Madhusmita Behera

Proliferation of PD-1+ CD8 T cells in peripheral blood after PD-1-targeted therapy in lung cancer patients.

Significance Therapies that harness the immune system have recently been approved for cancer treatment. Identification of biomarkers to monitor or predict patients’ responses to immunotherapies would help guide treatment decisions. Herein we analyzed changes in peripheral blood T cells from lung cancer patients receiving immunotherapy blocking the PD-1 inhibitory pathway. We detected CD8 T-cell responses following treatment in most patients. In addition, our data suggest that an increase in proliferation of PD-1+ CD8 T cells in the blood within 4 wk of treatment initiation may be associated with positive clinical outcome. Our analysis provides valuable insights into cancer patients’ responses to PD-1–targeted therapies and warrant further studies on peripheral blood biomarkers. Exhausted T cells in chronic infections and cancer have sustained expression of the inhibitory receptor programmed cell death 1 (PD-1). Therapies that block the PD-1 pathway have shown promising clinical results in a significant number of advanced-stage cancer patients. Nonetheless, a better understanding of the immunological responses induced by PD-1 blockade in cancer patients is lacking. Identification of predictive biomarkers is a priority in the field, but whether peripheral blood analysis can provide biomarkers to monitor or predict patients’ responses to treatment remains to be resolved. In this study, we analyzed longitudinal blood samples from advanced stage non–small cell lung cancer (NSCLC) patients (n = 29) receiving PD-1–targeted therapies. We detected an increase in Ki-67+ PD-1+ CD8 T cells following therapy in ∼70% of patients, and most responses were induced after the first or second treatment cycle. This T-cell activation was not indiscriminate because we observed only minimal effects on EBV-specific CD8 T cells, suggesting that responding cells may be tumor specific. These proliferating CD8 T cells had an effector-like phenotype (HLA-DR+, CD38+, Bcl-2lo), expressed costimulatory molecules (CD28, CD27, ICOS), and had high levels of PD-1 and coexpression of CTLA-4. We found that 70% of patients with disease progression had either a delayed or absent PD-1+ CD8 T-cell response, whereas 80% of patients with clinical benefit exhibited PD-1+ CD8 T-cell responses within 4 wk of treatment initiation. Our results suggest that peripheral blood analysis may provide valuable insights into NSCLC patients’ responses to PD-1–targeted therapies.

A systematic analysis of efficacy of second line chemotherapy in sensitive and refractory small cell lung cancer

Introduction: Small-cell lung cancer (SCLC) patients unresponsive or relapsing within 90 days after frontline chemotherapy have poor prognosis and are treated with regimens different from the first-line regimen. Potential differences in the efficacy of second-line therapy for refractory and sensitive SCLC have not been well studied. Methods: Studies that enrolled sensitive and refractory (relapse < 90 days or > 90 days) SCLC patients for second-line therapy were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library), and meeting abstracts databases. A systematic analysis was conducted using Comprehensive Meta Analysis (version 2.2.048) software to calculate the odds ratio of response and 95% confidence interval. Median overall survival time for sensitive and resistant SCLC patients was compared by two-sided Student’s t test. We tested for significant heterogeneity by Cochran’s chi-square test and I-square index. Results: Twenty-one studies published between 1984 and 2011 were eligible for this analysis with a total of 1692 patients enrolled; 912 with sensitive and 780 with refractory SCLC. The overall response rate was 17.9% with a higher response rate of 27.7% (range, 0%–77%) for sensitive SCLC versus 14.8% (range, 0%–70%) for refractory patients; p=0.0001. Pooled overall odds ratio of response was 2.235 (95% confidence interval: 1.518–3.291; p=0.001) favoring patients with sensitive disease. Median overall survival time was 6.7 months with a weighted survival of 7.7 and 5.4 months for sensitive and refractory SCLC, respectively (p = 0.0035). Conclusions: Refractory SCLC patients derive modest clinical benefit from second-line chemotherapy. However, response and survival outcomes are superior with chemosensitive disease.

Phase II study of docetaxel in combination with everolimus for second- or third-line therapy of advanced non-small-cell lung cancer.

