Background – Colorectal liver oligometastases (CLO) represents a subset of metastatic colorectal cancer (mCRC) patients who may be eligible to undergo curative intent resection which can improve survival. However, given the heterogeneity of this population, prognostic stratification of CLO patients is poorly understood, with a highly variable 5 year survival rate of 25-58%. A three-gene prognostic biomarker based on pathogenic mutations in RAS (KRAS or NRAS), SMAD4, and TP53 was previously described. Here, we validate the prognostication of this three-gene biomarker in a CLO real world data (RWD) cohort.

Methods – We leveraged clinico-molecular real world data to develop a retrospective, de-identified cohort of CLO patients for the assessment and development of prognostic biomarkers. Inclusion criteria include curative intent liver resections with negative or unknown surgical margins, tumor samples collected from the colon or liver, metastasis to only the liver at time of sample collection, and minimum 30 days follow up following resection. All samples were profiled with the Tempus xT assay (DNA-seq of 595-648 genes at 500x coverage). Real-world time to progression (rwTTP) was used to assess the prognostic value of the three-gene biomarker using a Cox proportional hazard model, treating gene mutations as both a continuous variable (the total number of genes mutated 0-3) and as categorical variables, while also controlling for neoadjuvant therapy, adjuvant therapy, and metachronous vs. synchronous colorectal cancer.

Results – We identified 276 patients that met the inclusion criteria for this study. Of these patients, 27 had three genes with mutations, 85 with two, 155 with one, and 9 with zero mutations. The three-gene biomarker represented as a continuous variable had a rwTTP hazard ratio (HR) of 1.42 (95% confidence interval 1.15-1.77, p=0.001). Comparing three mutations to zero mutations resulted in a HR of 10.60 (95% CI 2.2-50.8, p=0.003, n=36), HR=2.55 (95% CI 1.54-4.22, p=0.0003, n=182) compared to one mutation, and HR=2.47 (95% CI 1.44-4.22, p=0.001, n=112) compared to two mutations. Median rwTTP for patients with mutations in all three genes was 3.7 months compared to 31.0 months for patients with zero mutations from the three-gene biomarker, and 10.0 months for all patients in the cohort.

Conclusions – A novel clinico-molecular RWD cohort allowed independent rwTTP validation of a three-gene biomarker in the CLO setting. Although future prospective studies are warranted, the significance of the three-gene biomarker as a prognostic factor suggests that mutation status of RAS, SMAD4, and TP53 may be helpful to guide treatment decisions surrounding curative surgery.

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