Abstract 959: Aromatase inhibition shapes the clonal architecture of estrogen receptor-positive breast cancers
Authors: Miller Christopher A. , Gindin Yevgeniy , Lu Charles , Griffith Obi , Griffith Malachi , Shen Dong , Hoog Jeremy , Watson Mark , Davies Sherri R. , Hunt Kelly , Snider Jacqueline E. , DeSchryver Katherine , Wilson Richard K. , Ellis Mathew J. , Mardis Elaine 
Published: August 2015

Abstract
BACKGROUND:
Aromatase inhibitors are routinely used to treat estrogen receptor (ER)-positive breast cancer in postmenopausal women. Yet, one-third of ER positive tumors are resistant to aromatase inhibitors with a further one-third developing resistance over time. The underlying mechanism conferring resistance to endocrine therapy is poorly understood. In the current work, we study the effect of aromatase inhibitor therapy on the clonal evolution of breast cancer and how it relates to therapy response.
MATERIALS AND METHODS:
We selected 12 aromatase inhibitor sensitive (post-treatment Ki67 &lt; 10%) and 10 aromatase inhibitor resistant tumors (Ki67 &gt; 10%) that had previously been whole genome sequenced (Ellis, et al. 2014). We obtained surgical samples of the same tumors after ∼4 months of aromatase inhibitor treatment, whole-genome sequenced them, and also obtained RNA-sequencing data for 19 of the pre-treatment and 18 of the post-treatment tumors. To better understand spatial heterogeneity we also whole-genome sequenced 11 secondary core biopsies taken from a subset of both the baseline and surgical tumors.
RESULTS AND DISCUSSION:
We classified each tumor based on its clonal heterogeneity, as inferred with the sciClone R package, and found 3 ‘simple’ tumors, comprised of only a founding clone, and 19 ‘complex’ tumors that contain one or more subclones. We further classified each tumor based on a stability metric, where ‘stable’ tumors (n = 4) showed little or no evidence of evolution between baseline and surgical intervention and ‘complex’ tumors (n = 18) exhibited a spectrum of clonal changes. These changes ranged from moderate shifts in subclonal frequencies to whole-scale remodeling, where minor subclonal populations gained near-complete dominance. In one extreme case, we observed co-occurring tumors of independent origin, with selection against an ER-positive population and relative expansion of an ER-negative tumor. Spatial heterogeneity was widespread as well, with 6 out of 11 secondary cores containing clonal architecture that differed from the primary.
We find that the majority of tumors are both ‘complex’ and ‘dynamic’ in that they are made up of multiple subclones at baseline that undergo clonal selection following endocrine therapy. This clonal evolution may provide a path by which a tumor can bypass therapeutic intervention. Further study is needed to identify the genetic aberrations that underlie this differential response. Our results suggest that clonal heterogeneity is widespread in hormone positive breast cancer and has relevance to endocrine therapy response.
Citation Format: Christopher A. Miller, Yevgeniy Gindin, Charles Lu, Obi Griffith, Malachi Griffith, Dong Shen, Jeremy Hoog, Mark Watson, Sherri R. Davies, Kelly Hunt, Jacqueline E. Snider, Katherine DeSchryver, Richard K. Wilson, Mathew J. Ellis, Elaine Mardis. Aromatase inhibition shapes the clonal architecture of estrogen receptor-positive breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 959. doi:10.1158/1538-7445.AM2015-959