Abstract P2-09-08: c-MYC (MYC) Protein Expression and Associations with Trastuzumab Benefit in Early-Stage, HER2+ Breast Cancer in Context of the NCCTG Adjuvant Trial, N9831
Authors: Reinholz MM , Dueck AC , Wiktor AE , Lingle WL , Jenkins RB , Davidson NE , Martino S , Kaufman PA , Kutteh LA , Sledge GW , Harris LN , Gralow JR , Geiger X , Perez EA. 
Published: April 2011

Abstract
Previous findings suggested that patients (pts) with copy number alterations of MYC (8q24) and centromere 8 (CEN 8) in the setting of HER2-positive breast cancer may be associated with improved outcome to adjuvant trastuzumab. Our tissue microarray (TMA) data suggested that alternate cutpoints for MYC copy number anomalies [of 802 pts, those with MYC:CEN8 ratio ≥1.3 or &lt;1.3 & polysomy 8 (N=658; 82%) had a hazard ratio (HR) of 0.44 (P&lt;0.001) and those with MYC copy number ≥2.5 (N=669; 84%) had a HR of 0.42 (P&lt;0.001)] were potentially predictive of benefit from adjuvant trastuzumab when administered concurrently with chemotherapy in the NCCTG N9831 HER2+ phase III trial. Purpose: We were interested in determining whether MYC is the target protein responsible for the suggested benefit from trastuzumab. We evaluated the association between MYC protein expression and disease-free survival (DFS) of pts randomized to receive chemotherapy alone (Arm A) or chemotherapy with sequential (Arm B) or concurrent trastuzumab (Arm C) using N9831 TMAs. Patients/Methods: This analysis included 1220 pts from Arms A, B, and C. The percentage of strong (3+) nuclear staining was determined in TMA sections containing 3 cores per block using immunohistochemistry (IHC; clone 9E10, Sigma-Aldrich, St. Louis, MO). A patient's tumor was considered positive (MYC+) if the maximum nuclear 3+ staining percentage across cores was &gt;30% a priori. Median follow-up was 5.8 years. Results: Of 1220 pts with completed IHC analyses, 557 (46%) were MYC+. MYC+ was associated with a higher rate of hormone receptor positivity (58% vs 48%, chi-sq P&lt;0.001) and higher rate of nodal positivity (92% vs 84%, chi-sq P&lt;0.001) but not associated with age, race, tumor histology, tumor grade, or tumor size. In comparing DFS between arms C and A, MYC+ and MYC-pts had HRs of 0.46 (p=0.002; A: 187 pts, 57 events, C: 161 pts, 25 events) and 0.70 (p=0.09; A: 213 pts, 59 events, C: 208 pts, 38 events), respectively (interaction p=0.20). In comparing DFS between arms B and A, MYC+ and MYC-pts had HRs of 0.74 (p=0.11; B: 209 pts, 52 events) and 0.81 (p=0.29; B: 242 pts, 53 events), respectively (interaction p=0.80) (Figure). In addition, pts with nuclear MYC staining of 3+ in 0-9%, 10-30%, 31-60%, and 61-100% of cells had HRs (C vs A) of 0.98 (95% CI 0.53-1.82), 0.54 (95% CI 0.30-0.97), 0.55 (95% CI 0.27-1.12), and 0.37 (95% CI 0.19-0.75). Conclusions: In our analysis of 1220 pts, we observed that MYC protein expression positively correlated with hormone receptor positivity and nodal status. We observed a trend towards greater trastuzumab benefit among MYC+ as compared to MYC-pts. A rising trend in trastuzumab benefit was observed with increasing MYC protein expression. Analyses including pts with whole sections and outcome by MYC protein and gene copy number will be presented.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-08.