• Claus Hanusch, Andreas Schneeweiss, Sibylle Loibl, Michael Untch, Stefan Paepke, Sherko Kümmel, Christian Jackisch, Jens Huober, Jörn Hilfrich, Bernd Gerber, Holger Eidtmann, Carsten Denkert, Serban Costa, Jens Uwe Blohmer, Knut Engels, Nicole Burchardi, and Gunter von Minckwitz.
• Klinikum zum Roten Kreuz, Frauenklinik, München, Germany.
• Clin Cancer Res. 2015 Jul 1; 21 (13): 2924-31.

PurposeDual anti-HER2 blockade with trastuzumab/pertuzumab or trastuzumab/lapatinib in combination with anthracycline/taxane-based chemotherapy can reach pathologic complete response (pCR) rates of up to 60% in HER2-positive breast cancer. The DAFNE (Dual blockade with AFatinib and trastuzumab as NEoadjuvant treatment) phase II study (NCT015591477) investigated a dual blockade with the irreversible pan-HER inhibitor afatinib and trastuzumab in this setting.Experimental DesignParticipants with untreated, centrally HER2-positive breast cancer were treated for 6 weeks with afatinib (20 mg/d) and trastuzumab [(8) 6 mg/kg/3 weeks] alone; followed by 12-week treatment with paclitaxel (80 mg/m(2)/1 week), trastuzumab, and afatinib; followed by 12 weeks with epirubicin (90 mg/m(2)/3 weeks), cyclophosphamide (600 mg/m(2)/3 weeks), and trastuzumab before surgery. Primary objective was pCR rate, defined as ypT0/is ypN0. We expected a pCR rate of 70%; 65 patients were needed to exclude a rate of ≤55%.ResultspCR rate was 49.2% [90% confidence interval (CI), 38.5-60.1] in 65 treated patients. Patients with hormone receptor-negative (N = 19) or hormone receptor-positive (N = 46) tumors showed pCR rates of 63.2% and 43.5%, respectively (P = 0.153). Patients with (N = 9) or without (N = 56) lymphocyte predominant breast cancer (LPBC) showed pCR rates of 100% and 41.1%, respectively (P < 0.001). PCR rate was not different in patients with or without PIK3CA tumor mutations (P = 0.363). Clinical responses were seen in 96.3% of 54 evaluable patients, and breast conserving surgery was possible in 59.4% of 62 assessable patients. Most frequent nonhematologic grade 3-4 toxicities were diarrhea (7.7%), increased creatinine (4.6%), and infection (4.6%). One patient developed symptomatic congestive heart failure.ConclusionsNeoadjuvant treatment with afatinib, trastuzumab, and chemotherapy showed acceptable tolerability, and a pCR rate comparable with that of other anti-HER2 doublets but below challenging expectations.©2015 American Association for Cancer Research.

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