oncotomskСибирский онкологический журналSiberian journal of oncology1814-48612312-3168Tomsk National Research Medical Сепtеr of the Russian Academy of Sciences10.21294/1814-4861-2026-25-1-135-145oncotomsk-4120Research ArticleОБЗОРЫREVIEWSHER2-low рак молочной железы: новая биологическая сущность или терапевтическая дефиниция? Современный взгляд на проблемуHER2-low breast cancer: a new biological entity or a therapeutic defnition? A current view of the problemhttps://orcid.org/0000-0002-1195-4008ВторушинС. В.VtorushinS. V.

Вторушин Сергей Владимирович, доктор медицинских наук, профессор, заместитель директора по научной работе и трансляционной медицине, руководитель отделения общей и молекулярной патологии; профессор кафедры патологической анатомии Researcher ID (WOS): S-3789-2016. Author ID (Scopus): 26654562300. 

634009, г. Томск, пер. Кооперативный, 5;634050, г. Томск, Московский тракт, 2

Sergey V. Vtorushin, MD, DSc, Professor, Deputy Director for Research and Translational Medicine, Head of General and Molecular Pathology Department; Professor, Pathology Department Researcher ID (WOS): S-3789- 2016. Author ID (Scopus): 26654562300.

5, Kooperativny St., Tomsk, 634009;2, Moskovsky trakt, Tomsk, 634050

https://orcid.org/0000-0003-0829-0340ЧерняковА. А.ChernyakovA. A.

Черняков Александр Алексеевич, младший научный сотрудник отделения общей онкологии 

634009, г. Томск, пер. Кооперативный, 5

Aleksandr A. Chernyakov, MD, Junior Researcher, Department of General Oncology 

5, Kooperativny St., Tomsk, 634009

a.cherniackow@yandex.ruhttps://orcid.org/0000-0003-2061-8417ТаширеваЛ. А.TashirevaL. A.

Таширева Любовь Александровна, доктор медицинских наук, заведующая лабораторией молекулярной терапии рака Researcher ID (WОS): C-8222-2012. Author ID (Scopus): 55234960400.

634009, г. Томск, пер. Кооперативный, 5

Liubov A. Tashireva, MD, DSc, Head of the Laboratory of Molecular Cancer Therapy Researcher ID (WОS): C-8222-2012. Author ID (Scopus): 55234960400 

5, Kooperativny St., Tomsk, 634009

Научно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наук; ФГБОУ ВО «Сибирский государственный медицинский университет» Минздрава РоссииРоссияCancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences; Siberian State Medical University, Ministry of Health of RussiaRussian FederationНаучно-исследовательский институт онкологии, Томский национальный исследовательский медицинский центр Российской академии наукРоссияCancer Research Institute, Tomsk National Research Medical Center, Russian Academy of SciencesRussian Federation202607042026251135145Copyright © Вторушин С.В., Черняков А.А., Таширева Л.А., 20262026Вторушин С.В., Черняков А.А., Таширева Л.А.Vtorushin S.V., Chernyakov A.A., Tashireva L.A.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.siboncoj.ru/jour/article/view/4120

Введение. За последнее десятилетие представления о биологии HER2-негативного рака молочной железы существенно изменились благодаря выделению категорий HER2-low и HER2-ultralow, которые приобрели клиническое значение после появления антитело-лекарственных конъюгатов нового поколения. Цель исследования – систематизировать современные сведения о молекулярных и морфологических особенностях этой группы опухолей, обсудить диагностические сложности, связанные с интерпретацией низких уровней экспрессии HER2, а также привести данные ключевых клинических исследований, определивших роль ADC в лечении пациенток с HER2-low и HER2-ultralow раком молочной железы. Материал и методы. Поиск литературы осуществлялся в поисковых системах Medline, cochrane Library, Elibrary, включались публикации с 2004 по 2025 г. Заключение. В настоящее время HER2-low и HER2-ultralow рак молочной железы является сложной группой опухолей. Существует ряд нерешенных вопросов, требующих детального изучения в данной области, а также формируются перспективы дальнейших исследований, направленных на совершенствование диагностики и персонализацию терапевтических подходов.

Background. Over the past decade, the understanding of the biology of HER2-negative breast cancer has changed signifcantly due to the identifcation of the HER2-low and HER2-ultralow categories, which have gained clinical signifcance with the advent of new-generation antibody-drug conjugates. Goal: to systematize recent data on the molecular and morphological features of this group of tumors, discuss the diagnostic diffculties associated with interpreting low levels of HER2 expression, and provide data from key clinical studies that have determined the role of ADC in the treatment of patients with HER2-low and HER2-ultralow breast cancers. Material and Methods. The literature search was conducted in Medline, Cochrane Library, and Elibrary databases, covering the period from 2004 to 2025. Conclusion. HER2-low and HER2-ultralow breast cancers represent clinically signifcant subtypes, presenting diagnostic and therapeutic challenges. Further studies are needed for refning diagnostic criteria and developing targeted therapies.

