The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC)

Lung cancer is the leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for over 85% of all cases. Until recently, chemotherapy – characterized by some benefit but only rare durable responses – was the only treatment option for patients with NSCLC whose tumors lacked targetable mutations. By contrast, immune checkpoint inhibitors have demonstrated distinctly durable responses and represent the advent of a new treatment approach for patients with NSCLC. Three immune checkpoint inhibitors, pembrolizumab, nivolumab and atezolizumab, are now approved for use in first- and/or second-line settings for selected patients with advanced NSCLC, with promising benefit also seen in patients with stage III NSCLC. Additionally, durvalumab following chemoradiation has been approved for use in patients with locally advanced disease. Due to the distinct features of cancer immunotherapy, and rapid progress in the field, clinical guidance is needed on the use of these agents, including appropriate patient selection, sequencing of therapies, response monitoring, adverse event management, and biomarker testing. The Society for Immunotherapy of Cancer (SITC) convened an expert Task Force charged with developing consensus recommendations on these key issues. Following a systematic process as outlined by the National Academy of Medicine, a literature search and panel voting were used to rate the strength of evidence for each recommendation. This consensus statement provides evidence-based recommendations to help clinicians integrate immune checkpoint inhibitors into the treatment plan for patients with NSCLC. This guidance will be updated following relevant advances in the field

Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas

The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8 + T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and AI burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas

Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC

Major Pathologic Response and Prognostic Score Predict Survival in Patients With Lung Cancer Receiving Neoadjuvant Chemotherapy.

Complete pathologic response (CPR) is an acceptable surrogate for survival in clinical trials but it occurs infrequently in patients with NSCLC receiving neoadjuvant chemotherapy (NCT). Therefore, we studied the impact of major pathologic response (MPR) for predicting survival of patients with NSCLC receiving NCT. We also tested a newly reported scoring system-the prognostic score (PRSC)-which combines T category, lymph node status, and MPR status. We analyzed CPR and MPR, defined as 0% and less than or equal to 10% viable tumor cells, respectively, in 339 patients with NSCLC with various histologic types who had been treated with NCT followed by complete surgical resection. We evaluated the relationships between CPR, MPR, or PRSC and overall survival using the Kaplan-Meier method and Cox regression multivariate models, accounting for known prognostic factors, such as age, gender, histologic subtype, and pathologic stage. Among all 339 patients, the Kaplan-Meier method revealed that patients with CPR and MPR had better survival. MPR identified a favorable group of patients who experienced survival similar to patients with CPR. Nevertheless, patients with no MPR had a significantly reduced probability of survival. Furthermore, univariate and multivariate Cox proportional hazards regression analysis revealed that MPR and PRSC were significantly associated with overall survival. Our data suggest that MPR can be used as an end point for overall survival in different histologic types for evaluation of therapeutic agents in clinical trials exploring NCT. We also confirmed that PRSC had a prognostic impact, differentiating patients into three prognostic groups, but not superior compared with MPR alone or the TNM8 systems

Reflux-Associated Oxygen Desaturations: Usefulness in Diagnosing Reflux-Related Respiratory Symptoms

Background: Current diagnostic techniques establishing gastroesophageal reflux disease as the underlying cause in patients with respiratory symptoms are poor. Our aim was to provide additional support to our prior studies suggesting that the association between reflux events and oxygen desaturations may be a useful discriminatory test in patients presenting with primary respiratory symptoms suspected of having gastroesophageal reflux as the etiology. Methods: Thirty-seven patients with respiratory symptoms, 26 with typical symptoms, and 40 control subjects underwent simultaneous 24-h impedance-pH and pulse oximetry monitoring. Eight patients returned for post-fundoplication studies. Results: The median number (interquartile range) of distal reflux events associated with oxygen desaturation was greater in patients with respiratory symptoms (17 (9-23)) than those with typical symptoms (7 (4-11, p < 0. 001)) or control subjects (3 (2-6, p < 0. 001)). A similar relationship was found for the number of proximal reflux-associated desaturations. Repeat study in seven post-fundoplication patients showed marked improvement, with reflux-associated desaturations approaching those of control subjects in five patients; 20 (9-20) distal preoperative versus 3 (0-5, p = 0. 06) postoperative; similar results were identified proximally. Conclusions: These data provide further proof that reflux-associated oxygen desaturations may discriminate patients presenting with primary respiratory symptoms as being due to reflux and may respond to antireflux surgery. \ua9 2012 The Society for Surgery of the Alimentary Tract

Surgical resection for locoregional esophageal cancer is underutilized in the United States

Background Although esophagectomy provides the highest probability of cure in patients with esophageal cancer, many candidates are never referred for surgery. We hypothesized that esophagectomy for esophageal cancer is underused, and we assessed the prevalence of resection in national, state, and local cancer data registries. Study Design Clinical stage, surgical and nonsurgical treatments, age, and race of patients with cancer of the esophagus were identified from the Surveillance, Epidemiology and End Results (SEER) registry (1988 to 2004), the Healthcare Association of NY State registry (HANYS 2007), and a single referral center (2000 to 2007). SEER identified a total of 25,306 patients with esophageal cancer (average age 65.0 years, male-to-female ratio 3:1). HANYS identified 1,012 cases of esophageal cancer (average age 67 years, M:F ratio 3:1); stage was not available from NY State registry data. A single referral center identified 385 patients (48 per year; average age 67 years, M:F 3:1). For SEER data, logistic regression was used to examine determinants of esophageal resection; variables tested included age, race, and gender. Results Surgical exploration was performed in 29% of the total and only 44.2% of potentially resectable patients. Esophageal resection was performed in 44% of estimated cancer patients in NY State. By comparison, 64% of patients at a specialized referral center underwent surgical exploration, 96% of whom had resection. SEER resection rates for esophageal cancer did not change between 1988 and 2004. Males were more likely to receive operative treatment. Nonwhites were less likely to undergo surgery than whites (odds ratio 0.45, p < 0.001). Conclusions Surgical therapy for locoregional esophageal cancer is likely underused. Racial variations in esophagectomy are significant. Referral to specialized centers may result in an increase in patients considered for surgical therapy. \ua9 2010 American College of Surgeons