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Gebra Cuyún Carter,1 Maitreyee Mohanty,2 Keri Stenger,1 Claudia Morato Guimaraes,1 Shivaprasad Singuru,3 Pradeep Basa,3 Sheena Singh,3 Vanita Tongbram,2 Sherko Kuemmel,4,5 Valentina Guarneri,6 Sara M Tolaney7 1Eli Lilly and Company, Indianapolis, IN, USA; 2Global Health Economics and Outcomes Research, ICON Plc, New York, NY, USA; 3Global Health Economics and Outcomes Research, ICON Plc, Bangalore, Karnataka, India; 4Interdisciplinary Breast Unit, Kliniken Essen-Mitte (KEM), Essen, Germany; 5Charité – Universitätsmedizin Berlin, Department of Gynecology with Breast Center, Berlin, Germany; 6Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova, PD, Italy; Division of Medical Oncology 2, Istituto Oncologico Veneto IRCCS, Padova, PD, Italy; 7Dana-Farber Cancer Institute, Brookline, MA, 02215, USACorrespondence: Maitreyee MohantyGlobal Health Economics and Outcomes Research, ICON Plc., New York, NY, USAEmail Maitreyee.Mohanty@iconplc.comPurpose: Advanced breast cancer is a heterogeneous disease with several well-defined subtypes, among which, hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2–) is most prevalent. Determination of HR and HER2 status influences prognosis and, thus, disease management. Although literature on these prognostic factors exist, especially in the early breast cancer setting, it remains unclear to what extent these factors can guide clinical decision-making in the advanced disease setting. Therefore, we sought to identify the strength and consistency of evidence for prognostic factors in patients with HR+/HER2– advanced breast cancer.Methods: A systematic literature review (SLR) of the major electronic databases was conducted in November 2018 for primary research studies published since 2010. Endpoints of interest were tumor response, progression-free survival (PFS), overall survival (OS), and breast cancer-specific survival (BCSS).Results: Seventy-nine studies were included wherein all patients were diagnosed with advanced breast cancer and ≥ 50% of the population were HR+/HER2–. OS was the most commonly assessed endpoint (n=67) followed by PFS (n=33), BCSS (n=5) and tumor response (n=3). The prognostic factors with strongest evidence of association with worse OS were negative progesterone receptor status, higher tumor grade, higher circulating tumor cell (CTC) count and higher Ki67 level, number of metastatic sites (eg multiple vs single) and sites of metastases (eg presence of liver metastases vs absence), shorter time to recurrence or progression to advanced breast cancer, poor performance status, prior therapy attributes in the early or metastatic setting (type of therapy, treatment line, response of prior therapy), and race (black vs white). The prognostic factors that had strongest evidence of association with PFS included CTC count, number and sites of metastases, and absence of prior therapy or higher lines of therapy in the early or metastatic setting. The directionality of association was consistent for all prognostic factors except between lymph node and OS, and de novo metastatic breast cancer and PFS.Conclusion: Multiple disease, treatment, and patient-related prognostic factors impact survival, particularly OS, in patients with HR+/HER2– advanced breast cancer. Treatment outcomes can vary considerably due to these factors. Understanding poorer prognostic factors for patients can result in improved clinical decision-making.Keywords: advanced breast cancer, prognostic factors, survival