рак молочной железыHER2-lowHER2-ultralowиммуногистохимияантитело-лекарственные конъюгатытрастузумаб-дерукстеканвнутриопухолевая гетерогенностьперсонализированная терапияbreast cancerHER2-lowHER2-ultralowimmunohistochemistryantibody-drug conjugatestrastuzumab deruxtecanintratumoral heterogeneitypersonalized therapyReferencesBray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram I., Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3): 229–63. doi: 10.3322/caac.21834.Bray F., Laversanne M., Sung H., Ferlay J., Siegel R.L., Soerjomataram I., Jemal A. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024; 74(3): 229–63. doi: 10.3322/caac.21834.Состояние онкологической помощи населению России в 2023 году. Под ред. А.Д. Каприна, В.В. Старинского, А.О. Шахзадовой. М., 2024. 262 с. ISBN: 978-5-85502-297-1.Cancer care for the population of Russia in 2023. Ed. by A.D. Kaprin, V.V. Starinsky, A.O. Shakhzadova. Moscow, 2024. 262 p. (in Russian). ISBN: 978-5-85502-297-1.Тюляндин С.А., Артамонова Е.В., Жигулев А.Н., Жукова Л.Г., Королева И.А., Пароконная А.А., Семиглазова Т.Ю., Стенина М.Б., Фролова М.А. Рак молочной железы. Злокачественные опухоли. 2024; 14(3S2-1(2)): 32–81. doi: 10.18027/2224-5057-2024-14-3s2-1.2-01. EDN: KELJSW.Tyulyandin S.A., Artamonova E.V., Zhigulev A.N., Zhukova L.G., Koroleva I.A., Parokonnaya A.A., Semiglazova T.Yu., Stenina MB, Frolova M.A. Breast cancer. Malignant tumors. 2024; 14(3S2-1(2)): 32–81. (in Russian). doi: 10.18027/2224-5057-2024-14-3s2-1.2-01. EDN: KELJSW.Goldhirsch A., Wood W.C., Coates A.S., Gelber R.D., Thürlimann B., Senn H.J.; Panel members. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011; 22(8): 1736–47. doi: 10.1093/annonc/mdr304.Goldhirsch A., Wood W.C., Coates A.S., Gelber R.D., Thürlimann B., Senn H.J.; Panel members. Strategies for subtypes--dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol. 2011; 22(8): 1736–47. doi: 10.1093/annonc/mdr304.Duffy M.J., Harbeck N., Nap M., Molina R., Nicolini A., Senkus E., Cardoso F. Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM). Eur J Cancer. 2017; 75: 284–98. doi: 10.1016/j.ejca.2017.01.017.Duffy M.J., Harbeck N., Nap M., Molina R., Nicolini A., Senkus E., Cardoso F. Clinical use of biomarkers in breast cancer: Updated guidelines from the European Group on Tumor Markers (EGTM). Eur J Cancer. 2017; 75: 284–98. doi: 10.1016/j.ejca.2017.01.017.Франк Г.А., Андреева Ю.Ю., Виноградов И.Ю., Глатко С.Б., Горелик М.З., Завалишина Л.Э., Леенман Е.Е., Мационис А.Э., Петров С.В., Сазонов С.В. 10 лет тестирования HER2-статуса рака молочной железы в России. Архив патологии. 2012; 74(5): 36. EDN: PTTXAD.Frank G.A., Andreyeva Yu.Yu., Vinogradov I.Yu., Glatko S.B., Gorelik M.Z., Zavalishina L.E., Leenman E.E., Matsionis A.E., Petrov S.V., Sazonov S.V. 10 years of testing of the HER2 status in breast cancer in Russia. Russian Journal of Archive of Pathology. 2012; 74(5): 36. (in Russia). EDN: PTTXAD.Wolff A.C., Somerfeld M.R., Dowsett M., Hammond M.E.H., Hayes D.F., McShane L.M., Saphner T.J., Spears P.A., Allison K.H. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. Arch Pathol Lab Med. 2023; 147(9): 993–1000. doi: 10.5858/arpa.2023-0950-SA.Wolff A.C., Somerfeld M.R., Dowsett M., Hammond M.E.H., Hayes D.F., McShane L.M., Saphner T.J., Spears P.A., Allison K.H. Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer. Arch Pathol Lab Med. 2023; 147(9): 993–1000. doi: 10.5858/arpa.2023-0950-SA.Modi S., Jacot W., Yamashita T., Sohn J., Vidal M., Tokunaga E., Tsurutani J., Ueno N.T., Prat A., Chae Y.S., Lee K.S., Niikura N., Park Y.H., Xu B., Wang X., Gil-Gil M., Li W., Pierga J.Y., Im S.A., Moore H.C.F., Rugo H.S., Yerushalmi R., Zagouri F., Gombos A., Kim S.B., Liu Q., Luo T., Saura C., Schmid P., Sun T., Gambhire D., Yung L., Wang Y., Singh J., Vitazka P., Meinhardt G., Harbeck N., Cameron D.A; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022; 387(1): 9–20. doi: 10.1056/NEJMoa2203690.Modi S., Jacot W., Yamashita T., Sohn J., Vidal M., Tokunaga E., Tsurutani J., Ueno N.T., Prat A., Chae Y.S., Lee K.S., Niikura N., Park Y.H., Xu B., Wang X., Gil-Gil M., Li W., Pierga J.Y., Im S.A., Moore H.C.F., Rugo H.S., Yerushalmi R., Zagouri F., Gombos A., Kim S.B., Liu Q., Luo T., Saura C., Schmid P., Sun T., Gambhire D., Yung L., Wang Y., Singh J., Vitazka P., Meinhardt G., Harbeck N., Cameron D.A; DESTINY-Breast04 Trial Investigators. Trastuzumab Deruxtecan in Previously Treated HER2-Low Advanced Breast Cancer. N Engl J Med. 2022; 387(1): 9–20. doi: 10.1056/NEJMoa2203690.Tarantino P., Viale G., Press M.F., Hu X., Penault-Llorca F., Bardia A., Batistatou A., Burstein H.J., Carey L.A., Cortes J., Denkert C., Diéras V., Jacot W., Koutras A.K., Lebeau A., Loibl S., Modi S., Mosele M.F., Provenzano E., Pruneri G., Reis-Filho J.S., Rojo F., Salgado R., Schmid P., Schnitt S.J., Tolaney S.M., Trapani D., Vincent-Salomon A., Wolff A.C., Pentheroudakis G., André F., Curigliano G. ESMO expert consensus statements (ECS) on the defnition, diagnosis, and management of HER2-low breast cancer. Ann Oncol. 2023; 34(8): 645–59. doi: 10.1016/j.annonc.2023.05.008.Tarantino P., Viale G., Press M.F., Hu X., Penault-Llorca F., Bardia A., Batistatou A., Burstein H.J., Carey L.A., Cortes J., Denkert C., Diéras V., Jacot W., Koutras A.K., Lebeau A., Loibl S., Modi S., Mosele M.F., Provenzano E., Pruneri G., Reis-Filho J.S., Rojo F., Salgado R., Schmid P., Schnitt S.J., Tolaney S.M., Trapani D., Vincent-Salomon A., Wolff A.C., Pentheroudakis G., André F., Curigliano G. ESMO expert consensus statements (ECS) on the defnition, diagnosis, and management of HER2-low breast cancer. Ann Oncol. 2023; 34(8): 645–59. doi: 10.1016/j.annonc.2023.05.008.Rakha E.A., Tan P.H., van Bockstal M.R., Allison K.H., Brogi E., Callagy G., Cserni G., Jaffer S., Foschini M.P., Gobbi H., Kulka J., Li X., Provenzano E., Shaaban A.M., Tse G.M., Varga Z., Vincent-Salomon A., Yamaguchi R., Yang W., ElSheikh S., Bhargava R., De Brot M., CanasMarques R., Marchiò C., Warren M.V., van Deurzen C.H.M., Mir Y., Deb R., Wen H., Ellis I.O., Schnitt S.J., Pinder S.E., Raymond W., Quinn C.; UK National Coordinating Committee of Breast Pathology, the Association of Breast Pathology, the European Working Group for Breast Screening Pathology and the International Society of Breast Pathology. International Expert Consensus Recommendations for HER2 Reporting in Breast Cancer: Focus on HER2-Low and Ultralow Categories. Mod Pathol. 