We conducted a phase II study of docetaxel in combination with everolimus, a mammalian target of rapamycin (mTOR) inhibitor, for salvage therapy of advanced non–small-cell lung cancer (NSCLC) based on promising preclinical and early-phase clinical data. Patients with advanced-stage NSCLC treated with one or two previous systemic therapy regimens were given docetaxel (60 mg/m2) and everolimus (5 mg orally once daily on days 1–19) every 3 weeks. Archived tumor specimens were evaluated for markers of mTOR pathway activation (total and phosphorylated mTOR, Akt, S6, eIF4e, and 4EBP1). Twenty-eight patients were enrolled (median age: 62 years; male: 13; Caucasians: 19; adenocarcinoma: 20; performance status 0, 3; performance status 1, 23; 1 previous regimen, 16). A median of 3.5 cycles of therapy was administered. Two patients experienced partial response and 15 had stable disease (clinical benefit rate, 70%). The 6-month progression-free survival rate was 5%, and the median overall survival was 9.6 months. Low pAkt expression correlated with clinical benefit rate (p = 0.01) but not with progression-free survival or overall survival. The combination of everolimus and docetaxel was tolerated well, but the efficacy was relatively modest in an unselected population of patients with NSCLC.

Bortezomib-containing induction regimens in transplant-eligible myeloma patients: a meta-analysis of phase 3 randomized clinical trials.

The objective of this meta‐analysis in patients with myeloma was to test the hypothesis that the addition of bortezomib to induction therapy not only improves the depth of response but also improves post‐transplant progression‐free survival (PFS) and overall survival (OS) outcomes.

Class I HDACs are mediators of smoke carcinogen-induced stabilization of DNMT1 and serve as promising targets for chemoprevention of lung cancer.

DNA methylation is an early event in bronchial carcinogenesis and increased DNA methyltransferase (DNMT)1 protein expression is a crucial step in the oncogenic transformation of epithelia. Here, we investigate the role of class I histone deacetylases (HDAC) 1 to 3 in the stabilization of DNMT1 protein and as a potential therapeutic target for lung cancer chemoprevention. Long-term exposure of immortalized bronchial epithelial cells (HBEC-3KT) to low doses of tobacco-related carcinogens led to oncogenic transformation, increased HDAC expression, cell-cycle independent increased DNMT1 stability, and DNA hypermethylation. Overexpression of HDACs was associated with increased DNMT1 stability and knockdown of HDACs reduced DNMT1 protein levels and induced DNMT1 acetylation. This suggests a causal relationship among increased class I HDACs levels, upregulation of DNMT1 protein, and subsequent promoter hypermethylation. Targeting of class I HDACs with valproic acid (VPA) was associated with reduced HDAC expression and a profound reduction of DNMT1 protein level. Treatment of transformed bronchial epithelial cells with VPA resulted in reduced colony formation, demethylation of the aberrantly methylated SFRP2 promoter, and derepression of SFRP2 transcription. These data suggest that inhibition of HDAC activity may reverse or prevent carcinogen-induced transformation. Finally, immunohistochemistry on human lung cancer specimens revealed a significant increase in DNMT1, HDAC1, HDAC2, and HDAC3 expression, supporting our hypotheses that class I HDACs are mediators of DNMT1 stability. In summary, our study provides evidence for an important role of class I HDACs in controlling the stability of DNMT1 and suggests that HDAC inhibition could be an attractive approach for lung cancer chemoprevention. Cancer Prev Res; 7(3); 351–61. ©2014 AACR.

Real-World Effectiveness of Systemic Agents Approved for Advanced Non-Small Cell Lung Cancer: A SEER–Medicare Analysis

OBJECTIVES Disparity exists between patients with lung cancer enrolled in clinical trials and patients treated in the community setting. This study assessed the real-world effectiveness of cytotoxic agents that became available for the treatment of non-small cell lung cancer (NSCLC) in the last 2 decades. METHODS We employed the linked Surveillance, Epidemiology, and End Results (SEER)-Medicare database for patients diagnosed with stage IIIB/IV NSCLC between 1988 and 2005 to assess the effectiveness of newly approved agents. Effectiveness of specific agents was assessed at time periods immediately following the approval of the agent for NSCLC: baseline, 1988-1994; platinum, 1995-1999; docetaxel, 1999-2003; pemetrexed and bevacizumab, 2004-2005. Significant associations between specific drug treatment and survival improvement were determined using the Kaplan-Meier method, Cox proportional hazard model, and propensity score analyses. Significant differences were established by log-rank test. RESULTS This analysis employed data from 143,548 patients by sex (58% male, 42% female), cancer stage (35% stage IIIB, 65% stage IV), and age (12% 20-64 years, 22% 65-69 years, 45% 70-79 years, 22% 80 years and older). There was temporal improvement in survival for patients treated with newly approved chemotherapy (1-year survival rates: 32.41% in 1988-1994, 32.95% in 1995-1998, 37.40% in 1999-2003, and 39.55% in 2004-2005). Patients treated with a newly approved drug during the relevant treatment era had a significant reduction in the risk of death when compared with patients treated with chemotherapy other than the newly approved agent (hazard ratios [95% confidence interval] were 0.76 [0.71-0.81] for platinum, 0.73 [0.70-0.75] for docetaxel, 0.40 [0.37-0.44] for pemetrexed, and 0.33 [0.27-0.40] for bevacizumab; p < .001). Propensity score adjustment did not significantly alter these results. CONCLUSIONS Currently approved drugs for the treatment of advanced NSCLC are associated with improved survival in the U.S. Medicare patient population. Our findings support the effectiveness of these agents in the real-world oncology practice.

