Dataset Information

Differential expression of circulating biomarkers of tumor phenotype and outcomes in previously treated non-small cell lung cancer patients receiving erlotinib vs. cytotoxic chemotherapy.

ABSTRACT:

Background

The objective of this study was to identify serum biomarkers capable of predicting clinical outcomes in previously-treated NSCLC patients with wild-type for EGFR activating mutations or insufficient tissue for mutation status determination.

Methods

Sixty-six Luminex immunoassays representative of biological themes that emerged from a re-analysis of transcriptome data from the Cancer Genome Atlas (TCGA) were evaluate against pretreatment serum specimens from previously-treated advanced NSCLC patients received either cytotoxic chemotherapy (n=32) or erlotinib (n=79). Known EGFR mutation positive cases were excluded from analysis. Associations of biomarkers with outcome parameters and their differential interaction with treatment for survival outcomes were assessed using multivariate Cox PH analyses.

Results

Our EMT-based transcriptomic analysis revealed a range of biological processes associated with angiogenesis, apoptosis, cachexia, inflammation, and metabolism emerging as those most highly associated with patient outcome. These processes were evaluated via surrogate serum biomarkers. A treatment-biomarker interaction analysis revealed that higher pretreatment levels of c-Met signaling biomarkers (i.e. HGF levels), pro-inflammatory/ pro-cachexia (e.g. IL-8, sIL-2R?, FGF-2) processes and a pro-angiogenic (e.g. TGF-?, IL-8, VEGF) milieu were associated with inferior survival (HR=0.35, 0.29, 0.58, 0.50, 0.61, 0.45, respectively; all p<0.05) for patients receiving chemotherapy, relative to erlotinib. In contrast, high levels of decoy receptor for IL-1, sIL-1RII, and a high tissue vimentin/E-cadherin ratio were associated with a poor OS (HR=3.78; p=0.00055) in the erlotinib cohort.

Conclusions

Contemporary precision medicine initiatives that pair patient tumor characteristics with the optimal therapy type may maximize the use of agents targeting EGFR in the treatment of NSCLC.

SUBMITTER: Fidler MJ

PROVIDER: S-EPMC5601637 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature

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Publications

Differential expression of circulating biomarkers of tumor phenotype and outcomes in previously treated non-small cell lung cancer patients receiving erlotinib vs. cytotoxic chemotherapy.

Fidler Mary Jo MJ Frankenberger Casey C Seto Richard R Lobato Gabriela C GC Fhied Cristina L CL Sayidine Selina S Basu Sanjib S Pool Mark M Karmali Reem R Batus Marta M Lie Wen-Rong WR Hayes David D Mistry Jehangir J Bonomi Philip P Borgia Jeffrey A JA

Oncotarget 20170428 35

<h4>Background</h4>The objective of this study was to identify serum biomarkers capable of predicting clinical outcomes in previously-treated NSCLC patients with wild-type for EGFR activating mutations or insufficient tissue for mutation status determination.<h4>Methods</h4>Sixty-six Luminex immunoassays representative of biological themes that emerged from a re-analysis of transcriptome data from the Cancer Genome Atlas (TCGA) were evaluate against pretreatment serum specimens from previously-t ...[more]

