ER(+) Breast Cancers Resistant to Prolonged Neoadjuvant Letrozole Exhibit an E2F4 Transcriptional Program Sensitive to CDK4/6 Inhibitors.
Por:
Guerrero-Zotano, A, Stricker, T, Formisano, L, Hutchinson, K, Stover, D, Lee, K, Schwarz, L, Giltnane, J, Estrada, M, Jansen, V, Servetto, A, Gavila, J, Perez-Fidalgo, J, Lluch, A, Llombart-Cussac, A, Bayar, M, Michiels, S, Andre, F, Arnedos, M, Guillem, V, Ruiz-Simon, A and Arteaga, C
Publicada:
1 jun 2018
Ahead of Print:
26 mar 2018
Resumen:
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.
Filiaciones:
Guerrero-Zotano, A:
Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
Stricker, T:
Vanderbilt Univ, Med Ctr, Pathol Microbiol & Immunol, Nashville, TN 37232 USA
Formisano, L:
Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
Hutchinson, K:
Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
Stover, D:
Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA
Lee, K:
Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
Schwarz, L:
Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
Giltnane, J:
Vanderbilt Univ, Med Ctr, Pathol Microbiol & Immunol, Nashville, TN 37232 USA
Estrada, M:
Vanderbilt Univ, Med Ctr, Breast Canc Program, Nashville, TN 37232 USA
Jansen, V:
Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
Servetto, A:
Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
Gavila, J:
Inst Valenciano Oncol, Dept Med Oncol, Valencia, Spain
Perez-Fidalgo, J:
Univ Valencia, CIBERONC, Dept Hematol & Oncol, Hosp Clin Univ,INCLIVA Biomed Res Inst, Valencia, Spain
Lluch, A:
Univ Valencia, CIBERONC, Dept Hematol & Oncol, Hosp Clin Univ,INCLIVA Biomed Res Inst, Valencia, Spain
:
Hosp Arnau Vilanova, Dept Med Oncol, Valencia, Spain
Bayar, M:
Gustave Roussy, Serv Biostat & Epidemiol, Villejuif, France
Univ Paris Saclay, Univ Paris Sud, Fac Med UVSQ, CESP,Fac Med,INSERM, Villejuif, France
Michiels, S:
Gustave Roussy, Serv Biostat & Epidemiol, Villejuif, France
Univ Paris Saclay, Univ Paris Sud, Fac Med UVSQ, CESP,Fac Med,INSERM, Villejuif, France
Andre, F:
Univ Paris Saclay, Gustave Roussy Canc Campus, Dept Med Oncol, Villejuif, France
Arnedos, M:
Univ Paris Saclay, Gustave Roussy Canc Campus, Dept Med Oncol, Villejuif, France
Guillem, V:
Inst Valenciano Oncol, Dept Med Oncol, Valencia, Spain
Ruiz-Simon, A:
Inst Valenciano Oncol, Dept Med Oncol, Valencia, Spain
Arteaga, C:
Vanderbilt Univ, Med Ctr, Dept Med, Nashville, TN 37232 USA
Vanderbilt Univ, Med Ctr, Breast Canc Program, Nashville, TN 37232 USA
Vanderbilt Univ, Med Ctr, Vanderbilt Ingram Canc Ctr, Dept Canc Biol, Nashville, TN 37232 USA
Green Accepted
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