Tumor-Infiltrating Lymphocytes in Patients Receiving Trastuzumab/Pertuzumab-Based Chemotherapy


Michail Ignatiadis; Gert Van den Eynden; Salgado Roberto; Marco Fornili; Yacine Bareche; Christine Desmedt; Françoise Rothé; Marion Maetens; David Venet; Esther Holgado; Virginia McNally; Astrid Kiermaier; Heidi M. Savage; Timothy R. Wilson; Javier Cortes; Andreas Schneeweiss; Karen Willard-Gallo; Elia Biganzoli; Christos Sotiriou


J Natl Cancer Inst. 2019;111(1):69-77. 

In This Article

Abstract and Introduction


Background: There is an urgent requirement to identify biomarkers to tailor treatment in human epidermal growth factor receptor 2 (HER2)–amplified early breast cancer treated with trastuzumab/pertuzumab-based chemotherapy.

Methods: Among the 225 patients randomly assigned to trastuzumab/pertuzumab concurrently or sequentially with an anthracycline-containing regimen or concurrently with an anthracycline-free regimen in the Tryphaena trial, we determined the percentage of tumor-infiltrating lymphocytes (TILs) at baseline in 213 patients, of which 126 demonstrated a pathological complete response (pCR; ypT0/is ypN0), with 28 demonstrating event-free survival (EFS) events. We investigated associations between baseline TIL percentage and either pCR or EFS after adjusting for clinicopathological characteristics using logistic and Cox regression models, respectively. To understand TIL biology, we evaluated associations between baseline TILs and baseline tumor gene expression data (800 gene set by NanoString) in a subset of 173 patients. All statistical tests were two-sided.

Results: Among the patients with measurable TILs at baseline, the median level was 14.1% (interquartile range = 7.1%–32.4%). After adjusting for clinicopathological characteristics, baseline percentage TIL was not associated with pCR (adjusted odds ratio [aOR] for every 10-percentage unit increase in TILs = 1.12, 95% confidence interval [CI] = 0.95 to 1.31, P = .17). At a median follow-up of 4.7 years, for every increase in baseline TILs of 10%, there was a 25% reduction in the hazard for an EFS event (aOR = 0.75, 95% CI = 0.56 to 1.00, P = .05) after adjusting for baseline clinicopathological characteristics and pCR. Additionally, genes associated with epithelial-mesenchymal transition, angiogenesis, and T-cell inhibition such as SNAIL1, ZEB1, NOTCH3, and B7-H3were statistically significantly inversely correlated with percentage TIL.

Conclusions: Baseline TIL percentage provides independent prognostic information in patients treated with trastuzumab/pertuzumab-based neoadjuvant chemotherapy. However, further validation is required.


The percentage of stromal tumor-infiltrating lymphocytes (TILs) was associated with an increased pathological complete response (pCR) rate in patients with human epidermal growth factor receptor 2 (HER2)–amplified breast cancer receiving either neoadjuvant anthracycline and taxane-based chemotherapy alone in the GeparDuo and GeparTrio trials[1] or weekly paclitaxel with trastuzumab or lapatinib or both in the NeoALTTO trial.[2] Similarly, high expression of immune-related genes/gene signatures was associated with increased pCR rates in patients who received neoadjuvant anthracycline and taxane-based chemotherapy alone[3] or weekly paclitaxel in combination with trastuzumab and lapatinib.[4] In the Neosphere trial (randomizing patients between trastuzumab plus docetaxel vs trastuzumab/pertuzumab plus docetaxel vs trastuzumab/pertuzumab without chemotherapy vs pertuzumab plus docetaxel), TIL percentage as a continuous variable was not associated with pCR.[5]

However, TIL percentage as a continuous variable (10% increase in level of TILs) was associated with improved distant recurrence–free survival in the adjuvant trastuzumab arm of the Finher Trial.[6] Furthermore, TIL percentage as a continuous variable was associated with improved event-free survival (EFS) in the NeoALTTO trial.[2] However, in the pivotal N9831 Adjuvant Trial, TIL percentage as a continuous variable (10% increase in level of TILs) was not associated with a recurrence-free interval in the trastuzumab arm.[7]

No data are available for the prognostic associations of TILs with pCR and EFS in patients with early breast cancer receiving standard neoadjuvant chemotherapy (anthracycline/taxane or carboplatine/taxane) with dual HER2 blockade with trastuzumab and pertuzumab. We aimed to study these associations in the context of the TRYPHAENA neoadjuvant study.[8]