2026; 39(1): 100925. doi: 10.1016/j.modpat.2025.100925.Rakha E.A., Tan P.H., van Bockstal M.R., Allison K.H., Brogi E., Callagy G., Cserni G., Jaffer S., Foschini M.P., Gobbi H., Kulka J., Li X., Provenzano E., Shaaban A.M., Tse G.M., Varga Z., Vincent-Salomon A., Yamaguchi R., Yang W., ElSheikh S., Bhargava R., De Brot M., CanasMarques R., Marchiò C., Warren M.V., van Deurzen C.H.M., Mir Y., Deb R., Wen H., Ellis I.O., Schnitt S.J., Pinder S.E., Raymond W., Quinn C.; UK National Coordinating Committee of Breast Pathology, the Association of Breast Pathology, the European Working Group for Breast Screening Pathology and the International Society of Breast Pathology. International Expert Consensus Recommendations for HER2 Reporting in Breast Cancer: Focus on HER2-Low and Ultralow Categories. Mod Pathol. 2026; 39(1): 100925. doi: 10.1016/j.modpat.2025.100925.Won H.S., Ahn J., Kim Y., Kim J.S., Song J.Y., Kim H.K., Lee J., Park H.K., Kim Y.S. Clinical signifcance of HER2-low expression in early breast cancer: a nationwide study from the Korean Breast Cancer Society. Breast Cancer Res. 2022; 24(1): 22. doi: 10.1186/s13058-022-01519-x.Won H.S., Ahn J., Kim Y., Kim J.S., Song J.Y., Kim H.K., Lee J., Park H.K., Kim Y.S. Clinical signifcance of HER2-low expression in early breast cancer: a nationwide study from the Korean Breast Cancer Society. Breast Cancer Res. 2022; 24(1): 22. doi: 10.1186/s13058-022-01519-x.Alves F.R., Gil L., Vasconcelos de Matos L., Baleiras A., Vasques C., Neves M.T., Ferreira A., Fontes-Sousa M., Miranda H., Martins A. Impact of Human Epidermal Growth Factor Receptor 2 (HER2) Low Status in Response to Neoadjuvant Chemotherapy in Early Breast Cancer. Cureus. 2022; 14(2): e22330. doi: 10.7759/cureus.22330.Alves F.R., Gil L., Vasconcelos de Matos L., Baleiras A., Vasques C., Neves M.T., Ferreira A., Fontes-Sousa M., Miranda H., Martins A. Impact of Human Epidermal Growth Factor Receptor 2 (HER2) Low Status in Response to Neoadjuvant Chemotherapy in Early Breast Cancer. Cureus. 2022; 14(2): e22330. doi: 10.7759/cureus.22330.Tarantino P., Jin Q., Tayob N., Jeselsohn R.M., Schnitt S.J., Vincuilla J., Parker T., Tyekucheva S., Li T., Lin N.U., Hughes M.E., Weiss A.C., King T.A., Mittendorf E.A., Curigliano G., Tolaney S.M. Prognostic and Biologic Signifcance of ERBB2-Low Expression in EarlyStage Breast Cancer. JAMA Oncol. 2022; 8(8): 1177–83. doi: 10.1001/jamaoncol.2022.2286.Tarantino P., Jin Q., Tayob N., Jeselsohn R.M., Schnitt S.J., Vincuilla J., Parker T., Tyekucheva S., Li T., Lin N.U., Hughes M.E., Weiss A.C., King T.A., Mittendorf E.A., Curigliano G., Tolaney S.M. Prognostic and Biologic Signifcance of ERBB2-Low Expression in EarlyStage Breast Cancer. JAMA Oncol. 2022; 8(8): 1177–83. doi: 10.1001/jamaoncol.2022.2286.Denkert C., Seither F., Schneeweiss A., Link T., Blohmer J.U., Just M., Wimberger P., Forberger A., Tesch H., Jackisch C., Schmatloch S., Reinisch M., Solomayer E.F., Schmitt W.D., Hanusch C., Fasching P.A., Lübbe K., Solbach C., Huober J., Rhiem K., Marmé F., Reimer T., Schmidt M., Sinn B.V., Janni W., Stickeler E., Michel L., Stötzer O., Hahnen E., Furlanetto J., Seiler .S, Nekljudova V., Untch M., Loibl S. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021; 22(8): 1151–61. doi: 10.1016/S1470-2045(21)00301-6.Denkert C., Seither F., Schneeweiss A., Link T., Blohmer J.U., Just M., Wimberger P., Forberger A., Tesch H., Jackisch C., Schmatloch S., Reinisch M., Solomayer E.F., Schmitt W.D., Hanusch C., Fasching P.A., Lübbe K., Solbach C., Huober J., Rhiem K., Marmé F., Reimer T., Schmidt M., Sinn B.V., Janni W., Stickeler E., Michel L., Stötzer O., Hahnen E., Furlanetto J., Seiler .S, Nekljudova V., Untch M., Loibl S. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021; 22(8): 1151–61. doi: 10.1016/S1470-2045(21)00301-6.Buckley N.E., Forde C., McArt D.G., Boyle D.P., Mullan P.B., James J.A., Maxwell P., McQuaid S., Salto-Tellez M. Quantifcation of HER2 heterogeneity in breast cancer-implications for identifcation of sub-dominant clones for personalised treatment. Sci Rep. 2016; 6: 23383. doi: 10.1038/srep23383.Buckley N.E., Forde C., McArt D.G., Boyle D.P., Mullan P.B., James J.A., Maxwell P., McQuaid S., Salto-Tellez M. Quantifcation of HER2 heterogeneity in breast cancer-implications for identifcation of sub-dominant clones for personalised treatment. Sci Rep. 2016; 6: 23383. doi: 10.1038/srep23383.Perez E.A., de Haas S.L., Eiermann W., Barrios C.H., Toi M., Im Y.H., Conte P.F., Martin M., Pienkowski T., Pivot X.B., Burris H.A.3rd, Stanzel S., Patre M., Ellis P.A. Relationship between tumor biomarkers and efcacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer. BMC Cancer. 2019; 19(1): 517. doi: 10.1186/s12885-019-5687-0.Perez E.A., de Haas S.L., Eiermann W., Barrios C.H., Toi M., Im Y.H., Conte P.F., Martin M., Pienkowski T., Pivot X.B., Burris H.A.3rd, Stanzel S., Patre M., Ellis P.A. Relationship between tumor biomarkers and efcacy in MARIANNE, a phase III study of trastuzumab emtansine ± pertuzumab versus trastuzumab plus taxane in HER2-positive advanced breast cancer. BMC Cancer. 2019; 19(1): 517. doi: 10.1186/s12885-019-5687-0.Marchiò C., Dell’Orto P., Annaratone L., Geyer F.C., Venesio T., Berrino E., Verdun di Cantogno L., Garofoli A., Rangel N., Casorzo L., dell’Aglio C., Gugliotta P., Trisolini E., Beano A., Pietribiasi F., Orlassino R., Cassoni P., Pich A., Montemurro F., Mottolese M., Vincent-Salomon A., Penault-Llorca F., Medico E., Ng C.K.Y., Viale G., Sapino A. The Dilemma of HER2 Double-equivocal Breast Carcinomas: Genomic Profling and Implications for Treatment. Am J Surg Pathol. 