AACR GENIE analysis of 211,526 patients to evaluate hormone receptor alterations across solid tumors: Rationale for tissue-agnostic basket trials.

Abstract

3133 Background: Steroid Hormone receptors (HR) that include estrogen receptor (ER), progesterone receptor (PR), and androgen receptor (AR) were oncology's first predictive biomarkers, yet HR-directed therapies remain largely confined to breast, prostate, and endometrial cancers. Emerging data suggest broader HR relevance across tumor types. The development of oral SERDs (selective ER degraders) and next-generation AR degraders/antagonists creates new opportunities to target HR alterations across tumor types. We performed pan-cancer genomic profiling to define the landscape of ESR1/AR alterations and resistance co-alterations, providing rationale for biomarker-enriched basket trial designs. Methods: We analyzed the AACR Project GENIE v18 public dataset, comprising 250,018 tumor samples from 211,526 patients across multiple solid tumor types. Genomic alterations in ESR1 and AR were assessed, including mutations, copy-number alterations, and structural variants. Co-alterations with selected genes involved in resistance and cell-cycle regulation (PIK3CA, PTEN, AKT1, TP53, RB1, CDKN2A) were evaluated using pairwise co-occurrence analyses. Results: Across 250,018 solid tumor samples, ESR1 alterations were identified in 2.0% of cases, with highest prevalence in breast (8.4%) and endometrial cancers (4.6%), and lower frequencies in uterine sarcoma (2.7%) and melanoma (3.6%). Most ESR1 alterations were missense mutations localized to the ligand-binding domain, with recurrent hotspots at codons Y537 and D538. AR alterations were present in 2.4% of samples overall, most frequently in prostate cancer (7.6%), and were also detected in endometrial cancer (5.5%), lung cancer (~5%), and melanoma (4.9%). AR alterations consisted predominantly of copy-number amplifications, with additional ligand-binding domain mutations observed. Co-alteration analyses demonstrated frequent co-occurrence of ESR1 with PIK3CA, PTEN, and AKT1, and AR with TP53, RB1, and CDKN2A, whereas ESR1 and KRAS alterations did not significantly co-occur. Conclusions: Recurrent ESR1 and AR alterations occur in 2-5% of diverse solid tumors beyond breast, prostate, and endometrial cancers, with co-enrichment of PI3K-AKT and cell-cycle pathway alterations mirroring resistance patterns in canonical HR-driven malignancies. These findings support systematic evaluation of selective ER and AR degraders in biomarker-selected basket trials, expanding precision oncology beyond anatomically-defined indications.