Evaluation of the predictive role of tumor immune infiltrate in patients with HER2-positive breast cancer treated with neoadjuvant anti-HER2 therapy without chemotherapy

Carmine de Angelis, Chandandeep Nagi, Cliff C. Hoyt, Linying Liu, Kristin Roman, Chichung Wang, Yi Zheng, Jamunarani Veeraraghavan, Vidyalakshmi Sethunath, Paolo Nuciforo, Tao Wang, Anna Tsimelzon, Sufeng Mao, Susan G. Hilsenbeck, Meghana V. Trivedi, Maria Letizia Cataldo, Anne Pavlick, Antonio C. Wolff, Britta Weigelt, Jorge S. Reis-FilhoAleix Prat, Carolina Gutierrez, Charles Kent Osborne, Mothaffar F. Rimawi, Rachel Schiff

Research output: Contribution to journalArticle

Abstract

Purpose: Tumor-infiltrating lymphocytes (TIL) are associated with benefit to trastuzumab and chemotherapy in patients with early-stage HER2þ breast cancer. The predictive value of TILs, TIL subsets, and other immune cells in patients receiving chemotherapy-sparing lapatinib plus trastuzumab treatment is unclear. Experimental Design: Hematoxylin and eosin–stained slides (n ¼ 59) were used to score stromal (s-)TILs from pretreatment biopsies of patients enrolled in the neoadjuvant TBCRC006 trial of 12-week lapatinib plus trastuzumab therapy (plus endocrine therapy for ERþ tumors). A 60% threshold was used to define lymphocyte-predominant breast cancer (LPBC). Multiplexed immunofluorescence (m-IF) staining (CD4, CD8, CD20, CD68, and FoxP3) and multispectral imaging were performed to characterize immune infiltrates in single formalin-fixed paraffin-embedded slides (n ¼ 33). Results: The pathologic complete response (pCR) rate was numerically higher in patients with LPBC compared with patients with non-LPBC (50% vs. 19%, P ¼ 0.057). Unsupervised hierarchical clustering of the five immune markers identified two patient clusters with different responses to lapatinib plus trastuzumab treatment (pCR ¼ 7% vs. 50%, for cluster 1 vs. 2 respectively; P ¼ 0.01). In multivariable analysis, cluster 2, characterized by high CD4þ, CD8þ, CD20þ s-TILs, and high CD20þ intratumoral TILs, was independently associated with a higher pCR rate (P ¼ 0.03). Analysis of single immune subpopulations revealed a significant association of pCR with higher baseline infiltration by s-CD4, intratumoral (i-) CD4, and i-CD20þ TILs. Conclusions: LPBC was marginally associated with higher pCR rate than non-LPBC in patients with lapatinib plus trastuzumab treated HER2þ breast cancer. Quantitative assessment of the immune infiltrate by m-IF is feasible and may help correlate individual immune cell subpopulations and immune cell profiles with treatment response.

Original languageEnglish (US)
Pages (from-to)738-745
Number of pages8
JournalClinical Cancer Research
Volume26
Issue number3
DOIs
StatePublished - Feb 1 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    de Angelis, C., Nagi, C., Hoyt, C. C., Liu, L., Roman, K., Wang, C., Zheng, Y., Veeraraghavan, J., Sethunath, V., Nuciforo, P., Wang, T., Tsimelzon, A., Mao, S., Hilsenbeck, S. G., Trivedi, M. V., Cataldo, M. L., Pavlick, A., Wolff, A. C., Weigelt, B., ... Schiff, R. (2020). Evaluation of the predictive role of tumor immune infiltrate in patients with HER2-positive breast cancer treated with neoadjuvant anti-HER2 therapy without chemotherapy. Clinical Cancer Research, 26(3), 738-745. https://doi.org/10.1158/1078-0432.CCR-19-1402