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Copyright ©2008 The WJG Press and Baishideng. All rights reserved.
World J Gastroenterol. Mar 21, 2008; 14(11): 1682-1689
Published online Mar 21, 2008. doi: 10.3748/wjg.14.1682
Is human hepatocellular carcinoma a hormone-responsive tumor?
Massimo Di Maio, Bruno Daniele, Sandro Pignata, Ciro Gallo, Ermelinda De Maio, Alessandro Morabito, Maria Carmela Piccirillo, Francesco Perrone
Massimo Di Maio, Medical Oncology, “N.Giannettasio” Hospital, Rossano 87068, Italy
Bruno Daniele, Medical Oncology, “G.Rummo” Hospital, Benevento 82100, Italy
Sandro Pignata, Medical Oncology B, National Cancer Institute, Napoli 80131, Italy
Ciro Gallo, Department of Medicine and Public Health, Second University of Napoli, Napoli 80138, Italy
Ermelinda De Maio, Medical Oncology, Val D’Elsa Hospital, AUSL7 Siena, Poggibonsi 52036, Italy
Alessandro Morabito, Maria Carmela Piccirillo, Clinical Trials Unit, National Cancer Institute, Napoli 80131, Italy
Author contributions: Di Maio M performed literature search and drafted the article; Daniele B, Pignata S, Gallo C, De Maio E, Morabito A, Piccirillo MC and Perrone F revised the manuscript critically for important intellectual content.
Correspondence to: Francesco Perrone, Clinical Trials Unit, National Cancer Institute, Via M.Semmola, Napoli 80131, Italy. fr.perrone@agora.it
Telephone: +39-81-5903571
Fax: +39-81-7702938
Received: January 2, 2008
Revised: January 23, 2008
Published online: March 21, 2008
Abstract

Before the positive results recently obtained with multitarget tyrosine kinase inhibitor sorafenib, there was no standard systemic treatment for patients with advanced hepatocellular carcinoma (HCC). Sex hormones receptors are expressed in a significant proportion of HCC samples. Following preclinical and epidemiological studies supporting a relationship between sex hormones and HCC tumorigenesis, several randomized controlled trials (RCTs) tested the efficacy of the anti-estrogen tamoxifen as systemic treatment. Largest among these trials showed no survival advantage from the administration of tamoxifen, and the recent Cochrane systematic review produced a completely negative result. This questions the relevance of estrogen receptor-mediated pathways in HCC. However, a possible explanation for these disappointing results is the lack of proper patients selection according to sex hormones receptors expression, but unfortunately the interaction between this expression and efficacy of tamoxifen has not been studied adequately. It has been also proposed that negative results might be explained if tamoxifen acts in HCC via an estrogen receptor-independent pathway, that requires higher doses than those usually administered, but an Asian RCT conducted to assess dose-response effect was completely negative. Interesting, preliminary results have been obtained when hormonal treatment (tamoxifen or megestrol) has been selected according to the presence of wild-type or variant estrogen receptors respectively, but no large RCTs are available to support this strategy. Negative results have been obtained also with anti-androgen therapy. In conclusion, there is no robust evidence to consider HCC a hormone-responsive tumor. Hormonal treatments should not be part of the current management of HCC.

Keywords: Hepatocellular carcinoma; Sex hormones; Hormonal treatment; Tamoxifen