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Proteomic profiling shown more accurate than
traditional biomarkers in identifying Liver
Cancer
Newswise — As the incidence of liver cancer
continues to grow-- fueled in large part, by
rising rates of hepatitis C infections – so
too does the need for tests to help diagnose
the disease at an earlier stage.
A study appearing in the January 15 issue of
Clinical Cancer Research demonstrates that a
novel mass-spectrometry based form of
proteomic profiling is more accurate than
traditional biomarkers in distinguishing
liver cancer patients from patients with
hepatitis C liver cirrhosis, particularly
with regard to identifying patients with
small, curable tumors.
Led by researchers at Beth Israel Deaconess
Medical Center (BIDMC), the study could help
lead to earlier diagnostic methods – and
subsequent treatments -- for liver cancer.
“Proteomics represents a potentially
powerful tool for the serologic recognition
of protein profiles associated with cancer,”
explains co-senior author Towia Libermann,
PhD, Director of the Genomics Center at
BIDMC and Associate Professor of Medicine at
Harvard Medical School.
“Although this particular proteomics
technology, SELDI-TOF MS [surface enhanced
laser desorption/ionization time of flight
mass spectrometry] had already proven
capable of identifying liver cancer in some
limited studies, this was the first time
that the technology was compared
side-by-side with the clinical standard
biomarker in a cohort of patients at risk
for developing the disease,” adds
Liebermann, who is also Director of the
Dana-Farber/Harvard Cancer Center Proteomics
Core in the Division of Interdisciplinary
Medicine and Biotechnology at BIDMC.
Over a single decade, the incidence of liver
cancer (hepatocellular carcinoma) increased
from 1.8 to 2.5 per 100,000 patients, in
large part due to a rise in the spread of
hepatitis C virus.
“Hepatitis C has become a tremendous public
health problem,” explains co-senior author
Nezam Afdhal, MD, Director of the Liver
Center at BIDMC and Associate Professor of
Medicine at Harvard Medical School.
“And a significant number of hepatitis
C-infected patients will go on to develop
liver cirrhosis.”
Cirrhosis results when healthy tissue is
replaced by scar tissue, preventing the
liver from properly functioning. Cirrhosis
itself is responsible for more than 25,000
deaths each year. But, adds Afdhal,
secondarily, cirrhosis greatly increases a
person’s chances of developing liver cancer.
“Each year, cirrhosis patients have a two to
five percent chance that their condition
will escalate to cancer,” he explains.
“And the problem is that, right now, there
is no reliable means of detecting liver
cancer at an early stage, when surgical
treatment is an option. Typically by the
time the disease is discovered, the cancer
has advanced and treatment options become
much more limited.”
The best hope for early detection is cancer
biomarkers, serum proteins found in altered
amounts in blood or other body fluids.
The current biomarker for liver cancer in
clinical use is alpha fetoprotein (AFP). In
many cases, patients with hepatitis C
undergo routine monitoring for AFP levels as
an indicator of whether tumors may have
developed in their livers.
But, as Libermann explains, the AFP
biomarker has a number of shortcomings,
including false positives and false
negatives. “AFP not only fails to detect
many early tumors, but it also lacks
specificity.
Consequently, elevated AFP levels could be
indicators of not only cancer, but also of
other liver diseases or even benign
conditions, while on the other hand, many
patients with small tumors will test
negative for AFP.”
The authors, therefore, decided to evaluate
the sensitivy and specificity of SELDI-TOF
MS for the detection of liver cancer and to
compare its effectiveness with AFP.
Examining serum samples of 92 patients –
including 51 patients with liver cirrhosis
and 41 patients with liver cancer, and among
the cancer patients, individuals with both
large and small (less than 2 cm) tumors --
by SELDI-TOF mass spectrometry, the
investigators were able to identify an
11-protein signature that accurately
discriminated between the cirrhosis and
cancer patients, first in a training set
(made up of 26 cirrhosis and 20 liver cancer
patients), and then again in an independent
validation set (consisting of 25 cirrhosis
and 19 liver cancer patients).
The resulting diagnostic value – 74 percent
sensitivity and 88 percent specificity –
compared favorably with the diagnostic
accuracy of AFP (73 percent sensitivity and
71 percent specificity) as well as with two
other biomarkers currently in clinical
development for liver cancer, AFP-L3 and
PIVKA-IL.
“Most strikingly,” notes Libermann, “in
patients with small tumors (less than 2 cm),
where AFP identified only three, and AFP-L3
and PIVKA-II only one each, the 11-protein
signature correctly identified seven of
eight patients at this early stage of
disease.
“Biomarkers play a major role in all aspects
of personalized medicine, not only in early
disease detection, but also in outcome
prediction and evaluation of therapeutic
responses,” he adds.
“This study provides strong evidence that
serum contains early detection biomarkers
and supports the notion that a combination
of multiple biomarkers may prove more
effective than individual biomarkers for
diagnosis of liver cancer, as well as other
cancers.”
This study was funded by grants from the
National Institutes of Health.
In addition to Libermann and Afdhal, study
coauthors include BIDMC investigators Noah
Zinkin MD, and Franck Grall, PhD, (joint
first authors), Killimanagalam Bhaskar, MD,
Hasan Otu, PhD, Dimitrios Spentzos, MD,
Brett Kalmowitz, MD, Meghan Wells, Manuel
Guerrero, BSc, and John Asara, PhD.
Beth Israel Deaconess Medical Center is a
patient care, teaching and research
affiliate of Harvard Medical School and
consistently ranks among the top four in
National Institutes of Health funding among
independent hospitals nationwide.
BIDMC is clinically affiliated with the
Joslin Diabetes Center and is a research
partner of Dana-Farber/Harvard Cancer
Center. BIDMC is the official hospital of
the Boston Red Sox.
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