In the near future it may be possible to detect
cancer from DNA in a blood sample, a “liquid biopsy.”
That is one of the implications of a recent paper by a
team of scientists from Yale. Using a technique called
“ultra-deep sequencing,” they were able to detect
extremely low levels of tumor-derived mutant DNA
in the plasma of cancer patients. “I hope that this will
provide a clinically useful tool in the future,” said Abhijit
A. Patel, MD, PhD, Assistant Professor of Therapeutic
Radiology at Yale School of Medicine. “Ultimately we
want to use this for purposes such as early detection
of cancers.”
The researchers used 117 samples of plasma from 30
patients with non-small cell lung cancer. The samples
were taken before, during, and after treatment, then
run through a sequencer that analyzed them for DNA
containing tumor-specific mutations. To eliminate
false positives due to sequencing errors, the researchers
designed a strategy that essentially proofread each
DNA sequence by checking the forward and reverse
strands against each other. This produced an analysis
of ultrafine sensitivity – just one variant in 5,000
molecules – that identified mutant DNA released by
the tumors.
The method opens tantalizing possibilities
for detecting cancer through blood-borne DNA.
The advantages are many, noted Patel. For instance,
DNA is highly specific, unlike the protein biomarkers
now used to spot some cancers. Most protein biomarkers
are present in small amounts even in healthy people,
and these biomarkers can sometimes be elevated due
to conditions other than cancer. “But it would be very
unlikely to find a mutation in a cancer-related gene in
someone’s blood if they didn’t have cancer,” Dr. Patel
explained. “Tumor-specific mutant DNA in the blood
would be highly unusual in a healthy person, so we
expect the false positive rate to be very low. Specificity
is very important when developing a screening test.”
DNA-testing of blood could also deliver a more
comprehensive diagnosis of a patient’s mutation profile.
A biopsy provides information about an individual
tumor sample, a keyhole view. But what if that tumor
mutates? What if the patient has multiple tumors in
different phases and locations? A blood-based analysis
of DNA mutations may be able to detect all of this,
revealing the whole landscape and giving doctors a
roadmap to direct treatment.
“Based on the mutation profile that you find in
the blood,” Dr. Patel said, “you might have enough
information to tell you that a certain targeted therapy
would be most effective.” In their paper, Dr. Patel and his colleagues offer
some evidence that plasma sequencing might also be
used diagnostically to assess whether a treatment has
failed, is working, or is losing effectiveness – based on
changes in tumor DNA levels in the blood.
Dr. Patel is especially excited by the possibility of
using this technology for early detection. Most cancers
are characterized by distinctive mutations. “People at
high risk, such as those with a strong family history of
cancer or an extensive smoking history could be tested
for a broad panel of tumor mutations. If a particular set
of mutations suggestive of cancer was found, the patient
could be worked up to determine what is going on.
You could use the test to find the needle in the haystack
– a small tumor in a more curable stage.”
He and his collaborators are now widening their
search for mutations found in other cancers, including
colorectal, pancreatic, and ovarian cancers. He believes
they eventually will be able to test for many others.
The sequencing costs have dropped to less than $100
per sample and will keep dropping. Dr. Patel cautions
that much remains to be done before the test reaches
the clinic, but the potential to help patients is clear.
“My hope is that eventually blood-based DNA testing
may become a routine part of an annual physical.”