Background: Ribociclib + endocrine therapy (ET) showed significant progression-free survival (PFS) and overall survival (OS) benefits in the MONALEESA trials in patients with HR+ /HER2 - advanced breast cancer (ABC). We report efficacy, safety, and patient-reported outcomes (PROs) across age groups, including older patients, in these trials., Methods: Data from the MONALEESA-2, -3, and -7 trials for pre- and postmenopausal patients receiving first-line treatment for ABC were pooled and analyzed by age (<65y, 65-74y, and ≥75y). PFS, OS, time to first chemotherapy (TTC), and time to definitive deterioration (TTD) in PROs were evaluated using Kaplan-Meier methods; a Cox regression model stratified by study and liver/lung metastasis was used for hazard ratios., Results: Among 1229 patients included, 63 % were < 65y, 27 % were 65-74y, and 10 % were ≥ 75y. Baseline characteristics were generally well balanced. Regardless of patient age, ribociclib+ET showed a consistent PFS and OS benefit and delayed TTC. With ribociclib+ET, the most common first subsequent treatment was ET. Safety results were consistent with those in the overall trial population; no new signals were identified. Rates of discontinuation due to AEs with ribociclib+ET were numerically higher in patients ≥ 75y. Among patients who discontinued treatment due to AEs, the percentage without prior dose reduction was higher in those ≥ 75y. A PRO benefit with ribociclib+ET was observed across all age groups for pain and fatigue scores., Conclusions: This analysis demonstrated that ribociclib+ET is an effective and well-tolerated treatment for patients of all age groups with HR+ /HER2 - ABC, including older patients. (MONALEESA-2, NCT01958021; MONALEESA-3, NCT02422615; MONALEESA-7, NCT02278120)., Competing Interests: Declaration of Competing Interest L. Hart reports institutional grants and personal fees from Novartis. S-A. Im reports personal fees from AstraZeneca, Novartis, Hanmi, Pfizer, Eisai, Roche, Lilly, GSK, MSD, Daiichi Sankyo, Idience, Bertis; research grants from AstraZeneca, Pfizer, Eisai, Roche, Daewoong Pharm, Boryung Pharm, Daiichi Sankyo. S. M. Tolaney reports institutional grants from Eli Lilly, Novartis, AstraZeneca, Merck, Nektar, Pfizer, Genentech/Roche, Exelixis, Bristol Myers Squibb, Eisai, NanoString, Cyclacel, Sanofi, Odonate, Gilead; personal fees from Eli Lilly, Novartis, AstraZeneca, Merck, Nektar, Pfizer, Genentech/Roche, Exelixis, Bristol Myers Squibb, Eisai, NanoString, Puma, Sanofi, Odonate, Seagen, G1 Therapeutics, Athenex, OncoPep, Kyowa Kirin Pharmaceuticals, Daiichi Sankyo, CytomX, Samsung Bioepis Inc., Certara, Mersana Therapeutics, Gilead, OncoSec, Chugai Pharma, Ellipses Pharma, 4D Pharma, BeyondSpring Pharma, OncXerna, Infinity Therapeutics, Zentalis, Zymeworks. M. Campone reports institutional grants from Pfizer, AstraZeneca, Sanofi, Gilead, Novartis, Lilly, AbbVie, Servier, Sandoz, Accord. T. J. Pluard has nothing to disclose. B. Sousa has nothing to disclose. G. Freyer has nothing to disclose. T. Decker reports personal fees from Novartis, iOMEDICO. K. Kalinsky reports personal fees from Eli Lilly, Pfizer, Novartis, AstraZeneca, Daiichi Sankyo, Puma, 4D Pharma, OncoSec, Immunomedics, Merck, Seagen, Mersana, Cyclacel, Myovant; institutional research funding grants from Genentech/Roche, Novartis, Eli Lilly, AstraZeneca, Daiichi Sankyo, Ascentage; spouse was prior employee of EQRX, GRAIL for which employment and stock ownership is reported. G. Sopher, M. Gao, H. Hu report employment and stock ownership from Novartis. S. Kuemmel reports personal fees from Roche, Celgene, Novartis, AstraZeneca, Pfizer, Lilly, Amgen, Somatex, Daiichi Sankyo, PFM Medical, MSD Oncology, SonoScape, Gilead Sciences, Agendia; travel and accommodation support from Roche, Daiichi Sankyo; uncompensated relationship with WSG., (Copyright © 2025 Elsevier Ltd. All rights reserved.)

