Treatment Decision Drivers in Stage III Non-Small-Cell Lung Cancer: Outcomes of a Web-Based Survey of Oncologists in the United States.

PURPOSE: We conducted a cross-sectional survey of practicing medical oncologists in the United States to obtain insight into physician and patient treatment decision making in stage III non-small-cell lung cancer (NSCLC). METHODS: A convenience sample of 150 oncologists completed a 38-question Web-based survey in January 2019. RESULTS: Surveyed oncologists (82% community based) had an average of 15 years of clinical experience and had treated an average of 20 patients newly diagnosed with stage III NSCLC in the previous 6 months. Oncologists reported presenting 55% of their patients with stage III NSCLC to tumor boards. For patients with new unresectable stage III NSCLC seen in the previous 6 months, concurrent chemoradiation therapy (cCRT) was reported as the initial treatment in an average of 48% of patients. The most frequent reason for delays in starting the initial chosen treatment was insurance preauthorization processes (reported by 65% of oncologists). A total of 55% of all patients with unresectable stage III NSCLC who received cCRT went on to receive consolidation immunotherapy; for patients who received consolidation chemotherapy after cCRT, the rate of immunotherapy was lower (42%). Biomarker test results were given as the reason for oncologists not recommending immunotherapy after cCRT in approximately a quarter of cases. The 112 oncologists with eligible patients who declined immunotherapy reported previous treatment fatigue as the reason in 34% of patients and insurance challenges in 19% of patients. CONCLUSION: Oncologists reported notable deviations from treatment guidelines for stage III NSCLC. Our findings highlight important opportunities to improve decision making and the coordination of care in stage III NSCLC.

Tumor-infiltrating regulatory T cells inhibit endogenous cytotoxic T cell responses to lung adenocarcinoma.

Immune cells comprise a substantial proportion of the tumor mass in human nonsmall cell lung cancers (NSCLC), but the precise composition and significance of this infiltration are unclear. In this study, we examined immune complexity of human NSCLC as well as NSCLC developing in CC10-TAg transgenic mice, and revealed that CD4(+) T lymphocytes represent the dominant population of CD45(+) immune cells, and, relative to normal lung tissue, CD4(+)Foxp3(+) regulatory T cells (Tregs) were significantly increased as a proportion of total CD4(+) cells. To assess the functional significance of increased Tregs, we evaluated CD8(+) T cell-deficient/CC10-TAg mice and revealed that CD8(+) T cells significantly controlled tumor growth with antitumor activity that was partially repressed by Tregs. However, whereas treatment with anti-CD25-depleting mAb as monotherapy preferentially depleted Tregs and improved CD8(+) T cell-mediated control of tumor progression during early tumor development, similar monotherapy was ineffective at later stages. Because mice bearing early NSCLC treated with anti-CD25 mAb exhibited increased tumor cell death associated with infiltration by CD8(+) T cells expressing elevated levels of granzyme A, granzyme B, perforin, and IFN-γ, we therefore evaluated carboplatin combination therapy resulting in a significantly extended survival beyond that observed with chemotherapy alone, indicating that Treg depletion in combination with cytotoxic therapy may be beneficial as a treatment strategy for advanced NSCLC.

Downregulation of EMX2 is associated with clinical outcomes in lung adenocarcinoma patients.

BACKGROUND: The 5-year survival rate for stage I non-small-cell lung cancer (NSCLC) of 50% to 70% indicates that our current staging methods do not adequately predict outcome. Empty spiracles homeobox 2 (EMX2) is a homeo-domain-containing transcription factor that regulates a key developmental pathway known to promote lung tumorigenesis. This study assessed the significance of EMX2 as a prognostic biomarker in lung adenocarcinoma including bronchioloalveolar carcinoma (BAC). PATIENTS AND METHODS: 144 patients with lung adenocarcinoma undergoing surgical resection were studied. Quantitative real-time reverse transcriptase polymerase chain reaction and Immunohistochemistry were used to analyze EMX2 mRNA and protein expression, respectively. Association of EMX2 mRNA expression levels with clinical outcomes was evaluated using the Kaplan-Meier method and a multivariate Cox proportional hazards regression model. RESULTS: EMX2 mRNA expression was significantly downregulated in lung adenocarcinoma compared with matched adjacent normal tissue (P < .001). EMX2 protein expression was similarly found to be downregulated in lung adenocarcinoma. The EMX2-high mRNA expressing group had statistically significant better overall survival (OS) than the EMX2-low mRNA expressing group (P = .005). Subgroup analysis also demonstrated improved survival in stage I patients (P = .01) and patients with BAC (P = .03). Lastly, the EMX2-high mRNA expressing group had statistically significant better recurrence-free survival (RFS) than the EMX2-low mRNA expression group in patients with adenocarcinoma (P < .001). CONCLUSION: EMX2 expression is downregulated in lung adenocarcinoma. Low EMX2 mRNA expression is significantly associated with decreased OS and RFS in patients with lung adenocarcinoma, particularly with stage I disease and BAC.

Cancer stem cells in lung tumorigenesis.

