Methylation of breast cancer susceptibility gene 1 (BRCA1) predicts recurrence in patients with curatively resected stage I non–small cell lung cancer

BACKGROUND:

Even after early detection and curative resection of early stage non–small cell lung cancer (NSCLC), a significant fraction of patients develop recurrent disease. Molecular biomarkers that can predict the risk of recurrence thus need to be identified to improve clinical outcomes.

METHODS:

Using the methylation‐specific polymerase chain reaction assay, promoter methylation of the breast cancer susceptibility gene 1 (BRCA1) was assessed in cancer tissues from 70 patients with curatively resected stage I NSCLC. The clinical relevance of BRCA1 methylation status was evaluated in terms of outcome of the disease.

RESULTS:

Methylation of the BRCA1 promoter was detected in 13 of 70 patients (18.6%). Multiple logistic regression analysis revealed that BRCA1 methylation was an independent risk factor for recurrence (P = .0197) and that patients with BRCA1 methylation demonstrated significantly poorer recurrence‐free survival compared to those without (P = .0139). Cox's proportional hazard regression analysis revealed that BRCA1 methylation was an independent risk factor for recurrence‐free survival (P = .0155).

CONCLUSIONS:

Methylated BRCA1 can be a potential biomarker that predicts the prognosis after curative resection of stage I NSCLC. Considering that BRCA1 plays a role in chemotherapy‐induced apoptosis, it is plausible that identification of methylated BRCA1 could provide information that is clinically relevant to tailored adjuvant therapy. Cancer 2013. © 2013 American Cancer Society.     

Cancer‐associated fibroblast migration in non‐small cell lung cancers is modulated by increased integrin α11 expression

Cancer‐associated fibroblasts (CAFs) regulate cancer progression through the modulation of extracellular matrix (ECM) and cancer cell adhesion. While undergoing a series of phenotypic changes, CAFs control cancer–stroma interactions through integrin receptor signaling. Here, we isolated CAFs from patients with non‐small‐cell lung cancer (NSCLC) and examined their gene expression profiles. We identified collagen type XI α1 (COL11A1), integrin α11 (ITGA11), and the ITGA11 major ligand collagen type I α1 (COL1A1) among the 390 genes that were significantly enriched in NSCLC‐associated CAFs. Increased ITGA11 expression in cancer stroma was correlated with a poor clinical outcome in patients with NSCLC. Increased expression of fibronectin and collagen type I induced ITGA11 expression in CAFs. The cellular migration of CAFs toward collagen type I and fibronectin was promoted via ERK1/2 signaling, independently of the fibronectin receptor integrin α5β1. Additionally, ERK1/2 signaling induced ITGA11 and COL11A1 expression in cancer stroma. We, therefore, propose that targeting ITGA11 and COL11A1 expressing CAFs to block cancer–stroma interactions may serve as a novel, promising anti‐tumor strategy.     

KEYNOTE‐025: Phase 1b study of pembrolizumab in Japanese patients with previously treated programmed death ligand 1–positive advanced non–small‐cell lung cancer

Pembrolizumab, a humanized monoclonal antibody against programmed death 1 (PD‐1), has been shown to improve overall survival (OS) in patients with previously treated advanced non–small‐cell lung cancer (NSCLC) with programmed death ligand 1 (PD‐L1) tumor proportion score (TPS) ≥1%. We report safety and efficacy results from the phase 1b KEYNOTE‐025 study, which evaluated pembrolizumab in Japanese patients with previously treated NSCLC. Eligible patients had histologically/cytologically confirmed advanced NSCLC with PD‐L1 TPS ≥1% and had received ≥1 platinum‐doublet chemotherapy. Patients received pembrolizumab 10 mg/kg once every 3 weeks for 2 years or until disease progression/unacceptable toxicity. Primary objectives were to evaluate the safety of pembrolizumab in patients with PD‐L1 TPS ≥1% and the objective response rate (ORR) per RECIST version 1.1 in patients with PD‐L1 TPS ≥50%. Thirty‐eight patients were enrolled and received ≥1 pembrolizumab dose. The median (range) age was 66.0 (41‐78) years, and 61% had received ≥2 prior systemic therapies. Eleven patients (29%) experienced grade 3‐5 treatment‐related adverse events (AE); 9 patients (24%) experienced immune‐mediated AE and infusion reactions, with pneumonitis (11%; any grade) being most common. Among evaluable patients with PD‐L1 TPS ≥50% (n = 11), ORR was 27% (95% CI, 6‐61). Among evaluable patients with PD‐L1 TPS ≥1% (n = 37), ORR was 22% (95% CI, 10‐38). Median (95% CI) progression‐free survival and OS were 3.9 (2.0‐6.2) months and 19.2 (8.0‐26.7) months, respectively. In summary, pembrolizumab was generally well tolerated and showed promising antitumor activity in Japanese patients with previously treated PD‐L1–expressing NSCLC. Outcomes were consistent with those from the phase 3 KEYNOTE‐010 study. (Trial registration number: ClinicalTrials.gov, NCT02007070.)     