Background: Despite treatment advances for patients with early-stage triple-negative breast cancer (TNBC) and hormone receptor (HR)-low/human epidermal growth factor receptor 2-negative (HER2-) breast cancer, treatments that improve clinical outcomes while mitigating toxicity are needed. Datopotamab deruxtecan (Dato-DXd), a TROP2-directed antibody-drug conjugate consisting of a humanized IgG1 monoclonal antibody attached via a plasma-stable cleavable linker to a topoisomerase-I inhibitor payload, has shown efficacy alone or in combination with durvalumab, a selective, high-affinity anti-programmed cell death ligand 1 antibody, in early-phase clinical studies., Objectives: The primary objective of TROPION-Breast04 is to evaluate the efficacy and safety of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2- breast cancer., Design: This is an ongoing, international, phase III, open-label, randomized controlled study., Methods and Analysis: Approximately 1728 patients (aged ⩾18 years) will be randomized 1:1 to eight cycles of neoadjuvant Dato-DXd (6 mg/kg intravenously (IV) every 3 weeks (Q3W)) plus durvalumab (1120 mg IV Q3W) followed by nine cycles of adjuvant durvalumab (1120 mg IV Q3W) with or without chemotherapy versus eight cycles of pembrolizumab (200 mg IV Q3W) plus chemotherapy followed by nine cycles of adjuvant pembrolizumab (200 mg IV Q3W) with or without chemotherapy. Dual primary endpoints are pathological complete response by blinded central review and event-free survival by investigator assessment. Secondary endpoints include overall survival (key), distant disease-free survival, patient-reported outcomes, and safety., Ethics: The study is approved by independent ethics committees and/or institutional review boards at each study site. All patients will provide written informed consent., Discussion: This study will evaluate the potential use of neoadjuvant Dato-DXd plus durvalumab followed by adjuvant durvalumab with or without chemotherapy versus standard of care in patients with previously untreated early-stage TNBC or HR-low/HER2- breast cancer. The findings of this trial could lead to promising treatment options for these patients., Trial Registration: ClinicalTrials.gov identifier: NCT06112379., Competing Interests: H.L.M. has participated in advisory boards with Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Genentech/Roche, Immunomedics, Merck, OBI Pharma, Pfizer, Puma, Spectrum Pharmaceuticals, Syndax Pharmaceuticals, Peregrine, Calithera, Daiichi-Sankyo, Seattle Genetics, AstraZeneca, Gilead, Crown Bioscience, and TapImmune; has received research grants (institution) from Bristol-Myers Squibb, BTG/Boston Scientific, and Merck. S.M.T. has acted as a consultant or advisor for Novartis, Pfizer (SeaGen), Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Sanofi, Bristol Myers Squibb, CytomX Therapeutics, Daiichi-Sankyo, Gilead, Zymeworks, Zentalis, Blueprint Medicines, Reveal Genomics, Sumitovant Biopharma, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, Hengrui USA, Cullinan Oncology, Circle Pharma, and Arvinas; has received research funding (institution) from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, Eisai, AstraZeneca, NanoString Technologies, Gilead, Seattle Genetics, OncoPep, Daiichi-Sankyo; has received travel or accommodation expenses from Eli Lilly, Sanofi, Gilead, and Jazz Pharmaceuticals. R.D. has received consulting fees from AstraZeneca, MSD, Roche, Pfizer, Eisai, Novartis, and Lilly. P.S. has received consulting fees from AstraZeneca, Bayer, Boehringer Ingelheim, Merck, Novartis, Pfizer, Puma, Roche, Eisai, and Celgene; conducted contracted research for Astellas, AstraZeneca, Genentech, Novartis, OncoGenex Pharmaceuticals, Roche, and Medivation. J.A. has no conflicts of interest to declare. Q.L. has acted as a speaker for Roche, AstraZeneca, Pfizer, Eisai, and Novartis; reports participation in speakers’ bureaus for Roche, AstraZeneca, Pfizer, Eisai, and