ER+ breast cancers resistant to prolonged neoadjuvant letrozole exhibit an E2F4 transcriptional program sensitive to CDK4/6 inhibitors. - PubMed - NCBI
Clin Cancer Res. 2018 Mar 26. pii: clincanres.2904.2017. doi: 10.1158/1078-0432.CCR-17-2904. [Epub ahead of print]
ER+ breast cancers resistant to prolonged neoadjuvant letrozole exhibit an E2F4 transcriptional program sensitive to CDK4/6 inhibitors.
Guerrero-Zotano A1,
Stricker T2,
Formisano L1,
Hutchinson KE3,
Stover DG4,
Lee KM5,
Schwarz LJ6,
Giltnane JM7,
Estrada MV8,
Jansen VM5,
Servetto A9,
Gavilá J10,
Pérez-Fidalgo JA11,
Lluch A12,
Llombart-Cussac A13,
Bayar MA14,
Michiels S15,
Andre F16,
Arnedos M17,
Guillem V18,
Ruiz-Simon A19,
Arteaga CL20.
Abstract
PURPOSE:
This study aimed to identify biomarkers of resistance to endocrine therapy in ER+ breast cancers (BC) treated with prolonged neoadjuvant letrozole. Experimental Design: We performed targeted DNA and RNA-sequencing in 68 ER+ BC 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+ BC 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+ BC 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. Copyright ©2018, American Association for Cancer Research.
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