ASPO Abstracts
Intratumoral heterogeneity of prognostic multigene signatures for breast cancer
Category: Molecular Epidemiology & Environment
Conference Year: 2020
Abstract Body:
Purpose of the study
To assess whether clinically-relevant multigene scores are subject to intratumoral
heterogeneity.
Methods
Tumors from 37 patients were assayed repeatedly at different spatial locations, specifically
targeting regions that had distinct histological characteristics such as tumor cellularity,
differentiation, and inflammation. Using the FFPE block, up to two 1-mm cores were sampled
from each histologically distinct region and used for RNA extraction. A pathologist also
assessed heterogeneity in mitotic activity and presence of immune infiltration across samples.
Gene expression was quantified using a research version of the PAM50 assay, on the
Nanostring platform, and the expression data were normalized. Samples were classified for
intrinsic subtype (Luminal A, Luminal B, HER2-enriched, or basal-like) and for and risk of
recurrence score (ROR-P, high vs. med/low). The Euclidean distances between samples were
also calculated across the 50 genes, and compared for samples that were concordant and
discordant for each multigene classifier.
Results
Of the 37 tumors, 11 had samples with discordant PAM50 calls and 7 had samples with
discordant ROR-P group, corresponding to 75% and 83% agreement, respectively. The
Euclidean distance between paired samples with discordant PAM50 intrinsic subtype or ROR-P
score was significantly greater than that among concordant tumors. Samples discordant for
ROR-P had more heterogeneity in mitotic activity and immune infiltration, while discordance of
PAM50 call was not predicted by heterogeneity of these histological characteristics.
Conclusion
The high concordance of PAM50 subtype calls and ROR-P, despite oversampling of
heterogenous-appearing tumor regions, demonstrates the robustness of the PAM50 classifier
for breast cancer tumor intrinsic subtyping. However, a substantial proportion of tumors showed
intratumoral heterogeneity, suggesting that assay sampling strategies for histologically
heterogeneous tumors merit consideration.
Keywords: intratumoral heterogeneity, PAM50, risk of recurrence score