Prognostic Impact of DNA Repair Protein Expression in Non-Small Cell Lung Cancers Treated with Platinum-Based Chemotherapy and Subsequent Curative Lung Resection

Abstract

Objective: Multimodal treatments that include preoperative platinum-based chemotherapy are fundamental to the treatment of advanced non-small cell lung cancer (NSCLC). This study aimed to investigate the predictive value of DNA repair protein expression in surgically resected NSCLCs in terms of prognosis and responses to platinum-containing chemotherapy. Methods: This retrospective study included 136 patients with NSCLC who were treated with preoperative platinum-based chemotherapy, followed by curative lung resection. ATM, RAD51, LKB1, H2AX, and SIRT1 expression levels were analyzed in resected tumor specimens via immunostaining and were used to classify patients and compare survival and responses to chemotherapy. Results: SIRT1 expression correlated significantly with improved responses to platinum-based chemotherapy (odds ratio, 2.28; p = 0.024), progression-free survival (hazard ratio [HR], 0.74; p = 0.036), overall survival (HR, 0.63; p = 0.006), and tumor-bearing survival (HR, 0.62; p = 0.014). After adjusting for clinical variables, the HR of SIRT1 expression remained significant for overall survival (HR, 0.59; p = 0.039) but not for progression-free survival (HR, 0.74; p = 0.183). No prognostic stratification was observed for the other 4 markers. Conclusion: Patients with SIRT1-expressing NSCLC had superior responses to chemotherapy and longer survival durations than those with SIRT1-negative cancer.

Homologous recombination and DNA repair mutations in patients treated with carboplatin and nab-paclitaxel for metastatic non-small cell lung cancer

“…In NSCLC, DNA repair pathways have been evaluated as a predictor of clinical benefit from platinum-based chemotherapy. The DNA repair gene excision repair cross-complementation group-1 (ERCC1), a component of the nucleotide excision repair (NER) pathway, has been studied as a predictive biomarker for platinum-based chemotherapy in NSCLC [15,16]. However, encouraging findings of the predictive utility of ERCC1 protein expression were not replicated in subsequent studies, possibly due to differing isoforms of ERCC1 and limitations of the antibodies used for testing [31,32].…”

“…The mechanism by which platinum agents exert antineoplastic effect is largely through the creation of stable DNA adducts, leading to DNA damage and cell death [14]. This has led to DNA repair mechanisms being evaluated as a possible predictive biomarker for platinumbased therapy [15,16]. Understanding the role of DNA repair pathway mutations in response to platinum based chemotherapy is vital to determine optimal treatment approaches for patients with NSCLC.…”

DNA Damage Repair Proteins, HSP27, and Phosphorylated-HSP90α as Predictive/Prognostic Biomarkers of Platinum-based Cancer Chemotherapy: An Exploratory Study

“…Expression levels of the studied proteins were scored according to the staining intensity and percentage of positive stained areas of tumor cells. In the case of γH2AX and 53BP1, tumor staining was evaluated as the percentage of positive cells ranging from 0 to 100%; a 50% cut-off for γH2AX and 40% for 53BP1 were used to define low or high expression of these proteins 30,31. Nuclear expression of HSP27 and p-HSP90α were scored only according to the presence or absence of immunostaining.…”

“…In the case of γH2AX and 53BP1, tumor staining was evaluated as the percentage of positive cells ranging from 0 to 100%; a 50% cut-off for γH2AX and 40% for 53BP1 were used to define low or high expression of these proteins. 30,31 Nuclear expression of HSP27 and p-HSP90α were scored only according to the presence or absence of immunostaining. Cytoplasmic expression of HSPs as well as MLH1, MSH2, and ERCC1 expression was scored as proportion (P) of stained cells as follows: (a) 0, <1%; (b) 1, 1% to 10%; (c) 2, 11% to 30%, (d) 3, 31% to 66%, (e) 4, > 66%.…”