A Phase II trial of neoadjuvant MK2206, an AKT inhibitor, with anastrozole in clinical stage 2 or 3 PIK3CA mutant ER positive and HER2 negative breast cancer

Clin Cancer Res. 2017 Sep 5. pii: clincanres.1260.2017. doi: 10.1158/1078-0432.CCR-17-1260. [Epub ahead of print]



Hyper-activation 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.


Potential eligible patients with clinical stage II/III ER+/HER2- breast cancer were pre-registered 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 (150mg PO weekly, with prophylactic prednisone) on cycle 1 day 2 (C1D2) and to receive a maximum of 4 28-days cycles of combination therapy before surgery. Serial biopsies were collected at pre-registration, C1D1 and C1D17.


Fifty-one patients pre-registered 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). 13 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 post MK-2206 persisted. One patient acquired an ESR1 mutation at surgery.


MK2206 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.


Ma CX1, Suman V2, Goetz MP3, Northfelt DW4, Burkard ME5, Ademuyiwa F6, Naughton MJ7, Margenthaler J8, Aft R8, Gray RJ9, Tevaarwerk AJ10, Wilke LG11, Haddad TC12, Moynihan T13, Loprenzi C14, Hieken T9, Barnell EK15, Skidmore ZL16, Feng YY17, Krysiak K18, Hoog J6, Guo Z6, Nehring L17, Wisinski KB19, Mardis ER20, Hagemann IS21, Vij K6, Sanati S22, Al-Kateb H21, Griffith OL15, Griffith M23, Doyle A24, Erlichman C25, Ellis MJ26.