2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

MOLECULAR TESTING AND NSCLC
logic diagnosis and classification of tumors, particularly
when small tissue specimens are examined. Currently, IHC
markers are frequently used by pathologists to clinically
subtype NSCLC; for example, cytokeratin 7 and thyroid
transcription factor 1 are positive in most adenocarcinomas,
whereas p63, p40, and cytokeratin 5/6 are positive in most
squamous cell carcinomas. 24 Despite being readily available,
there are no validated molecular markers based on protein
expression by IHC being used to predict response to therapy
in lung cancer. One of the most important advantaged of
IHC is that it allows the identification of the protein expression
in specific types of cells as well as distinct subcellular
localization.
Conclusion
Most of the current biomarkers discovered and now used
in clinical applications to date consist of a single genetic
mutation, gene amplification, or translocation, but these
aberrations are rare and not sufficient to select the majority
of patients for targeted therapies. It is also known that, in
many cases, multiple changes in tumor cells, rather than a
single modification, lead to activation of selective and often
interactive molecular pathways promoting tumor growth
and survival. In addition, various targeted treatment regimens
have been shown to result in the activation of alternative,
compensatory molecular pathways that continue to
promote cancer cell survival.
The development of new technologies, such as highthroughput
arrays, has allowed researchers to screen the
whole genome, proteome, and transcriptome for new biomarkers
in tumor tissue, serum, plasma, or other human
body fluids and develop genomic and proteomic profiles, or
“signatures,” to better reflect the complex molecular aberrations
within a single tumor.
The rapid development of technologies for large-scale
Author’s Disclosures of Potential Conflicts of Interest
Author
Ignacio I. Wistuba*
*No relevant relationships to disclose.
Employment or
Leadership
Positions
Consultant or
Advisory Role
1. Jemal A, Siegel R, Xu J, et al. Cancer statistics, 2010. CA Cancer J Clin.
2010;60:277-300.
2. Wistuba II, Gelovani JG, Jacoby JJ, et al. Methodological and practical
challenges for personalized cancer therapies. Nat Rev Clin Oncol. 2011;8:135-
141.
3. Travis WD, Brambilla E, Muller-Hermelink HK, et al. Tumours of
the lung. In: Travis WD, Brambilla E, Muller-Hermelink HK, et al
(eds). Pathology and Genetics: Tumours of the Lung, Pleura, Thymus
and Heart. World Health Organization Classification of Tumours. Pathology
& Genetics. Lyon, France: International Agency for Research on Cancer;
2004:9-124.
4. Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med.
2008;359:1367-1380.
5. Pao W, Girard N. New driver mutations in non-small cell lung cancer.
Lancet Oncol. 2011;12:175-180.
6. Sun S, Schiller JH, Gazdar AF. Lung cancer in never smokers—a
different disease. Nat Rev Cancer. 2007;7:778-790.
7. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming
EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-
566.
sequencing (next-generation sequencing [NGS]) of DNA
and RNA has facilitated high-throughput molecular analysis,
holding various advantages over traditional sequencing.
These new technologies provide capabilities to fully
sequence large numbers of genes in a single test and
simultaneously detect deletions, insertions, copy number
alterations, translocations, and exome-wide base substitutions
(including known hotspot mutations) in all known
cancer-related genes. The amount of starting material (DNA
or RNA) needed for the newest NGS applications is getting
smaller, and currently, the analysis of a panel (approximately
200 to 300) of gene mutations and fusions can be
performed even in DNA extracted from FFPE tumor tissue
specimens. However, one of the potential difficulties in this
process is the large computing capacities needed to manage
the billions of small sequence readouts generated and to
assemble those with large databases to interpret the raw
data. Another challenge for the NGS is the identification of
meaningful driver mutations and the separation of “true”
mutations among a background of intrinsic sequence variations.
30 In addition, verifying and validating the discovered
“driver” mutations will require experimental and detailed
classic molecular pathology studies to bring NGS into clinical
context.
In summary, the recent advances in NSCLC targeted
therapy require the analysis of a panel of molecular abnormalities
of tumor specimens, including gene mutations,
amplifications, and fusions, by applying different methods
to the samples. In this new era of personalized therapy
in lung cancer using targeted agents, the role of the
pathologist in the analysis of molecular changes in lung
cancer tumor tissue specimens is becoming increasingly
important to properly integrate routine histopathologic diagnosis
and molecular testing into the clinical practice.
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REFERENCES
Research
Funding
Expert
Testimony
Other
Remuneration
8. Ju YS, Lee WC, Shin JY, et al. A transforming KIF5B and RET gene
fusion in lung adenocarcinoma revealed from whole-genome and transcriptome
sequencing. Genome Res. 2012;22:436-445.
9. Lipson D, Capelletti M, Yelensky R, et al. Identification of new ALK and
RET gene fusions from colorectal and lung cancer biopsies. Nat Med. Epub
2012 Feb 12.
10. Kohno T, Ichikawa H, Totoki Y, et al. KIF5B-RET fusions in lung
adenocarcinoma. Nat Med. Epub 2012 Feb 12.
11. Takeuchi K, Soda M, Togashi Y, et al. RET, ROS1 and ALK fusions in
lung cancer. Nat Med. Epub 2012 Feb 12.
12. Hammerman PS, Sos ML, Ramos AH, et al. Mutations in the DDR2
kinase gene identify a novel therapeutic target in squamous cell lung cancer.
Cancer Discov. 2011;1:78-89.
13. Weiss J, Sos ML, Seidel D, et al. Frequent and focal FGFR1 amplification
associates with therapeutically tractable FGFR1 dependency in squamous
cell lung cancer. Sci Transl Med. 2010;2:62ra93.
14. Yamamoto H, Shigematsu H, Nomura M, et al. PIK3CA mutations
and copy number gains in human lung cancers. Cancer Res. 2008;68:6913-
6921.
15. Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer:
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