ERþ Breast cancers resistant to prolonged neoadjuvant letrozole exhibit an e2f4 transcriptional program sensitive to cdk4/6 inhibitors

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 Gavila, J. Perez Fidalgo Alejandro, Ana Lluch, Antonio Llombart-Cussac, Mohamed Amine Bayar, Stefan Michiels, Fabrice Andre, Monica Arnedos, Vicente Guillem & 2 others Amparo Ruiz-Simon, Carlos L. Arteaga

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)2517-2529
Number of pages13
JournalClinical Cancer Research
Volume24
Issue number11
DOIs
StatePublished - Jun 1 2018

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letrozole
Estrogens
Breast Neoplasms
Neoplasms
Genes
RNA Sequence Analysis
Gene Expression

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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ERþ Breast cancers resistant to prolonged neoadjuvant letrozole exhibit an e2f4 transcriptional program sensitive to cdk4/6 inhibitors. / Guerrero-Zotano, Angel L.; Stricker, Thomas P.; Formisano, Luigi; Hutchinson, Katherine E.; Stover, Daniel G.; Lee, Kyung Min; Schwarz, Luis J.; Giltnane, Jennifer M.; Estrada, Monica V.; Jansen, Valerie M.; Servetto, Alberto; Gavila, Joaquín; Alejandro, J. Perez Fidalgo; Lluch, Ana; Llombart-Cussac, Antonio; Bayar, Mohamed Amine; Michiels, Stefan; Andre, Fabrice; Arnedos, Monica; Guillem, Vicente; Ruiz-Simon, Amparo; Arteaga, Carlos L.

In: Clinical Cancer Research, Vol. 24, No. 11, 01.06.2018, p. 2517-2529.

Research output: Contribution to journalArticle

Guerrero-Zotano, AL, Stricker, TP, Formisano, L, Hutchinson, KE, Stover, DG, Lee, KM, Schwarz, LJ, Giltnane, JM, Estrada, MV, Jansen, VM, Servetto, A, Gavila, J, Alejandro, JPF, Lluch, A, Llombart-Cussac, A, Bayar, MA, Michiels, S, Andre, F, Arnedos, M, Guillem, V, Ruiz-Simon, A & Arteaga, CL 2018, 'ERþ Breast cancers resistant to prolonged neoadjuvant letrozole exhibit an e2f4 transcriptional program sensitive to cdk4/6 inhibitors', Clinical Cancer Research, vol. 24, no. 11, pp. 2517-2529. https://doi.org/10.1158/1078-0432.CCR-17-2904
Guerrero-Zotano, Angel L. ; Stricker, Thomas P. ; Formisano, Luigi ; Hutchinson, Katherine E. ; Stover, Daniel G. ; Lee, Kyung Min ; Schwarz, Luis J. ; Giltnane, Jennifer M. ; Estrada, Monica V. ; Jansen, Valerie M. ; Servetto, Alberto ; Gavila, Joaquín ; Alejandro, J. Perez Fidalgo ; Lluch, Ana ; Llombart-Cussac, Antonio ; Bayar, Mohamed Amine ; Michiels, Stefan ; Andre, Fabrice ; Arnedos, Monica ; Guillem, Vicente ; Ruiz-Simon, Amparo ; Arteaga, Carlos L. / ERþ Breast cancers resistant to prolonged neoadjuvant letrozole exhibit an e2f4 transcriptional program sensitive to cdk4/6 inhibitors. In: Clinical Cancer Research. 2018 ; Vol. 24, No. 11. pp. 2517-2529.
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title = "ER{\th} Breast cancers resistant to prolonged neoadjuvant letrozole exhibit an e2f4 transcriptional program sensitive to cdk4/6 inhibitors",
abstract = "Purpose: This study aimed to identify biomarkers of resistance to endocrine therapy in estrogen receptor–positive (ER{\th}) breast cancers treated with prolonged neoadjuvant letrozole. Experimental Design: We performed targeted DNA and RNA sequencing in 68 ER{\th} 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 ER{\th} 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{\th} 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{\th} breast cancer cells and in patients' ER{\th} tumors, suggesting a potential benefit of adjuvant CDK4/6 inhibitors in patients with ER{\th} breast cancer who fail to respond to preoperative estrogen deprivation.",
author = "Guerrero-Zotano, {Angel L.} and Stricker, {Thomas P.} and Luigi Formisano and Hutchinson, {Katherine E.} and Stover, {Daniel G.} and Lee, {Kyung Min} and Schwarz, {Luis J.} and Giltnane, {Jennifer M.} and Estrada, {Monica V.} and Jansen, {Valerie M.} and Alberto Servetto and Joaqu{\'i}n Gavila and Alejandro, {J. Perez Fidalgo} and Ana Lluch and Antonio Llombart-Cussac and Bayar, {Mohamed Amine} and Stefan Michiels and Fabrice Andre and Monica Arnedos and Vicente Guillem and Amparo Ruiz-Simon and Arteaga, {Carlos L.}",
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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.

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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