American Association for Cancer Research
10780432ccr172904-sup-190207_2_supp_4616023_p52nms.xlsx (11.66 MB)

Supplementary Tables from ER+ Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors

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posted on 2023-03-31, 19:46 authored by Angel L. Guerrero-Zotano, Thomas P. Stricker, Luigi Formisano, Katherine E. Hutchinson, Daniel G. Stover, Kyung-Min Lee, Luis J. Schwarz, Jennifer M. Giltnane, Monica V. Estrada, Valerie M. Jansen, Alberto Servetto, Joaquín Gavilá, J. Alejandro Perez-Fidalgo, Ana Lluch, Antonio Llombart-Cussac, Mohamed Amine Bayar, Stefan Michiels, Fabrice André, Mónica Arnedos, Vicente Guillem, Amparo Ruiz-Simon, Carlos L. Arteaga

Supplemental Table S1: The Preoperative Endocrine Prognostic Index (PEPI score) Supplemental Table S2:* Baseline Ki67: 7 patients had missing values Supplemental Table S3a: Driver Mutations Supplemental Table S3b: Driver Copy Number Alterations Supplemental Table S3c: Mutations clinically actionable. Drug prescription Supplemental Table S4: Actionable CNAs. Drug prescription Supplemental Table S5: Overlap between genes upregulated in resistant tumors and transcription factor targets genes Suplemental Table S6: Change from baseline to surgery in gene expressions of the 47 most upregulated genes in the tumors resistant to prolonged neoadjuvant letrozole from 60 HR-positive/HER2-negative breast cancers in POP trial. A decreased gene expression translates into a geometric mean change < 1 . An increased or stable gene expression translates into a geometric mean change {greater than or equal to} 1. Supplemental Table S7: Mutations detected in this study(post-filtering) Supplemental Table S8: Gene expression values (FPKM)


NIH Breast SPORE grant

Vanderbilt-Ingram Cancer Center

Susan G. Komen for the Cure Breast Cancer Foundation

Breast Cancer Research Foundation

Sociedad Española de Oncología Médica (SEOM)

Asociación Española Contra el Cáncer (AECC)

Grupo Español de Investigación en Cáncer de Mama (GEICAM)



Purpose: This study aimed to identify biomarkers of resistance to endocrine therapy in estrogen receptor–positive (ER+) breast cancers treated with prolonged neoadjuvant letrozole.Experimental Design: We performed targeted DNA and RNA sequencing in 68 ER+ breast cancers from patients treated with preoperative letrozole (median, 7 months).Results: Twenty-four tumors (35%) exhibited a PEPI score ≥4 and/or recurred after a median of 58 months and were considered endocrine resistant. Integration of the 47 most upregulated genes (log FC > 1, FDR < 0.03) in letrozole-resistant tumors with transcription-binding data showed significant overlap with 20 E2F4-regulated genes (P = 2.56E−15). In patients treated with the CDK4/6 inhibitor palbociclib before surgery, treatment significantly decreased expression of 24 of the 47 most upregulated genes in letrozole-resistant tumors, including 18 of the 20 E2F4 target genes. In long-term estrogen-deprived ER+ breast cancer cells, palbociclib also downregulated all 20 E2F4 target genes and P-RB levels, whereas the ER downregulator fulvestrant or paclitaxel only partially suppressed expression of this set of genes and had no effect on P-RB. Finally, an E2F4 activation signature was strongly associated with resistance to aromatase inhibitors in the ACOSOG Z1031B neoadjuvant trial and with an increased risk of relapse in adjuvant-treated ER+ tumors in METABRIC.Conclusions: In tumors resistant to prolonged neoadjuvant letrozole, we identified a gene expression signature of E2F4 target activation. CDK4/6 inhibition suppressed E2F4 target gene expression in estrogen-deprived ER+ breast cancer cells and in patients' ER+ tumors, suggesting a potential benefit of adjuvant CDK4/6 inhibitors in patients with ER+ breast cancer who fail to respond to preoperative estrogen deprivation. Clin Cancer Res; 24(11); 2517–29. ©2018 AACR.

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