Immune checkpoint inhibitors in advanced non–small cell lung cancer

The emergence of immune checkpoint inhibitors for the treatment of cancer has led to major changes to the therapeutic landscape of lung cancer. Improvements in overall survival relative to standard chemotherapy have been observed in the first‐line and second‐line therapy settings for patients with advanced non–small cell lung cancer (NSCLC) who are treated with immune checkpoint inhibitors. Consequently, every patient with advanced‐stage NSCLC is now a candidate for immune checkpoint inhibitor therapy. However, it is clear that the benefit from therapy is not universal, and identification of biomarkers to select therapy has assumed importance. In addition to programmed cell death receptor ligand 1 expression, both tissue‐based and blood‐based markers are under evaluation to select patients. In an era of increasing costs of care and potential for toxicities related to immune checkpoint inhibition, proper patient selection is critical to the optimal use of this new class of agents. In addition, development of novel combination approaches has also emerged as an important way to improve the efficacy of immune checkpoint inhibition. Studies in earlier stages of NSCLC are already underway with the hope of improving the cure rate. In this article, the authors review the current landscape of immune checkpoint inhibitors in the treatment of advanced NSCLC. Cancer 2018;124:248‐61 . © 2017 American Cancer Society.     

Smoking status and survival in the national comprehensive cancer network non–small cell lung cancer cohort

BACKGROUND:

The objectives of this study were to evaluate survival among current smokers, former smokers, and never smokers who are diagnosed with non–small cell lung cancer (NSCLC).

METHODS:

The study included patients who participated in the National Comprehensive Cancer Network's NSCLC Database Project. Current, former, and never smokers were compared with respect to overall survival by fitting Cox regression models.

RESULTS:

Data from 4200 patients were examined, including 618 never smokers, 1483 current smokers, 380 former smokers who quit 1 to 12 months before diagnosis, and 1719 former smokers who quit >12 months before diagnosis. Among patients with stage I, II, and III disease, only never smokers had better survival than current smokers (hazard ratio, 0.47 [95% confidence interval, 0.26‐0.85] vs 0.51 [95% confidence interval, 0.38‐0.68], respectively). Among patients with stage IV disease, the impact of smoking depended on age: Among younger patients (aged ≤55 years), being a never smoker and a former smoker for ≥12 months increased survival. After age 85 years, smoking status did not have a significant impact on overall survival.

CONCLUSIONS:

Patients who were smoking at the time of diagnosis had worse survival compared with never smokers. Among younger patients with stage IV disease, current smokers also had worse survival compared with former smokers who quit >12 months before diagnosis. It is likely that tumor biology plays a major role in the differences observed; however, to improve survival, it is prudent to encourage all smokers to quit smoking if they are diagnosed with NSCLC. Cancer 2013. © 2012 American Cancer Society.     

Integrin α5 promotes migration and invasion through the FAK/STAT3/AKT signaling pathway in icotinib-resistant non-small cell lung cancer cells

Patients with non-small cell lung cancer (NSCLC) treated with EGFR-tyrosine kinase inhibitors (TKIs) ultimately develop drug resistance and metastasis. Therefore, there is a need to identify the underlying mechanisms of resistance to EGFR-TKIs. In the present study, colony formation and MTT assays were performed to investigate cell viability following treatment with icotinib. Gene Expression Omnibus datasets were used to identify genes associated with resistance. Wound healing and Transwell assays were used to detect cell migration and invasion with icotinib treatment and integrin α5-knockdown. The expression levels of integrin α5 and downstream genes were detected using western blotting. Stable icotinib-resistant (IcoR) cell lines (827/IcoR and PC9/IcoR) were established that showed enhanced malignant properties compared with parental cells (HCC827 and PC9). Furthermore, the resistant cell lines were resistant to icotinib in terms of proliferation, migration and invasion. The enrichment of function and signaling pathways analysis showed that integrin α5-upregulation was associated with the development of icotinib resistance. The knockdown of integrin α5 attenuated the migration and invasion capability of the resistant cells. Moreover, a combination of icotinib and integrin α5 siRNA significantly inhibited migration and partly restored icotinib sensitivity in IcoR cells. The expression levels of phosphorylated (p)-focal adhesion kinase (FAK), p-STAT3 and p-AKT decreased after knockdown of integrin α5, suggesting that FAK/STAT3/AKT signaling had a notable effect on the resistant cells. The present study revealed that the integrin α5/FAK/STAT3/AKT signaling pathway promoted icotinib resistance and malignancy in IcoR NSCLC cells. This signaling pathway may provide promising targets against acquired resistance to EGFR-TKI in patients with NSCLC.     

