Breakthrough in Diagnosis and Prognosis of HCC

October 16, 2017

A recent article published in Nature Materials details how a minimally invasive DNA test can help improve the diagnosis and prognosis of hepatocellular carcinoma (HCC). The multi-institutional, large-scale project was led by Prof. Xu from Sun Yat-sen University Cancer Center (SYSUCC) and Prof. Zhang Kang from the University of California San Diego School of Medicine.

HCC is one of the most common cancers in China. In 2015, the estimated number of new global HCC cases was 783,000 with 746,000 deaths. 466,000 of these occurred in China with 422,000 cancer deaths. HCC found at an early stage carries a much-improved prognosis compared to the advanced stage of the disease, in part due to the relative efficacy of local treatments compared with systemic therapy. People diagnosed with localized HCC have a five-year survival rate of 50% percent, and for those whose cancer has spread to nearby or distant regions, the five-year survival rate is less than 10 percent. Thus, early detection has significant potential in reducing the mortality rate of HCC.

The current blood-based method used for screening and diagnosing early stage HCC is to check the level of alpha-fetoprotein (AFP). However, the sensitivity of AFP is about 60%, which means that relying on AFP as an early diagnosis marker, 40 out of 100 cancer patients will go unnoticed. The new diagnostic and prognosis method for early detection HCC is to detect the methylation level of circulating tumor DNA (ctDNA) using a simple blood sample.

The non-invasive blood tests are called liquid biopsy and have become a hotspot in the field of tumor research. ctDNA consists of fragments of genetic material shed into the blood by tumor cells, it carries a methylation change consistent with the primary tumor, theoretically ctDNA can be used to create a methylation spectrum for tumor diagnosis. In a trace of ctDNA, the amount of blood is very small, about 20 ng per milliliter of blood, equivalent to one hundred millionth of a drop of water mixed within a larger amount of normal background DNA.

Circulating tumor DNA (ctDNA)

Using a ctDNA sample from a large cohort of 1,098 HCC patients and 835 healthy control subjects, the researchers constructed a diagnostic prediction model that showed high sensitivity (84.8%), specificity (93.1%) and was highly correlated with tumor burden, treatment response and stage of cancer. This means that using the new method, only 7% patients would be misdiagnosed, decreasing more than half compared with using AFP detection. They also constructed a prognostic prediction model that effectively predicted prognosis and survival. It accurately predicts survival and prognosis of different patients, and helps doctors choose a more individualized treatment strategy.

The results of the research were very compelling. In a large clinical cohort, the blood-based HCC diagnosis highly correlated with tumor burden, treatment response and stage of cancer. Right now, oncologists are quite limited in how they detect HCC and evaluate treatment. This study is a great demonstration of proof-of-concept for a new, more effective approach that applies to HCC, other solid malignancies and beyond.

Performing a liquid biopsy offers several potential advantages over the current method. First and foremost, it is simple and quick, requiring only a few milliliters of blood to complete the test. It is also non-invasive meaning patients can avoid unnecessary biopsies and radiation exposure. The specificity is also higher, the rate of misdiagnosis is greatly reduced and the tumor can be monitored in real time. Conventional imaging examinations can often take weeks or months to find tumor recurrence. It also helps to utilize and distribute resources for large-scale liver cancer screening more efficiently.

The liver cancer ctDNA methylation diagnostic kit research and development has made substantial progress. The tests for liver cancer based on this research will be used on people with a high risk of HCC at SYSUCC later this month. Further transformation and promotion will greatly improve the accuracy of early diagnosis of liver cancer, and is conducive to more individualized intensive treatment. It is foreseeable that the team led by Prof. Xu Rui-hua and Prof. Zhang Kang will continue to study the application of ctDNA methylation markers in other cancers to help improve screening, diagnosis, monitoring and prognosis models. At the same time, it is expected to greatly improve the SYSUCC’s academic influence and visibility at home and abroad with the hope of becoming a leader in cutting-edge technology of tumor liquid biopsy.

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