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38308298 2024 02 07 2024 12 18 1756-0500 17 1 2024 Feb 02 BMC research notes BMC Res Notes The relationship between high ratios of CD4/FOXP3 and CD8/CD163 and the improved survivability of metastatic triple-negative breast cancer patients: a multicenter cohort study. 44 44 44 10.1186/s13104-024-06704-z Triple-negative breast cancer (TNBC) has been documented as the most aggressive subtype of breast cancer. This study aimed to analyze antitumor and protumor immune activities, and their ratios as significant prognostic biomarkers in metastatic TNBC (mTNBC). A multicenter cohort study was conducted among 103 de novo mTNBC patients. The expression of CD8 and CD163 was evaluated using immunohistochemistry staining, CD4 and FOXP3 using double-staining immunohistochemistry, and PD-L1 using immunohistochemistry and RT-PCR. Multivariate analysis revealed that high CD4/FOXP3 (HR 1.857; 95% CI 1.049-3.288; p = 0.034) and the CD8/CD163 ratio (HR 2.089; 95% CI 1.174-3.717; p = 0.012) yield significantly improved 1 year overall survival (OS). Kaplan-Meier analysis showed that high levels of CD4 (p = 0.023), CD8 (p = 0.043), CD4/FOXP3 (p = 0.016), CD8/FOXP3 (p = 0.005), CD8/CD163 (p = 0.005) ratios were significantly associated with higher rate of 1 year OS. Furthermore, 1 year OS was directly correlated with antitumor CD4 (R = 0.233; p = 0.018) and CD8 (R = 0.219; p = 0.026) and was indirectly correlated with protumor CD163 and FOXP3 through CD4/FOXP3 (R = 0.282; p = 0.006), CD4/CD163 (R = 0.239; p = 0.015), CD8/FOXP3 (R = 0.260; p = 0.008), and CD8/CD163 (R = 0.258; p = 0.009). This is the first study to demonstrate that high levels of CD4/FOXP3 and CD8/CD163 significantly improved the 1 year OS in de novo mTNBC patients. Thus, we recommend the application of these markers as prognosis determination and individual treatment decision. © 2024. The Author(s). Tenggara Jeffry Beta JB Division of Hematology and Medical Oncology, Department of Internal Medicine, Dr. Cipto Mangunkusumo General Hospital-Faculty of Medicine Universitas Indonesia, Jl. Pangeran Diponegoro No. 71, RW.5, Kec. Senen, Central Jakarta, Jakarta, 10430, Indonesia. jeffry.tenggara@yahoo.com. Division of Hematology and Medical Oncology, Department of Internal Medicine, MRCCC Siloam Hospital Jakarta, Jakarta, Indonesia. jeffry.tenggara@yahoo.com. Rachman Andhika A Division of Hematology and Medical Oncology, Department of Internal Medicine, Dr. Cipto Mangunkusumo General Hospital-Faculty of Medicine Universitas Indonesia, Jl. Pangeran Diponegoro No. 71, RW.5, Kec. Senen, Central Jakarta, Jakarta, 10430, Indonesia. Division of Hematology and Medical Oncology, Department of Internal Medicine, MRCCC Siloam Hospital Jakarta, Jakarta, Indonesia. Prihartono Joedo J Department of Community Medicine, Dr. Cipto Mangunkusumo General Hospital-Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia. Rachmadi Lisnawati L Department of Anatomical Pathology, Dr. Cipto Mangunkusumo General Hospital-Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia. Panigoro Sonar Soni SS Department of Surgical Oncology, Dr. Cipto Mangunkusumo General Hospital-Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia. Heriyanto Didik Setyo DS Department of Anatomical Pathology, Dr. Sardjito Hospital-Faculty of Medicine, Public Health and Nursing, Universitas Gadjah Mada, Yogyakarta, Indonesia. Sutandyo Noorwati N Division of Hematology and Medical Oncology, Department of Internal Medicine, Dharmais National Cancer Hospital, Jakarta, Indonesia. Nasution Intan Russianna IR Division of Hematology and Medical Oncology, Gatot Soebroto Army