Citations

Abstract Purpose: This study investigated the association between tumor MYC protein expression and disease-free survival (DFS) of patients randomized to receive chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) in the N9831 (Alliance) adjuvant HER2+ trastuzumab breast cancer trial. Experimental Design: This analysis included 1,736 patients randomized to Arms A, B, and C on N9831. Nuclear MYC protein expression was determined in tissue microarray sections containing three biopsies per patient or whole tissue sections using standard immunohistochemistry (clone 9E10). A tumor was considered positive for MYC protein overexpression (MYC+) if the nuclear 3+ staining percentage was more than 30%. Results: Five hundred and seventy-four (33%) tumors were MYC+. MYC+ was associated with hormone receptor positivity (χ2, P = 0.006), tumors 2 cm or more (χ2, P = 0.02), and a higher rate of nodal positivity (χ2, P < 0.001). HRs for DFS (median follow-up: 6.1 years) for Arm C versus A were 0.52 (P = 0.006) and 0.65 (P = 0.006) for patients with MYC+ and MYC− tumors, respectively (Pinteraction = 0.40). For Arm B versus A, HRs for patients with MYC+ and MYC− tumors were 0.79 (P = 0.21) and 0.74 (P = 0.04), respectively (Pinteraction = 0.71). For Arm C versus B, HRs for patients with MYC+ and MYC− tumors were 0.56 (P = 0.02) and 0.89 (P = 0.49), respectively (Pinteraction = 0.17). Conclusions: Our data do not support an impact of tumor MYC protein expression on differential benefit from adjuvant trastuzumab. Clin Cancer Res; 19(20); 5798–807. ©2013 AACR.

Abstract Purpose: Patients with hormone receptor–negative breast cancer generally do not benefit from endocrine-targeted therapies. However, a subset with androgen receptor (AR) expression is predicted to respond to antiandrogen therapies. This phase II study explored bicalutamide in AR-positive, estrogen receptor (ER), and progesterone receptor (PgR)-negative metastatic breast cancer. Experimental Design: Tumors from patients with ER/PgR-negative advanced breast cancer were tested centrally for AR [immunohistochemistry (IHC) > 10% nuclear staining considered positive]. If either the primary or a metastatic site was positive, patients were eligible to receive the AR antagonist bicalutamide at a dose of 150 mg daily. Clinical benefit rate (CBR), the primary endpoint, was defined as the total number of patients who show a complete response (CR), partial response (PR), or stable disease (SD) > 6 months; secondary endpoints included progression-free survival (PFS) and toxicity. Correlative studies included measurement of circulating endocrine markers and IHC surrogates for basal-like breast cancer. Results: Of 424 patients with ER/PgR-negative breast cancer, 12% tested AR-positive. The 6-month CBR was 19% [95% confidence interval (CI), 7%–39%] for bicalutamide. The median PFS was 12 weeks (95% CI, 11–22 weeks). Bicalutamide was well-tolerated with no grade 4/5 treatment-related adverse events observed. Conclusion: AR was expressed in 12% of patients with ER/PgR-negative breast cancer screened for this trial. The CBR of 19% observed with bicalutamide shows proof of principle for the efficacy of minimally toxic androgen blockade in a select group of patients with ER/PgR-negative, AR-positive breast cancer. Clin Cancer Res; 19(19); 5505–12. ©2013 AACR.

Background BMS-927711 is a potent, selective, competitive human calcitonin gene-related peptide (CGRP) receptor antagonist that has shown in vivo efficacy without vasoconstrictor effect. The objective of the current study was to determine an effective and tolerable dose range of BMS-927711 for the acute treatment of migraine. Methods In this randomized, double-blind, placebo controlled, dose-ranging study, 885 patients were randomized using an adaptive design to one of the following dose groups: BMS-927711 (10, 25, 75, 150, 300, or 600 mg); sumatriptan 100 mg (active comparator); and placebo. Patients were treated for a single migraine attack. The primary endpoint was pain freedom at two hours post-dose. Results Of patients who took the study drug, 799 had one post-randomization efficacy evaluation. Significantly more patients in the BMS-927711 75 mg (31.4%, p = 0.002), 150 mg (32.9%, p < 0.001), and 300 mg (29.7%, p = 0.002) groups and the sumatriptan group (35%, p < 0.001) had pain freedom at two hours post-dose versus placebo (15.3%). For the secondary endpoint of sustained pain freedom from two to 24 hours post-dose, BMS-927711 doses (25–600 mg) were also statistically significant compared with placebo. No deaths or treatment-related serious adverse events (AEs) were reported, and no patients discontinued because of AEs. Conclusions BMS-927711 is superior to placebo at several different doses (75 mg, 150 mg, and 300 mg) and has an excellent tolerability profile.

CPT: Pharmacometrics & Systems Pharmacology (2013) 2, e68; doi:10.1038/psp.2013.48; advance online publication 21 August 2013