2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

Table 1. Summary of Molecular Abnormalities Associated
with the Lung Adenocarcinoma and Squamous Cell
Carcinoma Histologies
Gene Molecular Change Adenocarcinoma
pression of the protein and its ligands. 4 Mutations of EGFR
occur in approximately 24% of adenocarcinomas and up to
60% in tumors from never smokers. The mutations are
limited to the first four exons of the TK domain (exons 18 to
21). 15,16 The most frequent mutations are in-frame deletions
in exon 19 (44% of all mutations) and missense mutations in
exon 21 (41% of all mutations). 17 In addition, in-frame
duplications or insertions occurring in exon 20 have been
described in approximately 5% of the mutant cases, and rare
missense mutations occur in multiple sites. 17 EGFR mutations
occur predominantly in adenocarcinoma (approximately
20% to 48% vs. approximately 2% for other NSCLC
histologic subtypes) and are more frequent in never smokers
(54% vs. 16% in ever smokers) and female patients (49% vs.
19% in male patients). 17 EGFR mutation is the most important
criterion used to select patients for EGFR TK inhibitor
therapy in lung cancer. 18
HER2 Mutation
In lung cancer, HER2/Neu abnormalities include gene
mutation, gene amplification, and overexpression of the
protein. 19 HER2 gene mutations have been detected in 2%
KEY POINTS
Squamous cell
Carcinoma
EGFR Mutation 10–40% Very rare
Amplification/CNG 15% 30%
IHC overexpression 15–40% 60%
HER2 Mutation 2% Very rare
Amplification 4% 2%
EML4-ALK Translocation 7% Very rare
KIF5B-RET Translocation 2% Not reported
KRAS Mutation 10–30% Very rare
BRAF Mutation 1–3% Very rare
FGFR1 Amplification Not reported 20%
DDR2 Mutation Not reported 4%
PIK3CA Amplification/CNG 2–6% 30%
Mutation 2% 2%
Abbreviations: CNG, copy number gain; IHC, immunohistochemistry.
● Non-small cell lung carcinoma (NSCLC) can be molecularly
classified in multiple subtypes for selection
of targeted therapy.
● Currently, a panel of gene abnormalities (mutations,
amplifications, and translocations) can be tested in
NSCLC tumor biopsy and cytology specimens.
● The role of the pathologist is crucial to integrate
histology diagnosis and molecular testing of small
tumor samples.
● Quality control of tumor tissue and cell specimens for
adequacy is extremely important for successful molecular
testing.
● Novel methodologies, including multiplex mutation
detection platforms and next-generation sequencing,
are useful to test multiple genetic aberrations in
small tumor specimens.
460
of adenocarcinomas and occur mostly in exon 20. 19 HER2
mutations have been described predominantly in patients
with lung cancer with East-Asian ethnic background and a
history of never smoking. HER2 amplification has been
reported in 2 to 4% of NSCLCs and is more frequent in
adenocarcinoma (4%). 20
ALK Fusion Genes
In lung cancer, aberrant ALK expression has been identified
in a subset of adenocarcinomas, and this abnormality
consists of the formation of a fusion transcript with celltransforming
activity, which is the product of a inverted
translocation of EML4 gene located at chromosome 2p21 and
the ALK gene located at 2p23. 7 EML4-ALK translocations
have multiple distinct isoforms (up to 9) with demonstrated
transforming activity. EML4-ALK translocation has been
detected in 7% of lung adenocarcinomas, particularly in
patients with a history of never or light smoking, and is
associated with early onset of tumor. 21 Histologically,
EML4-ALK–rearranged adenocarcinomas have been described
to have a predominantly solid pattern with signet
ring cells, but combined acinar and cribriform patterns
also have been described in these tumors. 21 The standard
method to assess EML4-ALK fusion in lung cancer tumors is
fluorescence in situ hybridization (FISH) using a “breakapart”
probe, and samples are considered to have positive
FISH results for EML4-ALK fusion if more than 15% of
scored tumor cells have split ALK 5� and 3� probe signals or
have isolated 3� signals. 22 There are some reports that
suggest that ALK protein expression assessment by immunohistochemistry
(IHC) correlates with the presence of
EML4-ALK fusion, and there are ongoing studies testing
ALK protein expression as a screening method for ALK
fusions. 23
BRAF and KRAS Mutations
BRAF oncogene can be activated in NSCLC, particularly
adenocarcinoma (1% to 3%), by gene point mutations. 5
Contrary to melanoma, most BRAF mutations detected in
lung cancer are non-Val600Glu mutations that affect exons
11 and 15, and they are mutually exclusive to EGFR and
KRAS mutations.
KRAS mutations are more common in lung adenocarcinoma
than other NSCLC histologic types and are more
frequently found in tumors from patients with a smoking
history (approximately 30%). 6 In lung cancer, KRAS mutations
are found in codons 12, 13, and 61 (42% of all mutations),
which are mainly GGT to TGT transversions that
produce glycine to cysteine amino acid changes. 6 KRAS
mutations are rarely detected in EGFR-mutant tumors.
RAS is considered of untargetable molecule; therefore, recent
studies have evaluated the RAS downstream pathway,
RAS/RAF/MEK, as a potential target for therapy in lung
cancer.
FGFR1 Amplification
IGNACIO I. WISTUBA
FGFR1 is a transmembrane TK and member of the
fibroblast growth factor receptor (FGFR) TK family that
comprises four kinases (FGFR-1 to -4). 13 In lung cancer,
amplification of FGFR1 (chromosome 8p11-12) is a driver
event in NSCLC and is predominantly detected in squamous
cell carcinomas (approximately 20%) compared with adenocarcinomas
(1% to 3%). 13 Currently, the preferred method to