Hospital Jakarta, Jakarta, Indonesia. Rahadiati Familia Bella FB Department of Anatomical Pathology, Gatot Soebroto Army Hospital Jakarta, Jakarta, Indonesia. Steven Ricci R Division of Hematology and Medical Oncology, Department of Internal Medicine, Dr. Cipto Mangunkusumo General Hospital-Faculty of Medicine Universitas Indonesia, Jl. Pangeran Diponegoro No. 71, RW.5, Kec. Senen, Central Jakarta, Jakarta, 10430, Indonesia. Division of Hematology and Medical Oncology, Department of Internal Medicine, MRCCC Siloam Hospital Jakarta, Jakarta, Indonesia. Betsy Rachelle R Department of Internal Medicine, Dr. Cipto Mangunkusumo General Hospital-Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia. Juanputra Samuel S Department of Internal Medicine, Dr. Cipto Mangunkusumo General Hospital-Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia. Sudoyo Aru Wisaksono AW Division of Hematology and Medical Oncology, Department of Internal Medicine, Dr. Cipto Mangunkusumo General Hospital-Faculty of Medicine Universitas Indonesia, Jl. Pangeran Diponegoro No. 71, RW.5, Kec. Senen, Central Jakarta, Jakarta, 10430, Indonesia. Division of Hematology and Medical Oncology, Department of Internal Medicine, MRCCC Siloam Hospital Jakarta, Jakarta, Indonesia. eng Multicenter Study Journal Article 2024 02 02 England BMC Res Notes 101462768 1756-0500 0 B7-H1 Antigen 0 Forkhead Transcription Factors 0 FOXP3 protein, human 0 CD4 Antigens 0 CD8 Antigens 0 CD163 antigen IM Humans B7-H1 Antigen CD8-Positive T-Lymphocytes metabolism Cohort Studies Forkhead Transcription Factors genetics Lymphocytes, Tumor-Infiltrating metabolism pathology Neoadjuvant Therapy Triple Negative Breast Neoplasms pathology CD4 Antigens CD8 Antigens CD163 CD4 CD8 FOXP3 Metastatic Survival Triple-negative breast cancer The authors declared that they had no competing interests. 2023 7 19 2024 1 24 2024 2 5 6 42 2024 2 3 0 42 2024 2 2 23 58 2024 2 2 epublish 38308298 PMC10835864 10.1186/s13104-024-06704-z 10.1186/s13104-024-06704-z Almansour NM. Triple-negative breast cancer: a brief review about epidemiology, risk factors, signaling pathways, treatment and role of artificial intelligence. Front Mol Biosci. 2022 doi: 10.3389/fmolb.2022.836417. 10.3389/fmolb.2022.836417 PMC8824427 35145999 Oshi M, Newman S, Tokumaru Y, Yan L, Matsuyama R, Endo I, et al. Inflammation is associated with worse outcome in the whole cohort but with better outcome in triple-negative subtype of breast cancer patients. J Immunol Res. 2020;2020:1–17. doi: 10.1155/2020/5618786. 10.1155/2020/5618786 PMC7787871 33457427 Zheng H, Siddharth S, Parida S, Wu X, Sharma D. Tumor microenvironment: key players in triple negative breast cancer immunomodulation. Cancers. 2021;13:3357. doi: 10.3390/cancers13133357. 10.3390/cancers13133357 PMC8269090 34283088 Anders CK, Carey LA. Biology, metastatic patterns, and treatment of patients with triple-negative breast cancer. Clin Breast Cancer. 2009;9:S73–81. doi: 10.3816/CBC.2009.s.008. 10.3816/CBC.2009.s.008 PMC2919761 19596646 Bou Zerdan M, Ghorayeb T, Saliba F, Allam S, Bou Zerdan M, Yaghi M, et al. Triple negative breast cancer: updates on classification and treatment in 2021. Cancers. 2022;14:1253. doi: 10.3390/cancers14051253. 10.3390/cancers14051253 PMC8909187 35267561 Kassam F, Enright K, Dent R, Dranitsaris G, Myers J, Flynn C, et al. Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design. Clin Breast Cancer. 2009;9:29–33. doi: 10.3816/CBC.2009.n.005. 10.3816/CBC.2009.n.005 19299237 Kazmi S, Chatterjee D, Raju D, Hauser R, Kaufman PA. Overall survival analysis in patients with metastatic breast cancer and liver or lung metastases treated with eribulin, gemcitabine, or capecitabine. Breast Cancer Res Treat. 