Although stem cells were discovered more than 50 years ago, we have only recently begun to understand their potential importance in cancer biology. Recent advances in our ability to describe, isolate, and study lung stem cell populations has led to a growing recognition of the central importance cells with stem cell-like properties may have in lung tumorigenesis. This article reviews the major studies supporting the existence and importance of cancer stem cells in lung tumorigenesis. Continued research in the field of lung cancer stem cell biology is vital, as ongoing efforts promise to yield new prognostic and therapeutic targets.

A translational approach to lung cancer research: From EGFRs to Wnt and cancer stem cells.

Lung cancer remains the main cause of all cancer deaths in the United States. The prognosis for non-small cell lung cancer, despite advances in current therapies, is disappointing. Fortunately, we are steadily gaining significant insights into the heterogeneous molecular pathogenesis of lung cancer, which seems to occur in a stepwise manner, mainly secondary to tobacco smoking. With the emerging power of gene expression signatures for individual lung tumors and with the advancing field of stem cell biology and the paradigm of cancer stem cells, we are most certainly paving the way to developing novel tools for the early detection, chemoprevention, and treatment of these vastly morbid pathologies with enormous global burden. We will explore some of these issues and highlight how we are starting to translate them into clinically relevant tools for lung cancer patients.

Respiratory Homeostasis and Exploitation of the Immune System for Lung Cancer Vaccines.

Lung cancer is the leading cause of all cancer deaths in the US. The international scientific and clinical community has made significant advances toward understanding specific molecular mechanisms underlying lung carcinogenesis; however, despite these insights and advances in surgery and chemoradiotherapy, the prognosis for non-small-cell lung cancer (NSCLC) remains poor. Nonetheless, significant effort is being focused on advancing translational research evaluating the efficacy of novel targeted therapeutic strategies for lung cancer. Illustrative examples of this include antagonists of the epidermal growth factor receptor (EGFR), tyrosine kinase inhibitors (TKIs) such as gefitinib and erlotinib, and a diverse assortment of anti-angiogenic compounds targeting growth factors and/or their receptors that regulate tumor-associated angiogenic programs. In addition, with the increased awareness of the significant role chronically activated leukocytes play as potentiators of solid-tumor development, the role of innate and adaptive immune cells as regulators of lung carcinogenesis is being examined. While some of these studies are examining how novel therapeutic strategies may enhance the efficacy of lung cancer vaccines, others are evaluating the intrinsic characteristics of the immune response to lung cancer in order to identify rate-limiting molecular and/or cellular programs to target with novel anticancer therapeutics. In this article, we explore important aspects of the immune system and its role in regulating normal respiratory homeostasis compared with the immune response accompanying development of lung cancer. These hallmarks are then discussed in the context of recent efforts to develop lung cancer vaccines, where we have highlighted important concepts that must be taken into consideration for future development of novel therapeutic strategies and clinical trials assessing their efficacy.

The role of cancer stem cells in neoplasia of the lung: past, present and future.

Through the identification and subsequent targeting of an exquisitely unique and phenotypically defined cancer stem-cell population exhibiting discrete therapeutic vulnerabilities (a potential source of tumor recurrence) better survival rates for these patients may be achieved. It is this impetus that is making the field of pulmonary stem cell biology a growing field in biomedicine. These efforts are leading to the steady identification of multi-potent, self-renewing and proliferative progenitor cell populations throughout the bronchopulmonary tree. These cells give rise to both transiently amplifying (TA) and terminally differentiated (TD) cells, which (like in many other organs) are crucial for tissue homeostasis. In leukemia, it has been shown that partially committed cells, which are normally responsible for tissue maintenance after trauma, may undergo transformation via mutations resulting in the selective expression of genes that accentuate and perpetuate these cells' self-renewal capabilities. It is therefore perhaps legitimate to consider stem cells as protumorigenic. It is when these cells undergo genetic mutations which make them acquire the ability to metastasize, that cancer occurs, rendering the concept of "cancer stem cells" a rather attractive one indeed.

Inhibition of Hsp90 leads to cell cycle arrest and apoptosis in human malignant pleural mesothelioma.

INTRODUCTION: Heat shock protein 90 (Hsp90) is an abundant molecular chaperone that mediates the maturation and stability of a variety of proteins associated with the promotion of cell growth and survival. Inhibition of Hsp90 function leads to proteasomal degradation of its mis-folded client proteins. Recently, Hsp90 has emerged as being of prime importance to the growth and survival of cancer cells and its inhibitors have already been used in phase I and II clinical trials. METHODS: We investigated how 17-allylamino-17-demethoxygeldanamycin (17-AAG), a small molecule inhibitor of Hsp90, is implicated in human malignant pleural mesothelioma (MM). RESULTS: We found that 17-AAG led to significant G1 or G2/M cell cycle arrest, inhibition of cell proliferation, and decrease of AKT, AKT1, and survivin expression in all human malignant pleural mesothelioma cell lines examined. We also observed significant apoptosis induction in all MM cell lines treated with 17-AAG. Furthermore, 17-AAG induced apoptosis in freshly cultured primary MM cells and caused signaling changes identical to those in 17-AAG treated MM cell lines. CONCLUSION: These results suggest that Hsp90 is strongly associated with the growth and survival of MM and that inhibition of Hsp90 may have therapeutic potential in the treatment of MM.

