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two randomized phase III studies, the Iressa Pan-Asia advanced NSCLC should have their tumours assessed
Study (IPAS) and WJTOG3405, the use of gefitinib as for the presence of driver mutations. Guidelines by the
[10]
the first-line treatment for previously untreated metastatic College of American Pathologists (CAP), the International
adenocarcinoma of the lung leads to longer progression- Association for the Study of Lung Cancer (IASLC), and the
free survival (PFS) in patients with tumors positive for Association of Molecular Pathologists (AMP) recommend
EGFR mutations, compared to platinum-based doublet analysis of either the primary tumour or of a metastasis for
chemotherapy. Similar outcomes have been observed EGFR and ALK mutations for all patients with tumours that
[5]
for erlotinib in advanced NSCLC patients with EGFR exhibit features of an adenocarcinoma, regardless of their
mutations. These findings have important implications clinical characteristics. [11]
[6]
to lung cancer treatment regimes in India, where EGFR
mutations have been shown to occur in 25-50% of lung The most important requirements for molecular testing
cancer cases. However, the purpose of mutational studies modalities are that they should utilise clinically available
[7]
in adenocarcinoma and squamous cell carcinoma can be specimens (formalin- or paraffin-embedded tissue) and
very different. Researchers have made important progress that the turnaround time should be relatively short. The
in the understanding and development of treatments for instrument should be semi-automated and relatively
adenocarcinomas, which are the most common type of lung inexpensive. The most commonly used modalities are:
cancer. Unfortunately, these treatments have been largely (1) gene sequencing, the most comprehensive method for
ineffective in treating lung squamous cell carcinomas. Lung mutation testing; (2) next-generation sequencing, which uses
squamous cell carcinomas frequently develop in the large simultaneous evaluation of multiple genes or even whole
airways in the centre of the lungs, while adenocarcinomas genomes; (3) allele-specific testing, which analyzes DNA
often arise at the edges of the lungs. Lung adenocarcinomas for a predefined abnormality; (4) mass spectrometry, which
sometimes affect non-smokers, while lung squamous cell analyzes short fragments of DNA by their mass to charge
carcinomas arise almost exclusively in smokers. ratio and can detect fragments that have different molecular
weights than expected, a mutation; (5) fluorescence in situ
Another example of mutation-driven therapy is the hybridisation (FISH), which is typically used to detect gene
targeting of the echinoderm microtubule-associated translocations, amplifications, and other rearrangements;
protein like 4-anaplastic lymphoma kinase (EML4- (6) immunohistochemistry (IHC), which is considered an
ALK) rearrangement. The ALK gene encodes anaplastic alternative to FISH for determining ALK translocations; and
lymphoma kinase, a member of the receptor tyrosine (7) multiplex genotype testing, which allows an entire panel
kinase (RTK) family. RTKs transmit signals from the of genotypes of interest to be queried at a single time from a
cell surface into the cell through a process called signal single tissue sample instead of doing the tests sequentially.
transduction. The EML-ALK fusion leads to uncontrolled IHC is, however, not currently recommended for detecting
cell proliferation. This mutation occurs in about 3-7% of EGFR driver mutations since positive or negative IHC
unselected NSCLC. In one study, NSCLC patients treated results do not necessarily indicate the presence or absence,
[8]
with crizotinib, a tyrosine kinase inhibitor targeting ALK, respectively, of an EGFR mutation. In contrast, multiplex
showed a response rate of 65%. In cases where there was genotype testing is the most tissue-efficient approach,
[9]
disease progression after treatment with crizotinib, ceritinib particularly when dealing with small tumour samples.
can be used. Ceritinib is a new ALK inhibitor that has
been recently approved based on its encouraging response Mutations associated
rate of 56% in patients whose cancer has progressed after The identification of oncogenic activation of particular
treatment with crizotinib. tyrosine kinases in some advanced NSCLC tumours, most
notably mutations in the EGFR gene or rearrangements
MOLECULAR TESTING in of the ALK gene, has led to a paradigm shift and the
development of specific molecular treatments for patients.
The most useful biomarkers for predicting the efficacy of
targeted therapy in advanced NSCLC are somatic genome EGFR mutations
alterations known as driver mutations. These mutations EGFR is a transmembrane protein with cytoplasmic kinase
occur in cancer cells in genes encoding proteins that are activity that transduces growth signals to the cell. Among
critical to cell growth and survival. Driver mutations are Asians, the incidence of EGFR mutation is much higher, up
typically transformative, which means that they initiate to 62%, and occurs more frequently among non-smokers.
the evolution of a non-cancerous cell to a cancerous one. In advanced NSCLC, the presence of an EGFR mutation
In addition, driver mutations often impart an oncogene confers a favourable prognosis and is strongly indicative
addiction trait to the transformed cell. This means that of sensitivity to EGFR tyrosine kinase inhibitors such as
the mutated protein enables the cancer cell to receive erlotinib, gefitinib, and afatinib.
survival signals from the driver mutations. Hence, driver
mutations are good biomarkers for selecting patients Nevertheless, it has been observed that most of the patients
for targeted therapies. Whenever feasible, patients with who initially respond to an EGFR tyrosine kinase inhibitor

Journal of Cancer Metastasis and Treatment ¦ Volume 2 ¦ June 15, 2016 ¦ 215