2018; 42(9): 1190–200. doi: 10.1097/PAS.0000000000001100.Marchiò C., Dell’Orto P., Annaratone L., Geyer F.C., Venesio T., Berrino E., Verdun di Cantogno L., Garofoli A., Rangel N., Casorzo L., dell’Aglio C., Gugliotta P., Trisolini E., Beano A., Pietribiasi F., Orlassino R., Cassoni P., Pich A., Montemurro F., Mottolese M., Vincent-Salomon A., Penault-Llorca F., Medico E., Ng C.K.Y., Viale G., Sapino A. The Dilemma of HER2 Double-equivocal Breast Carcinomas: Genomic Profling and Implications for Treatment. Am J Surg Pathol. 2018; 42(9): 1190–200. doi: 10.1097/PAS.0000000000001100.Di Cosimo S., Pizzamiglio S., Ciniselli C.M., Duroni V., Cappelletti V., De Cecco L., De Marco C., Silvestri M., De Santis M.C., Vingiani A., Paolini B., Orlandi R., Iorio M.V., Pruneri G., Verderio P. A gene expression-based classifer for HER2-low breast cancer. Sci Rep. 2024; 14(1): 2628. doi: 10.1038/s41598-024-52148-7.Di Cosimo S., Pizzamiglio S., Ciniselli C.M., Duroni V., Cappelletti V., De Cecco L., De Marco C., Silvestri M., De Santis M.C., Vingiani A., Paolini B., Orlandi R., Iorio M.V., Pruneri G., Verderio P. A gene expression-based classifer for HER2-low breast cancer. Sci Rep. 2024; 14(1): 2628. doi: 10.1038/s41598-024-52148-7.Pavlenko I.A., Povilaitite P.E., Makarevich N.S., Kaciyaev V.Y., Petrov A.V. Kharakteristika mutatsii gena PIK3CA pri rake molochnoi zhelezy s nizkim urovnem ekspressii belka Her2/neu Characteristics of PIK3CA gene mutations in Her2-low breast cancer. Arkh Patol. 2023; 85(4): 5–11. doi: 10.17116/patol2023850415.Pavlenko I.A., Povilaitite P.E., Makarevich N.S., Kaciyaev V.Y., Petrov A.V. Kharakteristika mutatsii gena PIK3CA pri rake molochnoi zhelezy s nizkim urovnem ekspressii belka Her2/neu Characteristics of PIK3CA gene mutations in Her2-low breast cancer. Arkh Patol. 2023; 85(4): 5–11. doi: 10.17116/patol2023850415.Fernandes I., Scorsato A., Kaliks R., Corpa M., Damasceno E., Schvartsman G. Tumor-Infltrating Lymphocytes in HER2-Low Breast Cancer. Clin Breast Cancer. 2023; 23(7): e470–e479. doi: 10.1016/j.clbc.2023.07.007.Fernandes I., Scorsato A., Kaliks R., Corpa M., Damasceno E., Schvartsman G. Tumor-Infltrating Lymphocytes in HER2-Low Breast Cancer. Clin Breast Cancer. 2023; 23(7): e470–e479. doi: 10.1016/j.clbc.2023.07.007.Baez-Navarro X., van den Ende N.S., Nguyen A.H., Sinke R., Westenend P., van Brakel J.B., Stobbe C., Westerga J., van Deurzen C.H.M. HER2-low and tumor infltrating lymphocytes in triple-negative breast cancer: Are they connected? Breast Cancer Res. 2024; 26(1): 41. doi: 10.1186/s13058-024-01783-z.Baez-Navarro X., van den Ende N.S., Nguyen A.H., Sinke R., Westenend P., van Brakel J.B., Stobbe C., Westerga J., van Deurzen C.H.M. HER2-low and tumor infltrating lymphocytes in triple-negative breast cancer: Are they connected? Breast Cancer Res. 2024; 26(1): 41. doi: 10.1186/s13058-024-01783-z.van den Ende N.S., Smid M., Timmermans A., van Brakel J.B., Hansum T., Foekens R., Trapman A.M.A.C., Heemskerk-Gerritsen B.A.M., Jager A., Martens J.W.M., van Deurzen C.H.M. HER2-low breast cancer shows a lower immune response compared to HER2-negative cases. Sci Rep. 2022; 12(1): 12974. doi: 10.1038/s41598-022-16898-6.van den Ende N.S., Smid M., Timmermans A., van Brakel J.B., Hansum T., Foekens R., Trapman A.M.A.C., Heemskerk-Gerritsen B.A.M., Jager A., Martens J.W.M., van Deurzen C.H.M. HER2-low breast cancer shows a lower immune response compared to HER2-negative cases. Sci Rep. 2022; 12(1): 12974. doi: 10.1038/s41598-022-16898-6.Molinelli C., Jacobs F., Agostinetto E., Nader-Marta G., Ceppi M., Bruzzone M., Blondeaux E., Schettini F., Prat A., Viale G., Del Mastro L., Lambertini M., de Azambuja E. Prognostic value of HER2-low status in breast cancer: a systematic review and meta-analysis. ESMO Open. 2023; 8(4): 101592. doi: 10.1016/j.esmoop.2023.101592.Molinelli C., Jacobs F., Agostinetto E., Nader-Marta G., Ceppi M., Bruzzone M., Blondeaux E., Schettini F., Prat A., Viale G., Del Mastro L., Lambertini M., de Azambuja E. Prognostic value of HER2-low status in breast cancer: a systematic review and meta-analysis. ESMO Open. 2023; 8(4): 101592. doi: 10.1016/j.esmoop.2023.101592.Li Y., Abudureheiyimu N., Mo H., Guan X., Lin S., Wang Z., Chen Y., Chen S., Li Q., Cai R., Wang J., Luo Y., Fan Y., Yuan P., Zhang P., Li Q., Ma F., Xu B. In Real Life, Low-Level HER2 Expression May Be Associated With Better Outcome in HER2-Negative Breast Cancer: A Study of the National Cancer Center, China. Front Oncol. 2022; 11: 774577. doi: 10.3389/fonc.2021.774577.Li Y., Abudureheiyimu N., Mo H., Guan X., Lin S., Wang Z., Chen Y., Chen S., Li Q., Cai R., Wang J., Luo Y., Fan Y., Yuan P., Zhang P., Li Q., Ma F., Xu B. In Real Life, Low-Level HER2 Expression May Be Associated With Better Outcome in HER2-Negative Breast Cancer: A Study of the National Cancer Center, China. Front Oncol. 2022; 11: 774577. doi: 10.3389/fonc.2021.774577.Zattarin E., Presti D., Mariani L., Sposetti C., Leporati R., Menichetti A., Corti C., Benvenuti C., Fucà G., Lobefaro R., Ligorio F., Provenzano L., Vingiani A., Del Vecchio M., Griguolo G., Sirico M., Bernocchi O., Marra A., Zagami P., Agostinetto E., Jacobs F., Di Mauro P., Esposito A., Giorgi C.A., Lalli L., Boldrini L., Giacchetti P.P.B., Schianca A.C., Guarneri V., Pedersini R., Losurdo A., Zambelli A., Generali D., Criscitiello C., Curigliano G., Pruneri G., de Braud F., Dieci M.V., Vernieri C. Prognostic signifcance of HER2-low status in HR-positive/HER2-negative advanced breast cancer treated with CDK4/6 inhibitors. NPJ Breast Cancer. 2023; 9(1): 27. doi: 10.1038/s41523-023-00534-1.Zattarin E., Presti D., Mariani L., Sposetti C., Leporati R., Menichetti A., Corti C., Benvenuti C., Fucà G., Lobefaro R., Ligorio F., Provenzano L., Vingiani A., Del Vecchio M., Griguolo G., Sirico M., Bernocchi O., Marra A., Zagami P., Agostinetto E., Jacobs F., Di Mauro P., Esposito A., Giorgi C.A., Lalli L., Boldrini L., Giacchetti P.P.B., Schianca A.C., Guarneri V., Pedersini R., Losurdo A., Zambelli A., Generali D., Criscitiello C., Curigliano G., Pruneri G., de Braud F., Dieci M.V., Vernieri C. Prognostic signifcance of HER2-low status in HR-positive/HER2-negative advanced breast cancer treated with CDK4/6 inhibitors. NPJ Breast Cancer. 