Abstract 5255: Tumor heterogeneity in response to therapy and its association with outcome in patients with metastatic colorectal cancer (mCRC)

Abstract Background: Clinical benefit of therapies matched with genetic profiling remains limited in patients with mCRC, which is partially attributed to tumor heterogeneity. Compared to molecular tumor heterogeneity using modern multi-omics approach, tumor heterogeneity in response to therapy has not been adequately studied. We aimed to characterize such tumor heterogeneity and evaluate its association with outcome in patients with mCRC. Methods: We used individual patient data from a clinical trial (NCT00364013) in Project Data Sphere who received first-line FOLFOX for mCRC and had ≥2 baseline metastatic target lesions. We used standard deviations of following tumor features in an individual patient to represent tumor heterogeneity: percentage change in size of a target lesion from baseline to first radiographic evaluation (H1), average speed of such percentage change in size as defined in H1 (H2), percentage change in size of a target lesion from baseline to the time of its best response to therapy (H3), and average speed of such percentage change in size as defined in H3 (H4). Cox proportional hazards models were used to evaluate association of tumor heterogeneity with survival. Results: Mean age of 328 patients included was 61 years. Median follow-up time was 18.2 months. 85% of them had liver metastasis; 15% had lung metastasis. All tumor heterogeneity variables in response to therapy (H1-4) were higher (p<0.001) in patients with disease progression compared to those without. In univariate analyses, higher tumor heterogeneity H1 (HR 7.2, 95% CI 2.3-22.6), H2 (HR 3.1, 95% CI 1.7-5.7), H3 (HR 6.4, 95% CI 2.1-19.3), and H4 (HR 4.1, 95% CI 2.4-7.1) were associated with shorter progression-free survival (PFS) (p<0.001). H4 high group (median as cutoff) had a shorter median PFS of 7.3 months compared to H4 low group (9.1 months, p=0.005). In multivariable analysis, higher H1 (HR 8.0, 95% CI 2.2-28.9, p=0.002), H2 (HR 3.9, 95% CI 2.0-7.6, p<0.001), H3 (HR 6.4, 95% CI 1.9-21.9, p=0.003), or H4 (HR 5.1, 95% CI 2.9-9.1, p<0.001) was each associated with a shorter PFS, after adjusted for baseline number of metastatic sites, number of target lesions, tumor size, age, albumin, ECOG, and lymph node metastasis. Similar findings were found when ratio of maximal change to baseline sum of tumor size due to therapy was adjusted for and when H1-4 were calculated from liver lesions only. Higher H1 (HR 3.6, 95% CI 1.2-11.2, p=0.03), H2 (HR 1.9, 95% CI 1.1-3.4, p=0.02), H3 (HR 5.2, 95% CI 1.8-14.8, p=0.002), or H4 (HR 2.5, 95% CI 1.5-4.0, p<0.001) was also each associated with a shorter overall survival in multivariable analysis. Conclusion: Higher tumor heterogeneity in response to chemotherapy within an individual patient was independently associated with early disease progression and shorter survival. It could provide prognostic value complementary to existing tumor heterogeneity variables in patients with mCRC. Citation Format: Junjia Liu, Hao Xie. Tumor heterogeneity in response to therapy and its association with outcome in patients with metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5255.