Novartis; participated in advisory boards with AstraZeneca and Pfizer; has received funding from Eisai. J.L.M. has acted as a speaker for Prime Oncology and Targeted Oncology; participated in advisory boards with Sermonix; has acted as a Principal Investigator with Olema, Sermonix, and Seagen (now Pfizer); has acted as an advisor for Pfizer, Novartis, Puma, Seagen (now Pfizer), Olema, Genentech, GSK, AstraZeneca, and Sermonix. N.N. has received honoraria from AstraZeneca, Chugai Pharma, Daiichi-Sankyo/UCB Japan, Eisai, Kyowa Kirin, Lilly Japan, MSD, Novartis, Pfizer, and Taiho Pharmaceutical; has received research funding from Boehringer Ingelheim, Chugai Pharma, Daiichi-Sankyo, Eisai, Kyowa Kirin, Lilly Japan, Mochida Pharmaceutical Co. Ltd, Nihon Medi-Physics, Nippon Kayaku, Pfizer, Puma Biotechnology, Taiho Pharmaceutical, and Takeda. Y.H.P. has received honoraria from AstraZeneca, Daiichi-Sankyo, Eisai, Lilly, MSD, Novartis, Pfizer, and Roche; has acted as a consultant or advisor for AstraZeneca, Boryung, Daiichi-Sankyo, Eisai, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, and Roche; has received research funding from AstraZeneca, Gencurix, Genome Insight, NGeneBio, Pfizer, and Roche; has received travel and accommodation expenses from Gilead Sciences. G.W. has acted as a speaker for AstraZeneca, MSD, Pfizer, and Roche; participated in advisory boards with Novartis, Organon, Roche, MSD, and Daiichi-Sankyo; has received research grants from Astellas Pharma, AstraZeneca, Ipsen, Janssen, Novartis, Pfizer, Roche, Takeda, GlaxoSmithKline, Bayer, and Libbs; has acted as a Principal Investigator with AstraZeneca, BMS, Lilly, and MSD. G.B. has received honoraria from AstraZeneca/Daiichi-Sankyo, Eisai, Exact Sciences, Gilead Sciences, Lilly, Menarini, MSD, Novartis, Pfizer, Roche, and Seagen; has acted as a consultant or advisor for Agendia, AstraZeneca, AstraZeneca/Daiichi-Sankyo, Daiichi-Sankyo Europe GmbH, Eisai, Exact Sciences, Gilead Sciences, Lilly, MSD, Novartis, Pfizer, Roche, and Seagen; has received research funding (institution) from Gilead Sciences; has received travel or accommodations expenses from AstraZeneca/Daiichi-Sankyo, Gilead Sciences, Novartis, Pfizer, and Roche. J.C.A. has received honoraria from AstraZeneca, Genentech, Genomic Health, Novartis, and Puma Biotechnology; has acted as a consultant or advisor for AstraZeneca, Athenex, Daiichi-Sankyo Pharmaceutical, Genentech, Genomic Health, Immunomedics, Myriad Genetic Laboratories, Novartis, Pfizer, Puma Biotechnology, and Seagen; has participated in speakers’ bureaus with AstraZeneca, Genentech, Genomic Health, Novartis, and Puma Biotechnology. R.K. is an employee of AstraZeneca. N.R. is an employee of AstraZeneca. B.P. has received consulting fees (institutional) from AstraZeneca, Seagen, Gilead, Novartis, Lilly, MSD, Pierre Fabre (personal), and Daiichi-Sankyo (institutional/personal); has received research funding (institutional) from AstraZeneca, Daiichi-Sankyo, Gilead, Seagen, and MSD; has received travel support from AstraZeneca, Pierre Fabre, Lilly, Daiichi-Sankyo, and MSD. S.L. has acted as a consultant or advisor for AbbVie, Amgen, AstraZeneca/MedImmune, Bristol-Myers Squibb, Celgene, Daiichi-Sankyo, EirGenix, Eisai Europe, GlaxoSmithKline, Lilly, Menarini Group, Merck KGaA, MSD Oncology, Novartis, Olema Pharmaceuticals, Pfizer, Pierre Fabre, Relay Therapeutics, Roche, Sanofi, and Seagen; reports participation in speakers’ bureaus for AstraZeneca, Daiichi-Sankyo Europe GmbH, Gilead Sciences, Novartis, Pfizer, Roche, and Seagen; has received research funding from AbbVie, AstraZeneca, Celgene, Daiichi-Sankyo, Gilead Sciences, Menarini Group, Molecular Health, Novartis, Pfizer, and Roche; reports patents, royalties, or other intellectual property: Digital Ki67 Evaluator, VM Scope GmbH, Patent Issued EP15702464.7, Patent Pending EP14153692.0, Patent Pending EP19808852.8, Patent Pending EP21152186.9., (© The Author(s), 2025.)

