Martino, Simona Di

Abstract Background Obesity, as defined by body mass index (BMI), has been associated with increased recurrence rate, shorter DFS and increased death rates due to breast cancer (BC). Most of the studies to date have examined the relationship of BMI and DFS in patients with hormone receptor positive disease. To our knowledge, BMI and its relationship with outcome in early stage HER2 positive breast cancer has not previously been examined. The N9831 is a large phase III trial testing the role of trastuzumab in the adjuvant setting of high risk patients with early stage HER2+ BC. We hypothesized that the occurrence of overweight and obesity may correlate with outcome. Methods: This analysis presents BMI and its relation to tumor characteristics and DFS in patients (pts) enrolled in the N9831 clinical trial. Pts were categorized as normal weight, overweight or obese using the WHO BMI classification parameters of < 25%, 25–29% and ≥ 30% respectively. For patient characteristics, patients were grouped into non-obese (BMI< 30) and obese (≥ 30) cohorts. DFS was estimated by the Kaplan-Meier method. Comparisons between arms A (chemotherapy alone), B (chemotherapy plus sequential trastuzumab) and C (chemotherapy plus concurrent trastuzumab) were performed using the Cox proportional hazards model, stratified by BMI. Results: Analysis was completed on 3,017 eligible pts. Obese pts were more likely to be older and postmenopausal (p<0.0001 for both). There was no significant association between BMI and ER/PR status (p=0.07) or histologic tumor grade (p=0.33). Obese pts were found to have significantly larger tumors ≥ 2 cm (p=0.002) and more positive lymph nodes (p=0.02). There was no significant difference in DFS within each intrinsic arm (A, B and C) between the obese and non-obese pts at 3, 5 or 7 yrs of follow up. However, pts in the non-obese group had significantly improved DFS in arm B and C compared to arm A (p=0.001 and p<0.0001 respectively). Also obese pts in arm C had significantly improved DFS compared to obese pts in arm A (p=0.008). There was a trend of improved DFS in the obese group in arm B compared to arm A, but this was not statistically significant (p=0.09). Pts in the normal weight and overweight groups did significantly better in arm B (p=0.02 for both) and arm C (p=0.01 and p=0.002 respectively) compared to arm A. Conclusions: This analysis of data from the N9831 study confirms that obese pts with early stage HER2+ tumors have worse clinical outcome than pts with BMI < 30%. Adjuvant trastuzumab improved clinical outcome regardless of BMI. This study supports weight loss intervention for obese women with early stage HER2+ BC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-02.

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 <1.3 & polysomy 8 (N=658; 82%) had a hazard ratio (HR) of 0.44 (P<0.001) and those with MYC copy number ≥2.5 (N=669; 84%) had a HR of 0.42 (P<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 >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<0.001) and higher rate of nodal positivity (92% vs 84%, chi-sq P<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.