Table 4.

Summary of clinical validity of TILs as a prognostic marker and potential clinical utility in patients with early breast cancer.

BC Subtype	Clinical Validity (Prognostic)	LoE	Evaluation Endorsed by Guidelines	Potential Clinical Utility b (to be Demonstrated)
TNBC	High TILs are associated with improved outcome [19,21,22,23,31,33,34,35,36]. High TILs are associated with increased pCR rate after neoadjuvant chemotherapy [8,39]. In TNBC, high TILs on residual disease after neoadjuvant chemotherapy are associated with improved outcome [24,27].	IB a	Yes: Expert Opinion at the 16th St Gallen International Breast Cancer Conference [15]; ESMO 2019 Early Breast Cancer guidelines [16]; WHO classification of Tumors, Breast Tumors, 5th edition;	Integration with other clinicopathological variables to guide treatment de-escalation in low-risk patients (i.e., no anthracyclines or even no treatment; prognostic tool available at www.tilsinbreastcancer.org). Risk stratification in post-neoadjuvant setting based on TILs and RCB to guide the decision of further adjuvant treatment. Stratification factor in clinical trials.
HER2+ BC			Yes: ESMO 2019 Early Breast Cancer guidelines [16]; WHO classification of Tumors, Breast Tumors, 5th edition.	Integration in multiparametric scores to guide treatment escalation and de-escalation (i.e., HER2DX). Stratification factor in clinical trials.
HR+/HER2-BC	Not demonstrated: conflicting results from studies in the adjuvant setting; high TILs associated with increased pCR rate after neoadjuvant chemotherapy, but less favorable survival [8].	-	No	Unknown

^a Availability of reproducible results in archived tissues from independent randomized trials, conducted according to REMARK guidelines; ^b likelihood of improved outcomes when using TIL as a biomarker. Abbreviations: BC, breast cancer; LoE, level of evidence; TN, triple-negative; HR+, hormone receptor-positive; TILs, tumor-infiltrating lymphocytes; pCR, pathologic complete response; RCB, residual cancer burden.