Association Between Top2a And Response To Anthracycline-based Neoadjuvant Chemotherapy In Primary Breast Cancer

Background and Objective:Recent studies have suggested that HER2 gene amplification or overexpression have association with sensitivity of anthracycline-based chemotherapy. Preclinical studies found that TOP2A amplification or deletion only could be detected in HER2 amplification cases. And TOP2A protein is the target of anthracycline. In fact, the value of HER2 for predicting response to anthracycline-based chemotherapy in breast cancer may be more likely related to the concomitant amplification of the TOP2A gene. In this study we studied the association between TOP2A gene amplification and response to anthracycline-based preoperative chemotherapy.Methods:309 early and local advanced breast cancer cases were enrolled in our study. HER2 proteins were qualitatively analysed by IHC, and TOP2A gene alterations were quantified by real-time PCR in primary tumor core biopsies from all cases. The enrolled patients received an intense dose dense (CE (DD)) or conventionally (TE) scheduled anthracycline-based preoperative chemotherapy. The tumor was evaluated every two cycles. Median time on study for 309 patients with follow-up was 38 months.Results:The pCR was 14.3% and ORR was 76.4%. The pCR in primary tumor was higher than in all target disease (29.2% vs.14.3%, P<0.001). TE regiment got significant higher pCR than CE(DD) (17.3% vs.9.2%, P=0.034). Other factors that was associated with a significantly higher pCR rate was ER/PR negative in CE(DD) regimen. The patients who received TE regimen had significantly higher pCR rate than who received CE(DD) regimen. Nevertheless, TE cases got worse progression than CE(DD) cases in 3 years DFS rate (68.9% vs.73.9%, P=0.002). The probable reason is most of patients in CE(DD) received paclitaxel monotherapy every 2 weeks for 4 cycles after operation. In multivariate analysis, other prognostic factors included inflammatory breast cancer, without endocrine therapy after operation, clinical axillary lymphnode metastasis.HER2 overexpression was found in 80/309 (25.9%) breast cancer cases, of which 61/80 cases have been tested for TOP2A status. HER2 overexpression was associated with a significantly higher pCR rate compared to HER2 lower expression (27.5% vs. 9.6%, P<0.001).Further analysis was carried on and found the significantly higher pCR rate in TOP2A co-amplified cases compared toTOP2A deleted or normal cases (56.3% vs.13.8%, P=0.001). The interaction between HER2 or TOP2A and anthracycline-based regiment was observed not only in IDD but conventionally scheduled preoperative chemotherapy.Conclusion:TOP2A gene amplification may define a subtype of HER2-positive breast cancers. This subtype of breast cancer may be highly sensitive to anthracycline-based chemotherapy, which may improve progression in HER2 and TOP2A co-amplification cases. Adding Taxen to adjuvant or neoadjuvant chemotherapy and endocrine to adjuvant therapy can improve progression; Inflammatory disease, clinical axillary lymphnode metastasis are important risk factors of recurrence.