Relevance of Spatial Heterogeneity of Immune Infiltration for Predicting Risk of Recurrence After Endocrine Therapy of ER+ Breast Cancer.

Andreas Heindl,Andreas Heindl,Ivana Sestak,Kalnisha Naidoo,Yinyin Yuan,Yinyin Yuan,Mitchell Dowsett,Mitchell Dowsett,Mitchell Dowsett,Jack Cuzick

doi:10.1093/jnci/djx137

Abstract

Despite increasing evidence supporting the clinical utility of immune infiltration in the estrogen receptor-negative (ER-) subtype, the prognostic value of immune infiltration for ER+ disease is not well defined. Quantitative immune scores of cell abundance and spatial heterogeneity were computed using a fully automated hematoxylin and eosin-stained image analysis algorithm and spatial statistics for 1178 postmenopausal patients with ER+ breast cancer treated with five years' tamoxifen or anastrozole. The prognostic significance of immune scores was compared with Oncotype DX 21-gene recurrence score (RS), PAM50 risk of recurrence (ROR) score, IHC4, and clinical treatment score, available for 963 patients. Statistical tests were two-sided. Scores of immune cell abundance were not associated with recurrence-free survival. In contrast, high immune spatial scores indicating increased cell spatial clustering were associated with poor 10-year, early (0-5 years), and late (5-10 years) recurrence-free survival (Immune Hotspot: LR-χ2 = 14.06, P < .001, for 0-10 years; LR-χ2 = 6.24, P = .01, for 0-5 years; LR-χ2 = 7.89, P = .005, for 5-10 years). The prognostic value of spatial scores for late recurrence was similar to that of IHC4 and RS in both populations, but was not as strong as other tests in comparison for recurrence across 10 years. These results provide a missing link between tumor immunity and disease outcome in ER+ disease by examining tumor spatial architecture. The association between spatial scores and late recurrence suggests a lasting memory of protumor immunity that may impact disease progression and evolution of endocrine treatment resistance, which may be exploited for therapeutic advances.

Highlights

Estrogen receptor-positive (ER+) subtype accounts for about 80% of all breast cancers, the most common cancer in women
In this study, we aimed to establish the prognostic value of immune scores for recurrence in ER+ breast cancer patients treated with anastrozole or tamoxifen
While immune response and immunotherapy for ER- diseases have been under the spotlight, correlation of tumor-infiltrating lymphocytes (TILs) with outcomes in ER+ disease is less clear [16], with many studies reporting the lack of significant prognostic association [11, 15, 26, 27]

Summary

Introduction

Estrogen receptor-positive (ER+) subtype accounts for about 80% of all breast cancers, the most common cancer in women. A subset of patients is at risk for disease recurrence and death, after 5 years of adjuvant endocrine therapy. Differentiating these patients from low-risk patients who can safely avoid chemotherapy is a priority for breast cancer management [1]. Available prognostic tests to predict risk in endocrine-treated patients include the widely used Oncotype DX 21-gene recurrence score (RS) [2], the PAM50 risk of recurrence (ROR) score [3], and the immunohistochemistry-based IHC4 test that is combined with the clinical treatment score (CTS) to integrate clinicopathological parameters [4]. Despite increasing evidence supporting the clinical utility of immune infiltration in the estrogen receptor-negative (ER-) subtype, the prognostic value of immune infiltration for ER+ disease is not well defined

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Conclusion