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. Clin Cancer Res; 23(22); 6823-32. ©2017 AACR.

Figure 1.

Biomarker response to anastrozole alone on C1D1 and to the addition of MK-2206 on C1D17 tumor biopsies. A–C, Percent Ki67 labeling index (A), Allred scores of pAKT (Ser473; B), and Allred scores of pPRAS40 (Thr246; C), by IHC of tumor biopsies collected at preregistration, C1D1 (28 days after single-agent anastrozole), and C1D17 (after 2 weeks of adding MK-2206) are shown for individual patients with serial samples available. Sample IDs are shown in the figure legends. Representative IHC pictures (magnification, ×400) for Ki67, pAKT (Ser473), and pPRAS40 (Thr246) from 4 patients are shown in D. Quantitative comparisons of levels between C1D1 and preregistration or between C1D17 and C1D1 of each biomarker are described in Table 3.

Figure 2.

Somatic mutation profiles for 32 tumor samples from 14 patients obtained at indicated time points are shown. Histology subtype (invasive ductal vs. lobular) of the baseline or preregistration sample for each patient is also indicated. The mutation burden (mutations/Mb) was calculated for each sample as the total number of exonic mutations over the number of bases covered to ≥30× depth * 1000000. For situations in which there are multiple mutations in the same gene/sample combination, the most deleterious mutation is plotted following the order of the mutation type legend. Note that silent mutations are included for the mutation burden calculation. Specific amino acid changes in PIK3CA are indicated for each patient. All PIK3CA mutations remained present and are the same at all time points tested for each patient, except E726K, which was not detected at surgery time point for patient MK001. †, indicates the presence of a concurrent PIK3CA N1044K mutation in MK016.

Figure 3.

VAFs and Ki67 levels tracked over clinical time points. VAFs of somatic mutations by 83-gene panel sequencing, along with Ki67 level, were plotted over time for each of the 10 patients who have sequencing data available for at least two time points.