A phase II trial of neoadjuvant MK-2206, an AKT inhibitor, with anastrozole in clinical stage II or III PIK3CA-mutant ER-positive and HER2-negative breast cancer

Cynthia X. Ma, Vera Jean Suman, Matthew Philip Goetz, Donald W Northfelt, Mark E. Burkard, Foluso Ademuyiwa, Michael Naughton, Julie Margenthaler, Rebecca Aft, Richard Gray, Amye Tevaarwerk, Lee Wilke, Tufia C Haddad, Timothy Moynihan, Charles Lawrence Loprinzi, Tina J Hieken, Erica K. Barnell, Zachary L. Skidmore, Yan Yang Feng, Kilannin Krysiak & 14 others Jeremy Hoog, Zhanfang Guo, Leslie Nehring, Kari B. Wisinski, Elaine Mardis, Ian S. Hagemann, Kiran Vij, Souzan Sanati, Hussam Al-Kateb, Obi L. Griffith, Malachi Griffith, Laurence Doyle, Charles Erlichman, Matthew J. Ellis

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2- breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population.

Original languageEnglish (US)
Pages (from-to)6823-6832
Number of pages10
JournalClinical Cancer Research
Volume23
Issue number22
DOIs
StatePublished - Nov 15 2017

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Breast Neoplasms
Estrogens
Phosphorylation
Goserelin
Apoptosis
Biopsy
Neoplasms
Mutation
Neoadjuvant Therapy
Health Services Needs and Demand
Prednisone
MK 2206
anastrozole
Exanthema
Research Design
Cell Proliferation
Pharmaceutical Preparations
Therapeutics

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

A phase II trial of neoadjuvant MK-2206, an AKT inhibitor, with anastrozole in clinical stage II or III PIK3CA-mutant ER-positive and HER2-negative breast cancer. / Ma, Cynthia X.; Suman, Vera Jean; Goetz, Matthew Philip; Northfelt, Donald W; Burkard, Mark E.; Ademuyiwa, Foluso; Naughton, Michael; Margenthaler, Julie; Aft, Rebecca; Gray, Richard; Tevaarwerk, Amye; Wilke, Lee; Haddad, Tufia C; Moynihan, Timothy; Loprinzi, Charles Lawrence; Hieken, Tina J; Barnell, Erica K.; Skidmore, Zachary L.; Feng, Yan Yang; Krysiak, Kilannin; Hoog, Jeremy; Guo, Zhanfang; Nehring, Leslie; Wisinski, Kari B.; Mardis, Elaine; Hagemann, Ian S.; Vij, Kiran; Sanati, Souzan; Al-Kateb, Hussam; Griffith, Obi L.; Griffith, Malachi; Doyle, Laurence; Erlichman, Charles; Ellis, Matthew J.

In: Clinical Cancer Research, Vol. 23, No. 22, 15.11.2017, p. 6823-6832.

Research output: Contribution to journalArticle

Ma, CX, Suman, VJ, Goetz, MP, Northfelt, DW, Burkard, ME, Ademuyiwa, F, Naughton, M, Margenthaler, J, Aft, R, Gray, R, Tevaarwerk, A, Wilke, L, Haddad, TC, Moynihan, T, Loprinzi, CL, Hieken, TJ, Barnell, EK, Skidmore, ZL, Feng, YY, Krysiak, K, Hoog, J, Guo, Z, Nehring, L, Wisinski, KB, Mardis, E, Hagemann, IS, Vij, K, Sanati, S, Al-Kateb, H, Griffith, OL, Griffith, M, Doyle, L, Erlichman, C & Ellis, MJ 2017, 'A phase II trial of neoadjuvant MK-2206, an AKT inhibitor, with anastrozole in clinical stage II or III PIK3CA-mutant ER-positive and HER2-negative breast cancer', Clinical Cancer Research, vol. 23, no. 22, pp. 6823-6832. https://doi.org/10.1158/1078-0432.CCR-17-1260
Ma, Cynthia X. ; Suman, Vera Jean ; Goetz, Matthew Philip ; Northfelt, Donald W ; Burkard, Mark E. ; Ademuyiwa, Foluso ; Naughton, Michael ; Margenthaler, Julie ; Aft, Rebecca ; Gray, Richard ; Tevaarwerk, Amye ; Wilke, Lee ; Haddad, Tufia C ; Moynihan, Timothy ; Loprinzi, Charles Lawrence ; Hieken, Tina J ; Barnell, Erica K. ; Skidmore, Zachary L. ; Feng, Yan Yang ; Krysiak, Kilannin ; Hoog, Jeremy ; Guo, Zhanfang ; Nehring, Leslie ; Wisinski, Kari B. ; Mardis, Elaine ; Hagemann, Ian S. ; Vij, Kiran ; Sanati, Souzan ; Al-Kateb, Hussam ; Griffith, Obi L. ; Griffith, Malachi ; Doyle, Laurence ; Erlichman, Charles ; Ellis, Matthew J. / A phase II trial of neoadjuvant MK-2206, an AKT inhibitor, with anastrozole in clinical stage II or III PIK3CA-mutant ER-positive and HER2-negative breast cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 22. pp. 6823-6832.
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title = "A phase II trial of neoadjuvant MK-2206, an AKT inhibitor, with anastrozole in clinical stage II or III PIK3CA-mutant ER-positive and HER2-negative breast cancer",
abstract = "Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2- breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10{\%} (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population.",
author = "Ma, {Cynthia X.} and Suman, {Vera Jean} and Goetz, {Matthew Philip} and Northfelt, {Donald W} and Burkard, {Mark E.} and Foluso Ademuyiwa and Michael Naughton and Julie Margenthaler and Rebecca Aft and Richard Gray and Amye Tevaarwerk and Lee Wilke and Haddad, {Tufia C} and Timothy Moynihan and Loprinzi, {Charles Lawrence} and Hieken, {Tina J} and Barnell, {Erica K.} and Skidmore, {Zachary L.} and Feng, {Yan Yang} and Kilannin Krysiak and Jeremy Hoog and Zhanfang Guo and Leslie Nehring and Wisinski, {Kari B.} and Elaine Mardis and Hagemann, {Ian S.} and Kiran Vij and Souzan Sanati and Hussam Al-Kateb and Griffith, {Obi L.} and Malachi Griffith and Laurence Doyle and Charles Erlichman and Ellis, {Matthew J.}",
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TY - JOUR

