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

• Published in: Frontiers in oncology Vol. 9; p. 303
• Main Authors: 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
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 26-04-2019
• Subjects: breast cancer; gene expression; intrinsic subtype; non-luminal; Oncology; PAM50; PAM50; breast cancer; intrinsic subtype; non-luminal; gene expression
• ISSN: 2234-943X; 2234-943X
• DOI: 10.3389/fonc.2019.00303

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.
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).
In the training dataset (
= 903) and compared to luminal disease, non-luminal disease had lower percentage of ER-positive cells (median 65.2 vs. 86.2%,
< 0.01) and PR-positive cells (33.2 vs. 56.4%,
< 0.01) and higher percentage of Ki67-positive cells (18.2 vs. 13.1%,
= 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 (
= 514), NOLUS was found significantly associated with non-luminal disease (
< 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.
In the absence of gene expression data, NOLUS can help identify non-luminal disease within HR+/HER2-negative breast cancer.