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Clin Cancer Res. 2018 Jun 1;24(11):2517-2529. doi: 10.1158/1078-0432.CCR-17-2904. Epub 2018 Mar 26.

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

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Departments of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Pathology, Microbiology & Immunology, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
Breast Cancer Program, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Medical Oncology, Instituto Valenciano de Oncología, Valencia, Spain.
Department of Oncology and Hematology, Hospital ClinicoUniversitario, INCLIVA Biomedical Research Institute, University of Valencia, CIBERONC, Valencia, Spain.
Department of Medical Oncology, Hospital Arnau de Vilanova, Valencia, Spain.
Service de Biostatistique et d'Epidémiologie, Gustave Roussy, Villejuif, France.
CESP, Faculté de Médecine, Université Paris Sud, Faculté de Médecine UVSQ, INSERM, Université Paris Saclay, Villejuif, France.
Department of Medical Oncology, Université Paris-Saclay, Gustave Roussy Cancer Campus, Villejuif, France.
Departments of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee.
Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, Tennessee.


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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