Liver Transplantation for Non-resectable Colorectal Liver Metastases: Translational Research

The patients with non-resectable colorectal liver metastases (CRLM) have always being considered a particular subgroup of CRLM in which the therapeutic approach, is focused on strategies that allow a potential surgery like neoadjuvant systemic treatments. But, the underlying biology that causes this particular profile of spread in a proportion of patients that always recur and progress in the liver has not been properly characterized from a biological point of view. Unfortunately, these patients finally develop liver metastasis not amenable for local treatments and become refractory to systemic treatments even without developing extrahepatic liver metastases. As a result, liver transplantation (LT) is a potential for patients without extrahepatic involvement and nonresectable CRLM. There are several studies that aims to evaluate if LT increases overall survival compared to best alternative care. To our knowledge, none of these studies incorporate objectives focused on the underlying tumor biology of this particular population and the development of focused strategies including a dynamic disease monitoring and targeted treatments for this particular population.The METLIVER trial will permit to expand the genetic studies to the whole complexity of metastatic lesions and a more precise evaluation of their genetic heterogeneity. Moreover, it will help to precise the type of genetic analyses on liquid biopsies that can be designed for patients that will unfortunately relapse mostly with lung metastases after LT. Our proposal will maximize the opportunity to produce an unprecedented knowledge on CRLM evolution and will provide new opportunities for relapsed patients.

不可切除结直肠癌肝转移（colorectal liver metastases, CRLM）患者一直被视为结直肠癌肝转移的特殊亚群，其治疗策略聚焦于新辅助全身治疗等可实现潜在手术切除的方案。然而，导致这类患者中部分病例始终复发并在肝脏进展的潜在生物学机制，尚未从生物学层面得到充分阐明。遗憾的是，此类患者最终会发展为无法接受局部治疗的肝转移灶，即便未出现肝外转移，也会对全身治疗产生耐药性。因此，肝移植（liver transplantation, LT）对于无肝外受累且不可切除结直肠癌肝转移的患者而言是一种潜在治疗手段。目前已有多项研究旨在评估肝移植相较于最佳替代治疗能否提升总生存期。据我们所知，尚无此类研究聚焦于该特殊人群的潜在肿瘤生物学特征，也未开发针对该人群的针对性策略，包括动态疾病监测与靶向治疗。METLIVER试验将能够针对转移灶的整体复杂性开展遗传学研究，并更精准地评估其遗传异质性。此外，该试验还有助于明确适用于此类患者的液体活检遗传学分析类型——这类患者在接受肝移植后大概率会复发并伴肺转移。本研究提案将最大限度地提升对结直肠癌肝转移演变过程的创新性认知，并为复发患者提供全新的治疗机遇。