Pathologic complete response to trastuzumab-based neoadjuvant therapy is related to the level of HER-2 amplification.

PURPOSE: Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) are used to determine human epidermal growth factor receptor-2 (HER-2) status and patient eligibility for trastuzumab therapy. Using FISH and IHC, we analyzed the relationship between pathologic complete response to trastuzumab-based neoadjuvant therapy and level of HER-2 amplification in locally advanced breast cancer. EXPERIMENTAL DESIGN: Breast biopsies from 93 HER-2-positive patients treated with trastuzumab-based neoadjuvant therapy were centrally collected and analyzed retrospectively for HER-2 amplification using FISH and HER-2 overexpression using IHC. Tumors were classified by FISH as no, low, or high amplification. Biopsies were reassessed centrally by IHC and graded 0, 1+, 2+, or 3+. RESULTS: HER-2 status of tumor samples as assessed by FISH and IHC correlated: 16 no amplification (11 IHC 1+ and 5 IHC 2+), 27 low amplification (26 IHC 3+ and 1 IHC 2+), and 50 high amplification (all IHC 3+). Trastuzumab-based neoadjuvant therapy achieved pathologic complete response in 35 of 93 (37.6%) tumors. Pathologic complete response rate in low- and high-amplification tumors was significantly higher than in no-amplification tumors (44% versus 6%; P < 0.004). Pathologic complete response rate in high-amplification tumors was significantly higher compared with low-amplification tumors (56% versus 22%; P < 0.005). In the subgroup of low- plus high-amplification tumors, no correlation was found between pathologic complete response rate and IHC score, treatment regimen, T or N stage, tumor grade, or hormonal receptors. CONCLUSIONS: This is the first study to show positive correlation between level of HER-2 amplification assessed by FISH and rate of pathologic complete response to trastuzumab-based neoadjuvant treatment.

Multicenter phase II trial of neoadjuvant therapy with trastuzumab, docetaxel, and carboplatin for human epidermal growth factor receptor-2-overexpressing stage II or III breast cancer: results of the GETN(A)-1 trial.

PURPOSE: Trastuzumab plus chemotherapy has become the standard of care for human epidermal growth factor receptor-2 (HER-2) -positive breast cancer. Trastuzumab-based preoperative systemic therapy (PST; neoadjuvant therapy) also appears promising, warranting further investigation. PATIENTS AND METHODS: Patients with HER-2-positive, stage II/III, noninflammatory, operable breast cancer requiring a mastectomy (but who wanted to conserve the breast) received trastuzumab 4 mg/kg (day 1), followed by 2 mg/kg weekly, plus docetaxel 75 mg/m2 every 3 weeks, and carboplatin (area under curve, 6) for six cycles before surgery. The primary end point was pathologic complete response (pCR) rate, determined from surgical specimens. RESULTS: Seventy patients were enrolled. Most patients had clinical T2/T3 tumors (100%) or clinical N1/2 nodes (53%). Sixty-seven patients (96%) completed six cycles of therapy, one patient withdrew due to progressive disease, and two patients withdrew for toxicity. A complete or partial objective clinical response occurred in 95% of patients (85% and 10%, respectively). Surgery was breast conservative in 45 (64%) of 70 patients. In an intent-to-treat analysis, tumor and nodal pCR were seen in 27 (39%) of 70 patients. Centralized retrospective analysis of HER-2 status demonstrated a 43% pCR rate in the 24 of 56 confirmed HER-2-overexpressing (3+) and/or fluorescence in situ hybridization-positive tumors. Treatment was generally well tolerated. Grade 3/4 neutropenia and febrile neutropenia were uncommon (2%). Two patients withdrew prematurely due to a transient, asymptomatic decrease in left ventricular ejection fraction. No symptomatic cardiac dysfunction occurred. CONCLUSION: PST with trastuzumab plus docetaxel and carboplatin achieved promising efficacy, with a good pCR rate and favorable tolerability in stage II or III HER-2-positive breast cancer.