PMID: 28938541

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Project description:ImportanceDespite existing evidence of a benefit associated with cisplatin-based adjuvant chemotherapy (AC) after radical cystectomy (RC) for chemotherapy-naive patients with pT3/T4 and/or pN+ urothelial carcinoma of the bladder (UCB), to our knowledge, no studies have addressed the effectiveness of AC in those who received neoadjuvant chemotherapy (NAC) before surgery.ObjectiveTo assess the comparative effectiveness of AC vs observation for patients with pT3/T4 and/or pN+ UCB previously treated with NAC and RC.Design, setting, and participantsThis observational cohort study used the National Cancer Data Base (January 1, 2006, through December 31, 2012) to identify individuals who received NAC and RC followed by AC or observation for pT3/T4 and/or pN+ UCB.Main outcomes and measuresAfter multiple imputation was used to handle missing data, inverse probability of treatment weighting (IPTW)-adjusted Kaplan-Meier and Cox proportional hazards regression analyses were performed with a 6-month conditional landmark to compare overall survival (OS) among patients who received NAC and RC followed by AC vs observation. In addition, exploratory analyses were conducted to examine the heterogeneity of the treatment effect according to age (continuous), sex (female vs male), Charlson comorbidity index (?1 vs 0), pT/N stage (pT3/T4N0 vs pTanyN+), and surgical margin status (positive vs negative) by testing interaction terms within the IPTW-adjusted Cox proportional hazards regression model.ResultsOf the 788 patients with pT3/T4 and/or pN+ UCB (mean [SD] age, 65.3 [9.4] years; 603 [76.5%] male and 185 [23.5%] female), 184 (23.4%) received NAC and RC followed by AC and 604 (76.6%) received NAC and RC followed by observation. The 6-month conditional landmark, IPTW-adjusted Kaplan-Meier curves showed that median OS was significantly longer for NAC and RC followed by AC (29.9 months; interquartile range, 15.1-85.4 months) vs NAC and RC followed by observation (24.2 months; interquartile range, 12.9-58.9 months) (P?=?.046). The 5-year IPTW-adjusted rates of OS were 36.8% for NAC and RC followed by AC vs 24.7% for NAC and RC followed by observation. In the IPTW-adjusted Cox proportional hazards regression analysis, NAC and RC followed by AC was associated with a significant OS benefit (hazard ratio, 0.78; 95% CI, 0.61-0.99; P?=?.046). Interaction term analyses indicated that the OS benefit of NAC and RC followed by AC decreased significantly with age (hazard ratio, 0.97; 95% CI, 0.95-0.99; P?=?.02), whereas no significant interaction was observed with sex (P?=?.82), Charlson comorbidity index (P?=?.51), pT/N stage (P?=?.95), and surgical margin status (P?=?.29).Conclusions and relevanceThis study found that AC after NAC and RC may be associated with an OS benefit for patients with pT3/T4 and/or pN+ UCB. The present findings should be considered as preliminary evidence to conduct a randomized clinical trial to address this association.

Project description:BACKGROUND:Therapies targeting the epidermal growth factor receptor (EGFR) result in a painful rash, the most common and debilitating toxicity among patients with non-small cell lung cancer (NSCLC) who take EGFR tyrosine kinase inhibitor (TKI) therapy; however, predicting the development and the severity of the rash is difficult. OBJECTIVE:The aim of this study was to examine how erlotinib-an EGFR TKI that NSCLC patients take to stop or slow tumor growth-altered the transcriptome of dermal fibroblasts. METHODS:Dermal fibroblasts (ATCC PCS-201-012) were seeded in cell culture flasks, grown under standard conditions, and transferred to cell culture dishes. Cells were treated once daily for 3 days with erlotinib 100 nM (n = 5), erlotinib 1 ?M (n = 5), vehicle 1 ?M (dimethyl sulfoxide) (n = 5), or no treatment (n = 5). Total RNA was extracted using a standard TRIzol method and hybridized using Affymetrix GeneChip Human Genome U133 Plus 2.0 arrays. Raw intensities generated from the arrays were normalized using a Robust Multiarray Average method and analyzed using analysis of variance in Limma R software. Differentially expressed genes were analyzed using Ingenuity Pathway Analysis to identify canonical or noncanonical signaling pathways enriched in this dataset. RESULTS:We selected genes for investigation based on their potential role in wound healing (AQP3), rash development (CCL2), fibroblast activation (PALLD), cancer and cancer progression (GDF-15, SLC7A11, MMP12, and DIRAS3), and cell cycle control (CDC6). We were able to validate four of these genes by both Western blot analysis and quantitative polymerase chain reaction (MMP12, CCL2, CDC6, and SLC7A11). DISCUSSION:If found predictive of rash in future studies using patient samples, our findings may help to identify those at risk for severe rash so that (a) the dose of EGFR TKI therapy may be adjusted; (b) additional treatments for the rash can be developed; and/or (c) precise, patient-centered interventions can be developed so that patients with cancer can better self-manage their rash and adhere to EGFR TKI treatment.

Dataset Information

Differential expression of circulating biomarkers of tumor phenotype and outcomes in previously treated non-small cell lung cancer patients receiving erlotinib vs. cytotoxic chemotherapy.

Background

Methods

Results

Conclusions

Publications

Differential expression of circulating biomarkers of tumor phenotype and outcomes in previously treated non-small cell lung cancer patients receiving erlotinib vs. cytotoxic chemotherapy.

Similar Datasets

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