Adherence to National Comprehensive Cancer Network ALK Testing Guidelines for Patients with Advanced Non-Small Cell Lung Cancer in U.S. Community Medical Centers.

BACKGROUND: National Comprehensive Cancer Network (NCCN) guidelines recommend biomarker testing as the first step in the management of patients with advanced non-small cell lung cancer (aNSCLC). We assessed anaplastic lymphoma kinase (ALK) testing rates and factors related to underuse in community medical systems between 2012 and 2019 to understand guideline adoption. METHODS: A retrospective observational study using a nationwide electronic health record (EHR)-derived deidentified database was conducted. Patients with aNSCLC diagnosed in community medical centers from January 2012 to May 2019 were included to describe the ALK testing trend. This cohort was further restricted to patients diagnosed after 2015 to understand factors associated with testing underuse using mixed-effects multivariable logistic regression models. RESULTS: Trends for increased ALK testing rates by year were observed in both NCCN guideline-eligible patients (59.5% in 2012 to 84.1% in 2019) and -ineligible patients (15.6% to 50.8%) in a cohort of 41,728 patients. Histology type and smoking status had the greatest impact on test use. Compared with patients with nonsquamous histology and no smoking history, patients with squamous histology and no smoking history (adjusted odds ratio [aOR], 7.6; 95% confidence interval [CI], 5.6-10.4), NSCLC histology not otherwise specified (NOS) with smoking history (aOR, 3.4; 95% CI, 2.8-4.2); NSCLC NOS/nonsmoker (aOR, 1.8; 95% CI, 1.1-3.2), and nonsquamous/smoker (aOR, 1.5; 95% CI, 1.3-1.7) were less likely to be tested. Factors related to underuse also included Eastern Cooperative Oncology Group performance status, stage at initial diagnosis, and demographics. CONCLUSION: This analysis of real-world data shows increasing test use by year; however, one fifth of patients eligible for ALK testing still remain untested and potentially missing therapeutic options. IMPLICATIONS FOR PRACTICE: Advancement in treatment of lung cancer is accompanied by an increasing number of tests that should be run to determine potential therapy options for each patient. This study assessed adoption of testing recommendations for anaplastic lymphoma kinase rearrangements in a national database. Although test use increased over the time period studied (2012-2019), there is still room for improvement. Efforts are needed to increase test use in undertested groups, thus enabling eligible patients to benefit from novel lung cancer therapies.

Understanding Factors Associated With Anaplastic Lymphoma Kinase Testing Delays in Patients With Non-Small Cell Lung Cancer in a Large Real-World Oncology Database.

CONTEXT.­: With multiple therapeutic options available for patients with advanced non-small cell lung cancer, the timely ordering and return of results to determine therapy are of critical importance. OBJECTIVE.­: To assess factors impacting anaplastic lymphoma kinase (ALK) test ordering and time to result delivery. DESIGN.­: A retrospective study using a de-identified electronic health record database was performed. Postdiagnosis ALK tests (n = 14 657) were analyzed from 14 197 patients with advanced non-small cell lung cancer diagnosed between January 2015 and May 2019. Time from non-small cell lung cancer diagnosis to ALK sample receipt in the laboratory was a surrogate for test order time. Test ordering was considered delayed if order time was more than 20 days. Turnaround time from sample received to test result was calculated and considered delayed if more than 10 days. Multivariable logistic regression was used to assess factors associated with order time and turnaround time delays. RESULTS.­: Median ALK test order time was 15 days, and 36.4% (5342) of all 14 657 orders were delayed. Factors associated with delays were non-fluorescence in situ hybridization testing, send-out laboratories, testing prior to 2018, nonadenocarcinoma histology, and smoking history. Median turnaround time was 9 days, and 40.3% (5906) of all 14 657 test results were delayed. Non-fluorescence in situ hybridization testing, tissue sample, and orders combining ALK with other biomarkers were associated with delayed ALK result reporting. CONCLUSIONS.­: This study provides a snapshot of real-world ALK test ordering and reporting time in US community practices. Multiple factors impacted both test ordering time and return of results, revealing opportunities for improvement. It is imperative that patients eligible for targeted therapy be identified in a timely fashion.

Inflammation Mediated Metastasis: Immune Induced Epithelial-To-Mesenchymal Transition in Inflammatory Breast Cancer Cells.

