Abstract P3-05-06: Evolution of genomic alterations on endocrine therapy and mTOR inhibition in estrogen receptor (ER)-positive breast cancer
Authors: Massarweh S , Romond E , Stewart R , Sun J , Chmielecki J , Mehdi M , Black EP 
Published: May 2016

Abstract
Background: Endocrine therapy (ET) and mTOR inhibition are important treatment strategies in ER-positive breast cancer, but no specific genomic alterations reliably predict benefit. Because tumors are tested pretreatment, we hypothesized that this may not capture tumor interaction with therapy.
Methods: We studied tumors from protocol NCT00570921 using fulvestrant and everolimus for metastatic ER-positive breast cancer after aromatase inhibitor (AI) failure. DNA from FFPE tumor tissue was subjected to next-generation genomic profiling using the FoundationOne® assay and alterations were then compared between available paired samples: primary/metastatic, before/after everolimus, and upon progression on everolimus.
Results: The most common alterations encountered were in the PI3K/AKT/mTOR pathway with increased frequency of PIK3CA in endocrine-sensitive disease but no specific association with everolimus benefit (Massarweh et al, ASCO 2015). One patient with lobular carcinoma relapse on ET and a new contralateral primary, had PIK3CA, CDH1, and MAP3K1 in both tumors with no new alterations detected. Her disease was everolimus sensitive. Another patient with PIK3CA at baseline acquired a CTNNA1 mutation upon relapse with no everolimus benefit. Interestingly, one patient with liver metastasis and complete response to everolimus lasting 3 years had no known alterations reported in the primary tumor but had a PIK3CA mutation in one of two simultaneous biopsies of separate liver lesions. Another patient with liver metastasis and a GATA3 mutation at baseline had response to everolimus lasting 18 months, then developed a PIK3R2_c.1936A&gt;T mutation on progression reported as a variant of unknown significance (VUS). Another patient with metastatic lobular carcinoma to skin and bone had PIK3CA, CDH1, and ERBB2 mutations at baseline, and acquired KRAS and MCL1 amplification on two sequential skin biopsies in the first month on everolimus. She remained on therapy for 1 year. One patient with locally advanced disease and de novo bone metastasis had TP53 and GATA3 mutations at baseline with resistance to multiple chemotherapy and endocrine treatments. Upon progression on AI, her tumor acquired PDGFRA and SMAD4, detected on day 1 biopsy of everolimus treatment. Repeat biopsy on day 28 revealed loss of PDGFRA and SMAD4 with emergence of PIK3CA and MLL2 mutations and loss of STK11. After 1 year on everolimus her tumor progressed and repeat breast biopsy revealed loss of the PIK3CA, STK11, and MLL2 events, with appearance of AKT1 and NF1 mutations. Interestingly, her tumor also acquired ESR1_c.1607T&gt;G, MTOR_c.6104C&gt;T, and NSD1_c.5938G&gt;A mutations, all classified as VUS but were not previously encountered in her course. Further analysis and biologic relevance of these changes will be presented.
Conclusion: This small study suggests that ER-positive breast cancer is a dynamic disease with genomic evolution on endocrine therapy and mTOR inhibition. In some patients, this change occurs early on therapy, possibly through clonal selection, but may also be related to tumor heterogeneity. The significance of this change is not fully understood, but study of early on-treatment biopsies may help us better understand tumor response to therapy.
Citation Format: Massarweh S, Romond E, Stewart R, Sun J, Chmielecki J, Mehdi M, Black EP. Evolution of genomic alterations on endocrine therapy and mTOR inhibition in estrogen receptor (ER)-positive breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P3-05-06.