2023; 9(1): 27. doi: 10.1038/s41523-023-00534-1.Gampenrieder S.P., Rinnerthaler G., Tinchon C., Petzer A., Balic M., Heibl S., Schmitt C., Zabernigg A.F., Egle D., Sandholzer M., Singer C.F., Roitner F., Hager C., Andel J., Hubalek M., Knauer M., Greil R. Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry. Breast Cancer Res. 2021; 23(1): 112. doi: 10.1186/s13058-021-01492-x.Gampenrieder S.P., Rinnerthaler G., Tinchon C., Petzer A., Balic M., Heibl S., Schmitt C., Zabernigg A.F., Egle D., Sandholzer M., Singer C.F., Roitner F., Hager C., Andel J., Hubalek M., Knauer M., Greil R. Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry. Breast Cancer Res. 2021; 23(1): 112. doi: 10.1186/s13058-021-01492-x.Jacot W., Maran-Gonzalez A., Massol O., Sorbs C., Mollevi C., Guiu S., Boissière-Michot F., Ramos J. Prognostic Value of HER2-Low Expression in Non-Metastatic Triple-Negative Breast Cancer and Correlation with Other Biomarkers. Cancers (Basel). 2021; 13(23): 6059. doi: 10.3390/cancers13236059.Jacot W., Maran-Gonzalez A., Massol O., Sorbs C., Mollevi C., Guiu S., Boissière-Michot F., Ramos J. Prognostic Value of HER2-Low Expression in Non-Metastatic Triple-Negative Breast Cancer and Correlation with Other Biomarkers. Cancers (Basel). 2021; 13(23): 6059. doi: 10.3390/cancers13236059.Bo J., Yu B., Bi R., Xu X., Cheng Y., Tu X., Bai Q., Yang W., Shui R. Conversion of ER and HER2 Status After Neoadjuvant Therapy in Chinese Breast Cancer Patients. Clin Breast Cancer. 2023; 23(4): 436–46. doi: 10.1016/j.clbc.2023.03.002.Bo J., Yu B., Bi R., Xu X., Cheng Y., Tu X., Bai Q., Yang W., Shui R. Conversion of ER and HER2 Status After Neoadjuvant Therapy in Chinese Breast Cancer Patients. Clin Breast Cancer. 2023; 23(4): 436–46. doi: 10.1016/j.clbc.2023.03.002.Ma Y., Zhu M., Zhang J., Lv M., Chen X., Liu Z. Prognostic value of the evolution of HER2-low expression after neoadjuvant chemotherapy. Cancer Res Treat. 2023; 55: 1210–21. doi: 10.4143/crt.2022.1633.Ma Y., Zhu M., Zhang J., Lv M., Chen X., Liu Z. Prognostic value of the evolution of HER2-low expression after neoadjuvant chemotherapy. Cancer Res Treat. 2023; 55: 1210–21. doi: 10.4143/crt.2022.1633.Shang J., Sun X., Xu Z., Cai L., Liu C., Wu S., Liu Y. Evolution and clinical signifcance of HER2-low status after neoadjuvant therapy for breast cancer. Front Oncol. 2023; 13: 1086480. doi: 10.3389/fonc.2023.1086480.Shang J., Sun X., Xu Z., Cai L., Liu C., Wu S., Liu Y. Evolution and clinical signifcance of HER2-low status after neoadjuvant therapy for breast cancer. Front Oncol. 2023; 13: 1086480. doi: 10.3389/fonc.2023.1086480.Tarantino P., Gandini S., Nicolò E., Trillo P., Giugliano F., Zagami P., Vivanet G., Bellerba F., Trapani D., Marra A., Esposito A., Criscitiello C., Viale G., Curigliano G. Evolution of low HER2 expression between early and advanced-stage breast cancer. Eur J Cancer. 2022; 163: 35–43. doi: 10.1016/j.ejca.2021.12.022.Tarantino P., Gandini S., Nicolò E., Trillo P., Giugliano F., Zagami P., Vivanet G., Bellerba F., Trapani D., Marra A., Esposito A., Criscitiello C., Viale G., Curigliano G. Evolution of low HER2 expression between early and advanced-stage breast cancer. Eur J Cancer. 2022; 163: 35–43. doi: 10.1016/j.ejca.2021.12.022.Guan F., Ju X., Chen L., Ren J., Ke X., Luo B., Huang A., Yuan J. Comparison of clinicopathological characteristics, efcacy of neoadjuvant therapy, and prognosis in HER2-low and HER2-ultralow breast cancer. Diagn Pathol. 2024; 19(1): 131. doi: 10.1186/s13000-024-01557-3.Guan F., Ju X., Chen L., Ren J., Ke X., Luo B., Huang A., Yuan J. Comparison of clinicopathological characteristics, efcacy of neoadjuvant therapy, and prognosis in HER2-low and HER2-ultralow breast cancer. Diagn Pathol. 2024; 19(1): 131. doi: 10.1186/s13000-024-01557-3.Kang S., Lee S.H., Lee H.J., Jeong H., Jeong J.H., Kim J.E., Ahn J.H., Jung K.H., Gong G., Kim H.H., Lee S., Lee J., Kim S.B. Prognostic implications of HER2 changes after neoadjuvant chemotherapy in patients with HER2-zero and HER2-low breast cancer. Eur J Cancer. 2023; 191: 112956. doi: 10.1016/j.ejca.2023.112956.Kang S., Lee S.H., Lee H.J., Jeong H., Jeong J.H., Kim J.E., Ahn J.H., Jung K.H., Gong G., Kim H.H., Lee S., Lee J., Kim S.B. Prognostic implications of HER2 changes after neoadjuvant chemotherapy in patients with HER2-zero and HER2-low breast cancer. Eur J Cancer. 2023; 191: 112956. doi: 10.1016/j.ejca.2023.112956.Bergeron A., Bertaut A., Beltjens F., Charon-Barra C., Amet A., Jankowski C., Desmoulins I., Ladoire S., Arnould L. Anticipating changes in the HER2 status of breast tumours with disease progression-towards better treatment decisions in the new era of HER2-low breast cancers. Br J Cancer. 2023; 129(1): 122–34. doi: 10.1038/s41416-023-02287-x.Bergeron A., Bertaut A., Beltjens F., Charon-Barra C., Amet A., Jankowski C., Desmoulins I., Ladoire S., Arnould L. Anticipating changes in the HER2 status of breast tumours with disease progression-towards better treatment decisions in the new era of HER2-low breast cancers. Br J Cancer. 2023; 129(1): 122–34. doi: 10.1038/s41416-023-02287-x.Fernandez A.I., Liu M., Bellizzi A., Brock J., Fadare O., Hanley K., Harigopal M., Jorns J.M., Kuba M.G., Ly A., Podoll M., Rabe K., Sanders M.A., Singh K., Snir O.L., Soong T.R., Wei S., Wen H., Wong S., Yoon E., Pusztai L., Reisenbichler E., Rimm D.L. Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue. JAMA Oncol. 2022; 8(4): 1–4. doi: 10.1001/jamaoncol.2021.7239.Fernandez A.I., Liu M., Bellizzi A., Brock J., Fadare O., Hanley K., Harigopal M., Jorns J.M., Kuba M.G., Ly A., Podoll M., Rabe K., Sanders M.A., Singh K., Snir O.L., Soong T.R., Wei S., Wen H., Wong S., Yoon E., Pusztai L., Reisenbichler E., Rimm D.L. Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue. JAMA Oncol. 