Molecular Subtypes May Be Associated With Prognosis of Colorectal Liver Metastases

A novel classification system for molecular subtypes of colorectal liver metastases was found to be associated with prognosis in patients undergoing resection surgery with perioperative chemotherapy, according to a study published in JAMA Oncology.

The investigators conducted RNA sequencing of resected metastases from patients enrolled in the phase 3 New EPOC randomized, clinical trial. The New EPOC cohort comprised 147 patients with operable colorectal cancer liver metastases. Participants underwent resection with perioperative chemotherapy with or without cetuximab. Median follow-up was 53.4 months.

The team then utilized a neural network molecular classifier to assess the molecular subtypes of these specimens. The network was trained on data from a retrospective discovery cohort of patients with colorectal adenocarcinoma who underwent hepatic resection for limited liver metastases. Three molecular subtypes were defined: canonical, immune, and stromal. The classifier contained 24 messenger RNAs (mRNAs) and 7 microRNAs. A clinical risk score (CRS) was determined for each patient based on baseline demographic, clinical, and pathological information, and a clinical-molecular risk was designated for each patient. Low-risk patients exhibited an immune or canonical molecular subtype and low CRS (<2). Intermediate-risk patients had an immune subtype with high CRS (≥2) or a stromal subtype with low CRS. High-risk patients exhibited a canonical or stromal subtype with high CRS.

Regarding molecular subtypes, the authors found the following:

• The canonical subtype “exhibited increased enrichment scores corresponding to DNA repair pathways, cell cycle regulation/proliferation (including E2F, G2M, and mitotic spindle pathways), and MYC signaling.”
• The stromal subtype was associated with “enrichment for epithelial-mesenchymal transition, angiogenesis, inflammatory response, and KRAS”
• The immune subtype had “lower enrichment scores for KRAS signaling, angiogenesis, cell proliferation, and transforming growth factor β signaling pathways.”

The primary clinical outcomes were progression-free survival (PFS) and overall survival (OS). The researchers found that the immune subtype was associated with superior PFS and OS compared with the other subtypes. For immune, canonical, and stromal subtypes, the 5-year PFS was 43%, 14%, and 26%, respectively (log-rank P=.004), and the 5-year OS was 63%, 43%, and 49%, respectively (log-rank P=.08).

Notably, differences in PFS or OS were not associated with molecular subtypes when applied to expression data from the primary tumor, which implies that these “liver metastasis molecular subtypes were only prognostic when applied to the metastatic tumor,” the authors wrote.

The clinical-molecular risk score was also associated with both PFS and OS. When compared with the high-risk group, the hazard ratios for the low-risk group were 0.38 (P=.006) and 0.26 (P=.02) for PFS and OS, respectively. The authors noted no significant “interaction effects between molecular subtype and CRS.”

The researchers acknowledged that the population of patients undergoing surgery limits the wider application of these findings, and they pointed to studies of patients undergoing other therapies, such as radiation and ablation, to extend this investigation. They also noted considerable clinical heterogeneity of colorectal liver oligometastases and stated that studies in larger patient cohorts can help to “clarify the role of molecular subtyping in this context.”