Targeted Therapies in Lung Cancer

Abstract

An ongoing research and multiple clinical trials involve new targeted therapies and less aggressive treatment regimens that improve survival in patients with lung cancer. Targeted therapeutic agents are based on the concept of discovering genetic alterations and the signaling pathways altered in cancer and have added significantly to our armamentarium in order to prolong patient survival and minimizing drug toxicity. Among 34 molecularly targeted drugs approved by U.S. Food and Drug Administration (FDA) for treatment of various cancers since 1998 three targeted therapies have been approved for treatment of lung cancer (gefitinib in 2002, erlotinib in 2003, and bevacizumab in 2006).This review focuses on the targeted therapies in lung cancer, the molecular biomarkers that help identify patients that will benefit for these targeted therapies, describes the basic molecular biology principles and selected molecular diagnostic techniques and the pathological features correlated with molecular abnormalities in lung cancer. Lastly, new molecular abnormalities described in lung cancer that are predictive to novel promising targeted agents in various phases of clinical trials are discussed.

Figure 1

Clinically important oncogenic mutations of the lung adenocarcinoma.

Figure 2

Currently available therapies targeting EGFR signaling pathway.

Figure 3

Figure 3a. Fluorescence in situ hybridization (FISH) with an EGFR probe (green) and 7q control probe (red) in NSCLC sections demonstrating gene amplification. Figure 3b. The corresponding slides treated by chromogenic in situ hybridization (CISH) with the EGFR probe are illustrated in the same case of lung adenocarcinoma.

Figure 3

Figure 3a. Fluorescence in situ hybridization (FISH) with an EGFR probe (green) and 7q control probe (red) in NSCLC sections demonstrating gene amplification. Figure 3b. The corresponding slides treated by chromogenic in situ hybridization (CISH) with the EGFR probe are illustrated in the same case of lung adenocarcinoma.

Figure 4

Exon 19 deletion-specific antibody directly visualize the location of tumor cells with EGFR exon 19 deletion mutations and show heterogeneity in receptor overexpression among different tumor cells.

Figure 5

Bronchioloalveolar mucinous adenocarcinoma (mucinous BAC) is exclusively TTF-1 negative, EGFR mutation negative, but may have KRAS mutation.

Figure 6

ALK translocations with multiple gene partners.

Figure 7

ALK fusion products in lung adenocarcinoma.

Figure 8

The majority of ALK-rearranged adenocarcinomas had a distinct histology represented by solid tumor growth and frequent signet-ring cells with abundant intracellular mucin.

Figure 9

Identification of lung cancers with chromosomal translocations involving ALK requires fluorescence in situ hybridization (FISH) on formalin-fixed, paraffin-embedded tumor tissues using a break-apart probe to the ALK gene.

Figure 10

A novel immunoperoxidase assay that shows excellent sensitivity and specificity (100% and 99%, respectively) for the detection of ALK-rearranged lung adenocarcinomas in biopsy specimens with excellent interobserver agreement between pathologists.