TRAINING and EDUCATION
Demystifying the Lab
ASH Clinical News takes a look at the complex scientific techniques that
hematologists/oncologists hear about every day, with practical information
for the practicing clinician.
DEMYSTIFYING
Liquid Biopsies
Tumor biopsies have long been the standard
method for diagnosing, monitoring, and
treating cancer and, in the era of precision
medicine, molecular analyses of tissue samples
can reveal information that helps guide treat-
ment strategies. However, tissue biopsies can
be invasive and, depending on the site of the
tumors, difficult or impossible to perform. Ad-
ditionally, repeated surgical biopsies are often
an impractical method to track changes in a
patient’s disease over time.
Enter circulating tumor DNA (ctDNA)
assays: blood-based tests that cancer research-
ers say can provide a more comprehensive view
of a patient’s cancer than a single tissue biopsy.
These so-called “liquid biopsies” can allow
clinicians to detect tumors early and non-
invasively track tumor changes in real time.
Non-invasive ctDNA tests are still years away
from routine clinical use, though.
The goal of ctDNA research “is to un-
derstand whether these liquid biopsies are
a suitable proxy for conventional biopsies,”
Viktor Adalsteinsson, PhD, a group leader of
the Blood Biopsy Team at the Broad Institute
in Boston, who is working on blood tests using
ctDNA to profile cancer genomes, told ASH
Clinical News.
What makes ctDNA a promising biomarker
for cancer detection and monitoring, and will
“liquid biopsies” be replacing tissue biopsies
in the near future? ASH Clinical News spoke
with researchers developing and testing ctDNA
assays for answers.
Liquid Biopsies 101
Liquid biopsies take advantage of a concept
scientists observed more than 100 years ago:
Cells in the body turn over and, as they do,
their DNA is shed into the bloodstream. This
is known as cell-free DNA. Tumor cells also
turn over and fragments of their tumor DNA,
known as ctDNA, end up in the bloodstream. 1
Analyses of ctDNA can reveal much of the
same information as tumor biopsies, and col-
lecting a blood sample to measure ctDNA is
less invasive and more easily repeatable.
Investigators are now working to under-
stand the biology and refine the measurement
of ctDNA, including developing methods to
distinguish the small proportion of ctDNA in
the blood from the more abundant DNA from
non-malignant cells that also circulates in the
blood. For the most part, these methods home
in on the somatic DNA mutations unique to
tumor cells.
“It’s amazing how quickly this field
has progressed in the last five years,” said
Maximilian Diehn, MD, PhD, an associate
ASHClinicalNews.org
professor at Stanford
University and a radiation
oncologist whose lab
is developing ctDNA
detection assays for clinical
applications. “[We went]
from just a few researchers
discussing development
methods to [having
scientific] meetings focused
solely on ctDNA and the
start of clinical trials to test
these assays.”
In the Clinic
In June 2016, the U.S. Food and Drug
Administration (FDA) approved the first
DNA-based liquid biopsy: the cobas® EGFR
Mutation Test v2. The assay is a polymerase
chain reaction–based test that detects and
sequences the epidermal growth factor receptor
(EGFR) gene in patients with metastatic non-
small cell lung cancer. 2 The agreement between
the liquid biopsies and tissue biopsies was
demonstrated in the pivotal ENSURE trial: In
76.7 percent of EGFR-positive tissue specimens,
plasma also was positive for a mutation; plasma
was negative for an EGFR mutation in 98.2
percent of EGFR-negative tissue specimens.
Liquid biopsies
can allow clinicians
to detect tumors
early and non-
invasively track
tumor changes in
real time.
The test was approved as a companion diag-
nostic along with two EGFR-targeting therapies
(erlotinib and osimertinib).
The FDA has also permitted several other
companies designing commercial ctDNA tests
(developed in Clinical Laboratory Improve-
ment Amendments–certified labs) to accept
human samples for diagnostic testing, but,
according to the National Cancer Institute
(NCI), these tests still need to be rigorously
studied to understand limitations, sensitivity,
and whether the results can inform clinical
decision-making and improve patient care. 1
Andrew Spencer, MD, a myeloma researcher
and clinician who leads the Malignant Haemato-
logy and Stem Cell Transplantation Service at
The Alfred Hospital in Melbourne, Australia,
began exploring the potential of ctDNA to moni-
tor tumor burden and genetic abnormalities in
patients with myeloma after realizing the limits
of what a single bone marrow (BM) biopsy could
tell him about his patients’ disease.
“All the genetic information of a patient’s
myeloma was based on this single biopsy of the
BM, even tho