2022; 8(4): 1–4. doi: 10.1001/jamaoncol.2021.7239.Viale G., Basik M., Niikura N., Tokunaga E., Brucker S., PenaultLlorca F., Hayashi N., Sohn J., Teixeira de Sousa R., Brufsky A.M., O’Brien C.S., Schmitt F., Higgins G., Varghese D., James G.D., Moh A., Livingston A., de Giorgio-Miller V. Retrospective study to estimate the prevalence and describe the clinicopathological characteristics, treatments received, and outcomes of HER2-low breast cancer. ESMO Open. 2023; 8(4): 101615. doi: 10.1016/j.esmoop.2023.101615.Viale G., Basik M., Niikura N., Tokunaga E., Brucker S., PenaultLlorca F., Hayashi N., Sohn J., Teixeira de Sousa R., Brufsky A.M., O’Brien C.S., Schmitt F., Higgins G., Varghese D., James G.D., Moh A., Livingston A., de Giorgio-Miller V. Retrospective study to estimate the prevalence and describe the clinicopathological characteristics, treatments received, and outcomes of HER2-low breast cancer. ESMO Open. 2023; 8(4): 101615. doi: 10.1016/j.esmoop.2023.101615.Fehrenbacher L., Cecchini R.S., Geyer C.E. Jr., Rastogi P., Costantino J.P., Atkins J.N., Crown J.P., Polikoff J., Boileau J.F., Provencher L., Stokoe C., Moore T.D., Robidoux A., Flynn P.J., Borges V.F., Albain K.S., Swain S.M., Paik S., Mamounas E.P., Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020; 38(5): 444–53. doi: 10.1200/JCO.19.01455.Fehrenbacher L., Cecchini R.S., Geyer C.E. Jr., Rastogi P., Costantino J.P., Atkins J.N., Crown J.P., Polikoff J., Boileau J.F., Provencher L., Stokoe C., Moore T.D., Robidoux A., Flynn P.J., Borges V.F., Albain K.S., Swain S.M., Paik S., Mamounas E.P., Wolmark N. NSABP B-47/NRG Oncology Phase III Randomized Trial Comparing Adjuvant Chemotherapy With or Without Trastuzumab in High-Risk Invasive Breast Cancer Negative for HER2 by FISH and With IHC 1+ or 2. J Clin Oncol. 2020; 38(5): 444–53. doi: 10.1200/JCO.19.01455.Mosele F., Deluche E., Lusque A., Le Bescond L., Filleron T., Pradat Y., Ducoulombier A., Pistilli B., Bachelot T., Viret F., Levy C., Signolle N., Alfaro A., Tran D.T.N., Garberis I.J., Talbot H., Christodoulidis S., Vakalopoulou M., Droin N., Stourm A., Kobayashi M., Kakegawa T., Lacroix L., Saulnier P., Job B., Deloger M., Jimenez M., Mahier C., Baris V., Laplante P., Kannouche P., Marty V., Lacroix-Triki M., Diéras V., André F. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat Med. 2023; 29(8): 2110–20. doi: 10.1038/s41591-023-02478-2.Mosele F., Deluche E., Lusque A., Le Bescond L., Filleron T., Pradat Y., Ducoulombier A., Pistilli B., Bachelot T., Viret F., Levy C., Signolle N., Alfaro A., Tran D.T.N., Garberis I.J., Talbot H., Christodoulidis S., Vakalopoulou M., Droin N., Stourm A., Kobayashi M., Kakegawa T., Lacroix L., Saulnier P., Job B., Deloger M., Jimenez M., Mahier C., Baris V., Laplante P., Kannouche P., Marty V., Lacroix-Triki M., Diéras V., André F. Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial. Nat Med. 2023; 29(8): 2110–20. doi: 10.1038/s41591-023-02478-2.Turner N., Saura C., Aftimos P., van den Tweel E., Oesterholt M., Koper N., Colleoni M., Kaczmarek E., Punie K., Song X., Armstrong A., Bianchi G., Stradella A., Ladoire S., Lim J.S.J., Quenel-Tueux N., Tan T.J., Escrivá-de-Romaní S., O’Shaughnessy J; TULIP Trial Investigators. Trastuzumab Duocarmazine in Pretreated Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Breast Cancer: An Open-Label, Randomized, Phase III Trial (TULIP). J Clin Oncol. 2025; 43(5): 513–23. doi: 10.1200/JCO.24.00529.Turner N., Saura C., Aftimos P., van den Tweel E., Oesterholt M., Koper N., Colleoni M., Kaczmarek E., Punie K., Song X., Armstrong A., Bianchi G., Stradella A., Ladoire S., Lim J.S.J., Quenel-Tueux N., Tan T.J., Escrivá-de-Romaní S., O’Shaughnessy J; TULIP Trial Investigators. Trastuzumab Duocarmazine in Pretreated Human Epidermal Growth Factor Receptor 2-Positive Advanced or Metastatic Breast Cancer: An Open-Label, Randomized, Phase III Trial (TULIP). J Clin Oncol. 2025; 43(5): 513–23. doi: 10.1200/JCO.24.00529.Banerji U., van Herpen C.M.L., Saura C., Thistlethwaite F., Lord S., Moreno V., Macpherson I.R., Boni V., Rolfo C., de Vries E.G.E., Rottey S., Geenen J., Eskens F., Gil-Martin M., Mommers E.C., Koper N.P., Aftimos P. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019; 20(8): 1124–35. doi: 10.1016/S1470-2045(19)30328-6.Banerji U., van Herpen C.M.L., Saura C., Thistlethwaite F., Lord S., Moreno V., Macpherson I.R., Boni V., Rolfo C., de Vries E.G.E., Rottey S., Geenen J., Eskens F., Gil-Martin M., Mommers E.C., Koper N.P., Aftimos P. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lancet Oncol. 2019; 20(8): 1124–35. doi: 10.1016/S1470-2045(19)30328-6.Qu F., Lu R., Wu X., Liu Q., Zha M., Li H., Yuan Y., Han Z., Cai D., Huang X., Yin Y., Li W. Efcacy and safety of RC48-ADC in HER2-positive and HER2-low metastatic breast cancer: a multicenter, real-world study. Front Oncol. 2024; 14: 1435485. doi: 10.3389/fonc.2024.1435485.Qu F., Lu R., Wu X., Liu Q., Zha M., Li H., Yuan Y., Han Z., Cai D., Huang X., Yin Y., Li W. Efcacy and safety of RC48-ADC in HER2-positive and HER2-low metastatic breast cancer: a multicenter, real-world study. Front Oncol. 2024; 14: 1435485. doi: 10.3389/fonc.2024.1435485.Sun L., Jia X., Wang K., Li M. Unveiling the future of breast cancer therapy: Cutting-edge antibody-drug conjugate strategies and clinical outcomes. Breast. 2024; 78: 103830. doi: 10.1016/j.breast.2024.103830.Sun L., Jia X., Wang K., Li M. Unveiling the future of breast cancer therapy: Cutting-edge antibody-drug conjugate strategies and clinical outcomes. Breast. 2024; 78: 103830. doi: 10.1016/j.breast.2024.103830.Skidmore L., Sakamuri S., Knudsen N.A., Hewet A.G., Milutinovic S., Barkho W., Biroc S.L., Kirtley J., Marsden R., Storey K., Lopez I., Yu W., Fang S.Y., Yao S., Gu Y., Tian F. ARX788, a Site-specifc Anti-HER2 Antibody-Drug Conjugate, Demonstrates Potent and Selective Activity in HER2-low and T-DM1-resistant Breast and Gastric Cancers. Mol Cancer Ther. 2020; 19(9): 1833–43. doi: 10.1158/1535-7163.Skidmore L., Sakamuri S., Knudsen N.A., Hewet A.G., Milutinovic S., Barkho W., Biroc S.L., Kirtley J., Marsden R., Storey K., Lopez I., Yu W., Fang S.Y., Yao S., Gu Y., Tian F. ARX788, a Site-specifc Anti-HER2 Antibody-Drug Conjugate, Demonstrates Potent and Selective Activity in HER2-low and T-DM1-resistant Breast and Gastric Cancers. Mol Cancer Ther. 2020; 19(9): 1833–43. doi: 10.1158/1535-7163.Bardia A., Hurvitz S.A., Tolaney S.M., Loirat D., Punie K., Oliveira M., Brufsky A., Sardesai S.D., Kalinsky K., Zelnak A.B., Weaver R., Traina T., Dalenc F., Aftimos P., Lynce F., Diab S., Cortés