The immune profile of small HER2-positive breast cancers: a secondary analysis from the APT trial

Abstract

Background: Previous data suggest that the immune microenvironment plays a critical role in human epidermal growth factor receptor 2 (HER2) -positive breast cancer; however, there is little known about the immune profiles of small HER2-positive tumors. In this study, we aimed to characterize the immune microenvironment of small HER2-positive breast cancers included in the Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer (APT) trial and to correlate the immune markers with pathological and molecular tumor characteristics.

Patients and methods: The APT trial was a multicenter, single-arm, phase II study of paclitaxel and trastuzumab in patients with node-negative HER2-positive breast cancer. The study included 406 patients with HER2-positive, node-negative breast cancer, measuring up to 3 cm. Exploratory analysis of tumor infiltrating lymphocytes (TIL), programmed death-ligand 1 (PD-L1) expression (by immunohistochemistry), and immune gene signatures using data generated by nCounter PanCancer Pathways Panel (NanoString Technologies, Seattle, WA), and their association with pathological and molecular characteristics was carried out.

Results: Of the 406 patients, 328 (81%) had at least one immune assay carried out: 284 cases were evaluated for TIL, 266 for PD-L1, and 213 for immune gene signatures. High TIL (≥60%) were seen with greater frequency in hormone-receptor (HR) negative, histological grades 2 and 3, as well in HER2-enriched and basal-like tumors. Lower stromal PD-L1 (≤1%) expression was seen with greater frequency in HR-positive, histological grade 1, and in luminal tumors. Both TIL and stromal PD-L1 were positively correlated with 10 immune cell signatures, including Th1 and B cell signatures. Luminal B tumors were negatively correlated with those signatures. Significant correlation was seen among these immune markers; however, the magnitude of correlation did not indicate a monotonic relationship between them.

Conclusion: Immune profiles of small HER2-positive breast cancers differ according to HR status, histological grade, and molecular subtype. Further work is needed to explore the implication of these findings on disease outcome.

Clinical trial registration: clinicaltrials.gov identifier: NCT00542451.

Keywords: HER2-postitive breast cancer; PD-L1 expression, TIL; immune profile; stage I; tumor-inflamed signature.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Figures

Supplementary Data

Figure 1

Tumor-infiltrating lymphocyte (TIL) (A, D and G), stromal PD-L1 (B, E, and H), and tumor-inflamed signature (TIS) (C, F, I), respectively, according to hormonal receptor (HR) status, histologic grade and molecular subtypes.

Figure 2

Association between immune cell gene signatures, and tumor-inflamed signature (TIS) tumor-infiltrating lymphocyte (TIL) stromal and tumor PD-L1, hormonal-receptor (HR) status, and molecular subtype. Correlation coefficients (red, positively correlated; blue, negatively correlated). The size of the circle is proportional to the strength of the correlation. White cells reach statistical significance after correcting for multiple testing (false discovery rate at the 5% level using a Benjamini–Hochberg adjustment). DC, dendritic cells; HR, hormonal receptor status; NK, natural killer.