239P Genomic landscape of metastatic ER+/HER2- breast cancer (BC) with loss of estrogen (ER) and/or progesterone (PR) receptor

ER and PR loss might occur during metastatic progression of ER+/HER2- BC, but the underpinning molecular alterations remain elusive. We accessed data from metastatic HER2- BC within the MSK-2018 dataset to compare outcome, tumor characteristics and genomic alterations of BC with loss of ER (ER+/- n= 66) to those maintaining ER positivity (ER+/+ n= 364) or ER negativity (ER-/- n= 50). We also compared metastatic ER+/HER2- BC with loss of PR (PR+/- n= 111) to those maintaining PR (PR+/+ n= 192). ER+/- represented 15% of ER+/HER2- BC and were PR- in >90% cases. Compared to ER+/+, ER+/- BC were significantly (psecond-line) of metastatic biopsy. Outcome data and selected mutations (mut) according to ER classes are presented in the table. In line with previous data, median disease-free survival (DFS) and overall survival (OS) significantly differed among ER+/+, ER+/- and ER-/- groups. Interestingly, ESR1 mut and ER loss were mutually exclusive and ER+/- showed genomic context similar to ER-/-. PR +/- BC were 37% of ER+/PR+/HER2- primary BC and were significantly (p<0.05) associated with shorter DFS (51 vs 70 months; HR 1.4. 95% CI (1.1-1.7)), lower ESR1 mut (3% vs 24%) and, when selecting only biopsies obtained before first-line, with adjuvant aromatase inhibitors (51% vs 29% SERM) compared to PR+/+ BC. Of note, ER and PR loss were 20% and 43% of HR+/HER2- ESR1 wild-type BC, respectively.Table: 239PER +/+ER +/-ER -/-p value +/+ vs +/-q value +/+ vs +/-p value allq value allOutcomeDFS (months)6042 HR 1.4. 95% CI (1.1- 1.8)28 HR 2.5, 95% CI (1.8-3.3)p <0.0001OS (months)206105 HR 2.6, 95% CI (1.7-4)60 HR 5.5, 95% CI (3.6-8.4)p <0.0001GENE mutTP5397 (27%)43 (65%)44 (88%)1.9E-097.2E-075.5E-212.1E-18RB15 (1%)8 (12%)6(12%)1.7E-050.00311.8E-060.00033PIK3R13 (0.8%)4 (6%)6 (12%)0.010.345.8E-060.00072ESR159 (16%)000.00080.0762.2E-050.0021CDKN2A/p14ARF03 (4.5 %)00.0010.0767.7E-050.0058PIK3CA144 (40%)16 (24%)7 (14%)0.0250.620.00030.015GATA372 (20%)6 (9%)00.05710.00040.020MAP3K132 (0.5%)4 (6%)00.0030.180.00070.027 Open table in a new tab We show that ER+/- BC display a molecular profile similar to ER-/- and hypothesize that loss of ER and/or PR might be alternative to ESR1 mutations in the metastatic progression of ER+/HER2- BC. Further analyses on matched primary and metastatic samples are warranted.