MIRACLE

Background

Over 50% of colorectal cancer (CRC) patients will develop colorectal liver metastases (CRLM). In approximately 20% of CRLM patients the metastases can be surgically removed. Although surgeons intent to cure these patients, unfortunately around half of these patients are faced with recurrence of their disease within one year after surgery (early recurrence). We need to identify patients at high risk of early recurrence, as these patients might benefit from additional treatment.

Liquid biopsies (blood) can contain tumor-derived material and as such may provide a promising source to determine disease load before as well as remaining disease after surgery.

MIRACLE study

In the ongoing MIRACLE study blood is collected from participating patients with resectable CRLM at 4 time points before and after surgery. In these samples we measure a number of different tumor characteristics, including circulating tumor cells (CTCs), oncogenic mutations, DNA methylation and RNA expression. Subsequently we will investigate whether either baseline measurements (before surgery) or changes between measurements before and after surgery can predict recurrence of disease within 1 year after surgery.

Study aim

To identify the most optimal (combination of) tumor characteristics detectable in the blood for the identification of CRLM patients at high risk of rapid disease recurrence. 

Expected outcome

This study will establish whether blood-based measurements can improve prediction of early recurrence (within 1 year after surgery) in CRLM patients undergoing a partial liver resection. If successful, the resulting test for detection of these markers will improve current clinical prediction algorithms for early recurrence in CRLM patients. Future studies should subsequently investigate whether patients with a high risk of early recurrence according to our markers can benefit from adjuvant therapy. Ultimately this may further personalize treatment of CRLM patients.

Treatment of patients with colorectal liver metastases (CRLM)

Due to improvements in surgical techniques and neo-adjuvant systemic treatments, liver resection with curative intent has become available for up to 20% of CRLM patients. These partial liver resections have greatly increased 5-year survival rates in CRLM patients, but unfortunately half of these patients still develop recurrent disease within 1 year after surgery. Peri-operative chemotherapy was found not to increase overall survival, but a difference in progression-free survival was observed, suggesting selected patients at high risk of early recurrence may benefit from adjuvant chemotherapy after surgery.

Selection of high risk CRLM patients using clinical parameters

Several prognostic clinical risk scores based on characteristics of both the primary tumor and metastatic disease have been described for CRLM patients with resectable disease. However, even within the group of clinically high risk patients, 5-year survival rates of 20-40% are observed, whereas 40% of clinically low risk patients may relapse within 1 year after surgery, indicating that additional markers are urgently needed that can be used to accurately predict early recurrence and subsequently select patients in need of additional treatment.

Promise of liquid biopsies

Molecular alterations reflecting the tumor’s biology represent a promising source of biomarkers. However, it is known that these molecular characteristics are often subject to change during disease progression, necessitating the acquisition of multiple metastatic tissue biopsies. Unfortunately, metastatic biopsies are 1) highly invasive for the patient, 2) come with a considerable risk of complications and 3) are frequently impossible to obtain due to disease location.

Liquid biopsies (i.e. blood) may represent the perfect solution to this challenge as they are believed to reflect the actual disease state, are easy to obtain and can be sampled repeatedly.

Molecular markers in liquid biopsies

Several tumor-derived materials can be detected in the blood of cancer patients, including circulating tumor cells (CTCs) and tumor-derived DNA fragments (ctDNA). However, tumor-derived cells and DNA are very rare compared to the amount of normal cells and DNA fragments in the blood. 

Although only low numbers of intact CTCs are found in CRLM patients, we can detect cancer-specific RNA expression in CTC-enriched fractions of patients without CTCs. Tumor-specific hotspot mutations can be detected with very high sensitivity. Recent investigations highlight the universal occurrence of tumor-specific DNA methylation in the blood of cancer patients.

• KWF Alpe d’HuZes : “Determination of new biological parameters in patients with resectable colorectal liver metastases”
• KWF 11708 : “Prediction of early recurrence in patients with resectable colorectal cancer liver metastases using a blood-based expression profile”
• MLDS SK 18-02 : “Prediction of recurrence in patients with resectable colorectal cancer liver metastases (CRLM) by detection of cancer-specific DNA methylation in circulating cell-free DNA (cfDNA)”

In this project, we collaborate with the department of Surgical Oncology and the department of Developmental Biology.

Prof. Dr. Stefan Sleijfer
Prof. Dr. Kees Verhoef
Prof. Dr. John Martens
Dr. Maurice Jansen
Dr. Jaco Kraan
Dr. Saskia Wilting