Feng, Xiaodong_ Xie, Hong-Guang - Applying pharmacogenomics in therapeutics-CRC Press (2016)

Pharmacogenomics and Laboratory Medicine
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(Abbott Molecular) with HER2 labeled by fluorescence orange and centromere probe
for chromosome 17 (HER2 is located at 17q11.2q12) labeled by fluorescence green.
Figure 5.2a shows a normal specimen with an average of two copies of HER2 and
two copies of the centromere signals for chromosome 17 in each cell (marked by
arrows). Figure 5.2b shows amplification of the HER2 gene in this breast cancer
patient with an average ratio of HER2/CEP17 5.5/cell (arrows). Note that normal
cells (arrowhead) with two copies of HER2 gene and two copies of centromere signals
for chromosome 17 were also observed in this specimen, reflecting the heterogeneity
of cancer specimen. The HER2 test for this patient was reported as positive
for amplification, and HER2-targeted therapy was applied accordingly.
LUNG CANCER THERAPY TARGETS
Lung cancer is the leading cause of cancer-related death worldwide, with a mean fiveyear
survival rate of <15%, mostly because the majority of patients have an advanced
stage disease (stage IIIB or IV) at diagnosis. The majority of lung cancer patients
have the non–small cell lung cancer (NSCLC) subtype. Lung cancer is histologically
and biologically heterogeneous. The most common histology is adenocarcinoma
(about 45–55%), followed by squamous histology (20–30%), and large cell histology
(10–15%). Biologically, identification of ALK rearrangements and EGFR mutations in
NSCLC not only further subdivides patients with advanced NSCLC but also leads to
mutually exclusive targeted therapies. Patients carrying a known mutation in the EGFR
gene that encodes the EGFR can be treated with FDA-approved TKI targeting at the
EGFR as the first-line therapy option. The ALK inhibitors, such as crizotinib, are used
to treat patients with an ALK rearrangement without regard to the line of therapy.
EGFR Mutations in Lung Cancer
The EGFR gene is located at chromosome 7p12. EGFR, a transmembrane glycoprotein,
is a member of the tyrosine kinase superfamily and can bind to a number of
known ligands, including EGF, TGFA/TGF-α, amphiregulin, epigen/EPGN, BTC/
betacellulin, epiregulin/EREG, and HBEGF/heparin-binding EGF. In a normal cell,
binding of a ligand to EGFR induces receptor dimerization and tyrosine autophosphorylation,
activation of the receptor, recruitment of adapter proteins such as GRB2,
and subsequently triggering complex downstream signaling cascades that lead to
cell proliferation. The EGFR signaling pathway activates at least four major downstream
signaling cascades, including the RAS–RAF–MEK–ERK, PI3 kinase–AKT,
PLC-gamma–PKC, and STATs modules. The presence of an EGFR gene mutation
would result in the constant activation of the associated signaling pathways and consequently,
cell proliferation and other cancer processes.
Mutations in the EGFR gene are associated with lung cancer. In fact, EGFR is the
first identified target in NSCLC. In 2004, EGFR-activating mutations were identified
in an adenocarcinoma subtype of lung cancer and were rapidly associated with
response to EGFR-TKI. Clinical pathological features associated with these mutations
include East Asian ethnicity, adenocarcinoma histology, female sex, and a history
of not smoking. It is estimated that about 10–15% of all NSCLC patients have