Integrated Clinical-Molecular Classification of Colorectal Liver Metastases

1. The immune subtype demonstrated an improved progression-free survival (HR 0.37) and overall survival (HR 0.56) compared with the canonical subtype.

2. The low-risk integrated group demonstrated improved progression-free survival (HR 0.38) and overall survival (HR 0.26) compared to the high-risk group.

Evidence Rating Level: 2 (Good)

Study Rundown: Approximately 25% of colorectal cancer patients develop liver metastases, and oligometastatic colorectal cancer can exhibit a wide clinical spectrum that is often difficult to precisely treat. While existing clinical risk assessments lack consideration of underlying biological factors affecting metastasis and survival, distinct molecular subtypes of liver metastases have been identified (canonical, immune, stromal) and are independently predictive of outcomes. This prognostic study built on this knowledge with a newly validated 31-gene classifier that integrated clinical-molecular risk groups effectively and was able to prognosticate survival. The primary endpoints of this study were progression-free survival (PFS) and overall survival (OS). The 5-year PFS was 43%, 14%, and 26% for immune, canonical, and stromal subtypes, respectively. The 5-year OS was 63%, 43%, and 49% for immune, canonical, and stromal subtypes, respectively. It was found that only the liver metastasis molecular subtypes, and not the primary tumour expression nor subtype, were prognostic. An integrated clinical-molecular risk group also was designated for each patient which combined the computed molecular subtypes with a high or low clinical risk score, and 5-year PFS was 44%, 40%, and 16% for the low, intermediate, and high-risk groups, respectively. The 5-year OS was 78%, 56%, and 43% for the low, intermediate, and high-risk groups, respectively. It was found that the immune subtype demonstrated greater PFS (HR 0.37) and OS (HR 0.56) compared with canonical. This was similar to the integrated clinical-molecular risk group, which found that relative to the high-risk group, the low-risk group had an HR 0.38 for PFS and HR 0.26 for OS. The strengths of this study included using a validation cohort and the limitations included only investigating patients undergoing surgery. Overall, this study found that colorectal liver metastasis subtypes, when combined with clinical risk assessment, were associated with long-term survival after resection.

Click to read the study in JAMA Oncology

Relevant Reading: Integrated molecular subtyping defines a curable oligometastatic state in colorectal liver metastasis

In-Depth [retrospective cohort]: A neural network molecular classifier was trained from a retrospective discovery cohort which had 93 patients undergoing surgery with perioperative systemic therapy for limited colorectal cancer liver metastases to classify liver metastasis into the three molecular subtypes (canonical, immune, stromal). A later independent validation cohort who underwent molecular profiling consisted of 147 patients, and was similar to the previous cohort used a fusion clustering algorithm with previously defined molecular subtypes to create the final classifier which contained 31 features (24 mRNAs and 7 miRNAs). Specimen processing was done through whole transcriptome RNA sequencing and miRNA profiling in the discovery cohort vs the validation cohort used mRNA and miRNA profiling with microarray. The 5-year PFS was 43% (95%CI, 25-60), 14% (95%CI, 7-23), and 26% (95%CI, 14-39) for immune, canonical, and stromal subtypes, respectively, (p = .004). The 5-year OS was 63% (95%CI, 40-79), 43% (95%CI, 32-55), and 49% (95%CI, 34-63) for immune, canonical, and stromal subtypes, respectively, (p = .08), and the difference between immune vs canonical/stromal subtypes was p = .045. It was found that only the liver metastasis molecular subtypes, and not the primary tumour expression nor subtype, were prognostic. An integrated clinical-molecular risk group also was designated for each patient which combined the computed molecular subtypes with a high or low clinical risk score, and 5-year PFS was 44% (95%CI, 20-66), 40% (95%CI, 21-58), and 16% (95%CI, 10-24) for the low, intermediate, and high-risk groups, respectively (p = .002). The 5-year OS was 78% (95%CI, 44-93), 56% (95%CI, 34-74), and 43% (95%CI, 32-52) for the low, intermediate, and high-risk groups, respectively. It was found that the immune subtype demonstrated greater PFS (HR 0.37, 95%CI, 0.20-0.68, p=.001) and OS (HR 0.56 (95%CI, 0.36-0.89, p =.01) compared with canonical. This was similar to the integrated clinical-molecular risk group, which found that relative to the high-risk group, the low-risk group had an HR 0.38 (95%CI, 0.19-0.76, p = .006) for PFS and HR 0.26 (95%CI, 0.08-0.84, p = .02) for OS. Overall, this study found that colorectal liver metastasis subtypes, when combined with clinical risk assessment, were associated with long-term survival after resection.

Image: PD

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