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. ( The HER2/neu (HER2) gene is amplified in ∼25% of breast cancers (1). Gene amplification results in overexpression of the HER2 protein, which is associated with an aggressive clinical course to include a shorter disease-free interval after adjuvant therapy and decreased overall survival (OS; refs. 2-4). The natural history of HER2-overexpressing breast cancer has been altered, however, by the routine use of trastuzumab, a monoclonal antibody targeting the extracellular domain of the HER2 protein. Trastuzumab has been shown to improve survival in patients with metastatic HER2-positive breast cancer (5, 6) as well as in patients with earlier stage disease. Several large, multicenter adjuvant therapy trials showed that the addition of trastuzumab to systemic chemotherapy reduces recurrence by ∼50% and improves OS by 30% (7, 8). Trastuzumab has also been shown to be efficacious when given in the neoadjuvant setting with pathologic complete response (pCR) rates ranging from 7% to as high as 65% in patients with both early and locally advanced breast cancer (9)(10)(11)(12)(13)(14). Despite these successes with trastuzumab therapy, not all HER2-positive tumors respond and some patients whose tumors do respond will experience disease recurrence. Investigators from our group recently reported a case of a patient with HER2-p...

HER2 status in a population-derived breast cancer cohort: discordances during tumor progression

“…This is in line with a recent publication on neoadjuvant treatment with trastuzumab. In that study, the patients who retained a positive HER2 status had better prognosis compared with patients who changed HER2 status [15]. In the unchanged HER2 negative, unchanged HER2 positive, and in the changed HER2 groups, 55%, 34%, and 56% respectively, received adjuvant endocrine therapy.…”

Antitumor Activity of the Hsp90 Inhibitor IPI-504 in HER2-Positive Trastuzumab-Resistant Breast Cancer

“…With the exception of some cases in which trastuzumab resistance may occur as a result of loss of HER2 (11), the majority of mechanisms of resistance described to date are the result of continued hyperactivation of HER2 downstream signaling in the presence of trastuzumab-insensitive truncated receptors (12), HER2 dimerization with other receptors (13)(14)(15), downstream deletion of tumor suppressor genes such as PTEN (16), or activation mutations of phosphoinositide 3-kinase (PI3K; ref. 17).…”

Trastuzumab-Resistance and Breast Cancer

“…Moreover, HER2-overexpressing breast cancer cells rapidly up-regulate Met expression after trastuzumab treatment, promoting their own resistance (Shattuck et al, 2008). As mentioned in the previous paragraph, loss of HER2 expression in HER2-overexpression breast cancer cells could be another mechanism contributing to trastuzumab resistance (Mittendorf et al, 2009). HER2 receptor initiated downstream signaling promotes cell proliferation and cell survival by the activation of RAS-MAPK and PI3K/Akt/mTOR pathways (Hudis, 2007;Zhou et al, 2004).…”

“…These trastuzumab-resistant cell lines still overexpress HER2, suggesting that resistance to trastuzumab is not due to the loss of HER2 overexpression (Diermeier et al, 2005;Dokmanovic et al, 2009;Nagy et al, 2005;Ritter et al, 2007). Interestingly, it was reported recently that chronic exposure of BT-474 cells to trastuzumab gave rise to trastuzumab-resistant clones, which lost HER2 gene amplification and HER2 overexpression (Mittendorf et al, 2009). However, it is not clear whether trastuzumab eliminated HER2-overexpressing clones leaving only HER2-negative cancer clones or that the treatment with trastuzumab inhibited HER2 expression or induced downregulation of HER2, resulting in the loss of HER2 expression and resistance to trastuzumab.…”

“…In particular, in an analysis of 307 patients with metastatic breast cancer, individuals who did not achieve a significant decline (defined as ≥ 20%) in serum level of serum HER2 ECD after receiving trastuzumab had decreased benefit from trastuzumab-based therapy (Ali et al, 2008). The analysis of HER2 gene amplification before and after trastuzumab therapy suggested that patients who had lost HER2 gene amplification had a significantly decreased recurrence free survival (RFS) compared with patients whose tumors remained HER2 amplified after trastuzumab treatment (Mittendorf et al, 2009). Nagata et al revealed that patients with PTEN-deficient breast cancers had significantly reduced responses to trastuzumab-based therapy than those with normal PTEN, suggesting PTEN deficiency may be a predictor to trastuzumab resistance (Nagata et al, 2004).…”