2020;184:559–565. doi: 10.1007/s10549-020-05867-0. 10.1007/s10549-020-05867-0 PMC7599186 32808239 Benchama O, Malamas MS, Praveen K, Ethier EC, Williams MK, Makriyannis A, et al. Inhibition of triple negative breast cancer-associated inflammation and progression by N- acylethanolamine acid amide hydrolase (NAAA) Sci Rep. 2022;12:22255. doi: 10.1038/s41598-022-26564-6. 10.1038/s41598-022-26564-6 PMC9789040 36564457 Lan T, Chen L, Wei X. inflammatory cytokines in cancer: comprehensive understanding and clinical progress in gene therapy. Cells. 2021;10:100. doi: 10.3390/cells10010100. 10.3390/cells10010100 PMC7827947 33429846 Salem ML, Attia ZI, Galal SM. Acute inflammation induces immunomodulatory effects on myeloid cells associated with anti-tumor responses in a tumor mouse model. J Adv Res. 2016;7:243–253. doi: 10.1016/j.jare.2015.06.001. 10.1016/j.jare.2015.06.001 PMC4767798 26966565 Marusyk A, Tabassum DP, Altrock PM, Almendro V, Michor F, Polyak K. Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature. 2014;514:54–58. doi: 10.1038/nature13556. 10.1038/nature13556 PMC4184961 25079331 Lee JM, Lee M-H, Garon E, Goldman JW, Salehi-Rad R, Baratelli FE, et al. Phase I trial of intratumoral injection of CCL21 gene-modified dendritic cells in lung cancer elicits tumor-specific immune responses and CD8+ T-cell Infiltration. Clin Cancer Res. 2017;23:4556–4568. doi: 10.1158/1078-0432.CCR-16-2821. 10.1158/1078-0432.CCR-16-2821 PMC5599263 28468947 Hammond MEH, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American society of clinical oncology/college of american pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784–2795. doi: 10.1200/JCO.2009.25.6529. 10.1200/JCO.2009.25.6529 PMC2881855 20404251 Wolff AC, Hammond MEH, Hicks DG, Dowsett M, McShane LM, Allison KH, et al. Recommendations for Human epidermal growth factor receptor 2 testing in breast cancer: American society of clinical oncology/college of American pathologists clinical practice guideline update. J Clin Oncol. 2013;31:3997–4013. doi: 10.1200/JCO.2013.50.9984. 10.1200/JCO.2013.50.9984 24101045 Tavares MC, Sampaio CD, Lima GE, Andrade VP, Gonçalves DG, Macedo MP, et al. A high CD8 to FOXP3 ratio in the tumor stroma and expression of PTEN in tumor cells are associated with improved survival in non-metastatic triple-negative breast carcinoma. BMC Cancer. 2021;21:901. doi: 10.1186/s12885-021-08636-4. 10.1186/s12885-021-08636-4 PMC8343973 34362334 Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs working group 2014. Ann Oncol. 2015;26:259–271. doi: 10.1093/annonc/mdu450. 10.1093/annonc/mdu450 PMC6267863 25214542 Yip WK, Abdullah MA, Yusoff SM, Seow HF. Increase in tumour-infiltrating lymphocytes with regulatory T cell immunophenotypes and reduced ζ-chain expression in nasopharyngeal carcinoma patients. Clin Exp Immunol. 2009;155:412–422. doi: 10.1111/j.1365-2249.2008.03793.x. 10.1111/j.1365-2249.2008.03793.x PMC2669517 19220831 Bankhead P, Loughrey MB, Fernández JA, Dombrowski Y, McArt DG, Dunne PD, et al. QuPath: open source software for digital pathology image analysis. Sci Rep. 2017;7:16878. doi: 10.1038/s41598-017-17204-5. 10.1038/s41598-017-17204-5 PMC5715110 29203879 Park Y, Koh J, Na HY, Kwak Y, Lee K-W, Ahn S-H, et al. PD-L1 testing in gastric cancer by the combined positive score of the 22C3 PharmDx and SP263 assay with clinically relevant cut-offs. Cancer Res Treat. 2020;52:661–670. doi: 10.4143/crt.2019.718. 10.4143/crt.2019.718 PMC7373862 32019283 Yarso K, Bellynda M, Azmiardi A, Wasita B, Heriyanto D, Astuti I, et al. Chemotherapy negates the effect of SDF1 mRNA to distant metastasis and poor overall survival in breast cancer patients. Asian Pac J Cancer Prev. 2021;22:757–766. doi: 10.31557/APJCP.2021.22.3.757. 