Background: Cyclin-dependent kinase (CDK) 4/6 inhibitors can significantly extend survival when given in combination with endocrine therapy in hormone receptor-positive metastatic breast cancer patients. However, their activity has been relatively underexplored in patients with metastatic triple-negative breast cancer (mTNBC)., Methods: We conducted a single-arm phase II study of abemaciclib monotherapy in patients with retinoblastoma-positive (Rb+) mTNBC. Patients were treated with abemaciclib 200 mg orally twice daily until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint was objective response rate (ORR); secondary endpoints included progression-free survival (PFS), overall survival (OS), clinical benefit rate (CBR), disease control rate (DCR), and safety and tolerability., Results: A total of 27 patients were enrolled before the trial was closed early due to slow accrual. Patients had received a median of 2 lines of systemic therapy in the metastatic setting prior to enrollment. After a median follow-up of 28.5 months, the ORR was 0%, the CBR was 14.8%, and the DCR was 22.2%. The median PFS was 1.94 months (95% confidence interval (CI):1.84-11.47), and the median OS was 8.44 months (95% CI:4.57-15.57). Median PFS and OS did not differ significantly based on AR and PD-L1 status. Pre-treatment gene expression profiling of tumor tissue provided some hypothesis-generating insights into biological features associated with clinical benefit in this study. The most common treatment-related adverse events of grade 2 or higher were diarrhea (40.7%), neutropenia (40.7%), anemia (29.6%), and nausea (29.6%)., Conclusions: Abemaciclib monotherapy did not show clinical activity in patients with pretreated Rb+ metastatic TNBC.

Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is currently approved to treat metastatic triple-negative breast cancer and HR+/HER2- breast cancer, and is under clinical investigation for a range of other tumor types. This review describes its mode of action, development, and clinical outcomes. SG is composed of SN-38 (a topoisomerase I inhibitor derived from irinotecan) covalently linked to an anti-Trop-2 monoclonal antibody (sacituzumab; hRS7) via a hydrolysable CL2A linker. SN-38 was chosen due to its potent antitumor activity; CL2A occupies the most effective position on SN-38 for maintaining stability during transport, with pH-sensitive payload release in the tumor, and the antigen target (Trop-2) is highly expressed on many solid tumors. SG has an ~8:1 drug-to-antibody ratio and delivers therapeutic SN-38 concentration to Trop-2+ expressing tumor cells via rapid internalization and efficient payload release. Free SN-38 can subsequently enter the tumor microenvironment and kill adjacent tumor cells with or without Trop-2 expression (bystander effect). SN-38 induces DNA breakage and inhibits nucleic acid synthesis via a drug-induced topoisomerase 1:DNA complex that interferes with cell proliferation, causing apoptosis. Dose-finding studies support SG 10 mg/kg on days 1 and 8 of a 21-day cycle as the monotherapy dose for clinical use; this was determined by therapeutic index improvement based on efficacy and safety. Payload-linker dynamics and SG potency ensure continued tissue penetration. Neutropenia and diarrhea are the most common grade ≥ 3 treatment-emergent adverse events with SG, but they are manageable. Efficacy of SG has been demonstrated across a broad spectrum of solid tumors.

