The immunologic constant of rejection classification refines the prognostic value of conventional prognostic signatures in breast cancer

François Bertucci,Patrice Viens,Emilie Mamessier,Ines Simeone,Wouter Hendrickx,Davide Bedognetti,Francesco M Marincola,Michele Ceccarelli,Daniel Birnbaum,Ena Wang,Pascal Finetti

doi:10.1038/s41416-018-0309-1

Abstract

BackgroundThe immunologic constant of rejection (ICR) is a broad phenomenon of Th-1 immunity-mediated, tissue-specific destruction.MethodsWe tested the prognostic value of a 20-gene ICR expression signature in 8766 early breast cancers.ResultsThirty-three percent of tumours were ICR1, 29% ICR2, 23% ICR3, and 15% ICR4. In univariate analysis, ICR4 was associated with a 36% reduction in risk of metastatic relapse when compared with ICR1-3 (p = 2.30E–03). In multivariate analysis including notably the three major prognostic signatures (Recurrence score, 70-gene signature, ROR-P), ICR was the strongest predictive variable (p = 9.80E–04). ICR showed no prognostic value in the HR+/HER2− subtype, but prognostic value in the HER2+ and TN subtypes. Furthermore, in each molecular subtype and among the tumours defined as high risk by the three prognostic signatures, ICR4 patients had a 41–75% reduction in risk of relapse as compared with ICR1-3 patients. ICR added significant prognostic information to that provided by the clinico-genomic models in the overall population and in each molecular subtype. ICR4 was independently associated with achievement of pathological complete response to neoadjuvant chemotherapy (p = 2.97E–04).ConclusionICR signature adds prognostic information to that of current proliferation-based signatures, with which it could be integrated to improve patients’ stratification and guide adjuvant treatment.

Highlights

The immunologic constant of rejection (ICR) is a broad phenomenon of Th-1 immunity-mediated, tissue-specific destruction
The ICR consists in a signature including genes involved in Th-1 signalling interferon (IFNG, TBX21, CD8A/B, IL12B, STAT1, and IRF1), Th-1 chemoattraction, and cytotoxic functions (GNLY, PRF, GZMA, GZMB, and GZMH). The expression of these procytotoxic transcripts in tumours is associated with the counter activation of suppressive mechanisms, such as the expression of IDO1, CTLA4, CD274 (PD-L1), PDCD1 (PD-1), and FOXP3.26 In a study[27] centred on the TCGA data set, we found that breast cancers can be classified in four classes according to the ICR signature
ICR4 class was associated with age ≤ 50 years, ductal type, less pT1, less pN0, high grade, Estrogen Receptor (ER)− status, progesterone receptor (PR)− status, and TN subtypes

Summary

Introduction

The immunologic constant of rejection (ICR) is a broad phenomenon of Th-1 immunity-mediated, tissue-specific destruction. Multigene signatures prognostic and/or predictive for response to chemotherapy were developed.[2,3] Several commercially available prognostic classifiers have been cleared by the Food and Drug Administration for clinical use or endorsed by American Society of Clinical Oncology (ASCO), National Comprehensive Cancer Network (NCCN), and Saint-Gallen guidelines to assist clinicians in making decisions about adjuvant chemotherapy, in particular for patients with HR+/HER2− tumour. Those signatures, mainly based on genes involved in cell proliferation, provide modest prognostic information for patients with classically proliferative HER2+ or triple-negative (TN) tumours

Methods

Results

Conclusion