KIF5B‐RET fusions in Chinese patients with non–small cell lung cancer

BACKGROUND:

It has been established that “ret proto‐oncogene” (RET) fusions are oncogenic drivers in non–small cell lung cancer (NSCLC). The prevalence and clinicopathologic characteristics of RET fusions in Chinese patients with NSCLC remain unclear. The objective of the current study was to determine the prevalence and clinicopathologic characteristics of KIF5B‐RET fusions (fusions of the RET and kinesin family member 5B [KIF5B] genes) in Chinese patients with NSCLC.

METHODS:

The authors screened for KIF5B‐RET fusions in 392 patients with NSCLC using multiplex real‐time polymerase chain reaction assay and validated all positive samples using direct sequencing. The relations between KIF5B‐RET fusions and clinicopathologic characteristics were analyzed.

RESULTS:

In total, 6 patients (1.5%) were identified who harbored KIF5B‐RET fusions. Of these, 4 had adenocarcinoma, 1 had a malignant neuroendocrine tumor, and 1 had squamous cell carcinoma. All patients who were positive for a KIF5B‐RET fusion were never‐smokers. There was no statistically significant difference in age, sex, smoking status, pathologic stage, or histologic type between patients with and without KIF5B‐RET fusions. Patients without KIF5B‐RET fusions had a better prognosis than those with KIF5B‐RET fusions (median survival, 52.6 months vs 21.0 months; P = .06), with a hazard ratio of 2.398 (95% confidence interval, 0.982‐5.856; P = .055) on multivariate analysis. Disease stage (hazard ratio, 2.879) and younger age (<65 years; hazard ratio, 1.485) were identified as independent prognostic factors for better survival.

CONCLUSIONS:

KIF5B‐RET fusions were quite rare, with a prevalence of approximately 1.5% in Chinese patients with NSCLC, and they were a little more common in patients with adenocarcinoma than in those with squamous carcinoma (1.73% vs 0.84%). In addition, KIF5B‐RET fusions also existed in patients with low‐grade malignant neuroendocrine tumors. Cancer 2013. © 2013 American Cancer Society.     

PSAT1 regulates cyclin D1 degradation and sustains proliferation of non‐small cell lung cancer cells

Multiple nodes in the one‐carbon metabolism pathway play important regulatory roles in cancer cell growth and tumorigenesis. The specific biological functions of metabolic enzymes in regulating the signaling pathways that are associated with tumor cell growth and survival, however, remain unclear. Our current study found that phosphoserine aminotransferase 1 (PSAT1), an enzyme catalyzing serine biosynthesis, was significantly up‐regulated in non‐small cell lung cancer (NSCLC) and was involved in the regulation of E2F activity. Loss‐ and gain‐of‐function experiments demonstrated that PSAT1 promoted cell cycle progression, cell proliferation and tumorigenesis. Mechanistic study suggested that elevated PSAT1 led to inhibition of cyclin D1 degradation and subsequently an alteration in Rb‐E2F pathway activity, which in turn enhanced G1 progression and proliferation of NSCLC cells. Moreover, phosphorylation of cyclin D1 at threonine 286 by GSK‐3β was required for PSAT1‐induced blockage of cyclin D1 degradation. We also found that the activity of p70S6K mediated the effects of PSAT1 on GSK‐3β phosphorylation and cyclin D1 degradation. We further identified that PSAT1 was over‐expressed in NSCLC and predicted poor clinical outcome of patients with the disease. Correlation analysis showed that PSAT1 expression positively correlated with the levels of phosphorylated GSK‐3β, cyclin D1 and phosphorylated Rb in NSCLC primary tumors. These findings uncover a mechanism for constitutive activation of E2F via which unrestrained cell cycle progression occurs in NSCLC and may represent a prognostic biomarker and therapeutic target.     

Patterns of care for stage III non–small cell lung cancer in Australia

Stage III non–small cell lung cancer (NSCLC) makes up a third of all NSCLC cases and is potentially curable. Despite this 5‐year survival rates remain between 15% and 20% with chemoradiation treatment alone given with curative intent. With the recent exciting breakthroughs in immunotherapy use (durvalumab) for stage III NSCLC, further improvements in patient survival can be expected. Most patients with stage III NSCLC present initially to their general practitioner (GP). The recommended time from GP referral to first specialist appointment is less than 14 days with treatment initiated within 42 days. Our review found that there is a shortfall in meeting these recommendations, however a number of initiatives have been established in Australia to improve timely and accurate diagnosis and treatment patterns. The lung cancer multidisciplinary team (MDT) is critical to consistency of evidence‐based diagnosis and treatment and can improve patient survival. We aimed to review current patterns of care and clinical practice recommendations for stage III NSCLC across Australia and identify opportunities to improve practice in referral, diagnosis and treatment pathways.