Tumor response-speed heterogeneity as a novel prognostic factor in patients with mCRC

PurposeDifferential tumor response to therapy is partially attributed to tumor heterogeneity. Additional efforts are needed to identify tumor heterogeneity parameters in response to therapy that are easily applicable in clinical practice. We aimed to describe tumor response-speed heterogeneity and evaluate its prognostic value in patients with metastatic colorectal cancer (mCRC). Patients and MethodsIndividual patient data from Amgen (NCT00364013) and Sanofi (NCT00305188; NCT00272051) trials were retrieved from Project Data Sphere. Patients in the Amgen 5-fluorouracil, leucovorin, oxaliplatin (FOLFOX) arm were used to establish response-speed heterogeneity. Its prognostic value was subsequently validated in the Sanofi FOLFOX arms and the Amgen panitumumab + FOLFOX arm. Kaplan-Meier method and Cox proportional hazards models were used for survival analyses. ResultsPatients with high response-speed heterogeneity in the Amgen FOLFOX cohort had significantly shorter (P<0.001) median progression-free survival (PFS) of 7.27 months (95%CI 6.12-7.96 months) and overall survival (OS) of 16.0 months (95%CI 13.8-18.2 months) than patients with low response-speed heterogeneity with median PFS of 9.41 months (95%CI 8.75- 10.89 months) and OS of 22.4 months (95%CI 20.1-26.7 months), respectively. Tumor response-speed heterogeneity was a poor prognostic factor of shorter PFS (HR 4.17, 95%CI 2.49-6.99, P<0.001) and shorter OS (HR 2.57, 95%CI 1.64-4.01, P<0.001), after adjustment for other common prognostic factors. Comparable findings were found in the external validation cohorts. ConclusionTumor response-speed heterogeneity to first-line chemotherapy was a novel prognostic factor associated with early disease progression and shorter survival in patients with mCRC. Implications for PracticeRoutine clinical decision making heavily relies on radiographic assessment of disease response to therapy. For patients with heterogeneous tumors, the degree and kinetics of individual tumor response to the same therapy can sometimes be vastly different. We explored a novel quantitative parameter to describe response-speed heterogeneity by utilizing individual patient data from previous clinical trials. This parameter was an independent prognostic factor associated with early disease progression and shorter survival. Complementary to existing molecular and radiographic tumor heterogeneity parameters, it may help practicing oncologists describe tumor response disparity and serve as a new prognostic factor for patients with mCRC.