Loss of HER2 amplification following trastuzumab-based neoadjuvant systemic therapy and survival outcomes

Abstract

Purpose: To evaluate HER2 status in residual tumor identified at the time of surgery in patients not achieving a pathologic complete response (pCR) and to determine the effect of alterations in HER2 status on recurrence-free survival (RFS).

Experimental design: Clinicopathologic data for patients with HER2-overexpressing breast cancer receiving neoadjuvant therapy with a taxane, anthracycline, and concomitant trastuzumab between 2004 and 2007 were reviewed. Surgical specimens for patients achieving less than a pCR were assessed to determine if there was enough residual tissue to evaluate posttreatment HER2 status. RFS was determined using the Kaplan-Meier method and compared by the log-rank statistic.

Results: A pCR was achieved in 72 of the 142 (50.7%) patients. Residual tumor was sufficient to assess posttreatment HER2 status in 25 patients. Fluorescence in situ hybridization done on pretreatment specimens confirmed HER2 amplification before beginning therapy. Eight (32.0%) posttreatment tumors were found to be HER2-negative by fluorescence in situ hybridization. At a median follow-up of 37 months (range, 8-56 months), the RFS was significantly better for patients with tumors that retained HER2 amplification (87.5% versus 50%, P = 0.04).

Conclusion: High pCR rates are achieved in patients with HER2-positive breast cancer treated with neoadjuvant trastuzumab in combination with anthracyclines and taxanes. One third of patients with significant residual disease loses HER2 amplification, and this change is associated with poor RFS. Residual tumor identified at the time of surgery should be reassessed for HER2 status, and novel adjuvant therapy strategies need to be studied in this population.

Fig 1

FISH was performed to assess HER2 status. (A) FISH performed on biopsy specimen prior to treatment with a trastuzumab containing neoadjuvant chemotherapy regimen. Red = HER2 gene, green = centromere of chromosome 17 (CEP17). HER2/CEP17 = 6.22. Due to the intensity of HER2 staining, merged images were not obtained. (B) FISH performed on residual disease identified at the time of surgery from the same patient following completion of neoadjuvant chemotherapy. Image shown is a merged image of staining for HER2 and CEP 17. HER2/CEP17 = 1.1.

Fig 2

Kaplan-Meier plots of recurrence-free survival (RFS) by (A) pathologic complete response (pCR), and (B) status of HER2 gene amplification in patients with residual tissue identified at the time of surgery.

Fig 3

Loss of HER2 overexpression and amplification in BT-474R cells. (A) Western blot showing loss of HER2 overexpression in a representative clone of BT-474R cells. Ponceau staining serves as the loading control. (B) Loss of HER2 overexpression by IHC and loss of HER2 gene amplification by FISH (red = HER2 gene, green = CEP17) of a representative clone of BT-474R cells.