Background: Treatment for HER2-positive (+) metastatic breast cancer has improved in the last decade. We analyzed treatment changes over time and their impact on patients outcomes in a real-world dataset., Methods: Data from 637 HER2+ patients with metastatic breast cancer enrolled in the multicenter Italian GIM14/BIOMETA study were retrieved. Progression-free survival (PFS) over time was evaluated according to the type of anti-HER2 therapy, disease onset (de novo vs. relapsing), metastatic site, and year of treatment (2000-2013 vs. 2014-2020)., Results: Median follow-up was 64.4 months. Overall, for first-line therapies, mPFS was 16.5 vs 19.5 months for patients treated in 2000-2013 vs 2014-2020 (HR: 0.78, 95% CI:0.65-0.94, P = 0.008). mPFS improved over time in all patients except for those with brain metastasis. Interestingly mPFS was 17.4 vs13.4 months (HR, 1.49; 95% CI, 1.13-1.98, P = 0.005) in 2000-2013 and 24.4 vs 20.9 months (HR 1.04; 95% CI 0.78-1.40 p = 0.77) in 2014-2020 in pts without vs with liver metastases. For second line therapies, the overall median PFS was 9.6 months (95% CI, 8.31-10.97) and did not change over time., Conclusion: Median first-line PFS improved since 2014, mainly due to the introduction of pertuzumab. The outcome of patients with liver metastases appears to have improved in recent years. Patients with brain metastases had the worst PFS, which also did not improve over time., Competing Interests: Declaration of competing interest G.A. reports support for the present manuscript from Astra Zeneca and Istitutional Grant from Astra Zeneca; consulting fees from Astra Zeneca, Daiichi-Sankyo, Novartis, Roche, Pfizer, Eli Lilly, Gilead, Seagen; personal fees for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra Zeneca, Daichii Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, Novartis, Roche, Seagen, Viatris; support for attending meetings and/or travel from Daichii - Sankyo, Roche, Novartis; participation on a Data Safety Monitoring Board or Advisory Board for Astra Zeneca, Daichii - Sankyo, Eisai, Eli Lilly, Gilead, Novartis, Roche, Seagen. C.B. reports personal fees for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Eli Lilly, Novartis, Pfizer; personal fees for support for attending meetings and/or travel from Roche, Novartis; personal fees for participation on a Data Safety Monitoring Board or Advisory Board from Roche, Novartis. C.D.A. reports personal fees from AstraZeneca, Lilly, GSK, Novartis, Seagen, and Pfizer, Advisory Board for Roche, AstraZeneca, Lilly, GSK, Novartis, Seagen, and Pfizer, support for attending meetings and/or travel AstraZeneca, Lilly, GSK, Novartis, Celgene, and Pfizer, grants (to the Institution) from Novartis. M.D.L. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Eli Lilly, Menarini; support for attending meetings and/or travel from Gilead, Roche, Astra Zeneca, Novartis, Roche, Pfizer, Gilead, Seagen, Daiichi-Sankyo, Pfizer, Eli Lilly, Genetic, Pierre Fabre, GSK, Exact Sciences, Tomalab, Eisai, MSD and participation on a Data Safety Monitoring Board or Advisory Board for Seagen, Eli Lilly, Novartis, Pierre Fabre, Sanofi Genzyme, GSK, Gilead, Astra-Zeneca, Daiichi-Sankyo, MSD; Roche, Eisai, Exact Scences. L.D.M. reports grants to the Institution for patient enrollment in studies from Eli Lilly, Novartis, Roche, Daiichi - Sankyo, Seagen; consulting fees from Ely Lilli, Roche, Novartis, Pfizer, Astra Zeneca, MSD, Seagen, Gilead, Pierre Fabre, Eisai, Exact sciences, Ipsen, Agendia, GSK, Daiichi – Sankyo; support for attending meetings and/or travel from Roche, Pfizer, Eisai, Daiichi - Sankyo; participation on a Data Safety Monitoring Board or Advisory Board for Novartis, Roche, Eli Lilly, Pfizer, Daiichi - Sankyo, Exact sciences, Gilead, Pierre Fabre, Eisai, Astra Zeneca, Agendia, GSK. M.D.M reports personal fees for Advisory boards or consultant role: Astra Zeneca, Novartis, Roche, Pfizer, Eisai, MSD, Janssen, Boehringer Ingelheim, Takeda, Amgen, Merck, Servier and research grant to the Institution: Tesaro, GlaxoSmithKline. A.F. reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Astra Zeneca, Eli Lilly, Pfizer, Novartis, Gilead; support for attending meetings and/or travel for Astra Zeneca, Roche, Gilead, Eli Lilly; participation on a Data Safety Monitoring Board or Advisory Board for Roche, Novartis, Lilly, Pfizer, MSD, Dompè, Pierre Fabre, Eisai, Sophos, Epionpharma, Gilead, Seagen, Astra Zeneca, Exact Science. M.G. reports consulting fees from Lilly, Celgene, Novartis, Pfizer, Astra Zeneca, Daiichi-Sankyo, MSD, Gilead, payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events for Lilly, Celgene, Novartis, Pfizer, Istituto Gentili, Eisai Europe Ltd, Roche Astra Zeneca, Daiichi - Sankyo, MSD, Gilead, support for attending meetings and/or travel from Novartis, Pfizer, Roche. L.M. reports personal fees from MSD for lectures, presentations, speakers’ bureaus, manuscript writing or educational events and support for attending meetings and/or travel from Janssen. F.P. reports consulting fees from Astra Zeneca, Daichii - Sankyo, Novartis, Roche; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Astra Zeneca, Daichii – Sankyo, Eisai, Eli Lilly, Exact Sciences, Gilead, Novartis, Roche, Seagen, Viatris; support for attending meetings and/or travel from Daichii - Sankyo, Roche; participation on a Data Safety Monitoring Board or Advisory Board for Astrazeneca, Daichii – Sankyo, Eisai, Eli Lilly, Gilead, Novartis, Roche, Seagen, Viatris. F.R reports payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Roche, Astra Zeneca, Lilly, Pfizer, Novartis, Gilead; support for attending meetings and/or travel from Astra Zeneca, Roche, Gilead, Lilly; participation on a Data Safety Monitoring Board or Advisory Board for Roche, Novartis, Eli Lilly, Pfizer, MSD, Dompè, Pierre Fabre, Eisai, Sophos, Epionpharma, Gilead, Seagen, Astra Zeneca, Exact Science. F.S. reports honoraria for presentations and educational materials from Novartis. Authors not mentioned declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)