Multigene germline panel testing is recommended for Pancreatic Cancer (PC) patients; however, for non-BRCA1/2 genes, the clinical utility is unclear. A comprehensive multi-gene assessment in unselected Italian PC patients is missing. We evaluated the prevalence and impact of Pathogenic Variants (PV) in 51 PC susceptibility genes in a real-world series of 422 Italian PC patients unselected for Family History (FH), compared the clinical characteristics and conducted survival analyses. 17% of patients had PVs (70/422), mainly in BRCA1/2 (4.5%, all <70 y), CDKN2A (4.5%, all >50 y), ATM (2.1%). PV carriers were younger (64 vs. 67; p = 0.02) and had more frequent personal/FH of PC, melanoma and breast/ovarian cancer (all p < 0.05). The Overall Survival (OS) was longer in patients carrying PVs (HR 0.78; p = 0.090), comprising ATM carriers (HR 0.33; p = 0.054). In the oxaliplatin-treated subset, PV carriers showed better control of the disease, although this was not statistically significant (67% vs. 56%). CDKN2A, BRCA2 and ATM were the most frequently altered genes. ATM PVs were positively associated with OS in 41% of PV carriers, 60% of whom carried CDKN2A, BRCA2 or ATM PVs, had negative FH and would have been missed by traditional referral. Thus, CDKN2A and ATM should be added to BRCA1/2 testing regardless of FH.

Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15–20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors.

Objective Androgen deprivation therapy alters body composition promoting a significant loss in skeletal muscle (SM) mass through inflammation and oxidative damage. We verified whether SM anthropometric composition and metabolism are associated with unfavourable overall survival (OS) in a retrospective cohort of metastatic castration-resistant prostate cancer (mCRPC) patients submitted to 18F-Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography (FDG PET/CT) imaging before receiving Radium-223. Patients and methods Low-dose CT were opportunistically analysed using a cross-sectional approach to calculate SM and adipose tissue areas at the third lumbar vertebra level. Moreover, a 3D computational method was used to extract psoas muscles to evaluate their volume, Hounsfield Units (HU) and FDG retention estimated by the standardized uptake value (SUV). Baseline established clinical, lab and imaging prognosticators were also recorded. Results SM area predicted OS at univariate analysis. However, this capability was not additive to the power of mean HU and maximum SUV of psoas muscles volume. These factors were thus combined in the Attenuation Metabolic Index (AMI) whose power was tested in a novel uni- and multivariable model. While Prostate-Specific Antigen (PSA), Alkaline Phosphatase (ALP), Lactate Dehydrogenase and Hemoglobin, Metabolic Tumor Volume, Total Lesion Glycolysis and AMI were associated with long-term OS at the univariate analyses, only PSA, ALP and AMI resulted in independent prognosticator at the multivariate analysis. Conclusion The present data suggest that assessing individual 'patients' SM metrics through an opportunistic operator-independent computational analysis of FDG PET/CT imaging provides prognostic insights in mCRPC patients candidates to receive Radium-223. Graphical abstract