Abstract 967: Real-world transcriptomic biomarkers as replacement for immunohistochemistry and FISH studies in breast cancer

Abstract

Abstract Background: Human epidermal growth factor receptor-2 (HER2) and hormone receptors are typically used as binary biomarkers for selecting breast cancer therapy. There is a need to explore the clinical relevance of these biomarkers as continuous variables. This is particularly relevant for the new class of antibody-drug conjugates (ADC), in which a relatively low HER2 expression level is adequate for targeting tumor cells. We explored the potential of RNA profiling, determined by next generation sequencing (NGS), to provide more flexible clinical biomarkers as compared with immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH). Methods: Clinical and laboratory data from 57 breast cancers collected by the COTA real-world data company were used to study biomarker levels as detected by routine clinical transcriptomic tests. HER2 (ERBB2), estrogen receptor alpha (ESR1), and androgen receptor (AR) mRNA levels were compared with reported HER2 and estrogen receptor (ER) IHC and FISH results. Results: RNA levels accurately reflected and predicted HER2 amplification (see table below). Importantly, RNA data showed significant variation and overlap in the levels of ERBB2 mRNA between cases scored by IHC as zero, 1+, and 2+. This variation correlated with progression-free survival (PFS). Similarly, the ESR1 RNA levels accurately reflected ER status and demonstrated significant variation between positive cases. RNA data also showed significant variations in the AR levels. Patients wssith high AR mRNA levels had significantly better PFS (P=0.05). Patients expressing high ER and AR levels had significantly better PFS than those expressing low ESR1 and AR levels (P=0.03). Conclusions: These findings suggest that RNA analysis using NGS is an alternative to IHC and FISH. RNA provides continuous data that can determine cut-off points predicting response to therapy and should be explored in predicting ADC response. ERBB2 mRNA levels (FPKM) in various HER2 IHC groupss IHC Score Valid N Mean Median Minimum Maximum Quartile Range Std.Dev. Zero 19 231 243 63 537 170 110 Zero vs one 3 151 155 45 253 208 104 Zero to one vs one 18 397 302 172 845 365 222 One Vs two 13 495 423 159 1094 273 284 Two vs three 4 7523 7649 937 13859 7183 5310 Citation Format: Maher Albitar, Andre Goy, Andrew Pecora, Deena Graham, Donna Donna McNamara, Ahmad Ahmad Charifa, Andrew IP, Wanlong Ma, Stanley Waintraub. Real-world transcriptomic biomarkers as replacement for immunohistochemistry and FISH studies in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 967.