AUTHOR=Pascual Tomás , Martin Miguel , Fernández-Martínez Aranzazu , Paré Laia , Alba Emilio , Rodríguez-Lescure Álvaro , Perrone Giuseppe , Cortés Javier , Morales Serafín , Lluch Ana , Urruticoechea Ander , González-Farré Blanca , Galván Patricia , Jares Pedro , Rodriguez Adela , Chic Nuria , Righi Daniela , Cejalvo Juan Miguel , Tonini Giuseppe , Adamo Barbara , Vidal Maria , Villagrasa Patricia , Muñoz Montserrat , Prat Aleix 

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

JOURNAL=Frontiers in Oncology

VOLUME=9

YEAR=2019

URL=https://www.frontiersin.org/journals/oncology/articles/10.3389/fonc.2019.00303

DOI=10.3389/fonc.2019.00303

ISSN=2234-943X

ABSTRACT=<p><bold>Background:</bold> 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.</p><p><bold>Methods:</bold> 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).</p><p><bold>Results:</bold> In the training dataset (<italic>n</italic> = 903) and compared to luminal disease, non-luminal disease had lower percentage of ER-positive cells (median 65.2 vs. 86.2%, <italic>p</italic> &lt; 0.01) and PR-positive cells (33.2 vs. 56.4%, <italic>p</italic> &lt; 0.01) and higher percentage of Ki67-positive cells (18.2 vs. 13.1%, <italic>p</italic> = 0.01). A NOLUS formula was derived: −0.45<sup>*</sup>ER −0.28<sup>*</sup>PR +0.27<sup>*</sup>Ki67 + 73.02. The proportion of non-luminal tumors in NOLUS-positive (≥51.38) and NOLUS-negative (&lt;51.38) groups was 52.6 and 8.7%, respectively. In the testing dataset (<italic>n</italic> = 514), NOLUS was found significantly associated with non-luminal disease (<italic>p</italic> &lt; 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.</p><p><bold>Conclusions:</bold> In the absence of gene expression data, NOLUS can help identify non-luminal disease within HR+/HER2-negative breast cancer.</p>