PAM50 Intrinsic Subtype Profiles in Primary and Metastatic Breast Cancer Show a Significant Shift toward More Aggressive Subtypes with Prognostic Implications

Abstract

Background: PAM50 breast cancer intrinsic subtyping adds prognostic information in early breast cancer; however, the role in metastatic disease is unclear. We aimed to identify PAM50 subtypes in primary tumors (PTs) and metastases to outline subtype changes and their prognostic role. Methods: RNA was isolated from PTs, lymph node metastases (LNMs), and distant metastases (DMs) in metastatic breast cancer patients (n = 140) included in a prospective study (NCT01322893). Gene expression analyses were performed using the Breast Cancer 360 (BC360) assay from Nano-String. The subtype shifts were evaluated using McNemar and symmetry tests, and clinical outcomes were evaluated with log-rank tests and Cox regression. Results: The PAM50 subtype changed in 25/59 of paired samples between PTs and LNMs (Psymmetry = 0.002), in 31/61 between PTs and DMs (Psymmetry < 0.001), and in 16/38 between LNMs and DMs (Psymmetry = 0.004). Shifts toward subtypes with worse outcomes were the most common. Patients with shifts from the luminal PT to non-luminal DM subtypes had worse progression-free survival compared to patients with a stable subtype (hazard ratio (HR): 2.3; 95% confidence interval (CI): 1.14–4.68, p = 0.02). Conclusion: Strong evidence of PAM50 subtype shifts toward unfavorable subtypes were seen between PTs and metastatic samples. For patients with a shift in subtype from luminal PT to non-luminal DM, a worse prognosis was noted.

Multiplatform Analysis of Primary and Metastatic Breast Tumors from the AURORA US Network identifies microenvironment and epigenetics drivers of metastasis

“…Acquisition of the HER2E subtype in the absence of gain of HER2-amplification in metastatic samples has been reported 3,16,34 , but this is the first instance to demonstrate its' association with a DNA clonality change.…”

High PANX1 Expression Leads to Neutrophil Recruitment and the Formation of a High Adenosine Immunosuppressive Tumor Microenvironment in Basal-like Breast Cancer

“…The GSE103091 dataset (normalized gene expression data, GPL570, Affymetrix Human Genome U133 Plus 2.0 Array) [ 19 , 20 ] was downloaded from the GEO database ( ) (accessed on 12 April 2021) using R package GEOquery for further CIBERSORT analysis. The METABRIC and TCGA-BRCA samples were classified into molecular subtypes using the PAM50 algorithm [ 21 ] using R package genefu [ 22 ].…”

Breast Cancer Heterogeneity

“…Discordant expression rates can be observed in a not irrelevant quota of patients and varies from 9–30% for ER, 15–45% for PR and 4–16% for HER2 expressions, and can affect tumor behavior and treatment response [ 49 , 50 , 51 , 52 , 53 , 54 , 55 , 56 , 57 ]. According to PAM50 gene expression, breast primary tumors shift toward unfavorable subtypes in metastases, with a worse prognosis associated with a change from luminal primary tumor to non-luminal distant metastasis [ 58 ]. The status of ER, PR, HER2 and Ki-67 expression can also change following neoadjuvant treatment (NAT).…”