Biomarkers of Chronic Inflammation in Lung Cancer

Chronic inflammation has been implicated in the development of airway dysplasia and lung cancer. C-reactive protein (CRP), a biomarker for inflammation in the blood, can help to identify individuals whose abnormal precancerous lesions will advance closer to invasive lung cancer. Plasma CRP, in concert with lung function and pack-years of smoking, appears to have excellent predictive powers in identifying participants with bronchial dyplastic lesions whose lesions progress to more advanced stages of dysplasia. The odds of developing progressive disease are 9.6- fold higher in the group with CRP >0.5 mg per liter compared with the group less than this threshold.

Biomarkers for Predicting Sensitivity to Chemotherapy in Lung Cancer

Platinum-based chemotherapy is the standard treatment in advanced NSCLC and as adjuvant treatment in a substantial subgroup of patients with stage II-IIIA. Therefore, there is an interest in biomarkers for predicting sensitivity to platinum compounds. The expression of genes involved in DNA repair pathways, particularly genes involved in the nucleotide excision repair, has an important role in predicting response to platinum-based chemotherapy. Therefore, patients with low DNA repair capacity should have a favorable response to gemcitabine plus carboplatin chemotherapy, whereas they could be resistant to docetaxel. However, cisplatin can induce ERCC1 (excision repair cross-complementing 1) mRNA levels, which might be a principal reason for short-lived response to platinum agents. Although several trials evaluated the level of expression of ERCC1, no consensus was reached regarding a method for evaluation. A study has used the 8F1 antibody to measure the level of expression of ERCC1 by IHC analysis in a validation set of samples obtained from patients in two independent phase III trials (Friboulet et al. 2013). Unique functional ERCC1 isoform was not specifically detected; therefore, its usefulness in guiding therapeutic decision making is limited. BRCA1 complexes are also central to DNA repair response, and the influence of RAP80 expression in conjunction with BRCA1 expression is now being investigated in phase III randomized clinical trials of customized chemotherapy.

In patients with inoperable SCLC, the efficacy of chemotherapy can be predicted early in the course of therapy by baseline values of serum nucleosomes as independent parameters. In prospectively collected sera of patients with recurrent NSCLC receiving second-line chemotherapy, the courses of nucleosomes, cyto- keratin-19 fragments (CYFRA 21-1), CEA, neuron-specific enolase, and progastrin-releasing peptide were investigated and correlated with therapy response

(Holdenrieder et al. 2009). At high specificity for detection of progressive disease, most sensitive biomarkers were identified and included in a combination model. High levels and insufficient decreases of nucleosomes and CYFRA 21-1 during the first cycle of therapy indicated poor outcome. Combination of nucleosome concentrations and CYFRA 21-1 enabled the early detection of progressive disease. Nucleosomes and CYFRA 21-1 were shown to be valuable for the individual management of patients with recurrent NSCLC.

Platinum-based chemotherapy is a primary treatment for patients with advanced NSCLC. There is need for a convenient method is to identify the sensitivity of individual patient to platinum-based regimen. Genetic variants in DNA repair genes represent important determinants of drug efficacy. Xeroderma pigmentosum group A (XPA) codon23 and xeroderma pigmentosum group D (XPD) codon751 SNPs are involved in clinical response to platinum-based chemotherapy in advanced NSCLC patients. A study has confirmed that XPA A23G, a SNP in blood cells detected by 3D polyacrylamide gel-based DNA microarray method, might be a promising biomarker in predicting favorable prognosis of NSCLC patients and designing individualized treatments (Cheng et al. 2013).

Several other biomarkers of response of lung cancer to chemotherapy have been identified. There is need for clinical trials to prospectively validate the benefits of customizing chemotherapy for translation into an improvement in outcome of NSCLC patients.

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