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Pathologic Complete Response to Trastuzumab-Based Neoadjuvant Therapy Is Related to the Level of HER-2 Amplification

Authors' Affiliations: ¹ CLCC G-F Leclerc and 1FR100, Dijon, France; ² CLCC Institut Curie; ³ Hôpital Tenon, Paris, France; ⁴ CLCC A Lacassagne, Nice, France; ⁵ Hopital Laënnec, Nantes, France; ⁶ CLCC Jean Perrin, Clermont-Ferrand, France; and ⁷ Laboratoire Roche-Pharma, Neuilly sur Seine, France

Requests for reprints: Laurent Arnould, Department of Pathology, Centre G-F Leclerc, 1 Rue Pr Marion, 21000 Dijon Cedex, France. Phone: 33-380-737-723; Fax: 33-380-737-717; E-mail: larnould{at}dijon.fnclcc.fr.

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.

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