NeoPalAna: Neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor–positive breast cancer

Cynthia X. Ma, Feng Gao, Jingqin Luo, Donald W. Northfelt, Matthew Goetz, Andres Forero, Jeremy Hoog, Michael Naughton, Foluso Ademuyiwa, Rama Suresh, Karen Anderson, Julie Margenthaler, Rebecca Aft, Timothy Hobday, Timothy Moynihan, William Gillanders, Amy Cyr, Timothy J. Eberlein, Tina Hieken, Helen Krontiras & 14 others Zhanfang Guo, Michelle V. Lee, Nicholas C. Spies, Zachary L. Skidmore, Obi L. Griffith, Malachi Griffith, Shana Thomas, Caroline Bumb, Kiran Vij, Cynthia Huang Bartlett, Maria Koehler, Hussam Al-Kateb, Souzan Sanati, Matthew J. Ellis

Research output: Contribution to journalArticle

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Abstract

Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor–positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design: Eligible patients with clinical stage II/III ER+/HER2 breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1–21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect.

Original languageEnglish (US)
Pages (from-to)4055-4065
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2017
Externally publishedYes

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Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinase 4
Estrogens
Breast Neoplasms
Cell Cycle Checkpoints
Goserelin
palbociclib
anastrozole
Mutation
Transcriptome
Research Design
Cell Proliferation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

NeoPalAna : Neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor–positive breast cancer. / Ma, Cynthia X.; Gao, Feng; Luo, Jingqin; Northfelt, Donald W.; Goetz, Matthew; Forero, Andres; Hoog, Jeremy; Naughton, Michael; Ademuyiwa, Foluso; Suresh, Rama; Anderson, Karen; Margenthaler, Julie; Aft, Rebecca; Hobday, Timothy; Moynihan, Timothy; Gillanders, William; Cyr, Amy; Eberlein, Timothy J.; Hieken, Tina; Krontiras, Helen; Guo, Zhanfang; Lee, Michelle V.; Spies, Nicholas C.; Skidmore, Zachary L.; Griffith, Obi L.; Griffith, Malachi; Thomas, Shana; Bumb, Caroline; Vij, Kiran; Huang Bartlett, Cynthia; Koehler, Maria; Al-Kateb, Hussam; Sanati, Souzan; Ellis, Matthew J.

In: Clinical Cancer Research, Vol. 23, No. 15, 01.08.2017, p. 4055-4065.

Research output: Contribution to journalArticle

Ma, CX, Gao, F, Luo, J, Northfelt, DW, Goetz, M, Forero, A, Hoog, J, Naughton, M, Ademuyiwa, F, Suresh, R, Anderson, K, Margenthaler, J, Aft, R, Hobday, T, Moynihan, T, Gillanders, W, Cyr, A, Eberlein, TJ, Hieken, T, Krontiras, H, Guo, Z, Lee, MV, Spies, NC, Skidmore, ZL, Griffith, OL, Griffith, M, Thomas, S, Bumb, C, Vij, K, Huang Bartlett, C, Koehler, M, Al-Kateb, H, Sanati, S & Ellis, MJ 2017, 'NeoPalAna: Neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor–positive breast cancer' Clinical Cancer Research, vol. 23, no. 15, pp. 4055-4065. https://doi.org/10.1158/1078-0432.CCR-16-3206
Ma, Cynthia X. ; Gao, Feng ; Luo, Jingqin ; Northfelt, Donald W. ; Goetz, Matthew ; Forero, Andres ; Hoog, Jeremy ; Naughton, Michael ; Ademuyiwa, Foluso ; Suresh, Rama ; Anderson, Karen ; Margenthaler, Julie ; Aft, Rebecca ; Hobday, Timothy ; Moynihan, Timothy ; Gillanders, William ; Cyr, Amy ; Eberlein, Timothy J. ; Hieken, Tina ; Krontiras, Helen ; Guo, Zhanfang ; Lee, Michelle V. ; Spies, Nicholas C. ; Skidmore, Zachary L. ; Griffith, Obi L. ; Griffith, Malachi ; Thomas, Shana ; Bumb, Caroline ; Vij, Kiran ; Huang Bartlett, Cynthia ; Koehler, Maria ; Al-Kateb, Hussam ; Sanati, Souzan ; Ellis, Matthew J. / NeoPalAna : Neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor–positive breast cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 15. pp. 4055-4065.
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title = "NeoPalAna: Neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor–positive breast cancer",
abstract = "Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor–positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design: Eligible patients with clinical stage II/III ER+/HER2– breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1–21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10{\%}, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7{\%}). Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87{\%} vs. C1D1 26{\%}, P < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect.",
author = "Ma, {Cynthia X.} and Feng Gao and Jingqin Luo and Northfelt, {Donald W.} and Matthew Goetz and Andres Forero and Jeremy Hoog and Michael Naughton and Foluso Ademuyiwa and Rama Suresh and Karen Anderson and Julie Margenthaler and Rebecca Aft and Timothy Hobday and Timothy Moynihan and William Gillanders and Amy Cyr and Eberlein, {Timothy J.} and Tina Hieken and Helen Krontiras and Zhanfang Guo and Lee, {Michelle V.} and Spies, {Nicholas C.} and Skidmore, {Zachary L.} and Griffith, {Obi L.} and Malachi Griffith and Shana Thomas and Caroline Bumb and Kiran Vij and {Huang Bartlett}, Cynthia and Maria Koehler and Hussam Al-Kateb and Souzan Sanati and Ellis, {Matthew J.}",
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T1 - NeoPalAna