Inflammatory breast cancer (IBC) is the most insidious form of locally advanced breast cancer; about a third of patients have distant metastasis at initial staging. Emerging evidence suggests that host factors in the tumor microenvironment may interact with underlying IBC cells to make them aggressive. It is unknown whether immune cells associated to the IBC microenvironment play a role in this scenario to transiently promote epithelial to mesenchymal transition (EMT) in these cells. We hypothesized that soluble factors secreted by activated immune cells can induce an EMT in IBC and thus promote metastasis. In a pilot study of 16 breast cancer patients, TNF-α production by peripheral blood T cells was correlated with the detection of circulating tumor cells expressing EMT markers. In a variety of IBC model cell lines, soluble factors from activated T cells induced expression of EMT-related genes, including FN1, VIM, TGM2, ZEB1. Interestingly, although IBC cells exhibited increased invasion and migration following exposure to immune factors, the expression of E-cadherin (CDH1), a cell adhesion molecule, increased uniquely in IBC cell lines but not in non-IBC cell lines. A combination of TNF-α, IL-6, and TGF-ß was able to recapitulate EMT induction in IBC, and conditioned media preloaded with neutralizing antibodies against these factors exhibited decreased EMT. These data suggest that release of cytokines by activated immune cells may contribute to the aggressiveness of IBC and highlight these factors as potential target mediators of immune-IBC interaction.

Alterations in T lymphocyte profiles of bronchoalveolar lavage fluid from SIV- and Pneumocystis carinii-coinfected rhesus macaques.

The goal of this study was to examine SIV- and Pneumocystis carinii-coinfected rhesus macaques as a model of P. carinii infection in HIV-seropositive humans. The influence of P. carinii infection on the cellular composition of bronchoalveolar lavage (BAL) fluid from SIV-infected and normal rhesus macaques was examined by flow cytometric analysis and polymerase chain reaction (PCR). BAL fluid from SIV- and P. carinii coinfected macaques showed a substantial T lymphocyte influx composed of more than 90% CD8+ T cells. These results are in contrast to BAL fluid from SIV-infected macaques with no detectable P. carinii-specific PCR product, where CD4+ T cells were present in significant numbers and the CD8+ T cell population was less than 70% of total CD3+ lymphocytes. We observed no significant differences in peripheral blood CD4+ or CD8+ T cell levels in the SIV-infected animals, regardless of P. carinii status, indicating that the CD8+ T cell infiltration in the lungs of the P. carinii-positive animals was likely the result of P. carinii infection. These results demonstrate that although peripheral blood CD4+ T cell levels are predictive of susceptibility to P. carinii infection in this model, the levels are not reflective of the T cell profile in the lung during SIV and P. carinii coinfection. The SIV- and P. carinii-coinfected macaques showed a spectrum of lung disease severity that was histologically similar to human P. carinii pneumonia (PCP). Interestingly, even mild P. carinii infection was sufficient to alter the normal CD4+/CD8+ T cell profiles in the lungs of SIV-infected rhesus macaques. These results are similar to immunologic findings in human AIDS-associated PCP and support the usefulness of this model in the study of immune responses to P. carinii.

Experimental Mycobacterium tuberculosis infection of cynomolgus macaques closely resembles the various manifestations of human M. tuberculosis infection.

Nonhuman primates were used to develop an animal model that closely mimics human Mycobacterium tuberculosis infection. Cynomolgus macaques were infected with low doses of virulent M. tuberculosis via bronchoscopic instillation into the lung. All monkeys were successfully infected, based on tuberculin skin test conversion and peripheral immune responses to M. tuberculosis antigens. Progression of infection in the 17 monkeys studied was variable. Active-chronic infection, observed in 50 to 60% of monkeys, was characterized by clear signs of infection or disease on serial thoracic radiographs and in other tests and was typified by eventual progression to advanced disease. Approximately 40% of monkeys did not progress to disease in the 15 to 20 months of study, although they were clearly infected initially. These monkeys had clinical characteristics of latent tuberculosis in humans. Low-dose infection of cynomolgus macaques appears to represent the full spectrum of human M. tuberculosis infection and will be an excellent model for the study of pathogenesis and immunology of this infection. In addition, this model will provide an opportunity to study the latent M. tuberculosis infection observed in approximately 90% of all infected humans.