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TIL Densities Association with Disease-Free Survival Differs by Primary Tumour Sidedness in Stage III Colon Cancer

Findings from the NCCTG N0147 Alliance study analysis
23 Aug 2022
Gastrointestinal cancers

The NCCTG N0147 Alliance researchers found significantly higher tumour infiltrating lymphocyte (TIL) densities in right- versus left-sided colon cancers. Moreover, a low versus high TIL density was significantly and independently associated with poorer disease-free survival (DFS) in patients with stage III colon cancer. Patient tumours with high TILs of either anatomic location had similarly favourable survival rates. In contrast to mismatch repair (MMR) that was not prognostic in the overall cohort, TILs were significantly associated with DFS multivariately indicating that TILs are a more robust prognostic variable. If validated in a separate clinical trial cohort, these findings suggest that TIL densities should be interpreted in the context of tumour site for prognostication. Findings are published by Prof. Frank A. Sinicrope of the Department of Medicine and Division of Oncology, Mayo Clinic & Mayo Comprehensive Cancer Center in Rochester, MN, US and colleagues on 10 August 2022 in the Annals of Oncology.

The authors wrote in the study background that identifying patients who are more likely to have disease recurrence and metastasis after surgical resection is a major unmet need. TILs reflect the host anticancer immune response. In multiple studies in non-metastatic colorectal cancer, TIL density in the tumour microenvironment has been shown to be a statistically significant and independent predictor of survival. TIL densities are typically increased in tumours with deficient MMR which are more commonly located in the right colon, as are tumours harbouring BRAFV600E point mutations and the CpG island methylator phenotype. Differences in immune-related gene expression and tumour transcriptomic profiles, including consensus molecular subtypes, are observed in relationship to primary tumour sidedness.

Primary tumour sidedness has become of much scientific interest given that it’s a source of biological heterogeneity and the finding that colon cancer prognosis and response to treatment can differ by anatomic tumour location. In particular, clinical benefit of anti- EGFR antibody treatment in patients with metastatic colorectal cancer is limited to tumours of the left colon.

The study team quantified TIL densities in colon cancers and determined whether their association with patient prognosis differs by primary tumour sidedness. They examined the interaction between TIL densities and tumour sidedness in relationship to DFS in patients with stage III colon cancer treated in a phase III clinical study of adjuvant FOLFOX-based chemotherapy (North Central Cancer Treatment Group [NCCTG] N0147). They also studied the association of TILs with DFS by sidedness in clinical low-risk (T1-3, N1) and high-risk (T4 and/or N2) groups that are used to guide the recommended duration of adjuvant treatment with a fluoropyrimidine plus oxaliplatin in patients with stage III colon cancer.

In this phase III study of FOLFOX-based adjuvant chemotherapy, TIL densities were analyzed and dichotomised in 1532 colon cancers based on a previously determined cut point optimised for DFS. Right-sided tumours were defined as proximal to the splenic flexure. Associations of TILs and sidedness with 5-year DFS were examined using Kaplan-Meier methodology along with multivariable modeling and relative contribution analysis by Cox regression.

Lower TIL densities were found in left- versus right-sided tumours (p < 0.0001). The association of TIL densities with DFS differed significantly by tumour sidedness (pinteraction = 0.045). Overall, patient tumours with low versus high TILs had significantly poorer DFS in right-sided (hazard ratio [HR] 2.02, 95% confidence interval [CI] 1.45-2.82); padj < 0.0001], but not left-sided tumours (padj = 0.1731).

Among clinical low-risk patients, low versus high TILs were adversely prognostic only in right-sided tumours (padj = 0.0058). Among high-risk patients, low TILs were prognostic independent of sidedness (padj < 0.025). The relative contribution of TILs to DFS was substantially greater in right- versus left-sided tumours (24% versus 1.5%). In high-risk tumours, TILs had the highest relative contribution to DFS (42%) of all variables.

The authors commented that in the overall cohort, TILs were second only to N stage for prediction of DFS and their relative contribution was substantially greater (16-fold), in right- vs left-sided tumours. Analysis by clinical risk group revealed that TIL density had the highest relative contribution to DFS among high-risk tumours that was followed by sidedness. Among low-risk tumours, TILs were second to KRAS, followed then by MMR for prediction of DFS.

Strengths of this study include same stage patients from a well-characterised clinical trial cohort with mature survival data, as the investigators studied a relatively large clinical trial cohort of well annotated cases with meticulous documentation of patient outcomes. Limitations include the fact that all patients received adjuvant chemotherapy for 6 months and predictive utility of TILs for chemotherapy outcomes could not be studied.

Overall, low versus high TILs were significantly associated with poorer DFS among right-sided, but not left-sided tumours. Prognostic impact of TILs was limited to right-sided tumours among clinical low-risk tumours. Relative contribution of TILs to DFS was greater in right- versus left-sided tumours. In clinical high-risk tumours, TILs had the highest relative contribution to DFS of all variables. The authors concluded that association of TIL densities with patient survival differed by primary tumour sidedness and clinical risk group, suggesting that TILs should be interpreted in this context in stage III colon cancer.

Research reported in this publication was supported by the US National Cancer Institute of the National Institutes of Health awards to the Alliance for Clinical Trials in Oncology and individual authors. It was also supported in part by funds from Sanofi.


Saberzadeh-Ardestani B, Foster NR, Lee HE, et al. Association of Tumor-infiltrating Lymphocytes (TILs) with Survival Depends on Primary Tumor Sidedness in Stage III Colon Cancers (NCCTG N0147) [Alliance]. Annals of Oncology; Published online 10 August 2022.

DOI: https://doi.org/10.1016/j.annonc.2022.07.1942

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