Purpose: Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake value corrected for lean body mass (SULmax) on 18 F-labeled fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) would predict pathologic complete response (pCR) to pertuzumab and trastuzumab (PT)., Patients and Methods: Patients with stage II or III, estrogen receptor-negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. 18 F-labeled fluorodeoxyglucose positron emission tomography-computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percent change in SULmax by C1D15 predicting pCR is ≤ 0.65, with a one-sided type I error rate of 10%., Results: Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 22%. Receiver operator characteristic analysis of percent change in SULmax by C1D15 yielded an area under the curve of 0.72 (80% CI, 0.64 to 0.80; one-sided P = .12), which did not reject the null hypothesis. However, between patients who obtained pCR and who did not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 41.8%; P = .004) and SULmax reduction ≥ 40% was more prevalent (83% v 52%; P = .03; positive predictive value, 31%). Participants not obtaining a 40% reduction in SULmax by C1D15 were unlikely to obtain pCR (negative predictive value, 91%)., Conclusion: Although the primary objective was not met, early changes in SULmax predict response to PT in estrogen receptor-negative and HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate tailoring of therapy in this setting., Competing Interests: Roisin M. ConnollyResearch Funding: Genentech/Roche, Puma Biotechnology, Novartis, Merck, MacrogenicsOther Relationship: Pfizer Lilja SolnesConsulting or Advisory Role: ProgenicsResearch Funding: AAA/Novartis, Progenics Vandana AbramsonEmployment: HCA HealthcareConsulting or Advisory Role: Eisai, Daiichi Sankyo, AbbvieResearch Funding: Genentech/Roche, Lilly Lisa A. CareyResearch Funding: Innocrin Pharma, Syndax, Immunomedics, Novartis, NanoString Technologies, Abbvie, Seattle GeneticsPatents, Royalties, Other Intellectual Property: Royalty-sharing agreement, investorship interest in licensed IP to startup company, Falcon Therapeutics, that is designing neural stem cell-based therapy for glioblastoma multiformeUncompensated Relationships: Sanofi, Novartis, G1 Therapeutics, Genentech/Roche, GlaxoSmithKline, Exact Sciences, AstraZeneca/Daiichi Sankyo, Aptitude HealthOpen Payments Link: https://openpaymentsdata.cms.gov/physician/179671 Minetta C. LiuResearch Funding: Eisai, Seattle Genetics, Novartis, Roche/Genentech, GRAIL, Merck, Tesaro, Menarini Silicon Biosystems, Genomic HealthTravel, Accommodations, Expenses: Grail, Merck, Menarini Silicon Biosystems, Pfizer, Genomic Health, AstraZeneca, Ionis Pharmaceuticals Mothaffar RimawiConsulting or Advisory Role: Macrogenics, Daiichi Sankyo, Seattle Genetics, GenentechResearch Funding: Pfizer Jennifer SpechtHonoraria: Nektar, Genomic Health, Daiichi SankyoConsulting or Advisory Role: Genomic Health, Nektar, Daiichi SankyoResearch Funding: Pfizer, Nektar, Merck, Myriad Pharmaceuticals, Cascadian Therapeutics, Pfizer, Minerva Biotechnologies, Seattle Genetics, Novartis, Chalasani, Xencor, Johns Hopkins University, Genentech, Dana-Farber Cancer Institute, NCITravel, Accommodations, Expenses: Nektar Anna Maria StornioloEmployment: Sophren Therapeutics, Q32Bio IncLeadership: Sophren Therapeutics, Q32Bio IncStock and Other Ownership Interests: Gilead Sciences, Moderna