10.31557/APJCP.2021.22.3.757 PMC8286657 33773539 Lechner MG, Liebertz DJ, Epstein AL. Characterization of cytokine-induced myeloid-derived suppressor cells from normal human peripheral blood mononuclear cells. J Immunol. 2010;185:2273–2284. doi: 10.4049/jimmunol.1000901. 10.4049/jimmunol.1000901 PMC2923483 20644162 National Comprehensive Cancer Network. NCCN Guidelines. 2022. https://www.nccn.org/guidelines/category_1. Accessed 19 Nov 2022. Tay RE, Richardson EK, Toh HC. Revisiting the role of CD4+ T cells in cancer immunotherapy—new insights into old paradigms. Cancer Gene Ther. 2021;28:5–17. doi: 10.1038/s41417-020-0183-x. 10.1038/s41417-020-0183-x PMC7886651 32457487 Borst J, Ahrends T, Bąbała N, Melief CJM, Kastenmüller W. CD4+ T cell help in cancer immunology and immunotherapy. Nat Rev Immunol. 2018;18:635–647. doi: 10.1038/s41577-018-0044-0. 10.1038/s41577-018-0044-0 30057419 Hor JL, Whitney PG, Zaid A, Brooks AG, Heath WR, Mueller SN. Spatiotemporally distinct interactions with dendritic cell subsets facilitates CD4+ and CD8+ T cell activation to localized viral infection. Immunity. 2015;43:554–565. doi: 10.1016/j.immuni.2015.07.020. 10.1016/j.immuni.2015.07.020 26297566 Smith CM, Wilson NS, Waithman J, Villadangos JA, Carbone FR, Heath WR, et al. Cognate CD4+ T cell licensing of dendritic cells in CD8+ T cell immunity. Nat Immunol. 2004;5:1143–1148. doi: 10.1038/ni1129. 10.1038/ni1129 15475958 Laidlaw BJ, Craft JE, Kaech SM. The multifaceted role of CD4+ T cells in CD8+ T cell memory. Nat Rev Immunol. 2016;16:102–111. doi: 10.1038/nri.2015.10. 10.1038/nri.2015.10 PMC4860014 26781939 Kennedy R, Celis E. Multiple roles for CD4 + T cells in anti-tumor immune responses. Immunol Rev. 2008;222:129–144. doi: 10.1111/j.1600-065X.2008.00616.x. 10.1111/j.1600-065X.2008.00616.x 18363998 Jackute J, Zemaitis M, Pranys D, Sitkauskiene B, Miliauskas S, Bajoriunas V, et al. The prognostic influence of tumor infiltrating Foxp3+CD4+, CD4+ and CD8+ T cells in resected non-small cell lung cancer. J Inflamm. 2015;12:63. doi: 10.1186/s12950-015-0108-x. 10.1186/s12950-015-0108-x PMC4657296 26604855 Mandapathil M, Szczepanski MJ, Szajnik M, Ren J, Lenzner DE, Jackson EK, et al. increased ectonucleotidase expression and activity in regulatory T cells of patients with head and neck cancer. Clin Cancer Res. 2009;15:6348–6357. doi: 10.1158/1078-0432.CCR-09-1143. 10.1158/1078-0432.CCR-09-1143 PMC2763335 19825957 Liu C, Sun B, Hu X, Zhang Y, Wang Q, Yue J, et al. Stereotactic ablative radiation therapy for pulmonary recurrence-based oligometastatic non-small cell lung cancer: survival and prognostic value of regulatory T cells. Int J Radiation Oncol Biol Phys. 2019;105:1055–64. doi: 10.1016/j.ijrobp.2019.08.012. 10.1016/j.ijrobp.2019.08.012 31437470 Togashi Y, Shitara K, Nishikawa H. Regulatory T cells in cancer immunosuppression — implications for anticancer therapy. Nat Rev Clin Oncol. 2019;16:356–371. doi: 10.1038/s41571-019-0175-7. 10.1038/s41571-019-0175-7 30705439 Ren X, Song Y, Pang J, Chen L, Zhou L, Liang Z, et al. Prognostic value of various immune cells and Immunoscore in triple-negative breast cancer. Front Immunol. 2023 doi: 10.3389/fimmu.2023.1137561. 10.3389/fimmu.2023.1137561 PMC10117828 37090736 Farhood B, Najafi M, Mortezaee K. CD8 + cytotoxic T lymphocytes in cancer immunotherapy: a review. J Cell Physiol. 2019;234:8509–8521. doi: 10.1002/jcp.27782. 