Abstract
Background: Gene amplification plays a significant role in the transcriptional regulation of the genome; in breast cancer, amplification of the HER2 gene occurs in 20-30% of patients and confers a poor prognosis. Trastuzumab is now widely used in HER2-positive breast carcinomas and has significantly changed outcomes in this aggressive subtype of breast cancer. C-myc, another oncogene, is reported to be amplified in breast cancer; c-myc regulates cell proliferation. Bcl-2, the prototype anti-apoptotic gene, is overexpressed in human breast carcinomas. The anti-apoptotic action of bcl-2 is located downstream from HER2 and may serve as a potential drug target. This study evaluated the rate of c-myc and bcl-2 overexpression in a cohort of HER2-amplified breast carcinomas and correlated the dysregulation of these genes with patient demographics and histologic characteristics.
Design: The study population consisted of 96 patients with HER2-positive invasive breast carcinoma treated with surgical excision or mastectomy at Northwestern Memorial Hospital (2009-12) (mean age 53, range 18-80). Electronic medical records were reviewed for patient demographics. Pathologic tumor characteristics (histologic type, size, grade, lymph node status) and tumor marker profile at the time of diagnosis (ER, PR, p53 and ki-67) were evaluated. Tissue microarrays were constructed (3 cores from each case to account for tumor heterogeneity) for immunohistochemical evaluation of c-myc (Epitomics, clone V69) and bcl-2 (DAKO, clone 124).
Results: Overall, these HER2-amplified breast carcinomas were almost exclusively infiltrating ductal carcinomas (92/96, 96%) of high histologic grade: 68/96 (71%) were grade 3, while the other 28 were grade 2 tumors. C-myc was overexpressed in 49/96 (51%) of the cases and bcl-2 was expressed in 60/96 (62%). There was no association of c-myc or bcl-2 expression with age, patient race, tumor grade, tumor size, lymph node status, p53 expression or ki-67 proliferation index. Expression of both c-myc and bcl-2 was seen in 30/96 (31%) of the cases. Of interest, c-myc-positive/bcl-2-positive tumors more often had positive lymph nodes and higher ki-67 proliferation index compared to tumors with c-myc-negative/bcl-2-negative phenotype (46.7% v 29.4% and 75.8% v 56.2% respectively).
Conclusions: (1) C-myc is expressed in over 50% and bcl-2 in over 60% of HER2-amplified carcinomas. (2) C-myc and bcl-2 expression do not appear to have differential expression between age groups or racial groups and do not correlate with histologic tumor characteristics. (3) HER2-amplified carcinomas expressing both c-myc and bcl-2 are highly proliferative tumors with a high rate of lymph node positivity. These findings suggest that coupled c-myc and bcl-2 overexpression may contribute to the biologic aggressiveness of HER2-amplified breast carcinomas. Additional studies into the molecular mechanisms that drive HER2-amplified tumors are currently underway in this aggressive subtype of breast cancer.
Citation Format: Alexandra L Larson, Denise M Scholtens, Adriana A Rosca, Virginia Kaklamani, Kalliopi P Siziopikou. C-myc and bcl-2 overexpression in HER2-positive breast carcinomas [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-01-21.
Volume 75, Issue 9 Supplement
