In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P2-11-05-P2-11-05
Abstract:
Background: Estrogen (ER) and progesterone (PR) receptor staining with immunohistochemistry (IHC) forms the basis for endocrine therapy (ET) eligibility. However, ER protein level does not necessarily reflect ER functionality and is insufficient as a predictor of response or as a pharmacodynamic (PD) biomarker to assess the impact of ET on ER activity. Furthermore, assessing PD modulation based on a single ER target gene, PR, lacks robustness and cannot be utilized in PR- tumors. We established a transcriptional signature that more comprehensively reflects ER pathway activity. We showcase, in vitro, in vivo, and in patients enrolled in a Phase I trial of GDC-9545 -a novel, potent, orally bioavailable, selective estrogen receptor antagonist / degrader- that this signature may have utility as a predictive and PD biomarker. Methods: A signature of 21 estradiol (E2)-induced and 17 E2-repressed genes was experimentally derived by transcriptional profiling of 8 E2-stimulated ER+ breast cancer (BC) cell lines in vitro, and refined by leveraging TCGA RNA-seq data. The effect of ER inhibition by GDC-9545 on cellular proliferation was determined in an 8 day in vitro viability assay, and correlated with pre-treatment ER pathway activity as determined by the signature. The signature was evaluated in an in vivo efficacy study with GDC-9545 (0.1, 1 or 10 mg/kg) in PDX breast model HCI-013, measured using a Fluidigm® panel. Paired pre- and on-treatment tumor biopsies from 7 patients enrolled in the Phase I dose escalation study of GDC-9545 (10, 30 or 90 mg) in ER+/HER2- advanced or metastatic BC were collected to retrospectively assess ER pathway modulation. ER, PR and Ki67 protein levels were analyzed by IHC, while gene expression analysis from FFPE tissue was performed using Illumina’s RNA Access protocol and HiSeq. The ER pathway activity score was defined as the difference in average expression of the E2-induced versus E2-repressed genes, relative to ER pathway activity in a reference collection of 139 procured ER+/HER2- breast tumors. Results: A panel of 14 ER+/HER2- BC cell lines exhibited a spectrum of in vitro responses to GDC-9545 that strongly correlated with the pre-treatment ER pathway activity score. GDC-9545 had little anti-proliferative effect in cell lines with lowest scores, while having a considerably greater impact on cell lines exhibiting higher scores. Besides potential applicability as a predictive biomarker, we explored the utility of the ER activity score in vivo as a PD biomarker. We observed enhanced transcriptional pathway suppression with increased dose of GDC-9545, and a concomitant greater impact on Ki67 expression, in the in vivo HCI-013 PDX breast model. The ER signature was further evaluated in pre- and on-treatment tumor biopsy pairs from 7 patients enrolled in the GDC-9545 Phase I trial. ER activity scores of tumors from these patients were benchmarked against a cohort of 139 procured ER+/HER2- breast tumors, revealing a range in ER pathway activity prior to treatment with GDC-9545. Two tumors exhibiting profound Ki67 responses (post-treatment IHC & lt;1%, 10 or 30 mg) were amongst the 3 with highest pre-treatment ER activity scores, and additionally exhibited robust decreases in ER pathway activity following treatment with GDC-9545. An on-treatment decrease in ER pathway activity was observed at all dose levels in 6 patients total, covering both PR+ and PR- BC. The degree of pathway suppression was largely concordant with decreases in ER and PR (for PR+ tumors) protein levels, though ER IHC levels remained high in two patients with a low on-treatment ER activity score. Conclusions: The ER pathway activity signature introduced herein may have utility as a biomarker of drug-induced PD response and as a predictive biomarker to better identify patients who have the greatest potential to benefit from endocrine therapy, versus who may need combination therapy. Citation Format: Anneleen Daemen, Jill M Spoerke, Wei Zhou, Jane Guan, Ellen Ingalla, Amy Young, Marc Hafner, Junko Aimi, Ching-Wei Chang, Jennifer M Giltnane, Mary Gates, Ingrid A Mayer, Analia Azaro, Eric P Winer, Sherene Loi, Komal Jhaveri, Jennifer Lauchle, Steven Gendreau, Eric W Humke, Ciara Metcalfe. ER pathway activity signature as a biomarker for endocrine agent GDC-9545 [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-05.
Type of Medium:
Online Resource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.SABCS19-P2-11-05
Language:
English
Publisher:
American Association for Cancer Research (AACR)
Publication Date:
2020
detail.hit.zdb_id:
2036785-5
detail.hit.zdb_id:
1432-1
detail.hit.zdb_id:
410466-3
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