c-MYC amplification and correlation with patient outcome in early stage HER2+ breast cancer from the NCCTG adjuvant intergroup trial N9831.

Abstract

#56 Background: Recent findings from NSABP B-31 suggested that breast cancer (BC) patients (pts) with c-MYC (MYC)/HER2 co-amplification in their primary tumors may benefit more in terms of disease-free survival (DFS) from adjuvant trastuzumab (n=471; p<0.0001, HR 0.24; 13 vs. 51 events) than those pts with only HER2 amplification in their primary tumors (n=1078, p=0.007, HR 0.63; 55 vs. 82 events).
 Purpose: The overall objective of this analysis is to determine the association between MYC/HER2 co-amplification and outcome of pts randomized to receive chemotherapy alone (Arm A) or chemotherapy with concurrent trastuzumab (Arm C) on N9831.
 Patients/Methods: This analysis included 868 pts from the HER2+ NCCTG N9831 Intergroup adjuvant trastuzumab phase III clinical trial on Arms A or C. Fluorescent in situ hybridization (FISH) was performed at a central laboratory, Mayo Clinic Clinical Cytogenetics Laboratory, using dual probe mixtures for HER2 (17q11.2-12/centromere 17) and for MYC (8q24/centromere 8). The HER2 amplification status in whole tissue sections was evaluated to determine eligibility of pts for N9831. Tissue microarrays containing three cores from each patient's tumor were analyzed for MYC amplification status. The gene and centromere copy number as well as the distribution of the signals for each marker were determined in sixty non-overlapping interphase nuclei.
 Results: Of 273 pts with completed FISH analyses, 34 (12%) pts had MYC amplification. The rate of MYC amplification was similar across arms (18/135 [13%] vs. 16/138 [12%]; ChiS p=0.66). Co-amplification of MYC/HER2 was observed in 32 (12%) pts with similar co-amplification rates across arms (17/135 [13%] vs. 15/138 [11%]; ChiS p=0.66). Based on preliminary analyses, MYC amplification and MYC/HER2 co-amplification do not appear to be associated with race, menopausal status, hormone receptor status, nodal status, tumor histology, tumor grade, or tumor size (all ChiS p>0.05); however, MYC amplified pts were significantly younger than MYC non-amplified pts (mean 46.4 vs. 51.0, t-test p=0.02) and MYC/HER2 co-amplified pts were significantly younger than MYC/HER2 non-co-amplified pts (mean 45.9 vs. 51.0, t-test p=0.01).
 Conclusions: In our initial analyses of 239 pts, we observed a lower frequency of MYC/HER2 co-amplification than the previously reported 30% for NSABP B-31. Complete FISH analyses of 868 pts in N9831 and association with DFS will be presented. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 56.

c-Myc and Her2 cooperate to drive a stem-like phenotype with poor prognosis in breast cancer

“…A mean score for MYC, CEP8 and the MYC/CEP8 ratio was calculated. Using the criteria of Perez et al, 82 an MYC/CEP8 ratio of 41.3 or a mean tumour cell MYC copy number of 45 was used to determine cases with MYC amplification.…”

C-MYC Alterations and Association With Patient Outcome in Early-Stage HER2-Positive Breast Cancer From the North Central Cancer Treatment Group N9831 Adjuvant Trastuzumab Trial

“…[1][2][3][4] However, many women who receive trastuzumab develop resistance within 1 year, and 15% to 25% of women diagnosed with HER2-positive, early-stage disease develop tumor relapse within 3 years, despite therapy. 5 Thus, identifying patients who would respond best to trastuzumab is critical to the appropriate management of patients with HER2-positive breast cancer.…”

“…2,6,7 MYC, located on chromosome 8, is a proto-oncogene with a central role in proliferation and malignant transformation of human and animal cells. 8 Its protein product (MYC) is a transcription factor that critically participates in most aspects of normal cellular function, including replication, proliferation, metabolism, differentiation, and apoptosis.…”

Neo(adjuvant) trastuzumab treatment: current perspectives

“…A previous report showed that c-MYC may be candidate molecule to select for trastuzumab therapy, because of increased responsiveness. Perez et al [23] corroborated that c-MYC amplification is not associated with added benefit to trastuzumab treatment in the N9831 trial (a global study using adjuvant trastuzumab). As yet, there are no confirmed molecules for individualized adjuvant treatment in HER2-positive breast cancer.…”