A Pathology-Based Combined Model to Identify PAM50 Non-luminal Intrinsic Disease in Hormone Receptor-Positive HER2-Negative Breast Cancer

Tomás Pascual,Daniela Righi,Blanca González-Farré,Patricia Galván,Giuseppe Tonini,Montserrat Muñoz,Javier Cortés,Pedro Jares,Patricia Villagrasa,Juan Miguel Cejalvo,Aranzazu Fernández-Martínez,Giuseppe Perrone,Ana Lluch,Aleix Prat,Serafín Morales,Emilio Alba,Laia Paré,Ander Urruticoechea,A Rodríguez-Lescure ,Miguel Martín ,Núria Chic ,María Vidal ,Bárbara Adamo ,Alegría Borrás Rodríguez

doi:10.3389/fonc.2019.00303

Abstract

Background: In hormone receptor-positive (HR+)/HER2-negative breast cancer, the HER2-enriched and Basal-like intrinsic subtypes are associated with poor outcome, low response to anti-estrogen therapy and high response to chemotherapy. To date, no validated biomarker exists to identify both molecular entities other than gene expression.Methods: PAM50 subtyping and immunohistochemical data were obtained from 8 independent studies of 1,416 HR+/HER2-negative early breast tumors. A non-luminal disease score (NOLUS) from 0 to 100, based on percentage of estrogen receptor (ER), progesterone receptor (PR) and Ki67 tumor cells, was derived in a combined cohort of 5 studies (training dataset) and tested in a combined cohort of 3 studies. The performance of NOLUS was estimated using Area Under the ROC Curve (AUC).Results: In the training dataset (n = 903) and compared to luminal disease, non-luminal disease had lower percentage of ER-positive cells (median 65.2 vs. 86.2%, p < 0.01) and PR-positive cells (33.2 vs. 56.4%, p < 0.01) and higher percentage of Ki67-positive cells (18.2 vs. 13.1%, p = 0.01). A NOLUS formula was derived: −0.45*ER −0.28*PR +0.27*Ki67 + 73.02. The proportion of non-luminal tumors in NOLUS-positive (≥51.38) and NOLUS-negative (<51.38) groups was 52.6 and 8.7%, respectively. In the testing dataset (n = 514), NOLUS was found significantly associated with non-luminal disease (p < 0.01) with an AUC 0.902. The proportion of non-luminal tumors in NOLUS-positive and NOLUS-negative groups was 76.9% (56.4–91.0%) and 2.6% (1.4–4.5%), respectively. The sensitivity and specificity of the pre-specified cutoff was 59.3 and 98.7%, respectively.Conclusions: In the absence of gene expression data, NOLUS can help identify non-luminal disease within HR+/HER2-negative breast cancer.

Highlights

Gene expression profiling has had a considerable impact on our understanding of hormone receptor-positive (HR+)/HER2negative breast cancer biology [1, 2]
We aimed to identify a pathology-based model that is easy, fast and with the potential to be widely implemented to identify non-luminal disease within HR+/HER2-negative breast cancer when gene expression data is not available
The importance of intrinsic subtyping was highlighted in one of the most complete molecular characterization studies that has ever been performed in breast cancer [4]

Summary

Introduction

Gene expression profiling has had a considerable impact on our understanding of hormone receptor-positive (HR+)/HER2negative breast cancer biology [1, 2]. Two intrinsic molecular subtypes within HR+/HER2-negative disease (i.e., Luminal A and Luminal B) have been identified and intensively studied [3,4,5] These studies have led to wellvalidated prognostic gene expression-based tests such as Prosigna [6], OncotypeDX [7], MammaPrint [8], Breast Cancer Index [9],and EndoPredict [10]. In hormone receptor-positive (HR+)/HER2-negative breast cancer, the HER2-enriched and Basal-like intrinsic subtypes are associated with poor outcome, low response to anti-estrogen therapy and high response to chemotherapy. No validated biomarker exists to identify both molecular entities other than gene expression

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Conclusion