Abstract BS3-2: Breast cancer intra-tumor heterogeneity and its clinical implications

Abstract

Abstract Breast cancer is a known heterogeneous disease with significant inter-tumor differences being manifested on many levels including histology, response to therapy, and patient survival outcomes. Importantly, even within an individual tumor, significant heterogeneity may exist. This intra-tumor heterogeneity (ITH) poses a challenge to understanding the biology of breast cancer, and an open question is what impact does ITH have on the clinical decision making process? Over the past ten years, a rich body of genetic, genomic, and proteomic data has been accumulated concerning the ITH of breast cancers. Much of these data is coming from Massively Parallel Sequencing, and it is yielding a wealth of quantitative data concerning DNA- and RNA-based ITH. This variation can be in the form of somatic mutations, DNA copy number changes, and gene expression differences due to epigenetic differences (i.e. cell state changes) and or microenvironmental influences. Notable recent examples of DNA-based ITH include PIK3CA mutation heterogeneity across different metastatic sites within the same patient with some lesions responding to PI3K inhibitors while others did not. Another key example of ITH are ESR1 mutations that arise within the setting of aromatase inhibitor treatment, where it is sometimes seen that within an individual, multiple different mutations in ESR1 can occur and that confer estrogen independence. Lastly, significant epigenetic ITH can also occur, with a prime example being epithelial tumor cell plasticity, which is often manifested as “state changes”. Examples of this include chemotherapy induced changes that may select for epithelial cells with more mesenchymal features (often referred to as EMT), and which is also typically linked to a more treatment resistant state. Another important concept that is emerging is that it might be better to target the clonal (or trunk) alterations, as opposed to targeting the subclonal variation. The latter, by definition, is not present within all tumor cells, and thus even if that therapy is effective, it will not target all tumor cells. Conversely, if clonal variants (i.e. those present within the founding clone) are targeted, the treatment may be more effective and cause regression and/or complete response. These multiple examples of ITH are biologically important, but the question still remains, what are the clinical implications? These ITH topics will be presented and discussed within the context of how these findings might affect treatment options and decision making. Citation Format: Perou Perou CM. Breast cancer intra-tumor heterogeneity and its clinical implications [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr BS3-2.