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Open Access Research article

Tumor-infiltrating lymphocytes predict response to anthracycline-based chemotherapy in estrogen receptor-negative breast cancer

Nathan R West12, Katy Milne1, Pauline T Truong3, Nicol Macpherson4, Brad H Nelson1256 and Peter H Watson127*

Author Affiliations

1 Trev & Joyce Deeley Research Centre, British Columbia Cancer Agency, 2410 Lee Ave., Victoria, British Columbia, V8R 6V5, Canada

2 Department of Biochemistry and Microbiology, University of Victoria, PO Box 3055, STN CSC, Victoria, British Columbia, V8W 3P6, Canada

3 Department of Radiation Oncology, British Columbia Cancer Agency Vancouver Island Centre, 2410 Lee Avenue, Victoria, British Columbia, V8R 6V5, Canada

4 Department of Medical Oncology, British Columbia Cancer Agency Vancouver Island Centre, 2410 Lee Avenue, Victoria, British Columbia, V8R 6V5, Canada

5 Department of Medical Genetics, University of British Columbia, 4500 Oak St. Unit C201, Vancouver, British Columbia, V6H 3N1, Canada

6 Department of Biology, University of Victoria, PO Box 3020, Station CSC, Victoria, British Columbia, V8W 3N5, Canada

7 Department of Pathology and Laboratory Medicine, University of British Columbia, Rm. G227 - 2211, Wesbrook Mall, Vancouver, British Columbia, Canada

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Breast Cancer Research 2011, 13:R126  doi:10.1186/bcr3072

Published: 8 December 2011

Abstract

Introduction

Infiltration of breast tumors by tumor-infiltrating lymphocytes (TIL) has been associated with sensitivity to anthracycline-based chemotherapy. However, it is unclear whether this is true within the estrogen receptor-alpha (ER)-negative subset of breast tumors that frequently manifest high TIL levels.

Methods

The association of TIL with short-term and long-term clinical response to anthracycline-based therapy was assessed in two independent ER-negative breast cancer cohorts in which patients were categorized as TIL-high or TIL-low. We defined an eight-gene lymphocyte mRNA expression signature (including CD19, CD3D, CD48, GZMB, LCK, MS4A1, PRF1, and SELL) and used unsupervised hierarchical clustering to examine the association between TIL and short-term response to neoadjuvant chemotherapy in a previously published cohort of ER-negative tumors (n = 113). We also examined the association between TIL and long-term chemotherapeutic efficacy in a second cohort of ER-negative tumors (n = 255) with longer than 6 years of median follow-up by using tissue microarrays and immunohistochemistry (IHC) for detection of CD3, CD8, CD4, CD20, and TIA-1.

Results

In patients with ER-negative tumors treated with neoadjuvant anthracycline-based chemotherapy, pathologic complete responses (pCRs) were achieved by 23 (74%) of 31 TIL-high patients and 25 (31%) of 80 TIL-low patients (odds ratio (OR), 6.33; 95% confidence interval (CI), 2.49 to 16.08; P < 0.0001). Multivariate logistic regression with standard clinicopathologic features demonstrated that only tumor size (P = 0.037) and TIL status (P = 0.001) were independent predictors of anthracycline response. In the second cohort, adjuvant anthracycline-based therapy was associated with increased disease-free survival (DFS) only in patients with high levels of intraepithelial CD3+ TIL (P = 0.0023). In contrast, outcomes after CMF treatment (cyclophosphamide, methotrexate, and fluorouracil) showed no association with CD3 status. In both cohorts, cytotoxic T-cells were the primary TIL subtype associated with anthracycline sensitivity. Finally, TIL significantly predicted anthracycline sensitivity for both the Her2-positive and triple-negative tumor phenotypes.

Conclusions

ER-negative breast cancers with high levels of TIL have heightened sensitivity to anthracycline-based chemotherapy, as assessed by the immediate response to neoadjuvant therapy and long-term outcome following adjuvant therapy. Investigations of TIL-based predictive tests to identify patients likely to benefit from anthracycline-based treatments are warranted.