Survival and mutational differences based on <i>ESR1</i> and <i>ESR2</i> expression in non-small cell lung cancer (NSCLC).
Authors: Robert Hsu, Alexis Leyba, Denaly Chen, Harris Benjamin Krause, Andrew Elliott, Wendy Cozen, Evanthia T. Roussos Torres, Misako Nagasaka, Hirva Mamdani, Gilberto Lopes, Hossein Borghaei, Stephen V. Liu, Patrick C. Ma, Ari M. Vanderwalde, Jorge J. Nieva
Journal: Journal of Clinical Oncology (2024)

8526 Background: Estrogen receptor (ER) can activate MAPK signaling but the contribution of the two classical receptors—ER-alpha ( ESR1) and ER-beta ( ESR2) is unclear. Past trials targeting ER and EGFR in NSCLC lacked efficacy. We evaluated the association of ESR1&amp; 2 expression with the genomic landscape and overall survival (OS) in NSCLC. Methods: NSCLC tumors (N = 21603) were tested at Caris Life Sciences (Phoenix, AZ) with NextGen Sequencing of DNA (592-gene or whole exome) and RNA (whole transcriptome). Mutation prevalence (-Mt) was calculated for pathogenic SNVs/indels. ESR1&amp; 2 expression was split into quartiles (transcripts per million, top (-H) and bottom (-L) quartiles were compared). A transcriptomic signature associated with MAPK activation (MPAS, arbitrary units: AU) was applied. The X 2 test was applied, p-value was adjusted for multiple comparisons ( p &lt; .05). Real-world OS was obtained from insurance claims and Kaplan-Meier estimates were calculated. Results: There was a greater proportion of females in ESR1-H (53%) versus (v) -L (45%, p &lt; .05) but not in ESR2-H v -L (50% v 50%). There was a greater proportion of adenocarcinoma (AD) in ESR1-H (65%) v -L (44%) and a greater proportion of squamous (SCC) tumors in ESR2-H (27%) v -L (15%) ( p &lt; .001 all). The prevalence of EGFR-Mt and KRAS-Mt was greater in ESR1-H v -L and smaller in ESR2-H v -L. (Table) Of all KRAS-Mt, there was a greater percent of KRAS G12C-Mt in ESR1-H (44%) v -L (39%, p = .001). In EGFR-Mt, ESR1-H/ ESR2-H had a higher MPAS (1.4 AU) than ESR1-H/ ESR2-L (.52), ESR1-L/ ESR2-H (.59) or ESR1-L/ ESR2-L (-1.6, p &lt; .05). In KRAS-Mt, ESR1-H/ ESR2-H (1.7 AU) and ESR1-L/ ESR2-H (1.8) had a higher MPAS than ESR1-H/ ESR2-L (.7) or ESR1-L/ ESR2-L (-.7, p &lt; .001). ESR1-H had longer median OS v -L (22 months (m) v 16 m, p &lt; .001) as did ESR2-H v -L (23 m v 15 m p&lt; .001). ESR1-H/ ESR2-H had the longest OS (25 m) followed by ESR1-H/ ESR2-L (18 m), ESR1-L/ ESR2-H (16 m) and ESR1-L/ ESR2-L (14 m, p &lt; .001). In EGFR-Mt, a significant difference in survival since treatment (SST) with osimertinib was seen for ESR1-L/ ESR2-H (40 m, N = 13), ESR1-H/ ESR2-L (36 m, N = 62), ESR1-H/ ESR2-H (34 m, N = 161) and ESR1-L/ ESR2-L (30 m, N = 138, p = .03). In KRAS G12C-Mt, a significant difference in SST was seen with sotorasib; ESR1-H/ ESR2-H had the longest SST (median not reached, N = 17), followed by ESR1-H/ ESR2-L (17 m, N = 17), ESR1-L/ ESR2-L (13 m, N = 34) and ESR1-L/ ESR2-H (1 m, N = 1, p = .002). Conclusions: ESR1-H had a higher percentage of females, AD, and EGFR/ KRAS-mt v ESR1-L while ESR2-H had no sex difference, more SCC, and fewer EGFR/ KRAS-mt v ESR2-L. ESR1-H/ ESR2-H tumors had the highest MPAS and longest OS and there were SST differences with EGFR and KRAS G12C inhibition. ESR1&amp; 2 may play key roles in activating the MAPK pathway and future trials could consider targeted therapy combined with ER inhibition based on ESR1&amp;2 expression. [Table: see text]