Abstract PD9-01: Genomic alterations associated with loss of HR expression in metastatic breast cancer
Authors: Garrido-Castro AC , Hughes ME , Cherniack A , Barroso-Sousa R , Bychkovsky BL , Di Lascio S , Berger A , Mittendorf EA , Files JL , Guo H , Kumari P , Cerami E , Krop IE , Wagle N , Lindeman NI , MacConaill LE , Dillon DA , Winer EP , Lin NU 
Published: May 2019

Background: Discordance in hormone receptor (HR) status between primary (p) tumors and metastatic (m) recurrences has been widely described. Loss of estrogen and progesterone receptor expression occurs in ˜12% of asynchronous recurrences, leading to triple-negative (TN) status in the metastasis. Genomic mechanisms driving HR loss and its prognostic and therapeutic implications have not been fully elucidated.

Methods: Targeted NGS (Oncopanel, OP) at Dana-Farber Cancer Institute using multiplexed copy number variation and mutation (mut) detection across the full coding regions of 300 genes and selected intronic regions of 35 genes was prospectively performed on either archival primary or metastatic samples collected in patients (pts) with metastatic breast cancer (MBC). Receptor status at initial diagnosis and recurrence were reviewed using a 1% cutoff to define HR-positivity and excluding HER2+ cases. Fisher´s exact test was used to compare frequency of alterations. Tumor mut burden (TMB) was computed normalizing the sum of reported exon mut in each pt by the exonic-bait-set size of the panel.

Results: Between 8/2013-9/2016, 929 pts with MBC underwent OP testing. Of 517 pts diagnosed with primary HR+/HER2- breast cancer, at time of recurrence 388 remained HR+/HER2- (pHR+/mHR+), 39 switched to HR-/HER2- (pHR+/mTN, of which 23 (59%) had initial HR expression &gt;10%), 10 switched to HER2+ and 80 had unknown metastatic receptor status. Comparison between primary samples in pHR+/mHR+ (n=245) and pHR+/mTN (n=24) showed that pHR+/mTN was significantly more likely to harbor mut in TP53, STK11 and MSH6, amplifications (amp) in CCNE1 and FGFR2, and less likely to have PIK3CA mut or CCND1 amp. Median TMB in primary pHR+/mHR+ was 6.05 mut/Mb (0-37.5) and 5.68 mut/Mb (1.2-10.9) in pHR+/mTN (p=0.45). Metastatic samples in pHR+/mTN (n=15) were enriched in ARID1A, CRTC2 and CDH1 mut compared to metastases (n=40) in pts who remained TN (pTN/mTN). Deletions in CDKN2A/2B and RB1, and mut in TP53, NOTCH2 and ERCC2 were more prevalent in recurrent tumors of pHR+/mTN than pHR+/mHR+. In metastases, TMB was higher in pHR+/mTN than pTN/mTN or pHR+/mHR+ (10.9 vs. 7.0 vs. 7.3 mut/Mb, respectively; p=0.002). Median OS from initial diagnosis was 9.4 yrs in pHR+/mTN, less than pHR+/mHR+ (15.9 yrs; p=0.009) and greater than pTN/mTN (4.3 yrs; p=0.008). Median OS from MBC diagnosis was 1.8 yrs in pHR+/mTN, less than pHR+/mHR+ (6.4 yrs; p=0.001) but not significantly different than pTN/mTN (1.5 yrs, p=0.3).

 pHR+/mHR+ (n=245)pHR+/mTN (n=24)p value NFreq (%)NFreq (%) MutTP536325.72083.3&lt;0.00001PIK3CA9438.4000GATA33514.3000.053STK1152.0312.50.026MSH641.6312.50.017AmpFGFR20028.30.008CCNE10028.30.008CCND14418.0000.018

Conclusion: Targeted NGS shows that alterations in DNA damage and cell-cycle regulation pathways in primary HR+ tumors are associated with HR loss in the metastatic setting. Primary tumors that lose HR appear more similar to basal-like than luminal tumors, despite &gt;10% baseline HR expression in most pts, and once metastatic, survival is comparable to pTN/mTN. Metastases with HR loss have higher TMB than those that remain HR+ or TN throughout the course of the disease. These findings, if confirmed, may influence treatment and pt selection for clinical trials.

Citation Format: Garrido-Castro AC, Hughes ME, Cherniack A, Barroso-Sousa R, Bychkovsky BL, Di Lascio S, Berger A, Mittendorf EA, Files JL, Guo H, Kumari P, Cerami E, Krop IE, Wagle N, Lindeman NI, MacConaill LE, Dillon DA, Winer EP, Lin NU. Genomic alterations associated with loss of HR expression in metastatic breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD9-01.