Background For primary triple-negative breast cancer (TNBC) treated with neoadjuvant chemotherapy (NAC), higher pretreatment tumor-infiltrating lymphocytes (TILs) correlates with increased pathologic complete response (pCR) rates, and improved survival. We evaluated the added prognostic value of residual disease (RD) TILs to residual cancer burden (RCB) in predicting survival post-NAC. Patients and methods We combined four TNBC NAC patient cohorts who did not achieve pCR. RD TILs were investigated for associations with recurrence-free survival (RFS), and overall survival (OS) using Cox models with stromal TILs as a continuous variable (per 10% increment). The likelihood ratio test was used to evaluate added prognostic value of RD TILs. Results A total of 375 RD TNBC samples were evaluable for TILs and RCB. The median age was 50 years, with 62% receiving anthracycline/taxane chemotherapy. The RCB class after NAC was 11%, 50%, and 39% for I, II, and III, respectively. The median RD TIL level was 20% (IQR 10-40). There was a positive correlation between RD TIL levels and CD8+ T-cell density (Ï = 0.41). TIL levels were significantly lower with increasing post-NAC tumor (P = 0.005), nodal stage (P = 0.032), but did not differ by RCB class (P = 0.84). Higher RD TILs were significantly associated with improved RFS (HR: 0.86; 95% CI 0.79-0.92; P < 0.001), and improved OS (HR: 0.87; 95% CI 0.80-0.94; P < 0.001), and remained significant predictors in multivariate analysis (RFS P = 0.032; OS P = 0.038 for OS). RD TILs added significant prognostic value to multivariate models including RCB class (P < 0.001 for RFS; P = 0.021 for OS). The positive prognostic effect of RD TILs significantly differed by RCB class for RFS (P Int =0.003) and OS (P Int =0.008) with a greater magnitude of positive effect observed for RCB class II than class III. Conclusions TIL levels in TNBC RD are significantly associated with improved RFS and OS and add further prognostic information to RCB class, particularly in RCB class II.
Bibliographical noteFunding Information:
The authors wish to acknowledge Vassilena Tsvetkova for her role in preparation and evaluation of immunohistochemistry samples in this study. SJL is supported by the University of Melbourne. SL is supported by National Breast Cancer Foundation (NBCF) of Australia and the John Colebatch Cancer Council Victoria Clinical fellowship.
SJL reports receipt of travel funding from Pfizer; honoraria from Novartis. RS reports research funding from Roche, Puma, Merck; participates on the advisory board for BMS; travel funding from Roche, Merck, and Astra Zeneca. MVD reports consulting or advisory role for Eli Lilly, Genomic Health, Celgene. SD receives research funding to her institution from Lytix Biopharma and Nanobiotix. She reports consulting or advisory role for Eisai, Lytix Biopharma, EMD Serono, AstraZeneca, AbbVie, Cytune Pharma. SM is a co-inventor of a patent describing the prognostic value of a four-gene signature for predicting high levels of TILs after anthracycline-containing NACT and outcome in patients with triple-negative breast cancer. SL receives research funding to her institution from Novartis, Bristol Meyers Squibb, Merck, Roche-Genentech, Puma Biotechnology and Pfizer. She has acted as consultant (not compensated) to Seattle Genetics, Pfizer, Novartis, BMS, Merck and Roche-Genentech. All remaining authors have declared no conflicts of interest.
This work was supported by the Breast Cancer Research Foundation (BRCF NY) (BCRF grant number-16-199).
© The Author(s) 2018. Published by Oxford University Press on behalf of the European Society for Medical Oncology.