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Evaluation of the Predictive Role of Tumor Immune Infiltrate in Patients with HER2-Positive Breast Cancer Treated with Neoadjuvant Anti-HER2 Therapy without Chemotherapy

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

Online: http://clincancerres.aacrjournals.org/lookup/doi/10.1158/1078-0432.CCR-19-1402

Issue: Clin Cancer Res. 2020 Feb 1;26(3):738-745.


Purpose: Tumor-infiltrating lymphocytes (TIL) are associated with benefit to trastuzumab and chemotherapy in patients with early-stage HER2+ 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 = 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 ER+ 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 = 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 = 0.057). Unsupervised hierarchical clustering of the five immune markers identified two patient clusters with different responses to lapatinib plus trastuzumab treatment (pCR = 7% vs. 50%, for cluster 1 vs. 2 respectively; P = 0.01). In multivariable analysis, cluster 2, characterized by high CD4+, CD8+, CD20+ s-TILs, and high CD20+ intratumoral TILs, was independently associated with a higher pCR rate (P = 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-CD20+ TILs.

Conclusions: LPBC was marginally associated with higher pCR rate than non-LPBC in patients with lapatinib plus trastuzumab treated HER2+ 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.