J., O’Shaughnessy J., Diéras V., Ferrario C., Schmid P., Carey L.A., Gianni L., Piccart M.J., Loibl S., Goldenberg D.M., Hong Q., Olivo M.S., Itri LM., Rugo H.S; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021; 384(16): 1529–41. doi: 10.1056/NEJMoa2028485.Bardia A., Hurvitz S.A., Tolaney S.M., Loirat D., Punie K., Oliveira M., Brufsky A., Sardesai S.D., Kalinsky K., Zelnak A.B., Weaver R., Traina T., Dalenc F., Aftimos P., Lynce F., Diab S., Cortés J., O’Shaughnessy J., Diéras V., Ferrario C., Schmid P., Carey L.A., Gianni L., Piccart M.J., Loibl S., Goldenberg D.M., Hong Q., Olivo M.S., Itri LM., Rugo H.S; ASCENT Clinical Trial Investigators. Sacituzumab Govitecan in Metastatic Triple-Negative Breast Cancer. N Engl J Med. 2021; 384(16): 1529–41. doi: 10.1056/NEJMoa2028485.Bardia A., Rugo H.S., Tolaney S.M., Loirat D., Punie K., Oliveira M., Brufsky A., Kalinsky K., Cortés J., Shaughnessy J.O., Diéras V., Carey L.A., Gianni L., Piccart-Gebhart M., Loibl S., Yoon O.K., Pan Y., Hofsess S., Phan S.C., Hurvitz S.A. Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression. J Clin Oncol. 2024; 42(15): 1738–44. doi: 10.1200/JCO.23.01409.Bardia A., Rugo H.S., Tolaney S.M., Loirat D., Punie K., Oliveira M., Brufsky A., Kalinsky K., Cortés J., Shaughnessy J.O., Diéras V., Carey L.A., Gianni L., Piccart-Gebhart M., Loibl S., Yoon O.K., Pan Y., Hofsess S., Phan S.C., Hurvitz S.A. Final Results From the Randomized Phase III ASCENT Clinical Trial in Metastatic Triple-Negative Breast Cancer and Association of Outcomes by Human Epidermal Growth Factor Receptor 2 and Trophoblast Cell Surface Antigen 2 Expression. J Clin Oncol. 2024; 42(15): 1738–44. doi: 10.1200/JCO.23.01409.Rugo H.S., Bardia A., Marmé F., Cortes J., Schmid P., Loirat D., Trédan O., Ciruelos E., Dalenc F., Pardo P.G., Jhaveri K.L., Delaney R., Fu O., Lin L., Verret W., Tolaney S.M. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022; 40(29): 3365–76. doi: 10.1200/JCO.22.01002.Rugo H.S., Bardia A., Marmé F., Cortes J., Schmid P., Loirat D., Trédan O., Ciruelos E., Dalenc F., Pardo P.G., Jhaveri K.L., Delaney R., Fu O., Lin L., Verret W., Tolaney S.M. Sacituzumab Govitecan in Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer. J Clin Oncol. 2022; 40(29): 3365–76. doi: 10.1200/JCO.22.01002.Bardia A., Jhaveri K., Im S.A., Pernas S., De Laurentiis M., Wang S., Martínez Jañez N., Borges G., Cescon D.W., Hattori M., Lu Y.S., Hamilton E., Zhang Q., Tsurutani J., Kalinsky K., Rubini Liedke P.E., Xu L., Fairhurst R.M., Khan S., Denduluri N., Rugo H.S., Xu B., Pistilli B.; TROPION-Breast01 Investigators. Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01. J Clin Oncol. 2025; 43(3): 285–96. doi: 10.1200/JCO.24.00920.Bardia A., Jhaveri K., Im S.A., Pernas S., De Laurentiis M., Wang S., Martínez Jañez N., Borges G., Cescon D.W., Hattori M., Lu Y.S., Hamilton E., Zhang Q., Tsurutani J., Kalinsky K., Rubini Liedke P.E., Xu L., Fairhurst R.M., Khan S., Denduluri N., Rugo H.S., Xu B., Pistilli B.; TROPION-Breast01 Investigators. Datopotamab Deruxtecan Versus Chemotherapy in Previously Treated Inoperable/Metastatic Hormone Receptor-Positive Human Epidermal Growth Factor Receptor 2-Negative Breast Cancer: Primary Results From TROPION-Breast01. J Clin Oncol. 2025; 43(3): 285–96. doi: 10.1200/JCO.24.00920.Schram A.M., Odintsov I., Espinosa-Cotton M., Khodos I., Sisso W.J., Mattar M.S., Lui A.J.W., Vojnic M., Shameem S.H., Chauhan T., Torrisi J., Ford J., O’Connor M.N., Geuijen C.A.W., Schackmann R.C.J., Lammerts van Bueren J.J., Wasserman E., de Stanchina E., O’Reilly E.M., Ladanyi M., Drilon A., Somwar R. Zenocutuzumab, a HER2xHER3 Bispecifc Antibody, Is Efective Therapy for Tumors Driven by NRG1 Gene Rearrangements. Cancer Discov. 2022; 12(5): 1233–47. doi: 10.1158/2159-8290.CD-21-1119.Schram A.M., Odintsov I., Espinosa-Cotton M., Khodos I., Sisso W.J., Mattar M.S., Lui A.J.W., Vojnic M., Shameem S.H., Chauhan T., Torrisi J., Ford J., O’Connor M.N., Geuijen C.A.W., Schackmann R.C.J., Lammerts van Bueren J.J., Wasserman E., de Stanchina E., O’Reilly E.M., Ladanyi M., Drilon A., Somwar R. Zenocutuzumab, a HER2xHER3 Bispecifc Antibody, Is Efective Therapy for Tumors Driven by NRG1 Gene Rearrangements. Cancer Discov. 2022; 12(5): 1233–47. doi: 10.1158/2159-8290.CD-21-1119.Fontana E., Torga G., Fostea R., Cleator S., Wasserman E., Murat A., Arkenau H.T. Sustained Tumor Regression With Zenocutuzumab, a Bispecifc Antibody Targeting Human Epidermal Growth Factor Receptor 2/Human Epidermal Growth Factor Receptor 3 Signaling, in NRG1 FusionPositive, Estrogen Receptor-Positive Breast Cancer After Progression on a Cyclin-Dependent Kinase 4/6 Inhibitor. JCO Precis Oncol. 2022; 6: e2100446. doi: 10.1200/PO.21.00446.Fontana E., Torga G., Fostea R., Cleator S., Wasserman E., Murat A., Arkenau H.T. Sustained Tumor Regression With Zenocutuzumab, a Bispecifc Antibody Targeting Human Epidermal Growth Factor Receptor 2/Human Epidermal Growth Factor Receptor 3 Signaling, in NRG1 FusionPositive, Estrogen Receptor-Positive Breast Cancer After Progression on a Cyclin-Dependent Kinase 4/6 Inhibitor. JCO Precis Oncol. 2022; 6: e2100446. doi: 10.1200/PO.21.00446.Sajjadi E., Venetis K., Ivanova M., Fusco N. Improving HER2 testing reproducibility in HER2-low breast cancer. Cancer Drug Resist. 2022; 5: 882–88. doi: 10.20517/cdr.2022.29.Sajjadi E., Venetis K., Ivanova M., Fusco N. Improving HER2 testing reproducibility in HER2-low breast cancer. Cancer Drug Resist. 2022; 5: 882–88. doi: 10.20517/cdr.2022.29.Bardia A., Hu X., Dent R., Yonemori K., Barrios C.H., O’Shaughnessy J.A., Wildiers H., Pierga J.Y., Zhang Q., Saura C., Biganzoli L., Sohn J., Im S.A., Lévy C., Jacot W., Begbie N., Ke J., Patel G., Curigliano G.; DESTINY-Breast06 Trial Investigators. Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. N Engl J Med. 2024; 391(22): 2110–22. doi: 10.1056/NEJMoa2407086.Bardia A., Hu X., Dent R., Yonemori K., Barrios C.H., O’Shaughnessy J.A., Wildiers H., Pierga J.Y., Zhang Q., Saura C., Biganzoli L., Sohn J., Im S.A., Lévy C., Jacot W., Begbie N., Ke J., Patel G., Curigliano G.; DESTINY-Breast06 Trial Investigators. Trastuzumab Deruxtecan after Endocrine Therapy in Metastatic Breast Cancer. N Engl J Med. 2024; 391(22): 2110–22. doi: 10.1056/NEJMoa2407086.Trastuzumab Deruxtecan Is Effective in HER2-Low Breast Cancer. Cancer Discov. 