By Emily Mullin
July 27, 2015 | In a win for liquid biopsy, researchers from University of
Texas MD Anderson Cancer Center have identified a protein that could spot
pancreatic cancer in its early stages. The protein, which is shed from cancer
cells, could serve as a target for early stage diagnostic tests for several
hard-to-diagnose cancers.
In a study published
online last month in Nature,
investigators described how they zeroed in on a protein called proteoglycan glypican-1
(GPC1) that presents itself on cancer exosomes—tiny, virus-sized particles
released by cancer cells that contain DNA, RNA and other molecular material.
The researchers isolated and monitored circulating exosomes containing the GPC1
protein—GPC1+ crExos—from the blood of pancreatic cancer patients.
The study first examined the levels of these proteins in serum
from 100 healthy donors, 32 breast cancer patients and 190 pancreatic cancer
patients. Elevated GPC1+ crExos was found in both types of cancers. Among the
patients with pancreatic cancer, scientists were able to distinguish patients
with early- and late-stage pancreatic cancer. The test was 100% accurate at differentiating
cancer from normal, healthy tissue.
Pancreatic cancer and several others—such as ovarian, some
types of lung cancer and kidney, or renal cell, cancers—have proven very
difficult to detect. These tumors don’t present noticeable signs in the early
stages of disease, or their symptoms mimic those of other illnesses. Coupled
with a lack of effective screening tests, these cancers are often not caught until
they’ve already advanced to a later, more deadly stage.
Effective liquid biopsy could change that. Blood tests are
less expensive and noninvasive – win-wins for both patients and doctors.
Researchers also believe these tests provide a window into assessing genomic
changes in hidden tumors that will help clinicians monitor patients throughout
treatment, avoid unnecessary surgeries, and make more informed decisions about
which drugs are the best fit for patients.
For pancreatic cancer, MD Anderson researchers noted that
their biomarker, GPC1+ crExos, appears to be a more reliable option for screening
blood samples than the commonly used CA 19-9 Radioimmunoassay blood test, which
measures the level of tumor-associated antigens found in the blood.
When pancreatic cancer is caught early, surgical removal of
the tumor is fairly straightforward. But only about 15% of patients are
diagnosed early enough for surgery. The MD Anderson researchers were able to measure
GPC1+ crExos levels in patients who had tumors removed. Their levels of GPC1+
crExos were markedly lower than patients with tumors intact, further indicating
that the new biomarker could have clinical significance.
Diagnostic Challenges
“There’s really nothing available at the moment for early
detection of pancreatic cancer,” says study author Dr. Raghu Kalluri, a
professor and chair of the MD Anderson’s Department of Cancer Biology.
“One of the ways people talk about diagnosing pancreatic
cancer is doing imaging like MRI, Kalluri says. “But unfortunately, it’s very
hard to employ such a tedious and expensive imaging modality for just screening
purposes.” Kalluri says routine screening of the general population for
pancreatic cancer using MRIs or CTs would be cost-prohibitive and likely
produce many false positives.
Instead, the technique Kalluri and his team report
demonstrates how researchers hope liquid biopsy will work. Liquid biopsy is an
alternative to traditional tissue biopsy, which is not only unpleasant for the
patient but can be difficult to administer depending on the location of the
cancer. In patients who showed elevated levels of GPC1+ crExos, Kalluri
suggests following up with imaging to spot the location and size of a tumor and
monitor the cancer’s progression.
Liquid biopsy could be useful for other cancers as well. “Ovarian
cancer is commonly considered hard to diagnose, and as a result, most cases are
identified at a late stage,” says M. Robyn Andersen, a member of the Molecular
Diagnostics Program in the Public Health Sciences Division at Fred Hutchinson
Cancer Research Center.
The mainstay diagnostic for ovarian cancer is the CA-125
blood test, which measure levels of a protein called CA-125 that is made by
ovarian cancer cells. CA-125 is a blood test but differs from a liquid biopsy
in that it doesn’t measure circulating tumor cells or allow access to the DNA
of the tumor. Instead, the biomarker is used in the hopes of finding cancer
before there are circulating tumor cells, but the test doesn’t always work. Andersen
says the problem with this test it can only detect 60% to 80% of ovarian cancer
cases.
“Some portion of ovarian cancers don’t have the error that
causes them to spew out CA-125,” Andersen says. And some noncancerous
conditions can also increase CA-125 levels and produce false positives. Because
of this, the test isn’t recommended for routine use and is instead used in
high-risk patients with a family history of ovarian cancer or when patients are
undergoing treatment for ovarian cancer. A better diagnostic approach could replace the
CA-125 test.
A JAMA Oncology study published in
February examined the feasibility of using a liquid biopsy test in patients
with advanced non-small-cell lung cancer as a surrogate for tumor biopsy to
spot tumor-causing epidermal growth factor receptor (EGFR) mutations.
Researchers were able to correlate that data with expected patient outcomes.
Though liquid biopsies show tremendous promise for
diagnostic and treatment use in oncology, some cancer experts believe
clinicians should proceed with caution when using these tests, which haven’t
yet been widely studied.
“The key issue with any test is that it needs to make a
difference with patients,” says Dr. J. Leonard Lichtenfeld, deputy chief
medical officer for the American Cancer Society. Lichtenfeld says he’s excited
about new technology that’s able to find previously hard-to-diagnose cancers,
but he worries that these tests aren’t yet making a difference in terms of
survival for patients. “The reality is that we’re a long way from having a
screening test that can actually find cancers that are more amenable to treatment,”
he says.
Commercial Applications
Meanwhile, commercial interest in the liquid biopsy field is
taking off. Most companies’ efforts thus far are focused on analyzing the
genetic profile of tumors to better guide treatment, not on the initial
detection of cancer presence.
One of those companies, Biocept, recently launched liquid
biopsy diagnostics for non-small cell lung cancer and breast cancer that aim to
identify particular mutations in tumors. Industry giant Qiagen is also
marketing kits that analyze the genetic profile of circulating tumor cells for
personalized treatment. Genomic Health, RainDance Technologies and Trovagene
are all working on liquid biopsy tests.
Researchers at the University College London Cancer
Institute just announced plans to use technology from noninvasive prenatal
testing company Natera to analyze circulating DNA in a non-small cell lung
cancer study with the goal of understanding how the cancers mutate, adapt and
become resistant to therapy.