The Landscape of EGFR Pathways and Personalized Management of Non-small-cell Lung Cancer

Liang Cheng; Shaobo Zhang; Riley Alexander; Yongxue Yao; Gregory T MacLennan; Chong-xian Pan; Jiaoti Huang; Mingsheng Wang; Rodolfo Montironi; Antonio Lopez-Beltran

Disclosures

Future Oncol. 2011;7(4):519-541. 

In This Article

Abstract and Introduction

Abstract

Two classes of anti-EGF receptor (EGFR) agents, monoclonal anti-EGFR antibodies and small-molecule EGFR tyrosine kinase inhibitors, have been used for the treatment of non-small-cell lung cancer (NSCLC). However, only a subset of patients will benefit from EGFR-targeted therapy. The discovery of biomarkers that select the appropriate patients for the therapy and predict the responses to the therapy is urgently needed. Molecular genetic analyses provide new insights into EGFR pathway alterations and demonstrate promise for predicting the clinical outcome of patients with NSCLC. In this article, we summarize the latest available knowledge on the clinical impact of EGFR mutations, gene copy number, EGFR overexpression, phosphorylation expression and the alteration of the EGFR pathway downstream factors in predicting the response to EGFR-targeted therapy in NSCLC patients. The role of KRAS and BRAF mutations and ALK rearrangement in lung cancer-targeted therapy, are also reviewed.

Introduction

Non-small-cell lung cancer (NSCLC) accounts for approximately 80% of lung cancers and is one of the leading causes of cancer death in North America. It is often diagnosed at an advanced stage, with only 30–40% of metastatic NSCLC patients surviving for 12 months.[1–3]

Surgery is the most effective treatment for NSCLC; however, it is usually reserved for patients whose tumors are confined to the primary site and who have no or minimal lymph node involvement – a small portion of NSCLC cases. In addition, many patients who undergo curative surgery will later develop recurrence. Platinum-based chemotherapy is the mainstay of treatment in advanced or recurrent NSCLC, but the results of the treatment are far from encouraging.[1]

Approximately 85% of all primary lung cancers are NSCLCs, which are classified into three major histologic types: adenocarcinoma, squamous cell carcinoma and large-cell carcinoma.[4] Adenocarcinoma is the most frequent histologic type of NSCLC in both genders in many parts of the world (Figure 1). It accounts for approximately 40% of lung cancers and is usually found in the periphery of the lungs.[1] The most common histologic subtypes of adenocarcinoma are papillary (37%), acinar (30%), solid (25%) and bronchioloalveolar (7%).[5] Squamous cell carcinoma accounts for approximately 25–30% of all lung cancers and is often linked to a history of smoking. This cancer tends to occur in the hilar region of the lungs near the bronchus. Large-cell carcinoma accounts for approximately 10–15% of lung cancers and may appear in any part of the lung. It tends to grow and spread quickly and carries a poor prognosis.

Figure 1.

Adenocarcinoma of the lung. (A) Gross appearance. (B) Microscopic view (hematoxylin and eosin stain; magnification: 200×).

Cigarette smoking remains the principal cause of lung cancer. It is estimated that 85–90% of all lung cancer patients have smoked cigarettes at some time.[6] As such, 87% of lung cancer deaths are thought to result from smoking. The US Environmental Protection Agency reports that radon is the second leading cause of lung cancer after cigarette smoking and is the leading environmental cause for nonsmokers. The risk of developing NSCLC from radon is much higher in people who smoke than in those who do not. Workplace exposure to asbestos fibers is another important, but less common, risk factor for lung cancer.[7–9]

In recent years, attention has turned to the role that the EGF receptor gene (EGFR) plays in tumorigenesis and its utility as a target for therapy. Biomarkers that can reliably predict which patients may benefit from anti-EGFR therapy are urgently needed. Pathologists will play a central role in the process to determine suitable testing and interpretation of the test results. In this article, we summarize the impact of EGFR alterations in predicting response to anti-EGFR therapies and discuss currently proposed technologies and their potential clinical implications.

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