Biomarker Research For Tumor Response, Radiation Toxicity And Outcome Of Non-Small Cell Lung Cancer After Radio (Chemo)therapy

Lung cancer is the leading cause of cancer-related death in the United States and worldwide. About85%of lung cancer is non-small cell lung carcinoma (NSCLC). Currently, therapeutic decisions for NSCLC are mainly based on disease stage, performance status, and co-morbidities, and rarely on histological or molecular classification. Surgical resection is the major treatment for patients with early stage NSCLC; for locally advanced, unresectable NSCLC, definitive radiotherapy with concurrent chemotherapy has become the standard treatment. Unfortunately even with this aggressive treatment, the5-year survival rate for NSCLC is still low, about17%in United States. The1-year survival rate of NSCLC reported in United States is about44.5%, which is increased30%for improvements in surgical techniques and chemoradiation. Thus, early diagnosis, accurate staging, treatment optimization and response monitoring is critical to improve prognosis of NSCLC.To predict the radiation toxicity, response to therapy and prognosis for patients with NSCLC before treatment begins or at early stage of treatment, abundant research has been undertaken in search of biomarkers from various resources, including genomics, proteomics, metabolomics and imaging etc. With these biologic molecular and image biomarkers, researchers are making effort on building a platform for personalized cancer therapy which can match tumors with molecular vulnerability and image features for maximum efficacy. Identifying patient who will respond to specific therapies with optimal efficacy, minimal toxicity and lowest cost would be the ultimate goal of personalized lung cancer therapy.Many molecular markers have been shown associated with NSCLC toxicity and prognosis in recent years. For example single nucleotide polymorphisms of heat shock protein beta-1(HSPB1) gene, transforming growth factor-β1(TGF-β1) pathway and vascular endothelial growth factor (VEGF) pathway were associated with both radiation pneumonitis and survival in NSCLC patients. High expression of miRNA-21and miRNA-155in tumor tissue and circulating blood were also reported predicting recurrence and poor survival of non-small cell lung cancer. In addition to molecular biomarkers, tumor features in computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography (PET) which usually used for diagnosis and staging were also reported as predictors of tumor treatment response and prognosis in patients with NSCLC.Based on above background, our study project aimed to find and validate selected molecular biomarkers for treatment response, normal tissue toxicity and prognosis of NSCLC. We started a prospective study to evaluate the association between serum expression levels before, during and after radiation therapy of three candidate microRNAs (miR-21, miR-155and miR-221) and radiation toxicity; the association between serum expression levels before, during and after radiation therapy of two candidate cytokines (TGF-β1and VEGF) and tumor response to therapy; the predictive role of candidate SNPs (rs2868371and rs2868370) in HSPB1gene for survival in US NSCLC population and intended to validate the prior result reported by a study in Chinese NSCLC population.We found that:1. Expression of serum TGF-β1and VEGF before treatment associated with gross tumor volume, in addition, TGF-β1expression associated with histology and VEGF expression associated with KPS. During treatment, level of serum TGF-β1and VEGF correlated with PET SUVmax at week4to6. Serum TGF-β1and VEGF expression were both decreased during radio(chemo)therapy and this decrease associated with PET SUVmax percentage change.2. The expression levels of miRNA-155and miR-21were changed during radiation therapy. High expression of miRNA-155, miR-21and miRNA-221in serum during the first two weeks of radiation was associated with severe RIET. In addition, high expression of miRNA-155during the first two weeks of radiation therapy might associate with severe radiation pneumonitis.3. SNP rs2868371in promoter region of HSPB1gene was associated with overall survival in U.S. NSCLC patients. Patients with mutation homozygous CC genotype had poor overall survival comparing patients with other two genotypes. However the association found in our study was contradict with the prior published result in Chinese NSCLC patients which would worth for further investigation.The present study identified five molecular biomarkers for radiation toxicity, tumor response and prognosis in NSCLC which will provide clinical references and guidance to personalized treatment if validated in study with larger sample size and.