116 ESR1 hotspot mutations in endometrial stromal sacromas may confer hormonal resistance

Abstract

<h3>Objectives</h3> Rare low-grade endometrial stromal sarcomas (LGESS) may show high-grade morphology in primary or recurrent tumors. These lesions are classified as high-grade endometrial stromal sarcomas (HGESS), which in general are more aggressive and have higher rates of resistance to endocrine therapy than LGESS. The pathogenesis of hormonal resistance in these tumors has yet to be defined. Here we describe two endocrine-resistant HGESS with <i>ESR1</i>hotspot mutations. <h3>Methods</h3> For case 1, DNA from the primary estrogen receptor (ER)-positive LGESS and two ER-positive HGESS recurrences, and for case 2, DNA from an ER-positive recurrent LGESS and ER-positive HGESS recurrence were subjected to sequencing targeting 468 cancer-related genes. RNA from each case was also evaluated for the presence of gene fusions using ARCHER FusionPlex. Sequencing data were analyzed using state-of-the-art bioinformatics algorithms. <h3>Results</h3> Both patients received at least two lines of hormonal suppressive therapy including letrozole and megestrol. Cases 1 and 2 harbored <i>JAZF1-PHF1</i>and <i>EPC1-PHF1</i>fusions, respectively. The primary LGESS and the two HGESS recurrences of case 1 shared <i>MST1</i>,<i>KDM5C</i>and <i>ARID1B</i>mutations; however in the second HGESS recurrence post endocrine treatment, clonal <i>STK40</i>(R128W) and <i>ESR1</i>hotspot (Y537S) mutations were detected. In contrast, both LGESS and HGESS recurrences of case 2 harbored a <i>LATS2</i>mutation and a clonal <i>ESR1</i>Y537S hotspot mutation. In addition, an <i>HRAS</i>Q61R hotspot mutation restricted to the recurrent LGESS was identified. <h3>Conclusions</h3> Our findings suggest that the <i>ESR1</i>Y537S hotspot mutation in LGESS, either pre-existing or acquired, may be associated with endocrine resistance and/or high-grade transformation in these lesions.