Can Next-Generation Sequencing Determine Clonality of Different Tumor Nodules in Multinodular HCC and Predict Survival after Transplantation?
*Michael Mallouh, *Emma Cammann, *Lloyd Hutchinson, *Xiuling Meng, *Samantha Kaliszewski, *Nicholas Jarostchuk, *Karen Dresser, *Xiaoqin Zhu, *Babak Movahedi, *Vijay Vanguri, Giles F. Whalen
UMass Chan Medical School, Worcester , MA, United States.
Background: Liver transplantation is an effective treatment for selected patients with cirrhosis and Hepatocellular Carcinoma (HCC). Because donor livers are a scarce resource relative to number of patients who need them, parameters (e.g. Milan Criteria) for their use in patients with HCC have been developed to avoid using that resource in patients who are likely to succumb to recurrent HCC in the near term even if their cirrhosis has been fixed by the transplant. One of these criteria is the number of HCC tumors seen in the cirrhotic liver ? with more tumors associated with a worse cancer-free survival. Since a cirrhotic liver represents a ?cancer field? which is generating new cancers, we have anticipated that multiple HCC tumors in a cirrhotic liver could represent either different new primary tumors or metastases from an index HCC. We have hypothesized that removal of a carcinogenic cirrhotic liver and transplantation of a new one would result in much better survival for those patients with multiple new primary tumors than for patients whose index tumor has already metastasized within the liver. We have tested that hypothesis by analyzing the HCC tumor nodules in the explants of patients with more than one HCC tumor who underwent a liver transplant at our institution (UMass Memorial Medical Center) between January 1998 to December 2018.
Study Design: 68 formalin-fixed explanted livers with more than one HCC nodule were used for this study. DNA was extracted and sequenced from each tumor nodule. We determined whether the tumor nodules represented new primaries or metastases in each liver by determining their clonality utilizing a clinically validated, targeted 50 gene next-generation sequencing panel. Uniclonal tumors in the same liver specimen were counted as metastases and multiclonal tumors that were genetically distinct were interpreted as separate new primaries. Specimens from 38 livers originally included in the study either did not have enough genetic material or did not yield a reliable enough genetic analysis to determine clonal status. However, the tumor nodules in 30 of the explants did (16 patients in multiclonal group, and 14 in the uniclonal group). We analyzed the post transplantation survival of those patients by the clonality of their tumors using Kaplan-Meier curves. We assessed statistical significance of the difference between the two groups in survivorship using a log-rank test.
Results: Uniclonal patient group had better post-transplant survival than the multiclonal group, though the difference was not statistically significant (p=0.21, Fig. 1).
Conclusion: Results did not support our hypothesis. Although the sample size was small, a large effect was expected and multiclonal status (new primaries) conferred an apparently worse survival than uniclonal status (metastases). Investigation of potential reasons and potential clinical utility is ongoing.
Figure 1. Kaplan Meier Survivorship Analysis for Multiclonal versus Uniclonal Multinodular HCC Patients and Log-Rank Test for Statistical Significance Determination
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