Effective x-ray attenuation measurements with full field digital mammography

This work shows that effective x-ray attenuation coefficients may be estimated by applying Beers Law to phantom image data acquired with the General Electric Senographe 2000D full field digital mammography system. Theoretical developments are provided indicating that an approximate form of the Beers relation holds for polychromatic x-ray beams. The theoretical values were compared with experimentally determined measured values, which were estimated at various detector locations. The measured effective attenuation coefficients are in agreement with those estimated with theoretical developments and numerical integration. The work shows that the measured quantities show little spatial variation. The main ideas are demonstrated with polymethylmethacrylate and breast tissue equivalent phantom imaging experiments. The work suggests that the effective attenuation coefficients may be used as known values for radiometric standardization applications that compensate for the image acquisition influences. The work indicates that it is possible to make quantitative attenuation coefficient measurements from a system designed for clinical purposes.

Role of race in oncogenic driver prevalence and outcomes in lung adenocarcinoma: Results from the Lung Cancer Mutation Consortium

The discovery of oncogenic drivers has ushered in a new era for lung cancer, but the role of these mutations in different racial/ethnic minorities has been understudied. The Lung Cancer Mutation Consortium 1 (LCMC1) database was investigated to evaluate the frequency and impact of oncogenic drivers in lung adenocarcinomas in the racial/ethnic minority patient population.

Atypical Carcinoid Tumor of the Lung: A Surveillance, Epidemiology, and End Results Database Analysis

Background: Atypical carcinoid (AC) of the lung is a rare form of thoracic malignancy. The limited knowledge of its biology and outcome stems largely from small, single institution experiences. We analyzed the Surveillance, Epidemiology, and End Results database (SEER) to better understand the clinical characteristics of this disease. Methods: Demographic, treatment, and outcome data on all patients with pulmonary AC were obtained from the SEER database with 18 reporting sites from 1973 to 2010 using SEER*Stat 8.1.2. Statistical analysis was performed using SAS 9.3 (SAS Institute, Inc., Cary, NC). Results: There were 947,463 patients diagnosed with lung and bronchus tumors in the SEER database, of which 441 had AC (0.05%). Median age of AC patients was 65 years; 69% were women and 87% of white ethnicity. Metastatic disease was present in 20% of patients at diagnosis. In terms of treatment, 78% of patients underwent resection and 12.5% received radiation. The overall 1-year and 3-year survival rates were 86% and 67%, respectively. The 3-year survival rates for distant (M1), regional (lymph node involvement), and localized (lung only) disease were 26% (13 of 50), 69% (50 of 72), and 85% (99 of 116), respectively. On univariate analysis, patients treated with surgery had reduced risk of death (hazard ratio, HR 0.19; p < 0.001), whereas radiation treatment was associated with increased risk of death (HR 2.45; p < 0.001). Conclusions: AC accounted for less than 1% of all lung cancers diagnosed and was more frequent in women. The best outcomes were observed with surgical resection for localized disease.

Comparison of the toxicity profile of PD-1 versus PD-L1 inhibitors in non-small cell lung cancer: A systematic analysis of the literature.

Monoclonal antibodies against programmed cell death protein 1 (PD‐1) and programmed death ligand 1 (PD‐L1) are effective therapies in patients with non‐small cell lung cancer (NSCLC). Herein, the authors performed a systematic review investigating differences in the toxicities of PD‐1 and PD‐L1 inhibitors.