10.1002/jcp.27782 30520029 Zhang L, Zhang W, Li Z, Lin S, Zheng T, Hao B, et al. Mitochondria dysfunction in CD8+ T cells as an important contributing factor for cancer development and a potential target for cancer treatment: a review. J Exp Clin Cancer Res. 2022;41:227. doi: 10.1186/s13046-022-02439-6. 10.1186/s13046-022-02439-6 PMC9306053 35864520 Hudson K, Cross N, Jordan-Mahy N, Leyland R. The extrinsic and intrinsic roles of PD-L1 and Its receptor PD-1: implications for immunotherapy treatment. Front Immunol. 2020 doi: 10.3389/fimmu.2020.568931. 10.3389/fimmu.2020.568931 PMC7609400 33193345 Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang T-H, et al. The immune landscape of cancer. Immunity. 2018;48:812–830.e14. doi: 10.1016/j.immuni.2018.03.023. 10.1016/j.immuni.2018.03.023 PMC5982584 29628290 Zhu Y, Zhang H, Pan C, He G, Cui X, Yu X, et al. Integrated tumor genomic and immune microenvironment analysis identifies predictive biomarkers associated with the efficacy of neoadjuvant therapy for triple-negative breast cancer. Cancer Med. 2023;12:5846–5858. doi: 10.1002/cam4.5372. 10.1002/cam4.5372 PMC10028167 36271505 Jiang X, Wang J, Deng X, Xiong F, Ge J, Xiang B, et al. Role of the tumor microenvironment in PD-L1/PD-1-mediated tumor immune escape. Mol Cancer. 2019;18:10. doi: 10.1186/s12943-018-0928-4. 10.1186/s12943-018-0928-4 PMC6332843 30646912 Medrek C, Pontén F, Jirström K, Leandersson K. The presence of tumor associated macrophages in tumor stroma as a prognostic marker for breast cancer patients. BMC Cancer. 2012;12:306. doi: 10.1186/1471-2407-12-306. 10.1186/1471-2407-12-306 PMC3414782 22824040 Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 2015;21:24–33. doi: 10.1016/j.molmed.2014.10.009. 10.1016/j.molmed.2014.10.009 PMC4282825 25440090 Purwanto I, Heriyanto DS, Ghozali A, Widodo I, Dwiprahasto I, Aryandono T, et al. Overexpression of programmed death-ligand 1 receptor MRNA as an independent negative prognostic factor for triple negative breast cancer. World J Oncol. 2020;11:216–222. doi: 10.14740/wjon1302. 10.14740/wjon1302 PMC7575275 33117465 Magaki S, Hojat SA, Wei B, So A, Yong WH. An introduction to the performance of immunohistochemistry. Berlin: Springer; 2019. PMC6749998 30539453 Wang R, Zhu Y, Liu X, Liao X, He J, Niu L. The clinicopathological features and survival outcomes of patients with different metastatic sites in stage IV breast cancer. BMC Cancer. 2019;19:1091. doi: 10.1186/s12885-019-6311-z. 10.1186/s12885-019-6311-z PMC6852913 31718602 trying2... trying...
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breast cancer "breast neoplasms"[MeSH Terms] OR ("breast"[All Fields] AND "neoplasms"[All Fields]) OR "breast neoplasms"[All Fields] OR ("breast"[All Fields] AND "cancer"[All Fields]) OR "breast cancer"[All Fields] "breast neoplasms"[MeSH Terms] OR ("breast"[All Fields] AND "neoplasms"[All Fields]) OR "breast neoplasms"[All Fields] OR ("breast"[All Fields] AND "cancer"[All Fields]) OR "breast cancer"[All Fields]
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39729313 2024 12 27 2574-3805 7 12 2024 Dec 02 JAMA network open JAMA Netw Open Changes to the US Preventive Services Task Force Screening Guidelines and Incidence of Breast Cancer. e2452688 e2452688 10.1001/jamanetworkopen.2024.52688 The 2009 US Preventive Services Task Force breast cancer screening guideline changes led to decreases in screening mammography, raising concern about potential increases in late-stage disease and more invasive surgical treatments. To investigate the incidence of breast cancer by stage at diagnosis and surgical treatment before and after the 2009 guideline changes. This population-based, epidemiologic cohort study of women aged 40 years or older used 2004 to 2019 data from