TY - JOUR
T1 - ERþ Breast cancers resistant to prolonged neoadjuvant letrozole exhibit an e2f4 transcriptional program sensitive to cdk4/6 inhibitors
AU - Guerrero-Zotano, Angel L.
AU - Stricker, Thomas P.
AU - Formisano, Luigi
AU - Hutchinson, Katherine E.
AU - Stover, Daniel G.
AU - Lee, Kyung Min
AU - Schwarz, Luis J.
AU - Giltnane, Jennifer M.
AU - Estrada, Monica V.
AU - Jansen, Valerie M.
AU - Servetto, Alberto
AU - Gavila, Joaquín
AU - Alejandro, J. Perez Fidalgo
AU - Lluch, Ana
AU - Llombart-Cussac, Antonio
AU - Bayar, Mohamed Amine
AU - Michiels, Stefan
AU - Andre, Fabrice
AU - Arnedos, Monica
AU - Guillem, Vicente
AU - Ruiz-Simon, Amparo
AU - Arteaga, Carlos L.
N1 - Funding Information:
This study was supported by NIH Breast SPORE grant P50 CA098131, Vanderbilt-Ingram Cancer Center Support grant P30 CA68485, Susan G. Komen for the Cure Breast Cancer Foundation grant SAC100013, a grant from the Breast Cancer Research Foundation, a grant from the Sociedad Española de Oncología Medica (SEOM), a grant from the Asociacion Española Contra el Cancer (AECC), and a grant from Grupo Español de Investigacion en Cancer de Mama (GEICAM).
Funding Information:
J.M. Giltnane is an employee of Genentech. J. Gavilá reports receiving speakers bureau honoraria from Novartis and Roche and is a consultant/ advisory board member for Novartis. F. Andre is a consultant/advisory board member for Lilly, Novartis, and Pfizer. M. Arnedos reports receiving commercial research grants from Lilly, speakers bureau honoraria from AstraZeneca and Novartis, and is a consultant/advisory board member for Seattle Genetics. No potential conflicts of interest were disclosed by the other authors.
Publisher Copyright:
© 2018 American Association for Cancer Research.
PY - 2018/6/1
Y1 - 2018/6/1
N2 - Purpose: This study aimed to identify biomarkers of resistance to endocrine therapy in estrogen receptor–positive (ERþ) breast cancers treated with prolonged neoadjuvant letrozole. Experimental Design: We performed targeted DNA and RNA sequencing in 68 ERþ 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 ¼ 2.56E15). 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 ERþ 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 ERþ 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 ERþ breast cancer cells and in patients' ERþ tumors, suggesting a potential benefit of adjuvant CDK4/6 inhibitors in patients with ERþ breast cancer who fail to respond to preoperative estrogen deprivation.
AB - Purpose: This study aimed to identify biomarkers of resistance to endocrine therapy in estrogen receptor–positive (ERþ) breast cancers treated with prolonged neoadjuvant letrozole. Experimental Design: We performed targeted DNA and RNA sequencing in 68 ERþ 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 ¼ 2.56E15). 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 ERþ 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 ERþ 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 ERþ breast cancer cells and in patients' ERþ tumors, suggesting a potential benefit of adjuvant CDK4/6 inhibitors in patients with ERþ breast cancer who fail to respond to preoperative estrogen deprivation.
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U2 - 10.1158/1078-0432.CCR-17-2904
DO - 10.1158/1078-0432.CCR-17-2904
M3 - Article
C2 - 29581135
AN - SCOPUS:85048092034
SN - 1078-0432
VL - 24
SP - 2517
EP - 2529
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 11
ER -