Molecular and Histological Changes in Post-Treatment Biopsies of Non-Squamous Non-Small Cell Lung Cancer: A Retrospective Study.

BACKGROUND: Recently, in advanced non-small cell lung cancer (NSCLC), standard chemotherapy was flanked by biological agents directed against genomic abnormalities, including EGFR and ALK alterations, that significantly improved patient outcome. Despite these achievements, tumour progression almost always occurs and a reassessment of the tumour genetic profile may contribute to modulating the therapeutic regimen. Resampling may provide tissue for additional tests to detect acquired resistance and/or new genetic alterations, but the currently available information is limited. PATIENTS AND METHODS: Histological and genetic reassessments of biopsy or surgical tissue samples from 50 non-squamous NSCLC patients before and after at least one systemic treatment were performed. EGFR, KRAS, BRAF, PIK3CA and HER2 mutations were sequenced, p.T790M was identified with real-time PCR, and ALK and MET genomic alterations by fluorescence in situ hybridization. RESULTS: Overall in baseline biopsies, 37/50 (74 %) tumours had genetic alterations, either single (52 %) or multiple (22 %). Among them, 16 were EGFR mutations and 6 ALK rearrangements. In the second tissue sampling, 54 % of cases had additional genomic changes, including newly acquired alterations (81 %) or losses (18 %). The commonest changes were MET amplification and p.T790M mutation. One case had a histological shift from adenocarcinoma to small cell carcinoma. CONCLUSIONS: The remarkable number of molecular changes following systemic therapy and the genetic complexity of some cases underline the value of histological and molecular re-evaluation of lung cancer to tailor the most appropriate therapy during disease progression.

ERCC1 and RRM1 gene expressions but not EGFR are predictive of shorter survival in advanced non-small-cell lung cancer treated with cisplatin and gemcitabine.

BACKGROUND: Pivotal studies indicate a role of excision repair cross-complementation 1 (ERCC1) gene and ribonucleotide reductase M1 (RRM1) gene in conferring a differential sensitivity to cytotoxic chemotherapy and epidermal growth factor receptor (EGFR) gene has been recently extensively investigated in non-small-cell lung cancer (NSCLC). DESIGN: Formalin-fixed, paraffin-embedded bronchoscopic/fine needle aspiration biopsies obtained from 70 patients with advanced NSCLC were retrospectively collected to investigate the expression level of ERCC1, RRM1 and EGFR by real-time PCR. Sufficient amounts of messenger RNA (mRNA) were successfully extracted from 61 (87%) specimens, reverse transcribed and amplified with intron-spanning primers. Forty-one patients had stage IV disease and 43 received cisplatin/gemcitabine chemotherapy. RESULTS: A strong correlation between ERCC1 and RRM1 mRNA levels (r(s) = 0.624, P < 0.0001) was found. Median survival time in patients with low ERCC1 was significantly longer (17.3 versus 10.9, P = 0.0032 log-rank test) as well as in patients with low RRM1 (13.9 versus 10.9, P = 0.0390 log-rank test). Concomitant low expression levels of ERCC1 and RRM1 (n = 33) were predictive of a better outcome (14.9 versus 10.0, P = 0.0345 log-rank test). Among cisplatin-treated patients, a low ERCC1 level was highly predictive of a longer survival (23.0 versus 12.4, P = 0.0001 log-rank test). No correlation between gene expression levels and histology was reported. No significant correlation between EGFR expression level and survival was found. At multivariate analysis, performance status, response to chemotherapy, presence of weight loss and ERCC1 were independent prognostic factors for survival. CONCLUSIONS: This retrospective study further validates ERCC1 and RRM1 genes as reliable candidates for customized chemotherapy and shows a higher impact on the survival of NSCLC patients treated with cisplatin/gemcitabine for ERCC1. Prospective pharmacogenomic studies represent a research priority in early and advanced NSCLC.