L. Garrigós, M. Ruiz-Borrego, J. M. Perez-Garcia, A. Guerrero-Zotano, A. Cortés-Salgado, S. Kuemmel, M. Colleoni, C. Reboredo-Rendo, B. Bermejo, I. Blancas, J. Gavila, A. Fabi, C. Morales, A. Stradella, V. Carañana, E. Martínez-de Dueñas, C. Albacar, O. Ballesteros-Cidras, G. Martrat, S. Iacobucci, O. Boix, P. Berenguer-Molins, D. Alcalá-López, J. Cortés, J. Cortés, A. Llombart-Cussac, L. Garrigós, M. Ruiz-Borrego, J.M. Pérez-García, A. Guerrero-Zotano, A. Cortés-Salgado, S. Kümmel, M. Colleoni, C. Reboredo-Rendo, B. Bermejo, I. Blancas, J. Gavila, A. Fabi, C. Morales, A. Stradella, V. Carañana, E. Martínez-de Dueñas, C. Albacar, S. Escrivá-de-Romaní, A. Musolino, E. Galve-Calvo, V. Quiroga, O. Gluz, A. López González, J. Ponce-Lorenzo, M. Cazzaniga, D. Fischer, P. Cortez-Castedo, P. Sanchez-Rovira, S. Morales, C. Zamagni, V. Iranzo, E. Collovà, A. Santaballa, L. Cavanna, O. Hoffmann, A. Bassam, J.Á. García-Sáenz, A. Medina, M. Palka, Y. Al-Farhat, O. Ballesteros-Cidras, G. Martrat, S. Iacobucci, O. Boix, P. Berenguer-Molins, D. Alcalá-López, J. Cortés, J. Cortés, A. Llombart-Cussac
BACKGROUND: PHERGain-2 is a multicenter, single-arm, phase II study evaluating a pathologic complete response (pCR)-guided de-escalation strategy to omit chemotherapy in selected patients with HER2-positive early breast cancer (EBC). PATIENTS AND METHODS: Eligible patients were adults, treatment-naive, centrally confirmed HER2-positive (immunohistochemistry 3+), node-negative EBC, with tumors 5-30 mm by magnetic resonance imaging. Patients received eight cycles of neoadjuvant trastuzumab-pertuzumab (HP) (600 mg H + 1200 mg P loading dose, followed by 600 mg H + 600 mg P maintenance dose) every 3 weeks. Patients with hormone receptor (HR)-positive tumors also received endocrine therapy. After surgery, patients received 10 cycles of adjuvant therapy guided by the pathological response: HP for patients with pCR (ypT0/is ypN0) (cohort A), trastuzumab emtansine (T-DM1; 3.6 mg/kg) for patients with residual invasive breast tumors and/or ypN0(i+/mol+), ypN1mi (cohort B), and optional chemotherapy followed by T-DM1 for patients with ypN1-3 (cohort C). Co-primary endpoints were 1-year health-related quality of life (HRQoL) decline (based on the European Organisation for Research and Treatment of Cancer Core Quality of Life questionnaire) and 3-year recurrence-free interval (based on the Standardized Definitions for Efficacy End Points). Key secondary endpoints included overall and HR-specific pCR rates and safety. RESULTS: From August 2021 to March 2024, 396 patients initiated neoadjuvant treatment, 391 (98.7%) underwent surgery. A total of 236 patients (59.6%) achieved pCR (cohort A). Among those with residual disease, 148 (37.8%) entered cohort B and 7 (1.8%) cohort C. One year after initiation of neoadjuvant treatment, ≥10% decline rate in global HRQoL was 42.8% [95% confidence interval (CI) 36.9% to 48.8%]; 37.3% (95% CI 30.1% to 44.9%) in patients with pCR and 51.9% (95% CI 41.9% to 61.7%) in those with residual disease. Treatment-related adverse events occurred in 86.6% of patients (5.6% grade ≥3). Serious adverse events occurred in 6.1% of patients. One death (0.3%) due to pneumonitis was attributed to T-DM1. CONCLUSIONS: PHERGain-2 shows meaningful HRQoL preservation, expected HP/T-DM1 toxicity, and an outstanding pCR rate comparable with standard chemotherapy plus HP regimens in this patient population.