Academic Journal
Molecular and immune profiling of HER2-low, HER2 ultra-low, and HER2-null male breast cancer.
| Τίτλος: | Molecular and immune profiling of HER2-low, HER2 ultra-low, and HER2-null male breast cancer. |
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| Συγγραφείς: | Trapani D; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: Dario.trapani@ieo.it., Deshmukh SK; Caris Life Sciences, Phoenix, AZ, USA., Wu S; Caris Life Sciences, Phoenix, AZ, USA., Xiu J; Caris Life Sciences, Phoenix, AZ, USA., Jayachandran P; El Camino Hospital, Mountain View, CA, USA., Gandhi S; Winship Cancer Institute, Emory University, Atlanta, GA, USA., Lin NU; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA., Curigliano G; European Institute of Oncology, IRCCS, Milan, Italy; Department of Oncology and Hemato-Oncology, University of Milano, Milano, Italy., Spanheimer PM; University of North Carolina at Chapel Hill, Chapel Hill, NC, USA., Abravanel DL; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA., Radovich M; Caris Life Sciences, Phoenix, AZ, USA., Lustberg M; Yale School of Medicine, Yale University, New Haven, CT, USA., Graff SL; Lifespan Cancer Institute, Legorreta Cancer Center, Brown University, Providence, RI, USA., Sledge GW Jr; Caris Life Sciences, Phoenix, AZ, USA., Tolaney SM; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA., Leone JP; Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA; Harvard Medical School, Boston, MA, USA. Electronic address: JoseP_Leone@DFCI.HARVARD.EDU. |
| Πηγή: | Breast (Edinburgh, Scotland) [Breast] 2026 Oct; Vol. 89, pp. 104901. Date of Electronic Publication: 2026 Aug 12. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 9213011 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1532-3080 (Electronic) Linking ISSN: 09609776 NLM ISO Abbreviation: Breast Subsets: MEDLINE |
| Imprint Name(s): | Publication: 2002- : Amsterdam : Elsevier Original Publication: Edinburgh ; New York : Churchill Livingstone, c1992- |
| Ιατρικοί όροι (MeSH): | Breast Neoplasms, Male*/genetics , Breast Neoplasms, Male*/immunology , Erb-b2 Receptor Tyrosine Kinases*/genetics , Erb-b2 Receptor Tyrosine Kinases*/metabolism, Biomarkers, Tumor/genetics ; Class I Phosphatidylinositol 3-Kinases/genetics ; Male ; Humans ; Mutation ; Gene Expression Profiling ; Middle Aged ; High-Throughput Nucleotide Sequencing ; Aged ; Adult ; Transcriptome |
| Περίληψη: | Background: HER2 expression is described along a biological continuum from null to positive and serves as a critical biomarker for therapeutic guidance in breast cancer (BC). While HER2-low and ultra-low categories have emerged as actionable targets for antibody-drug conjugates (ADCs) in female BC, their molecular and immune characteristics remain largely unexplored in male breast cancer. Methods: We profiled 214 male breast tumors using next-generation sequencing and whole-transcriptome sequencing to assess mutational, transcriptomic, and immune landscapes. Tumor mutational burden (TMB) was defined as high if > 10 mutations/Mb. Immune cell fractions were inferred using Quantiseq deconvolution. Results: Among 214 samples, 66 (30.8%) were HER2-null, 53 (24.8%) HER2 ultra-low, 80 (37.4%) HER2-low, and 15 (7.0%) HER2-positive. HER2 ultra-low tumors exhibited a higher prevalence of PIK3CA mutations (39.2% vs 22.6%, p ≤ 0.05) compared to HER2-null. No significant differences were observed in TMB-high frequency or PD-L1 expression across subgroups. Immune composition differed primarily between HER2-null and HER2-expressing subgroups: HER2-ultra-low tumors showed higher B-cell infiltration, whereas HER2-null tumors were enriched in neutrophils. Transcriptomic analysis revealed upregulation of selected stemness-associated genes (NANOG, KLF4, POU5F1) and CEACAM1 in HER2-null tumors, while HER2-low and HER2-ultra-low tumors were largely similar across most molecular and immune readouts in this cohort. Conclusions: HER2-null male breast cancer appears to represent the most biologically divergent subgroup within the HER2-negative spectrum, whereas HER2-low and HER2-ultra-low tumors were largely similar in this cohort. These findings support further investigation of HER2-null disease as a distinct biological state and provide hypothesis-generating data for biomarker development in this rare population. (Copyright © 2026 The Authors. Published by Elsevier Ltd.. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interestsNancy U. Lin reports institutional research support from Genentech, Pfizer, Merck, Seattle Genetics, Zion Pharmaceuticals (as part of Roche/GNE), Olema Pharmaceuticals, AstraZeneca, Iksuda, Stemline/Menarini; consulting honoraria from Pfizer/SeaGen, Daiichi Sankyo, AstraZeneca, Olema Pharmaceuticals, Stemline/Menarini, Artera Inc., Eisai, Shorla Oncology, Denali Therapeutics, Genentech; royalties from Up to date (book); and travel support from Olema, AstraZeneca, Daiichi Sankyo. Sara M. Tolaney reports consulting or advisory role at Novartis, Pfizer/SeaGen, Merck, Eli Lilly, AstraZeneca, Genentech/Roche, Eisai, Bristol Myers Squibb/Systimmune, Daiichi Sankyo, Gilead, Blueprint Medicines, Reveal Genomics, Artios Pharma, Menarini/Stemline, Bayer, Jazz Pharmaceuticals, Cullinan Oncology, Circle Pharma, Arvinas, BioNTech, Launch Therapeutics, Zuellig Pharma, Johnson&Johnson/Ambrx, Bicycle Therapeutics, BeiGene Therapeutics, Mersana, Summit Therapeutics, Avenzo Therapeutics, Aktis Oncology, Celcuity, Boehringer Ingelheim, Samsung Bioepis, Olema Pharmaceuticals, Tempus, Boundless Bio, Denali Therapeutics, Relay Therapeutics, Corcept, Ottima Pharma, Ellipses Pharma; institutional research funding from Genentech/Roche, Merck, Exelixis, Pfizer, Lilly, Novartis, Bristol Myers Squibb, AstraZeneca, NanoString Technologies, Gilead, SeaGen, OncoPep, Daiichi Sankyo, Menarini/Stemline, Jazz Pharmaceuticals, Olema Pharmaceuticals; scientific advisory board role at Valanx BioTech; and travel support from Lilly, Gilead, Jazz Pharmaceuticals, Pfizer, Roche, AstraZeneca. Jose Pablo Leone reports receiving research funding from Kazia Therapeutics, AstraZeneca, and Lilly, and consulting honoraria from Minerva Biotechnologies. Stephanie L. Graff reports receiving consulting honoraria from Pfizer, Seagen, AstraZeneca, Daiichi Sankyo, Gilead Sciences, Menarini Stemline, Genentech, Novartis, and Lilly/Loxo@Lilly; has stock ownership in HCA Healthcare; and has received research funds (to institution) from AstraZeneca, Novartis, Daiichi Sankyo. Giuseppe Curigliano reports serving on the advisory boards of Roche, Novartis, Lilly, Pfizer, Astra Zeneca, Daiichi Sankyo, Ellipsis, Veracyte, Exact Science, Celcuity, Merck, BMS, Gilead, Sanofi, and Menarini during the conduct of the study. Sachin Kumar Deshmukh, Sharon Wu, Joanne Xiu, Milan Radovich, and George W. Sledge Jr. Report being employed by Caris Life Sciences. Milan Radovich reports stock ownership in Caris Life Sciences. Maryam Lustberg reports consulting with AstraZeneca, Daiichi-Sankyo, Gilead, Novartis and Menarini. The remaining authors declare no conflicts of interest. |
| Grant Information: | R37 CA292075 United States CA NCI NIH HHS |
| Contributed Indexing: | Keywords: Genomic profile; HER2-Low; HER2-Null; Male breast cancer; PIK3CA |
| Substance Nomenclature: | EC 2.7.10.1 (Erb-b2 Receptor Tyrosine Kinases) EC 2.7.10.1 (ERBB2 protein, human) 0 (Biomarkers, Tumor) EC 2.7.1.137 (Class I Phosphatidylinositol 3-Kinases) EC 2.7.1.137 (PIK3CA protein, human) |
| Entry Date(s): | Date Created: 20260818 Date Completed: 20260916 Latest Revision: 20260916 |
| Update Code: | 20260917 |
| PubMed Central ID: | PMC13507845 |
| DOI: | 10.1016/j.breast.2026.104901 |
| PMID: | 42612560 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1532-3080 |
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| DOI: | 10.1016/j.breast.2026.104901 |