Colorectal cancer (CRC) is one of the most common malignancies worldwide. While an early diagnosis of CRC has excellent ten-year survival rates, the outlook for colorectal cancer liver metastasis (CRLM) is much more dire. For patients with CRLM, surgical resection represents the best chance for a cure, but recurrent rates are high, and 80% of patients are not candidates for traditional surgery.
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Cleveland Clinic performed the first liver transplant for CRLM in the United States in 2017, the first medical center in the country to do so, and since that time transplant has become an accepted surgical option for select patients with otherwise unresectable cases. In parallel, tumor DNA detected in peripheral blood, also known as circulating tumor DNA (ctDNA), has been shown to predict recurrence after colonic resection, and often “turns positive” much earlier than radiology evidence of recurrence is clear. However, data regarding its assessment in stage IV disease remains lacking, specifically regarding liver metastasis.
Initial results from two newly published studies help confirm that liver transplant is a viable option for certain patients with CRLM who aren’t otherwise candidates for surgery, and demonstrate that ctDNA can be considered during the pre-operative risk stratification and post-operative surveillance for patients with CRLM. The first study, appearing in the Journal of Gastrointestinal Surgery describes the experiences of five patients who underwent liver transplantation for unresectable CRLM or liver failure following CRLM treatment and had their ctDNA assessed pre- and post-operatively. The second study, which appears in Journal of Clinical Oncology CCI, added a cohort of patients receiving liver resection to the transplant cohort. The latter study indicates that routine program-wide ctDNA screening in patients with CRLM is logistically feasible and should be incorporated into the management of those undergoing liver transplant and liver resection to help risk-stratify risk pre-operatively and to monitor patients post-operatively.
“These papers represent our experience with liquid biopsy (detection of circulating tumor DNA) in patients undergoing liver resection and liver transplantation for CRLM,” says Federico Aucejo, MD, Director of the Liver Cancer Program and Surgical Director of the Liver Tumor Clinic in the Department of General Surgery at Cleveland Clinic and senior author of both papers. “Perioperative assessment of circulating tumor DNA will allow us to monitor better the risk of tumor recurrence and adjust accordingly surveillance protocols, and changes in tumor mutations offering potential useful information for selecting systemic therapy. These papers demonstrate that is possible to eradicate circulating tumor DNA after transplantation and considering the very advanced disease stage and the setting of immunosuppression, this is quite compelling.”
“Outcomes have really improved for patients undergoing liver transplant for unresectable CRLM, and a big reason for that is improved patient selection,” explains Chase Wehrle, MD, a resident fellow in Cleveland Clinic’s Digestive Disease Institute and lead author of the papers. “I think the findings from both papers reflect that — the first paper shows that liver transplant is a viable option in highly selective patients, and the second paper follows up on that finding by showing how ctDNA can be used to help stratify peri-operative risk among potential patients.”
The first study (J Gastrointest Surg. 2023 Jul;27(7):1498-1509)from Drs. Aucejo, Wehrle and colleagues tracked five patients who underwent liver transplantation for unresectable CRLM or liver failure following CRLM treatment from 2018 to 2022. As of the publishing date, all patients are alive without radiologic evidence of disease. Median follow-up of the patients was 32 months. Four of the patients were male, and all patients were between the ages of 44 years and 63 years. ctDNA was assessed in four patients before surgery and after surgery in five patients. One patient in the study experienced pulmonary recurrence that was resected, and pre-recurrence ctDNA data for that patient is unavailable. However, the other patients have not experienced recurrence.
“First off, having all five of our patients alive with four of them not having recurrence after transplant for CRLM is remarkable. Those four people were told at multiple centers that they had no options and would die of this disease, yet they are now alive and disease-free years after transplant. Additionally, following transplant, four of these patients did not show evidence of any ctDNA,” says Dr. Wehrle. “Two patients showed persistent ctDNA positivity post-transplant, but three of the four patients with positive pre-transplant ctDNA were ctDNA-negative post-transplant. We not only removed the disease from their liver, but it looks like their blood is now clear also.”