T1 - A phase II trial of neoadjuvant MK-2206, an AKT inhibitor, with anastrozole in clinical stage II or III PIK3CA-mutant ER-positive and HER2-negative breast cancer

AU - Ma, Cynthia X.

AU - Suman, Vera Jean

AU - Goetz, Matthew Philip

AU - Northfelt, Donald W

AU - Burkard, Mark E.

AU - Ademuyiwa, Foluso

AU - Naughton, Michael

AU - Margenthaler, Julie

AU - Aft, Rebecca

AU - Gray, Richard

AU - Tevaarwerk, Amye

AU - Wilke, Lee

AU - Haddad, Tufia C

AU - Moynihan, Timothy

AU - Loprinzi, Charles Lawrence

AU - Hieken, Tina J

AU - Barnell, Erica K.

AU - Skidmore, Zachary L.

AU - Feng, Yan Yang

AU - Krysiak, Kilannin

AU - Hoog, Jeremy

AU - Guo, Zhanfang

AU - Nehring, Leslie

AU - Wisinski, Kari B.

AU - Mardis, Elaine

AU - Hagemann, Ian S.

AU - Vij, Kiran

AU - Sanati, Souzan

AU - Al-Kateb, Hussam

AU - Griffith, Obi L.

AU - Griffith, Malachi

AU - Doyle, Laurence

AU - Erlichman, Charles

AU - Ellis, Matthew J.

PY - 2017/11/15

Y1 - 2017/11/15

N2 - Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2- breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population.

AB - Purpose: Hyperactivation of AKT is common and associated with endocrine resistance in estrogen receptor–positive (ER+) breast cancer. The allosteric pan-AKT inhibitor MK-2206 induced apoptosis in PIK3CA-mutant ER+ breast cancer under estrogen-deprived condition in preclinical studies. This neoadjuvant phase II trial was therefore conducted to test the hypothesis that adding MK-2206 to anastrozole induces pathologic complete response (pCR) in PIK3CA mutant ER+ breast cancer. Experimental Design: Potential eligible patients with clinical stage II/III ER+/HER2- breast cancer were preregistered and received anastrozole (goserelin if premenopausal) for 28 days in cycle 0 pending tumor PIK3CA sequencing. Patients positive for PIK3CA mutation in the tumor were eligible to start MK-2206 (150 mg orally weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of four 28-day cycles of combination therapy before surgery. Serial biopsies were collected at preregistration, C1D1 and C1D17. Results: Fifty-one patients preregistered and 16 of 22 with PIK3CA-mutant tumors received study drug. Three patients went off study due to C1D17 Ki67 >10% (n = 2) and toxicity (n = 1). Thirteen patients completed neoadjuvant therapy followed by surgery. No pCRs were observed. Rash was common. MK-2206 did not further suppress cell proliferation and did not induce apoptosis on C1D17 biopsies. Although AKT phosphorylation was reduced, PRAS40 phosphorylation at C1D17 after MK-2206 persisted. One patient acquired an ESR1 mutation at surgery. Conclusions: MK-2206 is unlikely to add to the efficacy of anastrozole alone in PIK3CA-mutant ER+ breast cancer and should not be studied further in the target patient population.

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U2 - 10.1158/1078-0432.CCR-17-1260

DO - 10.1158/1078-0432.CCR-17-1260

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SP - 6823

EP - 6832

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

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ER -