Association between stromal tumor-infiltrating lymphocytes (TILs) and pathologic complete response (pCR) in patients with early breast cancer (BC) treated with neoadjuvant chemotherapy and HER2-directed therapies in NSABP B-41.

3017 Background: In the phase 3 NSABP B-41 trial, there was an association between pCR and survival in 519 women with early HER2-positive BC treated with neoadjuvant chemotherapy in combination with trastuzumab (T), lapatinib (L), or both (TL). There is a need to identify prognostic biomarkers to tailor patients’ treatment, and the quantification of stromal TILs represents a promising, accessible, and reproducible option. In this analysis, we studied the association between TILs and pCR. Methods: Eligible patients had a baseline core biopsy sample, known pCR status, and no consent withdrawal for the use of specimens. Slides were scanned using an Aperio GT 450 automated scanner to create whole slide images. TIL analysis was then completed based on the international TIL working group guidelines (RS). Patients were grouped into three TIL score categories based on tumor TIL %: low (1-5%), intermediate (6-30%), and high (31-95%). The dose-response relationship between TIL percentage and pCR was explored via generalized linear models with splines. Results: 257 patients were included. 89 (35%) received T, 92 (36%) L, and 76 (29%) TL. 149 (58%) had ER-positive BC. TIL categories in this cohort: 49% low, 22% intermediate, and 29% high. TIL expression was similar across BC intrinsic subtypes and by ER. There was no association between the TIL group and pCR, irrespective of the treatment group (p=0.98). Among tumors with low TILs, T or TL had similar pCR compared to L alone (51.3 v 49%; p=0.95). Among tumors with high TILs, T or TL had higher pCR than L (61.2 v 40.4%; p=0.04). Among patients with ER-positive BC, high TILs were associated with a numerical increase in pCR rate (56% vs 39.6%; p=0.11). Among patients with ER-negative tumors, high TILs were associated with a numerical decreased rate of pCR (50% v. 66.7%; p=0.15). The p-value of the Breslow test of homogeneity of the odds ratios across ER status was 0.016, suggesting that the association between TILs (0-30 v. >30) and pCR varies across ER status.No interaction between the TIL percentage and age, nodal status, menopausal status, or histologic grade was noted. Conclusions: This analysis revealed that patients with a high TIL percentage treated with T or TL compared to L were more likely to achieve a pCR. These findings can be partially explained by the mechanism of action of the HER2-directed agents. T leads to antibody-dependent cell-mediated cytotoxicity, and a higher percentage of TILs may enhance this mechanism, whereas L has intracellular tyrosine kinase disruption. The association between TILs and pCR varied across ER status. Our next steps include additional studies assessing the interaction between TILs and long-term outcomes, as well as gene expression and TILs to validate this biomarker for future clinical trials in HER2+ early BC. Clinical trial information: NCT00486668 .