Dr. Aucejo says, “The results from this study indicated a couple of things to us. First, liver transplantation appears to be a valid surgical option for patients with CRLM that was considered incurable. Second, liquid biopsy and ctDNA are more accurate, more sensitive and more specific tumor biomarkers compared to the more traditional ones such as carcinoembryonic antigen (CEA). The clearance of ctDNA after transplant in these patients despite their immunosuppression was very exciting for us, and that spurred us to develop the second study.”
In their second study (JCO Clin Cancer Inform. 2023 Sep:7:e2300111), Drs. Aucejo, Wehrle and colleagues looked at 52 patients with CRLM who were seen in a multidisciplinary liver tumor clinic from January to August 2022. The patients were either planning for surgical intervention or had already undergone surgery. They received ctDNA testing, which was obtained using the Guardant360 platform. Of the 52 patients, 34 (65%) were tested pre-operatively and 18 (35%) tested post-operatively. Nine patients had testing before and after surgery.
“The median time for the test result was 12 days from blood draw,” says Dr. Wehrle. “This is a drastic improvement over the months that it usually takes to get results from other genomic tests. One of the other benefits of liquid biopsy is that the logistics involved with this kind of testing are much simpler. Rather than requiring patients to come in for an MRI or another kind of exam, the blood test can be done in the patient’s home. This is a big selling point for patients who live in rural areas— where many our patients come from — and who may not have easy access to a medical center with cutting-edge equipment. So not only can we identify high-risk patients faster, but we can expand care and prevent them from going on unnecessary chemotherapy if they don’t show any residual disease. We aren’t quite there in liver cancer yet, but colorectal cancer has been able to achieve this, and we hope liver cancer is soon to follow.”
The authors found a greater number of somatic mutations identified preoperatively (n = 29 versus n = 11) and a greater genomic heterogeneity (P = .0069). The mean tumor mutational burden (TMB) score was 12.77 among patients who did not show pathologic response to cytotoxic therapy. The TMB score was 6.0 in those with pathologic response (P = .10). All nine patients with sequential testing were positive preoperatively compared with just three (33.3%) post-operatively (P = .0090).
Most importantly, positive post-operative ctDNA was also associated with an increased likelihood of disease recurrence after resection (57%) compared with negative ctDNA (0%, P = .0419). This shows that we may be able to use this test as a better and earlier way to identify recurrence, so we can treat these patients sooner.
Drs. Aucejo and Wehrle note that both studies drive home the fact that liver resection and transplantation is a viable option for helping to clear circulating evidence of metastatic colorectal cancer. They also note that positive ctDNA pre-transplant should not necessarily preclude transplant in the case of CRLM. Rather, the presence of ctDNA pre-transplant should factor into multidisciplinary transplant evaluation and provide a baseline for evaluation of post-operative liquid biopsy results.
“At Cleveland Clinic, we obtain pre-operative ctDNA within 90 days of transplant, followed by post-transplant ctDNA at the time of surveillance imaging for a minimum of five years,” says Dr. Aucejo. “We’ve found that just by operating on this one area through liver resection or transplant, we’re able to reduce or eliminate to make nondetectable the tumor that’s circulating on the whole blood. Our thinking is we are reducing the level of disease to a point that the human’s innate immune system can clear that part of the cancer, even when they are on immunosuppression after transplant. By incorporating ctDNA tracking and liquid biopsy into care, we’re able to better identify who was really cured with surgery.”
Dr. Wehrle notes that there are a few next steps for the research. “Cleveland Clinic is starting to lead a multi-site consortium working on ctDNA in multiple liver cancers. We are planning on continuing to validate our findings on colorectal metastasis which can further help guide screening. We’re also working on another multi-center trial to better determine whether chemotherapy is needed based on the presence of ctDNA post-resection. Finally, we are using salivary genomics to find out if the ctDNA assay can be performed through the saliva rather in a blood test, which would make the test even less invasive.”