Proteomic Profiling Shown More Accurate Than Traditional Biomarkers In Identifying Liver Cancer

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Proteomic Profiling Shown More Accurate Than Traditional Biomarkers In

Identifying Liver Cancer

ScienceDaily (Jan. 16, 2008) — 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, Guerrero, BSc, and Asara, PhD.

Adapted from materials provided by Beth Israel Deaconess Medical Center.

http://www.sciencedaily.com/releases/2008/01/080115085354.htm

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