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Reply to letter entitled ‘How dense, how intense? Role of tumour‐infiltrating lymphocytes across colorectal cancer stages’. Re: Nosho et al. Tumour‐infiltrating T‐cell subsets, molecular changes in colorectal cancer, and prognosis: cohort study and literature review. J Pathol 2010; 222: 350–366

We are grateful for the opportunity to respond to the letter by Laghi et al. With regard to analysis of CD3 and other T cell markers, evidence from the study by Nosho et al [1] suggests that an evaluation of PTPRC (CD45RO)+ cells is superior to other markers, including CD3, CD8 and FOXP3. Similarly, another study [2] has reported that intraepithelial PTPRC (CD45RO)+ cell evaluation is superior to CD3+ cell evaluation. One issue in a number of previous studies is that those investigators did not perform comprehensive evaluation of markers using a large sample (eg a total sample size of at least 500 cases). Many studies analysed only CD3 [3,4], only CD8 [5–10] or only FOXP3 [11,12], and many used total sample sizes of less than 500 cases [3–9,11,12]. Small studies without appropriate validation cohorts have been problematic and publication bias might have been substantial [13]. For the next point, we agree that an immune cell evaluation can serve as a potential prognostic or predictive biomarker, although further studies are needed, particularly to assess its predictive roles. We believe that providing prognostic information in any disease stage is important for oncologists and patients. So far, most literature data are on the prognostic role of immune cell evaluation [1,3–9,11,12,14,15]. In contrast, there have not been enough data on the predictive roles of immune cell evaluation. Thus, there are few supporting data for aggressively treating a subset of stage II cases in a ‘high-risk’ category defined by certain immune cell data. What if we find in future studies that scantiness of immune cells turns out to be a marker predicting resistance against adjuvant chemotherapy? Finally, we would comment on frequent claims of prognostic biomarker studies that a certain marker has a prognostic role only at a particular disease stage (eg stage II). In fact, very few studies have formally tested the statistical significance of a difference in prognostic roles of a potential prognostic marker between stages (eg stage II versus III). As a result, only few such claims have been replicated and confirmed, indicating that many such claims actually represent chance associations. By definition, a prognostic biomarker needs to be associated with prognosis independent of disease stage. Unless evidence by well-powered studies supports a statistically significant difference between disease stages, all validated prognostic biomarkers should be regarded as prognostic regardless of disease stage, since a validation process should have assessed its prognostic role independent of disease stage [16].