ABSTRACT
A gene signature was previously found to be correlated with mosaic adenovirus 26 vaccine protection in simian immunodeficiency virus and simian-human immunodeficiency virus challenge models in non-human primates. In this report, we investigated the presence of this signature as a correlate of reduced risk in human clinical trials and potential mechanisms of protection. The absence of this gene signature in the DNA/rAd5 human vaccine trial, which did not show efficacy, strengthens our hypothesis that this signature is only enriched in studies that demonstrated protection. This gene signature was enriched in the partially effective RV144 human trial that administered the ALVAC/protein vaccine, and we find that the signature associates with both decreased risk of HIV-1 acquisition and increased vaccine efficacy (VE). Total RNA-seq in a clinical trial that used the same vaccine regimen as the RV144 HIV vaccine implicated antibody-dependent cellular phagocytosis (ADCP) as a potential mechanism of vaccine protection. CITE-seq profiling of 53 surface markers and transcriptomes of 53,777 single cells from the same trial showed that genes in this signature were primarily expressed in cells belonging to the myeloid lineage, including monocytes, which are major effector cells for ADCP. The consistent association of this transcriptome signature with VE represents a tool both to identify potential mechanisms, as with ADCP here, and to screen novel approaches to accelerate the development of new vaccine candidates.
Subject(s)
AIDS Vaccines/therapeutic use , Gene Expression Profiling , HIV Antibodies/immunology , HIV Infections/prevention & control , HIV-1/immunology , Monocytes/drug effects , Phagocytosis/drug effects , Transcriptome , Vaccines, DNA/therapeutic use , AIDS Vaccines/adverse effects , Clinical Trials as Topic , Databases, Genetic , HIV Infections/genetics , HIV Infections/immunology , HIV Infections/virology , HIV-1/pathogenicity , Host-Pathogen Interactions , Humans , Immunogenicity, Vaccine , Monocytes/immunology , Monocytes/metabolism , Oligonucleotide Array Sequence Analysis , RNA-Seq , Single-Cell Analysis , Time Factors , Treatment Outcome , Vaccination , Vaccines, DNA/adverse effectsABSTRACT
PURPOSE: To evaluate disease failure patterns and overall survival (OS) of women with triple-negative (TN) breast cancer who underwent breast-conserving therapy (BCT) and to understand the relationship of TN tumors with other prognostic factors. PATIENTS AND METHODS: The Surveillance, Epidemiology, and End Results (SEER) registry identified 562 women diagnosed and/or treated with unilateral invasive breast cancer during 2003-2004 at three Emory hospitals. After medical record review, 193 eligible women, with all tumor types, received BCT. Primary endpoints (local, regional, and distant recurrences) and secondary endpoint (OS) were evaluated using chi-square tests and Cox proportional hazards models. RESULTS: Of the 193 women, 33 (17.1%) had TN tumors and 160 (82.9%) had non-TN tumors. Patient characteristics were similar between the two tumor types; however, tumor grade and use of chemotherapy and hormones differed between the two groups. Median follow-up was 3.4 years; 22 patients had recurrence (12.2%), and 12 died (6.2%). Patients with TN tumors had higher local (12% versus 4% for non-TN) and distant recurrences (15% versus 4% for non-TN) rates (p = 0.01). On multivariate survival analyses, TN status [hazard ratio (HR) 1.8, 95% confidence interval (CI) 1.13-2.93] and African American (AA) race (HR 1.9, 95%CI 1.2-3.07) were independent predictors of inferior OS. CONCLUSIONS: Patients with TN breast cancer showed significant increases in local and distant metastatic recurrence rates after BCT, and TN status and AA race were independent negative predictors of survival. For the future, identification of these high risk features may bring personalized medicine closer to reality.
Subject(s)
Breast Neoplasms/mortality , Neoplasm Recurrence, Local/mortality , Receptor, ErbB-2/metabolism , Receptors, Estrogen/metabolism , Receptors, Progesterone/metabolism , Antineoplastic Agents/therapeutic use , Breast Neoplasms/metabolism , Breast Neoplasms/therapy , Combined Modality Therapy , Female , Follow-Up Studies , Humans , Middle Aged , Neoadjuvant Therapy , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/therapy , Retrospective Studies , SEER Program , Survival Rate , Treatment OutcomeABSTRACT
Erythropoietin-stimulating agents (ESA) are approved for use in treating chemotherapy-induced anemia in patients with nonmyeloid malignancies. However, recent clinical trials have shown evidence of inferior overall survival and/or locoregional control of tumors in patients receiving ESAs. Given these concerning data, current studies are focused on elucidating the biological mechanisms by which ESAs may contribute to cancer promotion. Evidence suggests that ESAs activate several signaling pathways that are important in altering tumor behavior and response to treatment. Although further research is needed to more precisely elucidate these mechanisms, caution should be exercised in the use of ESAs beyond their approved indication in cancer patients. [Cancer Res 2008;68(11):4013-7].
