Abstract P4-12-02: High HER2 gene amplification and clinical outcomes in localized HER2-positive breast cancer

BACKGROUND Anti-HER2 therapy with trastuzumab is associated with a significant improvement in disease-free survival as compared to chemotherapy alone, and is considered the standard of care for localized HER2 positive breast cancer. However, a subset of HER2 positive breast cancers do not respond to trastuzumab. While various mechanisms have been proposed for trastuzumab resistance, one potential contributor could be very high level of HER2 gene amplification. Since trastuzumab is a HER2 receptor antagonist, it is possible that single agent trastuzumab might be unable to block HER2 downstream signaling thresholds efficiently in the presence of very high HER2. The clinical outcomes for tumors with high HER2 gene amplification treated with trastuzumab have not been well studied. METHODS With IRB approval, we reviewed the clinical records of all Stage I-III breast cancer patients with HER2+ breast cancer at our institution from 2008-2012. HER-2 to Chromosome 17 FISH ratio was determined by two pathologists with high inter-person reliability using the PathVysion dual color probe (Abbott Laboratories). We abstracted data on demographics, tumor characteristics including tumor size (T), lymph node involvement, grade, DCIS, HER2 amplification levels, and clinical outcomes from the clinical charts. We defined high HER2 amplification as FISH ratio > 8.0, as used in the HERA trial. Categorical data are summarized by frequency and percentage and comparisons between groups are performed by chi-square tests. In addition, we conducted a meta-analyses and systematic review to evaluate the association between high HER2 gene amplification and clinical outcome with/without trastuzumab in the large adjuvant HER2 clinical trials. RESULTS A total of 503 patients with HER2+ breast cancer were seen between the years of 2008-2012, and 16% (N = 82) had tumors with high HER2 levels. The median age was 50.5 years (range 29-89). The majority of tumors were T1 (56.79%) or T2 (34.57%), and had HER2 IHC staining of 3+ (94.37%). Tumors with high HER2 levels were more likely to be ER-/PR- (48.4%) than ER+/PR+ (32.8%) or ER+/PR- (18.8%), and likely to have concomitant DCIS (82.5%) and high grade (grade 3 = 74%). Women (n = 16) with high HER2+ breast cancer treated with standard neoadjuvant therapy with single agent trastuzumab (AC-TH or TCH) had a low pathological complete response (pCR) rate of 7.14%. In addition, this group had a high recurrence risk of 42.9%. Two patients with recurrence had mutation profiling by multiplexed genotyping platform (SNaPshot) and mutations in PIK3CA and TP53 oncogene were identified.One patient with grade 3, high HER2+ (FISH 8.2) microinvasive DCIS, treated with mastectomy, developed pulmonary metastases 3 years after original diagnosis. The meta-analysis revealed adjuvant trastuzumab with chemotherapy did not result in improved disease free survival as compared to chemotherapy alone among tumors with high FISH ratio (Hazard Ratio: 0.89, 95% CI: 0.57, 1.38; p = 0.60). CONCLUSIONS: Our results suggest that tumors with high HER2 amplification, including small tumors, have an aggressive biology, are less likely to respond to standard trastuzumab based therapy, and more likely to have a recurrence, compared with historical HER2 controls. High FISH may predict a clone of cells that have resistance to single agent trastuzumab warranting more aggressive HER2 directed therapy such as dual HER2 or combined HER2 and PI3K/Akt/mTOR blockade. These findings need confirmation in additional studies. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-12-02.