T2 - Neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor–positive breast cancer

AU - Ma, Cynthia X.

AU - Gao, Feng

AU - Luo, Jingqin

AU - Northfelt, Donald W.

AU - Goetz, Matthew

AU - Forero, Andres

AU - Hoog, Jeremy

AU - Naughton, Michael

AU - Ademuyiwa, Foluso

AU - Suresh, Rama

AU - Anderson, Karen

AU - Margenthaler, Julie

AU - Aft, Rebecca

AU - Hobday, Timothy

AU - Moynihan, Timothy

AU - Gillanders, William

AU - Cyr, Amy

AU - Eberlein, Timothy J.

AU - Hieken, Tina

AU - Krontiras, Helen

AU - Guo, Zhanfang

AU - Lee, Michelle V.

AU - Spies, Nicholas C.

AU - Skidmore, Zachary L.

AU - Griffith, Obi L.

AU - Griffith, Malachi

AU - Thomas, Shana

AU - Bumb, Caroline

AU - Vij, Kiran

AU - Huang Bartlett, Cynthia

AU - Koehler, Maria

AU - Al-Kateb, Hussam

AU - Sanati, Souzan

AU - Ellis, Matthew J.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor–positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design: Eligible patients with clinical stage II/III ER+/HER2– breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1–21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect.

AB - Purpose: Cyclin-dependent kinase (CDK) 4/6 drives cell proliferation in estrogen receptor–positive (ER+) breast cancer. This single-arm phase II neoadjuvant trial (NeoPalAna) assessed the antiproliferative activity of the CDK4/6 inhibitor palbociclib in primary breast cancer as a prelude to adjuvant studies. Experimental Design: Eligible patients with clinical stage II/III ER+/HER2– breast cancer received anastrozole 1 mg daily for 4 weeks (cycle 0; with goserelin if premenopausal), followed by adding palbociclib (125 mg daily on days 1–21) on cycle 1 day 1 (C1D1) for four 28-day cycles unless C1D15 Ki67 > 10%, in which case patients went off study due to inadequate response. Anastrozole was continued until surgery, which occurred 3 to 5 weeks after palbociclib exposure. Later patients received additional 10 to 12 days of palbociclib (Cycle 5) immediately before surgery. Serial biopsies at baseline, C1D1, C1D15, and surgery were analyzed for Ki67, gene expression, and mutation profiles. The primary endpoint was complete cell cycle arrest (CCCA: central Ki67 ≤ 2.7%). Results: Fifty patients enrolled. The CCCA rate was significantly higher after adding palbociclib to anastrozole (C1D15 87% vs. C1D1 26%, P < 0.001). Palbociclib enhanced cell-cycle control over anastrozole monotherapy regardless of luminal subtype (A vs. B) and PIK3CA status with activity observed across a broad range of clinicopathologic and mutation profiles. Ki67 recovery at surgery following palbociclib washout was suppressed by cycle 5 palbociclib. Resistance was associated with nonluminal subtypes and persistent E2F-target gene expression. Conclusions: Palbociclib is an active antiproliferative agent for early-stage breast cancer resistant to anastrozole; however, prolonged administration may be necessary to maintain its effect.

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