2020; 10(4): 488. doi: 10.1158/2159-8290.CDRW2020-030.Trastuzumab Deruxtecan Is Effective in HER2-Low Breast Cancer. Cancer Discov. 2020; 10(4): 488. doi: 10.1158/2159-8290.CDRW2020-030.Wu Y., Mo H., Xu H., Wang Y., Wang J., Ma F., Xu B. Impact of HER2-low expression on the efcacy of endocrine therapy with or without CDK4/6 inhibitor in HR-positive/HER2-negative metastatic breast cancer: A prospective study. Thorac Cancer. 2024; 15(12): 965–73. doi: 10.1111/1759-7714.15282.Wu Y., Mo H., Xu H., Wang Y., Wang J., Ma F., Xu B. Impact of HER2-low expression on the efcacy of endocrine therapy with or without CDK4/6 inhibitor in HR-positive/HER2-negative metastatic breast cancer: A prospective study. Thorac Cancer. 2024; 15(12): 965–73. doi: 10.1111/1759-7714.15282.Carlino F., Diana A., Ventriglia A., Piccolo A., Mocerino C., Riccardi F., Bilancia D., Giotta F., Antoniol G., Famiglietti V., Feliciano S., Cangiano R., Lobianco L., Pellegrino B., De Vita F., Ciardiello F., Orditura M. HER2-Low Status Does Not Afect Survival Outcomes of Patients with Metastatic Breast Cancer (MBC) Undergoing First-Line Treatment with Endocrine Therapy plus Palbociclib: Results of a Multicenter, Retrospective Cohort Study. Cancers (Basel). 2022; 14(20): 4981. doi: 10.3390/cancers14204981.Carlino F., Diana A., Ventriglia A., Piccolo A., Mocerino C., Riccardi F., Bilancia D., Giotta F., Antoniol G., Famiglietti V., Feliciano S., Cangiano R., Lobianco L., Pellegrino B., De Vita F., Ciardiello F., Orditura M. HER2-Low Status Does Not Afect Survival Outcomes of Patients with Metastatic Breast Cancer (MBC) Undergoing First-Line Treatment with Endocrine Therapy plus Palbociclib: Results of a Multicenter, Retrospective Cohort Study. Cancers (Basel). 2022; 14(20): 4981. doi: 10.3390/cancers14204981.Yayli G., Tokofsky A., Nayar U. The intersection of the HER2-low subtype with endocrine resistance: the role of interconnected signaling pathways. Front Oncol. 2024; 14: 1461190. doi: 10.3389/fonc.2024.1461190.Yayli G., Tokofsky A., Nayar U. The intersection of the HER2-low subtype with endocrine resistance: the role of interconnected signaling pathways. Front Oncol. 2024; 14: 1461190. doi: 10.3389/fonc.2024.1461190.Mao P., Cohen O., Kowalski K.J., Kusiel J.G., Buendia-Buendia J.E., Cuoco M.S., Exman P., Wander S.A., Waks A.G., Nayar U., Chung J., Freeman S., Rozenblatt-Rosen O., Miller V.A., Piccioni F., Root D.E., Regev A., Winer E.P., Lin N.U., Wagle N. Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer. Clin Cancer Res. 2020; 26(22): 5974–89. doi: 10.1158/1078-0432.CCR-19-3958.Mao P., Cohen O., Kowalski K.J., Kusiel J.G., Buendia-Buendia J.E., Cuoco M.S., Exman P., Wander S.A., Waks A.G., Nayar U., Chung J., Freeman S., Rozenblatt-Rosen O., Miller V.A., Piccioni F., Root D.E., Regev A., Winer E.P., Lin N.U., Wagle N. Acquired FGFR and FGF Alterations Confer Resistance to Estrogen Receptor (ER) Targeted Therapy in ER+ Metastatic Breast Cancer. Clin Cancer Res. 2020; 26(22): 5974–89. doi: 10.1158/1078-0432.CCR-19-3958.Tarantino P., Gupta H., Hughes M.E., Files J., Strauss S., Kirkner G., Feeney A.M., Li Y., Garrido-Castro A.C., Barroso-Sousa R., Bychkovsky B.L., DiLascio S., Sholl L., MacConaill L., Lindeman N., Johnson B.E., Meyerson M., Jeselsohn R., Qiu X., Li R., Long H., Winer E.P., Dillon D., Curigliano G., Cherniack A.D., Tolaney S.M., Lin N.U. Comprehensive genomic characterization of HER2-low and HER2-0 breast cancer. Nat Commun. 2023; 14(1): 7496. doi: 10.1038/s41467-023-43324-w.Tarantino P., Gupta H., Hughes M.E., Files J., Strauss S., Kirkner G., Feeney A.M., Li Y., Garrido-Castro A.C., Barroso-Sousa R., Bychkovsky B.L., DiLascio S., Sholl L., MacConaill L., Lindeman N., Johnson B.E., Meyerson M., Jeselsohn R., Qiu X., Li R., Long H., Winer E.P., Dillon D., Curigliano G., Cherniack A.D., Tolaney S.M., Lin N.U. Comprehensive genomic characterization of HER2-low and HER2-0 breast cancer. Nat Commun. 2023; 14(1): 7496. doi: 10.1038/s41467-023-43324-w.Belli S., Esposito D., Ascione C.M., Messina F., Napolitano F., Servetto A., De Angelis C., Bianco R., Formisano L. EGFR and HER2 hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer. Cancer Lett. 2024; 593: 216968. doi: 10.1016/j.canlet.2024.216968.Belli S., Esposito D., Ascione C.M., Messina F., Napolitano F., Servetto A., De Angelis C., Bianco R., Formisano L. EGFR and HER2 hyper-activation mediates resistance to endocrine therapy and CDK4/6 inhibitors in ER+ breast cancer. Cancer Lett. 2024; 593: 216968. doi: 10.1016/j.canlet.2024.216968.Razavi P., Chang M.T., Xu G., Bandlamudi C., Ross D.S., Vasan N., Cai Y., Bielski C.M., Donoghue M.T.A., Jonsson P., Penson A., Shen R., Pareja F., Kundra R., Middha S., Cheng M.L., Zehir A., Kandoth C., Patel R., Huberman K., Smyth L.M., Jhaveri K., Modi S., Traina T.A., Dang C., Zhang W., Weigelt B., Li B.T., Ladanyi M., Hyman D.M., Schultz N., Robson M.E., Hudis C., Brogi E., Viale A., Norton L., Dickler M.N., Berger M.F., Iacobuzio-Donahue C.A., Chandarlapaty S., Scaltriti M., ReisFilho J.S., Solit D.B., Taylor B.S., Baselga J. The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers. Cancer Cell. 2018; 34(3): 427–38. doi: 10.1016/j.ccell.2018.08.008.Razavi P., Chang M.T., Xu G., Bandlamudi C., Ross D.S., Vasan N., Cai Y., Bielski C.M., Donoghue M.T.A., Jonsson P., Penson A., Shen R., Pareja F., Kundra R., Middha S., Cheng M.L., Zehir A., Kandoth C., Patel R., Huberman K., Smyth L.M., Jhaveri K., Modi S., Traina T.A., Dang C., Zhang W., Weigelt B., Li B.T., Ladanyi M., Hyman D.M., Schultz N., Robson M.E., Hudis C., Brogi E., Viale A., Norton L., Dickler M.N., Berger M.F., Iacobuzio-Donahue C.A., Chandarlapaty S., Scaltriti M., ReisFilho J.S., Solit D.B., Taylor B.S., Baselga J. The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers. Cancer Cell. 2018; 34(3): 427–38. doi: 10.1016/j.ccell.2018.08.008.

The authors declare that there are no conflicts of interest present.