An Immune-Related Gene Expression Signature Predicts Benefit from Adding Atezolizumab to FOLFOXIRI plus Bevacizumab in Metastatic Colorectal Cancer.

PURPOSE: AtezoTRIBE phase II randomized study demonstrated that adding atezolizumab to first-line FOLFOXIRI (5-fluorouracil, oxaliplatin, irinotecan) plus bevacizumab prolongs progression-free survival (PFS) of patients with metastatic colorectal cancer (mCRC), with a modest benefit among proficient mismatch repair (pMMR). DetermaIO is an immune-related 27-gene expression signature able to predict benefit from immune checkpoint inhibition in triple-negative breast cancer. In this analysis of AtezoTRIBE, we investigated the predictive impact of DetermaIO in mCRC. EXPERIMENTAL DESIGN: Patients with mCRC unselected for MMR status were randomly assigned (1:2) to FOLFOXIRI plus bevacizumab (control arm) or the same regimen with atezolizumab (atezolizumab arm). qRT-PCR by DetermaIO was performed on RNA purified from pretreatment tumors of 132 (61%) of 218 enrolled patients. A binary result (IOpos vs. IOneg) adopting the preestablished DetermaIO cut-off point (0.09) was obtained, and an exploratory optimized cut-off point (IOOPT) was computed in the overall population and in pMMR subgroup (IOOPTpos vs. IOOPTneg). RESULTS: DetermaIO was successfully determined in 122 (92%) cases, and 23 (27%) tumors were IOpos. IOpos tumors achieved higher PFS benefit from atezolizumab arm than IOneg (HR: 0.39 vs. 0.83; Pinteraction = 0.066). In pMMR tumors (N = 110), a similar trend was observed (HR: 0.47 vs. 0.93; Pinteraction = 0.139). In the overall population, with the computed IOOPT cut-off point (0.277), 16 (13%) tumors were IOOPTpos and they derived higher PFS benefit from atezolizumab than IOOPTneg (HR: 0.10 vs. 0.85, Pinteraction = 0.004). Similar results were found in the pMMR subgroup. CONCLUSIONS: DetermaIO may be useful to predict benefit of adding atezolizumab to first-line FOLFOXIRI plus bevacizumab in mCRC. The exploratory IOOPT cut-off point should be validated in independent mCRC cohorts.

Serum antibodies to selected Helicobacter pylori antigens are associated with active gastritis in patients seen at the University Teaching Hospital in Lusaka, Zambia.

Introduction: Little is known about specific bacterial characteristics of Helicobacter pylori (H. pylori) infection influencing gastric carcinogenesis in Zambia. The aim of this study was to evaluate the associations between pre-selected H. pylori antibodies with gastric cancer, premalignant lesions and active gastritis. Methods: This was cross-sectional study with multiple comparisons of patients with gastric cancer (GC), gastric premalignant (GP) lesions and active or chronic gastritis. A fluorescent bead-based antibody multiplex serology assay was used to quantify antibodies to thirteen immunogenic H. pylori antigens. Logistic regression models were used to examine the associations. Results: Included were 295 patients with: 59 GC, 27 GP lesions, 48 active and 161 chronic gastritis. Overall, 257/295 (87%) were H. pylori positive. H. pylori seropositivity was not associated with sex, age, body mass index, socio-economic status, HIV infection, alcohol consumption or cigarette smoking (p-values all above 0.05). When compared to the patients with chronic gastritis, the presence of catalase and cinnamyl alcohol dehydrogenase (Cad) antibodies was positively associated with GP lesions (OR 3.53; 95% CI 1.52-8.17 and OR 2.47; 95% CI 1.08-5.67 respectively). However, seropositivity to Cad antibodies was significantly lower in GC patients (OR 0.28; 95% CI 0.09-0.83). Compared to chronic, active gastritis was significantly associated with (p<0.05) H. pylori sero-positivity (OR 9.46; 95% CI 1.25-71.52) and specific antibodies including cytotoxin-associated gene A, vacuolating cytotoxin A, Helicobacter cysteine-rich protein C, hypothetical protein HP0305 and outer membrane protein HP1564. Conclusions: Among Zambian patients seen at a single center, antibodies to H. pylori (CagA, VacA, Omp, HcpC, HP0305 and HpaA) were associated with active gastritis.

DNA Transfer and Toll-like Receptor Modulation by Helicobacter pylori.

Helicobacter pylori is the most common bacterial infection worldwide, and virtually all infected persons develop co-existing gastritis. H. pylori is able to send and receive signals from the gastric mucosa, which enables both host and microbe to engage in a dynamic equilibrium. In order to persist within the human host, H. pylori has adopted dichotomous strategies to both induce inflammation as a means of liberating nutrients while simultaneously tempering the immune response to augment its survival. Toll-like receptors (TLRs) and Nod proteins are innate immune receptors that are present in epithelial cells and represent the first line of defense against pathogens. To ensure persistence, H. pylori manipulates TLR-mediated defenses using strategies that include rendering its LPS and flagellin to be non-stimulatory to TLR4 and TLR5, respectively; translocating peptidoglycan into host cells to induce NOD1-mediated anti-inflammatory responses; and translocating DNA into host cells to induce TLR9 activation.