Major Finding: Two gene signatures predicted early recurrence and overall recurrence at 48 months of follow-up.
Data Source: Genomic profiling of 287 patients with surgically resected early hepatocellular carcinoma.
Disclosures: Study was supported by grants from the Spanish National Health Institute, the U.S. National Institute of Diabetes and Digestive and Kidney Diseases, and the Samuel Waxman Cancer Research Foundation. Dr. Llovet has received consulting fees from numerous pharmaceutical companies.
VIENNA — A large-scale genomic profiling study has identified two gene signatures that are strong independent predictors of disease recurrence in patients with early-stage hepatocellular carcinoma.
These findings will provide physicians with practical genetic tools to gauge patient prognosis and select individuals for secondary chemoprevention. Moreover, the specific genes included in these signatures will be evaluated as potential targets for badly needed adjuvant therapies following surgical resection and other potentially curative therapies, Dr. Augusto Villanueva said at the annual International Liver Congress sponsored by the European Association for the Study of the Liver (EASL).
The U.S.-European study involved 287 patients with surgically resected early hepatocellular carcinoma (HCC) who underwent genomic profiling using whole genome expression platforms to scrutinize roughly 24,000 genes. The investigators evaluated 20 gene signatures that were previously reported in much smaller studies as showing promise for predicting patient survival and/or disease recurrence. Of these, 16 were tumor based, whereas the other 4 came from adjacent cirrhotic tissue, explained Dr. Villanueva of the University of Barcelona.
At a median 46 months of follow-up, 64% of the patients had experienced HCC recurrence, and 34% of patients were dead. The following two signatures were found to be independent predictors of outcome:
▸ The previously described tumor-based “proliferation-G3” signature (Hepatology 2007;45:42–52), which is marked by overexpression of genes controlling the cell cycle, predicted early recurrence (hazard ratio 1.94) and total recurrences (HR 1.72).
▸ The “poor-prognosis” 20-gene signature in adjacent nontumoral cirrhotic tissue previously described by Dr. Villanueva and coworkers (N. Engl. J. Med. 2008;359:1995–2004) also predicted both early recurrence (HR 2.06) and overall recurrence (HR 1.73).
Patients with both the proliferation-G3 and poor-prognosis gene signatures had a 2-year HCC recurrence rate of roughly 70%, compared with 20% for those with neither signature. Patients with either one of the two gene signatures had an intermediate recurrence rate.
The genomic information coming from the tumor and the surrounding tissue is complementary in predicting recurrence, as the tumor arises in a carcinogenic field of cirrhotic liver, Dr. Villanueva explained. Early recurrences represent true metastases, whereas later ones are de novo tumors. In early-stage disease, tumor biology isn't nearly as important in terms of patient prognosis as is the genomic information provided by the adjacent tissue. The more advanced the tumor, the greater the importance of the tumor's genomic signature in terms of patient prognosis.
Dr. Heiner Wedemeyer, EASL secretary-general, singled out this genetic signature study as one of the congress highlights. He described it as a major step forward in understanding the mechanism of HCC, a particularly complex malignancy that is the No. 3 cause of cancer-related mortality worldwide.
The immediate clinical implications of the genomic-profiling results are limited by the very few treatment options available today for HCC. The real clinical payoff will come several years from now, when a raft of investigational therapies for HCC that are well along in the developmental pipeline are expected to reach the market, said Dr. Wedemeyer of Hannover (Germany) Medical School.
Dr. Joseph M. Llovet, principal investigator of the gene signature study, agreed. “Only one drug is approved now for HCC—sorafenib—but others are coming. There are 12 high-end, randomized, phase III clinical trials ongoing that may change the landscape of treatment of this disease between 2011 and 2014,” said Dr. Llovet, professor of research at the University of Barcelona and professor of medicine and director of the HCC research program at the Mount Sinai School of Medicine in New York.
For example, to date there are no adjuvant therapies available for patients undergoing potentially curative surgery or ablative treatment for early HCC. This is a huge unmet medical need, as roughly 70% of patients undergoing resection will develop recurrent disease within 5 years. Two ongoing, phase III, placebo-controlled trials aim at rectifying this situation: one involving sorafenib (Nexavar), the other featuring retinoid therapy.
For patients with intermediate-stage HCC, there are two phase III trials, one involving chemoembolization plus sorafenib or placebo, the other focused on chemoembolization plus placebo or brivanib, a potent inhibitor of vascular endothelial growth factor receptor–2, Dr. Llovet continued.