1
the chances of uncovering clinically relevant
alterations.
- They require more tumor tissue, cost more
for data analysis and storage, and entail more
complex interpretation.
FDA-approved liquid biopsy using circulating
cell-free DNA is an excellent tool when tumor
tissue is inaccessible or limited (Nat Rev Clin
Oncol 2021;18:297). While liquid biopsy has a
faster turnaround time, it has a higher false-
negative rate than standard biopsy NGS.
NON-SMALL CELL LUNG
CARCINOMA (NSCLC)
Molecular proling is used to predict therapeu-
tic efcacies in NSCLCs and typically includes
EGFR, KRAS, ROS1, ALK, MET, BRAF, RET,
ERBB2 (HER2), and NTRK (Crit Rev Oncol
Hematol 2021;157:103194). Also useful is
PD-L1 (programmed cell death ligand-1) by
immunohistochemistry (IHC) to predict
response to immune checkpoint inhibitors.
EGFR mutations involve 10%-35% of lung
adenocarcinoma in Western populations (and as
high as 50% in Asian populations) and 3% of
lung squamous cell carcinoma (SqCC). Muta-
tions can predict therapeutic response to EGFR-
specic tyrosine kinase inhibitors (TKIs).
- Acquired resistance inevitably develops,
mostly commonly due to EGFR T790M
missense mutation, accounting for ~50% of
acquired resistance mutations. FDA-approved
EGFR-inhibiting drugs that specically
target T790M or exon 20 insertion mutation
are available.
- MET amplication (by FISH or NGS) is
responsible for 5%-20% of anti-EGFR
resistance.
KRAS mutations are detectable in 25%-35% of
lung adenocarcinoma, and 5% of SqCC.
Activating mutations in codons 12 and 13, and,
less commonly, codon 61, predict unfavorable
prognosis and EGFR-TKI resistance. A KRAS
inhibitor drug that specically targets the
G12C missense mutation (seen in ~13% of
Issue 16 || November 2021
WHAT’S NEW IN
MOLECULAR GENETIC
PATHOLOGY 2021:
SOLID TUMORS AND
NGS PANEL SELECTION
Guoli Chen and Patricia C. Tsang
Geisinger Medical Laboratories, Geisinger Health, Danville
and Wilkes-Barre, PA, USA
Corresponding Author: Patricia C. Tsang, MD
Geisinger Medical Laboratories, Geisinger Health,
Wilkes-Barre, PA, USA
E-mail: patctsang@hotmail.com
ORCID
Guoli Chen
https://orcid.org/0000-0002-4426-6156
Patricia C. Tsang
https://orcid.org/0000-0003-0523-9793
Abstract
The linchpin of precision medicine is molecular
genetic and genomic testing. Molecular biomark-
ers are important for establishing precise diagno-
ses and for predicting therapeutic responses that
enable cancer patients to receive personalized and
targeted treatment. Below are highlights of the
current considerations in next generation
sequencing (NGS) panel selection, and in
molecular testing of solid tumors of the lung,
digestive system, thyroid and soft tissue.
NEXT GENERATION SEQUENCING
PANEL SELECTION
The use of targeted NGS panels (comprising up
to several hundred genes) is more common than
whole exome sequencing (WES) in clinical
practice. Pros and cons of WES or large
targeted panels compared to small hotspot
panels include the following:
- Comprehensive tumor proling maximizes
NSCLCs) is available.
ALK activating rearrangements occur in ~5%
of lung adenocarcinoma, particularly in young
non-smokers. The most common fusion gene
product is EML4-ALK, which predicts response
to ALK inhibitors. FISH is the gold standard
for testing, but IHC, RT-PCR and NGS can
also be used.
ROS1 gene fusion (1%-2% of NSCLCs)
signies response to certain ALK inhibitors due
to homology between the rearranged ROS1 and
ALK genes.
MET exon 14 skipping mutations, BRAF
V600E mutation, RET gene fusion and NTRK
gene fusion can predict therapeutic response to
their respective inhibitors.
COLORECTAL CARCINOMA (CRC)
AND CHOLANGIOCARCINOMA
EGFR targeted treatment is effective in the
absence of KRAS and NRAS mutations.
Mutational analyses of KRAS and NRAS genes
should include codons 12, 13, 59, 61, 117 and
146. Other drug resistance biomarkers include
BRAF mutations and PIK3CA/PTEN deregu-
lation.
Despite its low prevalence in CRC (2-3%),
ERBB2 (HER2) amplication is emerging as a
potential therapeutic target (Lancet Oncol
2021;22:779). Furthermore, activation of
ERBB2 (HER2) signaling causes resistance to
anti-EGFR therapy in a subset of patients with
metastatic CRC.
NTRK fusions can be evaluated in CRC due to
the availability of targeted therapies.
FGFR gene fusion is detected in ~10% of
intrahepatic cholangiocarcinoma for which two
FGFR-targeted tyrosine kinase inhibitors have
been approved - pemigatinib and ingratinib.
THYROID CARCINOMA
Papillary thyroid carcinoma may harbor BRAF
mutations (especially V600E), TERT promoter
WHAT’S NEW
IN PATHOLOGY?
PathologyOutlines.com
Sponsored by an unrestricted grant from Geisinger Medical Laboratories: Dedicated to Laboratory Excellence