Crossing the Rubicon in Lung Adenocarcinoma: The Conundrum of EGFR Tyrosine Kinase Mutations

Abstract

Keyowrds: adenocarcinoma, epidermal growth factor, nonsmall cell lung cancer, tyrosine kinase mutations Chemotherapy in lung cancer: the state of the art In 2004 in Europe, there were an estimated 2,886,800 cases of cancer diagnosed, including data recorded in the 25 member states of the European Union. Lung cancer was the most common form, with a total of 381,500 cases (13.2%) and an estimated mortality of 341,800 cases (20% of the total) [1]. Approximately 85% of lung cancers are non-small cell lung cancer (NSCLC), and the majority of patients present with advanced disease, with dismal prognosis. A landmark study in NSCLC showed that the combination of gemcitabine (Gemzar®) plus cisplatin attained a median survival of 9.1 months in comparison with 7.6 months with cisplatin alone [2]. A Phase III trial of the European Organization for Research and Treatment of Cancer (EORTC) showed similar results with paclitaxel (Taxol®)– cisplatin and gemcitabine–cisplatin, with median survival times of 8.1 and 8.9 months, respectively. A third arm of paclitaxel–gemcitabine showed a shorter survival of 6.7 months [3]. A recent meta-analysis, which included a study encompassing 4556 patients, showed a median survival of 9 months for gemcitabine-based chemotherapy in contrast with 8.2 months for non-gemcitabine combinations [4]. One of the mechanisms of tumor resistance to cisplatin is increased nucleotide excision repair (NER) activity, in particular increased levels of excision repair cross-complementing (ERCC)1. The 5 incision made by the ERCC1–xeroderma pigmentosum group F (ERCC1–XPF) complex is thought to be a rate-limiting step in the NER pathway, as demonstrated by an increase in excision activity in extracts from non-cisplatin-resistant cells after addition of purified ERCC1–XPF protein, compared with no increase in excision activity after addition of ERCC1–XPF to extracts from cisplatin-resistant cells [5]. The potential use of ERCC1 mRNA expression as a predictive marker for the effectiveness of cisplatin-based chemotherapy is an important area of clinical translational research. Together with ERCC1, ribonucleotide reductase (RR) subunit M1 is also involved in gemcitabine metabolism as a participant in the NER pathway, providing nucleotides that fill gaps created by ERCC1 excision of the DNA strand-containing cisplatin bulky adducts. Tumor overexpression of RRM1 mRNA in gemcitabine/cisplatin-treated NSCLC patients was associated with a short median survival of 3.6 months in contrast with 13.7 months for patients with low RRM1 mRNA expression (p = 0.009) [6]. This data brings a new era of customized chemotherapy based on NER transcripts.