Determination of new biomarkers in patients with resectable colorectal liver metastases, the MIRACLE study

For colorectal cancer (CRC) patients presenting with isolated liver metastases,
a treatment comprising a liver metastasectomy is the only potentially curative
option. However, a substantial number of patients shows a relapse following
this procedure underlining the need for prognostic factors. Such prognostic
factors allow a more personalized treatment strategy; more intensified
treatments for those with a high risk for relapse and maybe less intensified
approaches for those with a low risk. In recent years, several pre-operative
prognostic factors in patients with isolated colorectal liver metastases have
been revealed for the risk of relapse after a metastasectomy including the
number and size of metastases, synchronicity and CEA serum levels. Although
this type of clinical risk scoring is well-validated and able to distinguish
between high-risk and low-risk patients, further fine-tuning is desperately
needed. Clinically low-risk patients may experience relapse rates of 40% at 1
year, whereas clinically high-risk patients may show a 5-year survival rate of
20-40%. This underlines the importance of novel pre-clinical and biological
prognostic factors. Relevant prognostic and predictive factors are required to
determine the most effective combination of treatments for each individual
patient with metastatic CRC.

To establish (i) whether or not pre-operative determination of cell-free DNA
(cfDNA) and circulating tumor cells (CTC), alone or in combination with each
other, in peripheral blood of CRC patients with isolated colorectal liver
metastases (CRLM) undergoing hepatic resection determined before and/or after
resection with or without pre-operative chemotherapy, can discriminate between
patients showing a recurrence within 1 year from those who do not, and (ii)
whether or not these novel factors significantly add to the current known
prognostic factors. Furthermore, to evaluate (iii) if cfDNA can be used in
patients who are recurrence free after >1 year to discriminate between patients
who will still develop recurrence during at least 2 remaining years of
scheduled follow-up. Lastly, to determine (iv) reference values and the
incidence of elevated cfDNA upon diagnosis of recurrence and prior to start of
treatment.

1.In total, 240 colorectal cancer patients with isolated liver metastases
undergoing a potentially curative hepatic resection will be studied.
2.Known pre-operative prognostic factors nowadays used in the prognostic
clinical scoring systems (including number and size of liver metastases, the
time interval from primary tumor to metastases, CEA levels, free resection
margins) will be established.
3.Peripheral blood samples for quantitative determination of cfDNA levels and
enumeration of CTCs will be drawn from all participating patients: before and
after the start of neoadjuvant chemotherapy, and before and after hepatic
resection.
4.Peripheral blood samples for quantitative determination of cfDNA levels will
be collected in 40 participants who are recurrence-free at >=12 months of
follow-up, on condition that the remaining regular follow-up duration is at
least 2 years at the moment of sample collection.
5.Peripheral blood samples for quantitative determination of cfDNA levels will
be collected from 10 participants upon diagnosis of recurrence within 12 months
of follow-up. These samples will be collected before treatment for recurrent
disease is initiated.
6.Patients will be monitored for recurrence of disease with traditional imaging
techniques such as ultrasound, CT-, MRI- and PET-scans, according to the
National guidelines.
7.Assessment whether or not determination of cfDNA, CTC, alone or in
combination with each other, improves the prognostic value of currently known
prognostic models to predict early recurrence in colorectal cancer patients
with isolated liver metastases undergoing a potentially curative hepatic
resection.
8.Assessment whether or not determination of cfDNA, CTC, alone or in
combination with each other, have predictive value with respect to the outcome
of neoadjuvant chemotherapy.
9.Exploratory analyses will be done using targeted next-generation sequencing
of a panel of genes thought to be involved in the outcome of colorectal cancer
to establish whether or not the genomic constitution of cfDNA taken at
different time points relative to treatment is associated with outcome.

Not applicable