Differential genomic landscape of estrogen receptor (ER)-low versus ER-positive (ER+) and ER-negative (ER-) metastatic breast cancer (MBC).

Abstract

1071 Background: Guidelines define ER+ breast cancer (BC) as ≥1% tumor nuclei staining positive by IHC. Data on managing ER-low tumors (1–10% ER staining) is limited, with mixed evidence suggesting outcomes similar to ER- but a higher risk of death with adjuvant endocrine therapy (ET) omission. We aimed to examine the genomic landscape of ER-low MBC compared to ER+ and ER-. Methods: This retrospective study included consecutive patients (pts) with MBC who consented to clinicopathologic data collection and genomic profiling (OncoPanel) on tumor samples with matched ER IHC through the EMBRACE (Ending Metastatic Breast Cancer for Everyone) program. For multiple sequencing timepoints, the first was analyzed. SNVs, CNVs and TMB were compared among ER groups. Genes altered in > 3% of pts were analyzed for ER status association, with Benjamini-Hochberg adjusted p < 0.2 subjected to Holm-corrected pairwise testing. Results: Between 10/2000-12/2020, 1199 pts were identified:48 ER-low, 797 ER+, and 354 ER-. Median age at diagnosis was 63.8 (34.8-86.8), 64.4 (30.8-96.3), and 62.6 (30.3-92.7) years for ER-low, ER+, and ER- groups, respectively. De novo stage IV disease was observed in 8.3% (4/48) of ER-low, 27.0% (215/797) of ER+, and 17.2% (61/354) of ER- cases. Overall, 801/1199 (66.8%) had metastatic and 398/1199 (33.2%) had primary samples sequenced. 27/48 ER-low (56.3%), 451/797 ER+ (56.6%), and 73/354 ER- (20.6%) pts received ET before sequencing. CDK4/6i were administered in 8/48 ER-low (16.7%), 107/797 ER+ (13.4%), and 5/354 ER- (1.4%) pts prior to sequencing. The most clinically relevant genomic alterations are shown in the Table. TP53 mutations (mts) were more frequent in ER-low vs ER+ BC, and not significantly different between ER-low and ER- tumors. PIK3CA and CDH1 alterations were more frequent in ER-low than ER- BC, with no significant difference compared to ER+. AKT1 and RB1 alterations were significantly higher in ER-low vs ER+ BC. ESR1 mts were not significantly different between ER+ and ER-low BC. Median TMB was higher in ER-low vs ER+ cases, without significant differences between ER-low and ER- cases. Conclusions: ER-low BC has a distinct genomic profile, with high TP53 mts (similar to ER-) and frequent PI3K pathway alterations (typical of ER+). Ongoing analyses of clinicopathologic features and survival across ER-low, ER+, and ER- cohorts will be presented. Characteristic ER+ (N = 797) ER-low (N = 48) ER- (N = 354) ER-low vs ER+ (p value) ER-low vs ER-(p value) ER+ vs ER-(p value) TP53 24% 79% 83% 1.45 x 10^-14 0.689 1.85 x 10^-79 PIK3CA 39% 31% 13% 0.291 0.00292 1.96 x 10^-21 CDH1 19% 17% 3% 0.85 0.00193 6.66x10^-14 AKT1 2% 15% 4% 0.0155 0.0155 0.635 RB1 1% 12% 9% 0.00354 0.35 0.000116 PTEN 9% 10% 14% 0.828 0.828 0.828 ESR1 11% 6% 0% 0.612 0.00322 3.06x10^12 CCND1 (CNV) 17% 12% 3% 0.551 0.0258 2.83 x 10^-11 TMB, median (IQR) 6.844 (4.562) 8.365 (6.917) 7.604 (4.562) 0.018 0.212 0.001