Tuesday, August 7, 2012

A New Liver Cancer Biomarker? Might Be Just for Chinese

From Medscape Medical News > Oncology

A New Liver Cancer Biomarker?
Might Be Just for Chinese

Nick Mulcahy

August 6, 2012 — A new biomarker for diagnosing hepatocellular carcinoma (HCC) — especially early-stage disease — has "great potential," according to Chinese researchers who have published a new study in the August edition of Lancet Oncology.

The marker, known as Dickkopf-1 (DKK1), can be measured in the blood. It has previously been shown to be minimally expressed in normal tissue and overexpressed in hepatocellular carcinoma (HCC) tissue, say the authors, led by Qiujin Shen, MD, of the Shanghai Jiao Tong University School of Medicine in China.

HCC is the third leading cause of cancer death worldwide and has a "dismal" outcome, with a 5-year survival rate of only 3% to 5%, they point out. The cancer is typically diagnosed after symptoms develop.

Thus, there is a great need for tools to diagnose the disease early, especially among high-risk candidates such as patients with chronic liver disease.

The current standard for surveillance of high-risk patients is abdominal ultrasound, according to an editorial that accompanies the study.

But this approach has great limitations, including the need for "state-of-the-art equipment" and "expert assessment of images," say editorialists Alejandro Forner, MD, of the University of Barcelona, and Jordi Bruix, MD, of the Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas in Spain.

Tumor biomarkers are "attractive potential alternative tools," say the pair, because they are noninvasive and objective.

But DKK1 has "a long way to go" before it can be a diagnostic or screening tool, they say.
Nevertheless, in the new retrospective study of 424 HCC patients and 407 non-HCC control participants from Chinese centers, Dr. Shen and colleagues made some important progress.
They confirmed that levels of DKK1 were "significantly higher" in patients with HCC than in control participants. They also showed that serum DKK1 was better than another marker currently used in these patients, serum α-fetoprotein (AFP), in tumors that had already been detected by imaging, histopathology, or both.

The specificity of DKK1 was 85% to 90% across subanalyses, which is well short of the 100% specificity that is desired for cancer diagnosis markers, but DKK1 might nonetheless be a good surveillance tool in patients at risk for the disease, according to the editorialists.

The marker "might be acceptable for surveillance, since high sensitivity is preferred to high specificity to avoid excessively high false-negative rates," they write.

The marker now has some "appealing data" but still "needs further investigation before it can be accepted in practice guidelines," they write.

One of the needs to be addressed in a validation study is related to establishing a baseline DKK1 measurement, which was not done in the new study, say the editorialists. "Sera collected in studies at baseline and during follow-up in patients undergoing screening will be instrumental to test whether measurement of DKK1 in serum can detect HCC before imaging," they write.

The study authors also offer an important caveat about the new findings — that they may be specific to the Chinese. "We based our study in clinical centres in China where most cases of HCC are related to cirrhosis or HBV infection. This pattern differs from that in the USA, Europe, and Japan. Thus, the diagnostic value of DKK1 still needs further investigation," they write.

Study Details
Culling patients from a number of Chinese centers, the investigators looked at DKK1 in the main test cohort as well as a validation cohort of 209 patients with HCC, 73 with chronic HBV infection, 72 with cirrhosis, and 99 healthy control participants.

Using receiver operating characteristics (ROC) curves, they showed that the optimum diagnostic cutoff was 2.153 ng/mL (area under curve [AUC], 0.848; 95% confidence interval [CI], 0.820 - 0.875); sensitivity was 69.1%, and specificity 90.6% in the test cohort, with similar figures in the validation cohort. Also, there were similar results for early-stage HCC in both cohorts.

DKK1 maintained diagnostic accuracy for patients with HCC who were AFP-negative in terms of the AUC, sensitivity, and specificity: 0.841 (95% CI, 0.801 - 0.882], 70.4%, and 90.0% in the test cohort; there were similar findings in the validation cohort. Again, this also held true for early-stage HCC. This finding is important, say the authors, because 30% to 40% of all patients with HCC are AFP-negative, which makes diagnosis and assessment of treatment response "difficult." However, "combined testing of DKK1 and AFP concentrations in serum could improve results," they write.
Raised concentrations of DKK1 in serum allowed for a differentiation of HCC from chronic HBV infection and cirrhosis for the 3 measures in the test cohort: 0.834 [95% CI, 0.798 - 0.871], 69.1%, and 84.7%; there were similar findings in the validation group.

This is important because the researchers found that in most AFP-positive patients with chronic HBV infection or cirrhosis, results were negative for DKK1. Thus, "patients with these chronic non-malignant diseases could be distinguished from those with HCC," they point out.

This is no small clinical issue, the authors suggest. Around 2 billion people have been infected with HBV worldwide, and about 350 million have chronic infections. AFP concentrations are raised in 11% to 58% of patients with chronic hepatitis or cirrhosis in the absence of HCC. "Therefore, measurement of DKK1 in serum can help to make a differential diagnosis of HCC in patients in these high-risk populations," the authors say.

The study was funded by the National Key Basic Research Programme of China, the National Key Sci-Tech Special Projects of Infectious Diseases, the National Natural Science Foundation of China, and the Research Fund for the Doctoral Programme of Higher Education of China. The authors of the study and the editorialists have disclosed no relevant financial relationships.
Lancet Oncol. 2012;13:817–26, 750-751.
Abstract, Editorial


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