Young breast cancer patients and molecular reclassification using RNA-sequencing.

Abstract

e12591 Background: Choice of breast cancer (BC) treatment is to a large extent based on immunohistochemistry (IHC) subtyping. Often genomically driven, young BC patients have a large proportion of non-luminal subtypes and unfavorable clinicopathologic profiles. In addition, a higher discordance between IHC and molecular BC subtyping has been shown in young BC patients. RNA-based classifiers may more accurately characterize the tumor biology. This study was conducted in Ethiopia, a Low-Income Country (LIC) in Eastern Africa. Here, almost all of the biomarker decision is based on histopathology and IHC. The aim of the study was to compare histopathology and IHC with RNA based classification of breast cancer in Ethiopia. Methods: This is a cross-sectional prospective cohort of 50 BC patients between the age of 18 and 39 enrolled between February 2021 and September 2023 at Tikur Anbessa Specialized Hospital (TASH), Ethiopia. Fresh frozen tissue samples were used for RNA extraction and RNA-sequencing. BC intrinsic subtypes were classified as Luminal A, Luminal B, HER2-enriched, and Basal using the SCAN-B, and as Luminal A-like, Luminal B-like, HER2-positive, and triple negative BC (TNBC), based on IHC method, which was available for 43 samples. The results between the two approaches were compared. Results: RNA based classification revealed a high-grade tumor in 84% while only 36% of the patients were classified as high-grade using histologic diagnosis. A higher proportion of HER2-enriched tumors were found (36%) using RNA-sequencing compared to the IHC (11.6%). Moreover, there was a high discordance in Luminal B classification between RNA classification (28%) and the IHC (53.5%) technique. Many of the tumors classified as Luminal B-like by IHC were molecularly HER2-enriched, accounting for 40% of the classification difference. Conclusions: In this cohort of young BC patients, we found a significant discordance between IHC and molecular subtyping. RNA-sequencing revealed a substantially higher proportion of biologically aggressive tumor than the conventional histopathology and IHC classification. High-grade tumors were markedly underestimated by histopathology and IHC compared with RNA-sequencing. The discordance was mainly observed for Luminal B and HER2-enriched BC. The differences seen in the study may be explained by several factors, including the young age of the patients, tissue type, preanalytical issues affecting IHC, and an obvious fundamental methodological difference between the two approaches, that might have a potential clinical implication. In LIC, where IHC plays a vital role in BC management and where a high proportion of patients are young, reliance on IHC classification may miss a considerable proportion of biologically aggressive diseases. Therefore, RNA-based molecular diagnostic approaches may offer an added value for a portion of selected BC patients in LMICs like Ethiopia.