Chapter One - Tissue and Blood Biomarkers in Lung Cancer: A Review
Introduction
Lung cancer is the most frequent malignancy worldwide both in terms of incidence and mortality [1], [2]. Traditionally, lung cancer has been divided into two main histological types, small cell lung cancer (SCLC) (15%–25% of total) and nonsmall cell lung cancer (NSCLC) (75%–85% of total), with the latter being subdivided into adenocarcinoma, squamous type, and large cell type. These subtypes, especially the adenocarcinomas can be further divided, based on the presence or absence of specific biomarkers (see below). Identification of the histological type and biomarker status is currently mandatory for the optimum management of patients with lung cancer.
For patients diagnosed with early stage (i.e., stages I and II) NSCLC, surgery is the main form of treatment (for review, see Refs. [1], [2]). For those diagnosed with locally advanced disease not suitable for surgery, radiotherapy in combination with platinum-based chemotherapy may be used. For patients diagnosed with advanced or metastatic NSCLC, the specific treatment administered depends on the biomarker status of the tumor such as the presence/absence of EGFR-activating mutations, ALK/ROS1 translocations, or PD-L1 levels [3], [4] (Table 1). Thus, patients that are positive for EGFR-activating mutations or ALK/ROS1 translocations are eligible to receive molecularly targeted therapies, whereas those positive for PD-L1 may be treated with immunotherapy (e.g., with pembrolizumab).
In patients with advanced NSCLC who are negative for the above biomarkers, the standard first-line treatment is platinum-based doublet chemotherapy (cisplatin or carboplatin plus another cytotoxic drug) with or without the anti-VEGF antibody, bevacizumab [3], [4]. For patients with squamous type NSCLC, however, bevacizumab should not be administered.
In contrast to NSCLC, biomarker-driven therapies are currently unavailable for patients with SCLC [5]. For patients with limited SCLC disease (stage 1-IIIB), chemotherapy and radiotherapy are recommended followed by prophylactic cranial irradiation to prevent cerebral metastases [5]. For extensive SCLC, the treatment of choice is combination chemotherapy, usually cis- or carboplatin and either etoposide, topoisomerase I inhibitor or a taxane [6].
The aim of this article is to review the current status of biomarkers in aiding diagnosis and guiding therapy in patients with lung cancer. In preparing this article, particular attention was given to reviews, including systematic reviews, prospective randomized trials that included the use of biomarkers, and guidelines on lung cancer published by expert panels.
Section snippets
EGFR Mutational Status for Predicting Benefit From EGFR Tyrosine Kinase Inhibitors
EGFR is a member of the HER/ErbB family of receptor tyrosine kinases that also includes HER2, HER3, and HER4 [7], [8]. These proteins share a common structure that is composed of an extracellular ligand-binding domain, a short hydrophobic transmembrane domain, and an intracellular tyrosine kinase domain. Activation of EGFR, which is normally mediated by ligand binding, results in homodimerization or heterodimerization (with other HER members), phosphorylation of specific tyrosine residues, and
Serum Biomarkers
Unlike the situation with tissue-based markers, serum protein biomarkers are not widely used in patients with lung cancer. Indeed, most published guidelines relating to the diagnosis and management of patients with lung malignancy do not recommend any serum biomarker. Despite this, serum biomarker assays are performed in some European and Asian countries. Although requiring further evidence for clinical utility, specific serum biomarkers are potentially useful in the differential diagnosis of
Conclusion
Major progress has been made with lung cancer biomarkers over the last decade. This is especially so for tissue-based therapy predictive biomarkers in NSCLC. Thus, in addition to EGFR, ALK, and ROS1 alterations discussed above, several other potentially actionable mutations may be present in NSCLC. These include MET mutations/amplifications, BRAF mutations, RET fusions, PIK3CA mutations, and HER2 mutations/amplifications. Rather than testing for these alterations individually, there is growing
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