Discordance of the PAM50 intrinsic subtypes compared with IHC-based surrogate in breast cancer patients: Potential implication of genomic alterations of discordance

Abstract

Background: In recent decades, 5 intrinsic molecular subtypes have been characterized according to variation in gene expression patterns of breast cancer. However, in realworld practice, immunohistochemistry (IHC)-based classification such as estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor (HER2) are routinely used. We aimed to analyze the discordance between IHC-based surrogate subtyping and PAM50 intrinsic subtypes and to assess overall survival (OS) according to discordance. Methods: A total of 607 patients were analyzed. Hormone receptor (HR) was evaluated by IHC and HER2 by IHC and/or FISH. PAM50 intrinsic subtypes were determined according to 50 cancer genes using NanoString nCounter Analysis System. In addition, we used Ion Ampliseq Cancer Panel v2 to identify the genomic alteration related with discordance between IHC subtype and PAM50 intrinsic subtype. The Kaplan-Meier method was used for estimation of OS. Results: Themajority of patients wereHR+(343/607, 56.5%) by IHCand luminal A/B (283/607, 46.6%) by PAM50.Wematched concordant tumor as luminal A andHR+/ HER2-, luminal B andHR+/HER2+, HR-/HER2+ andHER2-enriched, TNBC and Normal- or Basal-like. 233 patients (38.4%) were discordant between IHC-based subtypes and PAM50 intrinsic subtypes. The discordant patientsweremostlyHR+(176 of 234, 75.2%) and 12.4%(29 of 234) wereHER2+.Using targeted sequencing with Ampliseq, we detected somaticmutation related discordant breast cancer including VHL gene in HR+/ HER2- group (31% in concordant group, 0% in discordant group, P=0.03) and IDHand RET genes (7%vs. 12%, P=0.02, 0%vs. 25%, P=0.02, respectively) in TNBC group. In survival analysis, among the patients withHR+, basal-like group by PAM50 showed significantly inferiorOS compared with other intrinsic subtypes (p=0.010). Conclusions: A substantial portion of patients showed discrepancies between IHCbased subtypes and PAM50 intrinsic subtypes in our study. The survival analysis demonstrated that current IHC-based classification could misdirect treatment and result in poorer outcomes. Current guidelines of IHC for ER, PR, and HER2 would better be updated accordingly.