Therapeutics, Merck, Lilly, Gilead, Pfizer, Meridian Bioscience IncConsulting or Advisory Role: Q32bio, Tri-I TDI, Deerfield Management, Atlas Venture, Boston PharmaceuticalsResearch Funding: QUE Oncology, Pfizer Vicente ValeroHonoraria: Genentech/Roche, Merck, NovartisConsulting or Advisory Role: Genentech/Roche, Novartis, MerckTravel, Accommodations, Expenses: Genentech/Roche Christos VaklavasEmployment: Flatiron HealthHonoraria: Guidepoint GlobalConsulting or Advisory Role: Daiichi SankyoResearch Funding: Genentech, Roche, Pfizer, Incyte, Pharmacyclics, Novartis, TRACON Pharma, Innocrin Pharma, Zymeworks, H3 BiomedicineOther Relationship: Puma Biotechnology, Takeda, Daiichi SankyoUncompensated Relationships: GenentechOpen Payments Link: https://openpaymentsdata.cms.gov/physician/1306968 Ian E. KropEmployment: AMAG Pharmaceuticals, Freeline TherapeuticsLeadership: AMAG Pharmaceuticals, Freeline TherapeuticsStock and Other Ownership Interests: AMAG Pharmaceuticals, Freeline Therapeutics, VertexHonoraria: Genentech/Roche, AstraZeneca, CelltrionConsulting or Advisory Role: Genentech/Roche, Seattle Genetics, Daiichi Sankyo, Macrogenics, Taiho Pharmaceutical, Context Therapeutics, Novartis, Merck, Ionis Pharmaceuticals, Bristol Myers Squibb, AstraZenecaResearch Funding: Genentech, Pfizer Eric P. WinerHonoraria: Genentech/Roche, Genomic HealthConsulting or Advisory Role: Leap Therapeutics, Seattle Genetics, Jounce Therapeutics, GlaxoSmithKline, Carrick Therapeutics, Lilly, G1 Therapeutics, Syros Pharmaceuticals, Genentech/Roche, Gilead Sciences, ZymeworksResearch Funding: Genentech, AstraZenecaOther Relationship: InfiniteMD Antonio C. WolffConsulting or Advisory Role: Ionis PharmaceuticalsResearch Funding: Biomarin, CelldexPatents, Royalties, Other Intellectual Property: Antonio Wolff has been named as inventor on one or more issued patents or pending patent applications relating to methylation in breast cancer, and has assigned his rights to JHU, and participates in a royalty sharing agreement with JHUOpen Payments Link: https://openpaymentsdata.cms.gov/physician/357301/summary Ashley Cimino-MathewsEmployment: Vivante HealthHonoraria: Bristol Myers Squibb, RocheResearch Funding: Bristol Myers Squibb Ben H. ParkLeadership: LoxoStock and Other Ownership Interests: Loxo, CelcuityHonoraria: AstraZenecaConsulting or Advisory Role: Horizon Discovery, Foundation Medicine, Loxo, Casdin Capital, H3 Biomedicine, Jackson Laboratory for Genomic Medicine, Lilly, Celcuity, Sermonix Pharmaceuticals, PathovaxResearch Funding: Abbvie, Pfizer, GE Healthcare, LillyPatents, Royalties, Other Intellectual Property: Royalties paid through inventions at Johns Hopkins University by Horizon Discovery LtdTravel, Accommodations, Expenses: Lilly, LoxoUncompensated Relationships: Tempus Richard L. WahlStock and Other Ownership Interests: ProgenicsHonoraria: Siemens Healthineers, Bristol Myers Squibb, Jubilant DraxImage, Actinium Medical Advisory BoardConsulting or Advisory Role: Clarity PharmaceuticalsResearch Funding: Whiterabbit AI, Siemens Healthineers, Bristol Myers Squibb, Actinium PharmaceuticalsTravel, Accommodations, Expenses: Siemens Healthineers, Actinium PharmaceuticalsOther Relationship: Society of Nuclear Medicine Vered StearnsResearch Funding: Abbvie, Pfizer, Novartis, Puma Biotechnology, BioceptOther Relationship: ImmunomedicsNo other potential conflicts of interest were reported.