Precision Medicine in Pancreatic Ductal Adenocarcinoma: The Impact of Targeted Therapies on Survival of Patients Harboring Actionable Mutations

Background: Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of death by cancer worldwide. Mostly diagnosed with locally advanced or metastatic disease, patients lack treatment options. Gene alterations (GAs) are frequently observed in PDAC, some of which are considered for molecular targeted therapies (MTTs), with potential clinical benefits and improved outcomes. However, the applicability of molecular profiling (MP) for precision medicine in PDAC remains to be demonstrated. Methods: We conducted a retrospective analysis of all patients, aged ≥18 years with histologically confirmed PDAC, who underwent tumor MP between 2010 and 2020 in our institution as part of personalized medicine trials. The primary study endpoint was overall survival (OS), and (minimal follow-up was 6 months after MP). Results: Of 115 eligible patients, MP was successful in 102 patients (89%). KRAS mutations were the most frequent GAs, mostly G12D. Based on ESCAT classification, actionable GAs were found in 29 patients (28%), involving mainly BRCA1 or BRCA2 (5 (18%)), HER2 (5 (18%)), MTAP (5 (18%)), and FGFR (3 (11%)). Only 12 of these 29 patients (41%, or 10% of the whole population) received MTTs, with a median progression-free survival of 1.6 months. Median OS was 19 months in patients with actionable GAs treated with MTTs (n = 12 (11.8%)), 14 months in patients with actionable GAs treated with standard therapies (n = 17 (16.7%)), and 17 months in patients without actionable GAs treated with standard therapies (n = 73 (71.5%); p = 0.26). The absence of liver metastases was associated with better OS (HR = 0.471, p = 0.01). The highest OS following MTT was observed in patients with BRCA mutations treated with olaparib. Interpretation: Actionable GAs were found in more than a quarter of patients with advanced PDAC. Overall, targeting actionable GAs with MTTs was not associated with improved OS in this retrospective study with limited patient numbers. However, selected GA/MTT combinations (e.g., BRCA mutations/olaparib) were associated with a better outcome

Hepatitis B and survival after renal transplant: meta-analysis of observational studies

Summary Recent evidence has been accumulated suggesting that HBsAg seropositive status is significantly linked to lower patient and graft survival after renal transplant even if conflicting data on this point exist. The aim of this study was to conduct a systematic review of the published medical literature concerning the impact of HBV surface antigen seropositive status on all‐cause mortality and graft loss after RT. The relative risk of all‐cause mortality and graft loss was regarded as the most reliable outcome end‐point. Study‐specific relative risks were weighted by the inverse of their variance to obtain fixed‐ and random‐effect pooled estimates for mortality and graft loss with HBsAg across the published studies. We identified ten observational studies involving 82 690 unique renal transplant recipients. The summary estimate for adjusted relative risk (aRR) of all‐cause mortality was 2.214 with a 95% confidence interval (CI) of 1.56; 3.137 (P < 0.0001); heterogeneity statistics, Ri = 0.98 (P‐value by Q‐test = 0.0001). The overall estimate for adjusted RR of all‐cause graft loss was 1.44 (95% CI, 1.26; 1.63) (P < 0.0001) and heterogeneity statistics, Ri = 0.05 (P‐value by Q‐test = 0.4). Stratified analysis changed marginally the results. Meta‐regression showed that diabetes mellitus had a detrimental role on patient survival (P = 0.02). This meta‐analysis of observational studies supports the notion that HBsAg‐positive patients after RT have an increased risk of mortality and graft loss. The mechanisms underlying the relationship between HBsAg and mortality or graft dysfunction after renal transplant are an area of avid research