The therapeutic importance of subsetting patients with HER2-negative breast cancer according to their tumors' cellular HER2 expression (e.g., HER2-low vs. HER2-0) is relatively new, stemming from the dramatic results of the DESTINY-04 trial which established HER2-low expression as actionable. Most prior observational research of traditionally HER2-negative patients suggests that tumor behavior and biology do not vary according to HER2-low vs. HER2-0 expression, though some studies suggest otherwise. Here we studied this question in women with metastatic breast cancer (MBC) who were treated with standard single agent chemotherapy in the setting of clinical trials carried out in the pre-DESTINY-04 era. After pooling data from 142 female patients with MBC across historic clinical trials and categorizing them according to HER2 expression (i.e., HER2-0 or HER2-low), we evaluated associations between HER2 expression and the outcomes of both progression-free survival (PFS) and overall survival (OS) with both Kaplan-Meier and Cox proportional hazards methods. Studying data from an era when quantifying amounts of tumor HER2 expression in HER2-negative patients was neither standardized nor clinically actionable, we found no meaningful clinical differences in PFS or OS according to HER2-low vs. HER2-0 status, supporting prior findings of no biologic differences., Competing Interests: Declarations. Conflict of interest: Elizabeth Lamont: all support for the present manuscript: salaried employee of Medidata, Stock or stock options: dassault systemes. Emily Stein—none. Paolo Tarantino: consulting fees: Novartis, Eli Lilly, AstraZeneca, Genentech/Roche, Gilead, Honoraria: AstraZeneca, support for attending meetings and/or travel: Daiichi Sankyo, Sara Tolaney: Grants or contracts (to support DFCI): Genentech/Roche, Merck, Exelixis, BMS, Eisai, AstraZeneca, NanoString Technology, Gilead, Seattle Genetics, OncoPrep, Daiichi Sankyo, Consulting fees: Novartis, Pfizer, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, BMS, Eisai, Gilead, Seattle Genetics, OncoPrep, Daiichi Sankyo, Zentalis, Blueprint Medicines, Reveal Genomics, ARC Therapeutics, Infinity Therapeutics, Sumitovant Biopharma, Seattle Genetics, CytomX Therapeutics, OncXerna, Zymeworks, Zetagen, Umoja Biopharma, Artios Pharma, Menarini/Stemline, Aadi Bio, Bayer, Incyte Corp, Jazz Pharmaceuticals, Natera, Tango Therapeutics, Systimmune, eFFECTOR, Hengrui USA, Support for attending meetings and/or travel: Gilead, Eli Lilly, Sanofi, Participation in DSMB or advisory board: Eli Lilly, Stemline, SeaGen, AstraZeneca, BMS, Genentech/Roche, Daiichi Sankyo, Novartis. Corinne Ahlberg: Stock or stock options: Dassault Systemes. Krishna Chinnathambu—none. Jiezhi Qi—none. Jackie Bilan—none. Ruthie Davi: Stock or stock options: Dassault Systemes. Lisa Ensign: Grants or contracts: annual teaching contract at University of Colorado for course in the area of ethics and responsible conduct of research, Stock or stock options: Dassault Systemes, (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Background: The risk of recurrence in patients with small, lymph node-negative, human epidermal growth factor receptor 2 (HER2)-positive breast cancers untreated with adjuvant chemotherapy/HER2-directed therapy is uncertain. To investigate this, the authors conducted a retrospective, population-based study of chemotherapy use and breast cancer-specific survival (BCSS) among patients with stage IA HER2-positive breast cancer., Methods: The authors analyzed Surveillance, Epidemiology, and End Results data from patients diagnosed with stage IA HER2-positive breast cancer from 2010 to 2019. They examined the frequency of chemotherapy use by tumor size and hormone receptor (HR) status and applied multivariate logistic regression to assess the factors associated with receipt of chemotherapy. BCSS was evaluated and performed multivariable Cox regression was performed to evaluate the association between chemotherapy receipt and BCSS., Results: Among 12,896 patients, 74.0% had HR-positive/HER2-positive breast cancer, and 26.0% had HR-negative/HER2-positive breast cancer. Adjuvant chemotherapy was received by to 58.9% of patients, with lower utilization for those who were older, Hispanic or Asian/Pacific Islander, separated/divorced/widowed, or had a lower median household income. The median follow-up was 46 months. Among the patients who had pathologic T1 (pT1) microscopic, pT1a, or pT1b tumors, the 5-year BCSS rate was 97.6%-99.6% in those who had no evidence of chemotherapy receipt in the medical record versus 98.4%-100.0% in those who did receive chemotherapy. Among patients who had pT1c tumors and had no evidence of chemotherapy receipt, the 5-year BCSS rate was 92.1% for those with HR-negative/HER2-positive breast cancer and 96.0% for those with HR-positive/HER2-positive breast cancer. Patients who had pT1c tumors and received chemotherapy had a 5-year BCSS rate of 96.7% in those with HR-negative/HER2-positive breast cancer and 98.7% in those with HR-positive/HER2-positive breast cancer., Conclusions: In this large, population-based study of patients with stage IA HER2-positive breast cancer, patients who had tumors ≤1 cm had excellent outcomes with or without chemotherapy. Patients with pT1c tumors had a greater increase in BCSS with the receipt chemotherapy., (© 2025 The Author(s). Cancer published by Wiley Periodicals LLC on behalf of American Cancer Society.)