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 language | English (US) |
|---|---|
| Pages (from-to) | 6823-6832 |
| Number of pages | 10 |
| Journal | Clinical Cancer Research |
| Volume | 23 |
| Issue number | 22 |
| DOIs | |
| State | Published - Nov 15 2017 |
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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 journal › Article
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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
M3 - Article
VL - 23
SP - 6823
EP - 6832
JO - Clinical Cancer Research
JF - Clinical Cancer Research
SN - 1078-0432
IS - 22
ER -