HER2/Neu Genetic Heterogeneity (GH) in Breast Cancer as Defined by CAP Guidelines Correlates with Negative Prognostic Factors.
Hedyeh Shafi, Michael Schmidt, Shikha Bose. Cedars-Sinai Medical Center, Los Angeles
Background: HER2/neu (HER2) is overexpressed in about 20-30% of invasive breast carcinomas and is a significant determinant of prognosis and therapy. Intratumoral heterogeneity of HER2 amplification has been reported in 5% to 30%, raising concern that this may affect response to therapy owing to the selection of resistant sub-clones lacking HER2 amplification. Additionally, GH may potentially contribute to inaccurate assessment of HER2 status. Recently, guidelines established by CAP define HER2 GH as present when 5-50% of infiltrating carcinoma cells has a HER2/CEP17 ratio of greater than 2.2. In this prospective study, we sought to investigate the prevalence of HER2 GH as defined by the CAP guidelines and determine its effect on prognosis.
Design: Two hundred two consecutive cases of infiltrating ductal carcinoma diagnosed in our laboratory between 4/10-8/10 were reviewed. Fixation of breast tissue and evaluation of prognostic markers were performed according to CAP guidelines. IHC (by image analysis) and FISH were used for evaluation of ER, PR, Ki-67 and HER2 expression and HER2 amplification. FISH studies were performed using probes for both HER2 and CEP17. In each case, 20-40 cells were counted and ratio of HER2/CEP17 signal was calculated for each cell. Cases with GH were recorded to determine incidence and relationship to various prognostic markers including tumor size, tumor grade, lymph node metastasis, ER, PR, Ki-67, and Her-2/Neu expression. Statistical analyses were performed using the Fisher exact test. A two sided p value of 0.05 was considered significant.
Results: 53 (26%) of 202 cases showed GH. GH of 5% was noted in the majority (22/52, 42%) of cases. In the remainder GH ranged from 10-50%. All cases were negative or equivocal on IHC with the exception of one case that was positive (3+). Cases with GH showed greater tumor size (p=0.01), lymph node metastasis (p=0.005), a lower expression of PR (p=0.02), and higher Ki-67 positivity (p=0.01), as compared to those without GH. Higher levels of GH were associated with equivocal/positive IHC (p=0.03).
Conclusions: 1) Intratumoral heterogeneity for HER2/neu gene amplification was demonstrated in 26% of breast cancers. 2) Cancers with GH showed greater tumor size, lymph node metastasis, lower expression of PR, and higher Ki-67 positivity. 3) Higher levels of GH were associated with equivocal/positive IHC. 4) Additional studies are warranted to determine the effect of therapy on cancers with GH.
Tuesday, March 1, 2011 9:30 AM
Poster Session III # 43, Tuesday Morning