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Background: The current standard first-line treatment of human epidermal growth factor receptor 2 (HER2)-positive (+) metastatic breast cancer is the combination of pertuzumab, trastuzumab and a taxane (P + T + taxane), while standard second-line is ado-trastuzumab-emtansine (T-DM1). The registration trial of pertuzumab, however, did not include early-relapsing patients, defined as patients experiencing tumor relapse ≤12 months from the end of (neo)adjuvant anti-HER2 therapy. Conversely, the pivotal trial of T-DM1 included some patients relapsing ≤6 months after the end of (neo)adjuvant trastuzumab. Thus, a proportion of early-relapsing patients are currently eligible to receive T-DM1 as first-line treatment. Nevertheless, no direct comparison exists between the two regimens in this clinical setting., Patients and Methods: We retrospectively compared T-DM1 versus P + T + taxane as first-line treatment in two cohorts of early-relapsing patients in an Italian 'real-world' setting, involving 14 public health care institutions. The primary endpoint was progression-free survival. Secondary endpoints included patients' characterization, overall survival and post-progression survival. Univariate and multivariate analyses were carried out. All tests were two-sided and a P ≤ 0.05 was considered statistically significant., Results: Among 1252 screened patients, 75 met the inclusion criteria. Forty-four (58.7%) received P + T + taxane and 31 (41.3%) received T-DM1. The two cohorts showed similar characteristics of aggressiveness and no significant differences in treatment history. T-DM1, compared with P + T + taxane was associated with worse progression-free survival (adjusted hazard ratio: 2.26, 95% confidence interval: 1.13-4.52, P = 0.021) and overall survival (adjusted hazard ratio: 3.95, 95% confidence interval: 1.38-11.32, P = 0.010), irrespective of previous (neo)adjuvant treatment, age, hormone receptors status, time-to-relapse (≤6 months or within 6-12 months) and presence of visceral/brain metastases. No differences were observed in post-progression survival (P = 0.095)., Conclusions: Our study suggests superiority for P + T + taxane over T-DM1 as up-front treatment of early-relapsing HER2+ metastatic breast cancer, which merits further assessment in larger and prospective trials., Competing Interests: Disclosure MG, GA and SDP have declared honoraria from Roche, Pfizer, Astra-Zeneca, Novartis, Celgene, Eli Lilly, Amgen and Eisai outside the submitted work. ML acted as consultant for Roche, AstraZenenca, Novartis, and received speaker honoraria from Roche, Takeda, Novartis, Lilly, Pfizer, Sandoz outside the submitted work. LDM has declared honoraria from Roche, Pfizer, Ipsen, Eli Lilly, Eisai, Novartis, Takeda and Merck Sharp & Dohme (MSD), consulting/advisory role for Roche and Eli Lilly, travels, accommodations and expenses from Roche, Pfizer and Celgene outside the submitted work. MDL has declared consulting fees from Pfizer, Novartis, Eli Lilly, Roche, Eisai, Celgene. FP has declared honoraria for advisory boards, activities as a speaker, travel grants, research grants from Amgen, AstraZeneca, Celgene, Eisai, Eli Lilly, Ipsen, MSD, Novartis, Pierre-Fabre, Pfizer, Roche and Takeda, and research funding from AstraZeneca, Eisai, Roche and Italian Ministry of Health outside the submitted work. PFC reports grants from Merck KGaA, Roche and Bristol-Myers Squibb; grants and personal fees from Novartis and EliLilly; personal fees from AstraZeneca, outside the submitted work. VG reports personal fees from Novartis, Roche, EliLilly, MSD, outside the submitted work. DG has declared consulting fees from Novartis, Lilly and Pfizer, research funding from LILT, Novartis, AstraZeneca and University of Trieste outside the submitted work. GB received honoraria for speaker activities and travel grants from GlaxoSmithKline, Novartis, Pfizer, Roche, Genetic Spa, outside the submitted work. FM declared advisory role for Roche, Novartis, AstraZeneca, Pfizer, Eli Lilly, Pierre Fabre, Daiichi Sankyo, travel grants from Roche and financial support from the Fondazione Piemontese per la Ricerca sul Cancro (FPRC) Onlus 5 x mille funding from the Italian Ministry of Health 2017 outside the submitted work. AF has declared honoraria for advisory board from Roche and Novartis, activity as speaker for Pfizer and Lilly, travel grant from Roche, Novartis, Pfizer, Lilly and AstraZeneca outside the submitted work. The other authors have nothing to declare. Data sharing The anonymized database is available from the corresponding author upon reasonable request. The R codes used are available from the corresponding author upon reasonable request., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)