Predictive biomarkers in patients with resected non-small cell lung cancer treated with perioperative chemotherapy

Abstract

The aim of this article is to summarise the published data on prognostic and predictive biomarkers for early-stage non-small cell lung cancer (NSCLC), and discuss how to integrate them into clinical trials. Large phase III trials have been published in resected NSCLC with biomarkers identifying subsets of patients benefitting from perioperative chemotherapy. Initial findings of predictive implications for the DNA repair protein, ERCC1, were not confirmed in a larger series of patients due to the versatility of the commercially available monoclonal ERCC1 antibody. Prediction of survival by RRM1 tumour expression was not confirmed in a prospective phase III trial in 275 patients with stage IV disease, precluding its use in early-stage NSCLC. BRCA1 mRNA tumour content also failed to predict platinum resistance in 287 stage IV NSCLC patients included in a phase II trial, and the results of a similar trial in early-stage patients are still pending. Of the several cDNA gene expression studies in early-stage NSCLC with non-overlapping prognostic signatures, few have been replicated in independent cohorts for prognostic value, and none received external validation for predictive value. Therefore, use of biomarkers predicting chemotherapy efficacy still needs additional validation before becoming routine practice in oncogenedriven pan-negative NSCLC patients. @ERSpublications Predictive biomarkers to tailor NSCLC perioperative chemotherapy are not validated yet and better tools are still needed

A diagnostic microdosing approach to investigate platinum sensitivity in non-small cell lung cancer

“…However, enhancement of nucleotide excision repair by ERCC1 may not be relevant if other cellular drug resistance mechanisms predominate. Although other DNA repair mechanisms certainly act upon platinum-DNA adducts, the use of the related gene expression or protein levels as biomarkers of response have not proven to be clinically useful (reviewed in 45 ). For example, ERCC1 antibodies are known to have lot-to-lot variation in substrate binding.…”

“…Clearly, such tests still need substantial additional validation before inclusion into routine practice for cytotoxic chemotherapy. 45 …”

“…Clearly, such tests still need substantial additional validation before inclusion into routine practice for cytotoxic chemotherapy. 45 ERCC2 single nucleotide polymorphisms (SNPs) and clinical outcome in NSCLC have been intensively studied. However, inconsistent and in some cases contradictory results have been published.…”

Biomarkers for efficacy of adjuvant chemotherapy following complete resection in NSCLC stages I–IIIA

“…For both biomarkers and gene expression profiling the importance of validation is essential; however, this is both difficult and challenging [65,67]. Not only is validation of the specific biomarker or gene profile important but also a decision on a universal usable cut-off value that will be the same for all future analyses.…”

Heterogeneity of excision repair cross-complementation group 1 gene expression in non-small-cell lung cancer patients

“…A significant volume of evidence has been accumulated, indicating that the survival time of NSCLC patients treated with gemcitabine + cisplatin was reduced through an increase in the ERCC1 gene expression level (10)(11)(12)(13)(14).…”