogenic/likely pathogenic MSVs in BRCA1, BRCA2, and TP53 and PTVs in CHEK2 and PALB2 were associated with increased CBC risk [HRs (95% CIs): 2.88 (1.70-4.87), 2.31 (1.39-3.85), 8.29 (2.53-27.21), 2.25 (1.55-3.27), and 2.67 (1.33-5.35), respectively]. The strongest evidence of association with BCSS was for PTVs and pathogenic/likely pathogenic MSVs in BRCA2 (ER-positive BC) and TP53 and PTVs in CHEK2 [HRs (95% CIs): 1.53 (1.13-2.07), 2.08 (0.95-4.57), and 1.39 (1.13-1.72), respectively, after adjusting for tumor characteristics and treatment]. HRs were essentially unchanged when censoring for CBC, suggesting that these associations are not completely explained by increased CBC risk, tumor characteristics, or treatment. There was limited evidence of associations of PTVs and/or rare MSVs with CBC risk or BCSS for the 25 suspected BC genes. The CBC findings are relevant to treatment decisions, follow-up, and screening after BC diagnosis.

Despite advances in treatment, prostate cancer remains a significant cause of morbidity and mortality worldwide. While the vast majority of prostate cancer research has centered on malignant epithelial cells, the tumor mi croenvironment (TME) has recently become increasingly recognized as an important regulator of tumor progression and response to treatment. Among the diverse cell types within the TME, stromal fibroblasts, in particular cancer-associated fibroblasts (CAFs), play an important role in prostate cancer progression. This is highlighted by the prognostic value of CAF markers in prostate cancer, which can predict disease recurrence, metastasis, and patient survival. There are also an increasing number of studies that demonstrate the critical role of CAFs in mediating response to specific therapies and CAF signaling pathways as potential therapeutic targets. However, further investigation into the mechanisms that underpin the interactions between cancer cells and CAFs are required to develop novel therapeutic approaches and identify predictive and prognostic biomarkers in CAFs. In this review, we discuss the current knowledge of CAF-dependent regulatory pathways in prostate tumorigenesis and their prognostic and therapeutic potential. Furthermore, we explore the emerging models and technologies that are likely to progress this field of research in terms of discovery and translation to the clinic.

This review highlights the emerging role of genetics-lead medicine (GLM) in prostate cancer. We describe the benefits of GLM integration into prostate cancer screening, diagnosis and management. Imaging techniques enhancing prostate cancer detection are advancing concurrently, facilitating strategic active surveillance protocols for appropriately selected patients. We aim to improve clinician awareness of the role of GLM in current and future practice.We explore recent literature advancing the role of GLM in prostate cancer detection and management, particularly as this coexists with the development of imaging technology. Our current understanding of germline mutations implicated in familial prostate cancer development is summarized. We describe how these developments are being utilized to inform screening, surveillance and the development of novel therapies. We summarize current guidelines and explore factors inhibiting optimal implementation of recommendations in clinical practice.Integration and further development of genetics-lead medicine in the detection, surveillance and management of prostate cancer will improve clinical outcomes for men at risk of aggressive disease as a result of familial predispositions to prostate cancer. This review summarizes the pertinent developments in the field including improving clinician awareness to facilitate implantation of these strategies into current clinical practice.

Prostate cancer is the most commonly diagnosed solid-organ cancer amongst males worldwide. Metastatic castrate-resistant prostate cancer (mCRPC) is a rapidly fatal end-sequelae of prostate cancer. Therapeutic options for men with mCRPC are limited and are not curative in nature. The recent development of chimeric antigen receptor T-cell (CAR-T) therapy has revolutionised the treatment of treatment-resistant haematological malignancies, and several studies are underway investigating the utility of this technology in the treatment of solid tumours. In this review, we evaluate the current treatment options for men with mCRPC as well as the current landscape of preclinical and clinical trials of CAR-T cell therapy against prostate cancer. We also appraise the various prostate cancer-specific tumour-associated antigens that may be targeted by CAR-T cell technology. Finally, we examine the potential translational barriers of CAR-T cell therapy in solid tumours. Despite preclinical success, preliminary clinical trials in men with prostate cancer have had limited efficacy. Therefore, further clinically translatable preclinical models are required to enhance the understanding of the role of this investigational therapeutic in men with mCRPC. In the era of precision medicine, tailored immunotherapy administered to men in a tumour-agnostic approach provides hope to a group of men who otherwise have few treatment options available.