TY - JOUR
T1 - Progenitor cell markers predict outcome of patients with hepatocellular carcinoma beyond Milan criteria undergoing liver transplantation
AU - Miltiadous, Oriana
AU - Sia, Daniela
AU - Hoshida, Yujin
AU - Fiel, Maria Isabel
AU - Harrington, Andrew N.
AU - Thung, Swan N.
AU - Tan, Poh Seng
AU - Dong, Hui
AU - Revill, Kate
AU - Chang, Charissa Y.
AU - Roayaie, Sasan
AU - Byrne, Thomas J.
AU - Mazzaferro, Vincenzo
AU - Rakela, Jorge
AU - Florman, Sander
AU - Schwartz, Myron
AU - Llovet, Josep M.
N1 - Funding Information:
Josep M. Llovet was supported by grants from The European Commission Framework Programme 7 (HEPTROMIC, Proposal No: 259744 and HEP-CAR project, Proposal No: 667273-2), the Samuel Waxman Cancer Research Foundation, the Spanish National Health Institute (SAF2013-41027), and the Asociación Española Contra el Cáncer (AECC). Daniela Sia and Vincenzo Mazzaferro are supported by the Italian Association for Cancer Research and the Italian National Ministry of Health. Yujin Hoshida is supported by grants from the U.S. National Institute of Diabetes and Digestive and Kidney Diseases (R01 DK099558), the European Commission Framework Programme 7 (HEPTROMIC, Proposal No: 259744).
PY - 2015/12/1
Y1 - 2015/12/1
N2 - Background & Aims In patients with hepatocellular carcinoma (HCC), liver transplantation (LT) is an excellent therapy if tumor characteristics are within the Milan criteria. We aimed to define genomic features enabling to identify HCC patients beyond Milan criteria who have acceptable transplant outcomes. Methods Among 770 consecutive HCC patients transplanted between 1990 and 2013, 132 had tumors exceeding Milan criteria on pathology and were enrolled in the study; 44% of the patients satisfied the 'up-to-7 rule' [7 = sum of the size of the largest tumor and the number of tumors]. Explant tumors were assessed for genomic signatures and immunohistochemical markers associated with poor outcome. Results At a median follow-up of 88 months, 64 patients had died and 45 recurred; the 5-year overall survival (OS) and recurrence rates were 57% and 35%, respectively. Cytokeratin 19 (CK19) gene signature was independently associated with recurrence [Hazard ratio (HR) = 2.95, p <0.001], along with tumor size (HR = 3.37, p = 0.023) and presence of satellites (HR = 2.98, p = 0.001). S2 subclass signature was independently associated with poor OS (HR = 3.18, p = 0.001), along with tumor size (HR = 5.06, p <0.001) and up-to-7 rule (HR = 2.50, p = 0.002). Using the presence of progenitor cell markers (either CK19 or S2 signatures) patients were classified into poor prognosis (n = 58; 5-year recurrence 53%, survival 45%) and good prognosis (n = 74; 5-year recurrence 19%, survival 67%) (HR = 3.16, p <0.001 for recurrence, and HR = 1.72, p = 0.04 for OS). Conclusions HCC patients transplanted beyond Milan criteria without gene signatures of progenitor markers (CK19 and S2) achieved survival rates similar as those within Milan criteria. Once prospectively validated, these markers may support a limited expansion of LT indications.
AB - Background & Aims In patients with hepatocellular carcinoma (HCC), liver transplantation (LT) is an excellent therapy if tumor characteristics are within the Milan criteria. We aimed to define genomic features enabling to identify HCC patients beyond Milan criteria who have acceptable transplant outcomes. Methods Among 770 consecutive HCC patients transplanted between 1990 and 2013, 132 had tumors exceeding Milan criteria on pathology and were enrolled in the study; 44% of the patients satisfied the 'up-to-7 rule' [7 = sum of the size of the largest tumor and the number of tumors]. Explant tumors were assessed for genomic signatures and immunohistochemical markers associated with poor outcome. Results At a median follow-up of 88 months, 64 patients had died and 45 recurred; the 5-year overall survival (OS) and recurrence rates were 57% and 35%, respectively. Cytokeratin 19 (CK19) gene signature was independently associated with recurrence [Hazard ratio (HR) = 2.95, p <0.001], along with tumor size (HR = 3.37, p = 0.023) and presence of satellites (HR = 2.98, p = 0.001). S2 subclass signature was independently associated with poor OS (HR = 3.18, p = 0.001), along with tumor size (HR = 5.06, p <0.001) and up-to-7 rule (HR = 2.50, p = 0.002). Using the presence of progenitor cell markers (either CK19 or S2 signatures) patients were classified into poor prognosis (n = 58; 5-year recurrence 53%, survival 45%) and good prognosis (n = 74; 5-year recurrence 19%, survival 67%) (HR = 3.16, p <0.001 for recurrence, and HR = 1.72, p = 0.04 for OS). Conclusions HCC patients transplanted beyond Milan criteria without gene signatures of progenitor markers (CK19 and S2) achieved survival rates similar as those within Milan criteria. Once prospectively validated, these markers may support a limited expansion of LT indications.
KW - Gene expression
KW - Gene signature
KW - Prognosis
KW - Stem cell
KW - Survival
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U2 - 10.1016/j.jhep.2015.07.025
DO - 10.1016/j.jhep.2015.07.025
M3 - Article
C2 - 26220754
AN - SCOPUS:84983189783
SN - 0168-8278
VL - 63
SP - 1368
EP - 1377
JO - Journal of Hepatology
JF - Journal of Hepatology
IS - 6
ER -