Determinants of Homologous Recombination Deficiency in Pancreatic Cancer

Pancreatic cancer is a treatment-resistant malignancy associated with high mortality. However, defective homologous recombination (HR), a DNA repair mechanism required for high-fidelity repair of double-strand DNA breaks, is a therapeutic vulnerability. Consistent with this, a subset of patients with pancreatic cancer show unique tumor responsiveness to HR-dependent DNA damage triggered by certain treatments (platinum chemotherapy and PARP inhibitors). While pathogenic mutations in HR genes are a major driver of this sensitivity, another layer of diverse tumor intrinsic and extrinsic factors regulate the HR deficiency (HRD) phenotype. Defining the mechanisms that drive HRD may guide the development of novel strategies and therapeutics to induce treatment sensitivity in non-HRD tumors. Here, we discuss the complexity underlying HRD in pancreatic cancer and highlight implications for identifying and treating this distinct subset of patients

Utility of bevacizumab in advanced hepatocellular carcinoma: A veterans affairs experience

Abstract Hepatocellular carcinoma (HCC) is a challenging to treat malignancy with few available systemic therapies. Angiogenesis has been implicated in the pathogenesis of HCC and prior studies have suggested a role for anti‐VEGF therapy. Prior to FDA approval of second‐line therapy for advanced HCC, from 2008 until 2017, we initiated bevacizumab monotherapy (5‐10 mg/kg every 2‐3 weeks) in 12 patients with intolerance of or progression during sorafenib therapy. Bevacizumab therapy was well tolerated with only 1/12 patients experiencing a grade 3‐4 treatment‐related adverse event (transient ischemic attack) and only 2/12 patients discontinued the therapy due to adverse events. Median overall survival was 20.2 months (IQR, 7.0‐43.5), with a median time to radiologic progression of 10.4 months (IQR, 2.8‐16.1) and a disease control rate of 54%. Taken together, our experience provides rationale for further prospective investigation of bevacizumab for the treatment of advanced HCC

Immunotherapy in genitourinary malignancies

Purpose of reviewActive investigation suggests immune checkpoint inhibitor therapy and therapeutic cancer vaccines provide clinical benefit for genitourinary malignancies including prostate cancer, renal cell carcinoma, and bladder cancer. Recent developments in the utility of immune checkpoint inhibitor and vaccine therapy for the management of genitourinary malignancies are highlighted in this review.Recent findingsDramatic responses to checkpoint inhibitor therapy have been demonstrated in renal cell carcinoma and bladder cancer with recent Food and Drug Administration approvals in both indications. No benefit to checkpoint inhibitor therapy has yet been shown for the management of prostate cancer. Therapeutic cancer vaccines have also shown benefit in the treatment of genitourinary malignancies, specifically in the treatment of prostate cancer. Despite advances in these therapeutic modalities, benefit is limited to a subset of patients.SummaryCurrent evidence supports the use of immune checkpoint inhibitor therapy and therapeutic cancer vaccines for the management of genitourinary malignancies. Further development of biomarkers for predicting response and study of combination therapy is required to achieve optimal efficacy with these therapeutic interventions

Systemic inflammation is a determinant of outcomes of CD40 agonist–based therapy in pancreatic cancer patients

Agonistic anti-CD40 monoclonal antibody (mAb) therapy in combination with chemotherapy (chemoimmunotherapy) shows promise for the treatment of pancreatic ductal adenocarcinoma (PDA). To gain insight into immunological mechanisms of response and resistance to chemoimmunotherapy, we analyzed blood samples from patients (n = 22) with advanced PDA treated with an anti-CD40 mAb (CP-870,893) in combination with gemcitabine. We found a stereotyped cellular response to chemoimmunotherapy characterized by transient B cell, CD56+CD11c+HLA-DR+CD141+ cell, and monocyte depletion and CD4+ T cell activation. However, these cellular pharmacodynamics did not associate with outcomes. In contrast, we identified an inflammatory network in the peripheral blood consisting of neutrophils, cytokines (IL-6 and IL-8), and acute phase reactants (C-reactive protein and serum amyloid A) that was associated with outcomes. Furthermore, monocytes from patients with elevated plasma IL-6 and IL-8 showed distinct transcriptional profiles, including upregulation of CCR2 and GAS6, genes associated with regulation of leukocyte chemotaxis and response to inflammation. Patients with systemic inflammation, defined by neutrophil/lymphocyte ratio (NLR) greater than 3.1, had a shorter median overall survival (5.8 vs. 12.3 months) as compared with patients with NLR less than 3.1. Taken together, our findings identify systemic inflammation as a potential resistance mechanism to a CD40-based chemoimmunotherapy and suggest biomarkers for future studies