Reply:

We very much appreciate the kind comments of Drs. Fuks, Durand, and Belghiti regarding our article.1 We agree that the microenvironment around the tumor provides valuable information regarding the potential for recurrence and death. However, we feel that this approach is still not ready for conventional clinical practice. Our 186-gene signature is able to define ∼20%-30% of resected patients who will be at high risk of late recurrence, hence de novo tumors, and death.1 Nonetheless, according to recent guidelines this biomarker needs further validation before being adopted into clinical practice or having a role in decision-making.2 Certainly, we endorse testing this signature in prospective studies to confirm its usefulness. Likewise, our current study finds that the presence of stage 4 fibrosis, or cirrhosis, in the surrounding liver correlates with recurrences more than 1 year after resection. These de novo cancers can potentially be considered for repeated hepatic resection, which can achieve excellent results in this setting rather than being referred for preemptive liver transplantation.3 Second, even in a setting where a gene profile obtained by biopsy from the adjacent tissue has been accepted by the scientific community, the main clinical utility will not be derived from deciding between resection or transplantation in patients with a poor prognostic signature, but rather in defining patients suitable for adjuvant therapies after resection. This is clearly an unmet medical need. Such therapies are not available at this point and whether interferon or even sorafenib (STORM) are going to show efficacy as adjuvant treatments remain unclear, and we are eager to know the results of ongoing trials.4 Thus, the results of our study support selecting patients with small hepatocellular carcinomas for resection as first choice and supports performing anatomic resection even in patients with stage 4 fibrosis. Once our gene-signature is mature enough for clinical practice, it may be considered in tailoring adjuvant therapies in a more personalized and cost-effective manner when such therapies are available. Sasan Roayaie M.D.*, Josep Llovet M.D.*, Myron Schwartz M.D.*, Vincenzo Mazzaferro M.D.*, * Department of Surgery, Mount Sinai Medical Center, New York, NY.