Epigenetic alteration of the Wnt inhibitory factor-1 promoter occurs early in the carcinogenesis of Barrett's esophagus.

The role of Wnt antagonists in the carcinogenesis of esophageal adenocarcinoma (EAC) remains unclear. We hypothesized that downregulation of the Wnt inhibitory factor-1 (WIF-1) might be involved in the neoplastic progression of Barrett's esophagus (BE). We analyzed the DNA methylation status of the WIF-1 promoter in normal, preneoplastic, and neoplastic samples from BE patients and in EAC cell lines. We investigated the role of WIF-1 on EAC cell growth and the chemosensitization of the cells to cisplatin. We found that silencing of WIF-1 correlated with promoter hypermethylation. EAC tissue samples showed higher levels of WIF-1 methylation compared to the matched normal epithelium. In addition, we found that WIF-1 hypermethylation was more frequent in BE samples from patients with EAC than in BE samples from patients who had not progressed to EAC. Restoration of WIF-1 in cell lines where WIF-1 was methylation-silenced resulted in growth suppression. Restoration of WIF-1 could sensitize the EAC cells to the chemotherapy drug cisplatin. Our results suggest that silencing of WIF-1 through promoter hypermethylation is an early and common event in the carcinogenesis of BE. Restoring functional WIF-1 might be used as a new targeted therapy for the treatment of this malignancy.

Inhibition of Wnt-2 and galectin-3 synergistically destabilizes beta-catenin and induces apoptosis in human colorectal cancer cells.

Constitutive activation of the Wnt pathway as a result of APC, AXIN1 or CTNNB1 mutations has been found in most colorectal cancers. For a long time, this aberrant Wnt activation has been thought to be independent of upstream signals. However, recent studies indicate that upstream signals retain their ability to regulate the Wnt pathway even in the presence of downstream mutations. Wnt-2 is well known for its overexpression in colorectal cancer. Galectin-3 (Gal-3), a multifunctional carbohydrate binding protein implicated in a variety of biological functions, has recently been reported to interact with beta-catenin. In this study, we investigated roles of Wnt-2 and Gal-3 in the regulation of canonical Wnt/beta-catenin signaling. We found that siRNA silencing of either Wnt-2 or Gal-3 expression inhibited TCF-reporter activity, decreased cytosolic beta-catenin level and induced apoptosis in human colorectal cancer cells containing downstream mutations. More interestingly, we showed that inhibition of both Wnt-2 and Gal-3 had synergistic effects on suppressing canonical Wnt signaling and inducing apoptosis, suggesting that aberrant canonical Wnt/beta-catenin signaling in colorectal cancer can be regulated at multiple levels. The combined inhibition of Wnt-2 and Gal-3 may be of superior therapeutic advantage to inhibition by either one of them, giving rise to a potential development of novel drugs for the targeted treatment of colorectal cancer.

Optimal surgical management of Stage I non-small-cell lung cancer in an increasingly aging population: challenges and recent progress.

Lung cancer remains the main cause of cancer deaths in the USA. The dismal prognosis for non-small-cell lung cancer (NSCLC) despite current advances in chemotherapy is disappointing. In an increasingly aging population, computed tomography screening allows the detection of very early Stage I NSCLC lesions. Although many retrospective trials have indicated better prognosis for those undergoing lobectomy versus sublobar resection (anatomical segmentectomy or wedge resection), the issue remains equivocal. This is particularly true for patients with significant comorbid cardiorespiratory disease compromising postoperative recovery. This review will describe landmark retrospective studies related to the topic, in an attempt to highlight the difficulties associated with surgical decision making. Key factors in the characteristics of the lesions will be examined equally with the ultimate objective of allowing the decision of lobectomy versus sublobar resection to be centered around the need of the individual patient per se. This review article will also provide an insight into ongoing randomized, prospective clinical trials on the subject, investigating into some of the emerging technologies from the laboratory and the clinic that will hopefully enable the provision of a solidly acceptable treatment plan for the Stage I NSCLC patient, with maximum survival rates and low disease recurrence.

Novel therapies targeting signaling pathways in lung cancer.

Despite advances in chemotherapy, the prognosis for advanced non-small-cell lung cancer (NSCLC) remains dismal. Increasing understanding of the biological processes responsible for lung carcinogenesis has led to development of new therapeutic strategies targeting this disease at a molecular level. This article examines the molecular events believed to lead to cellular changes in lung cancer, and how knowledge of these is used to develop new agents used individually or in combination with available cytotoxic drugs to improve survival. Finally, it explores how a deeper understanding of the embryonic signaling pathways responsible for airway epithelial repair and tumorogenesis, such as Hedgehog (Hh), Notch, and Wingless (Wnt), can lead to the development of newer and more specific therapies for lung cancer.