the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. Age- and stage-specific breast cancer incidence rates and the proportion of breast cancers treated by partial mastectomy, total mastectomy, and total mastectomy with reconstruction were calculated. Data analyses were conducted from August 2023 to February 2024. Age group (40-49, 50-74, and ≥75 years). Annual percent changes (APCs) in stage-specific breast cancer incidence and proportions of cases treated with each surgery type. This cohort study included 2 022 250 women (354 263 [17.5%] aged 40-49 years, 1 279 542 [63.2%] aged 50-74 years, and 388 445 [19.2%] aged ≥75 age group, from a total of 2 023 541 women) diagnosed with breast cancer. Rates of in situ breast cancer decreased since 2009 (eg, APC, -0.69 [95% CI, -2.77 to -0.18] for women aged 50-74 years). Localized breast cancer rates increased steadily during 2004 to 2019 in women aged 40 to 74 years (eg, APC, 1.18 [95% CI, 1.02-1.34] for women aged 50-74 years), with no evidence of a change in trend during the study period. Regional cancer rates decreased or did not change. Distant cancer rates were flat since 2012 among women aged 40 to 74 years and increased steadily for those 75 years or older during 2004 to 2019 (APC, 1.40 [95% CI, 1.00-1.82]). The proportion of cases treated with partial mastectomy decreased during 2004 to 2012 (eg, APC, -0.77 [95% CI, -2.96 to -0.03] among women aged 50-74 years with localized cancer), whereas the proportion of cases treated with total mastectomy with reconstruction increased (eg, APC, 20.17 [95% CI, 16.50-33.16]). During 2012 to 2019, the proportion of cases treated with total mastectomy decreased (eg, APC, -2.44 [95% CI, -3.45 to -1.61] for women aged 50-74 years with localized cancer), and the proportion of cases treated with partial mastectomy increased (eg, APC, 1.70 [95% CI, 0.90-4.08] for women aged 50-74 years). In this cohort study, in situ breast cancer decreased since 2009, consistent with decreasing use of screening mammography since the 2009 guideline changes, but this decrease did not appear to have translated to more advanced breast cancer stages at diagnosis or decreases in the proportion of cases treated with partial mastectomy. Further research is needed to understand the long-standing increase in localized invasive breast cancer and the decrease in regional invasive breast cancer observed during the past 20 years in the context of decreased breast cancer screening. Zhang-Petersen Carina C Department of Surgery, University of Vermont, Burlington. Sowden Michelle M Department of Surgery, University of Vermont, Burlington. University of Vermont Cancer Center, Burlington. Chen Jennifer J Larner College of Medicine, University of Vermont, Burlington. Burns Julia J Department of Surgery, University of Vermont, Burlington. Sprague Brian L BL Department of Surgery, University of Vermont, Burlington. University of Vermont Cancer Center, Burlington. eng Journal Article 2024 12 02 United States JAMA Netw Open 101729235 2574-3805 IM 2024 12 27 12 20 2024 12 27 12 20 2024 12 27 11 33 epublish 39729313 10.1001/jamanetworkopen.2024.52688 2828497 39729292 2024 12 27 1880-4233 2024 Dec 27 Breast cancer (Tokyo, Japan) Breast Cancer Clinicopathological significance of androgen receptor expression and tumor infiltrating lymphocytes in triple-negative breast cancer: a retrospective cohort study. 10.1007/s12282-024-01662-7 Triple-negative breast cancer (TNBC) is a serious disease with limited treatment options. We explored the significance of androgen receptor (AR) expression and tumor-infiltrating lymphocytes (TILs) in predicting neoadjuvant chemotherapy (NAC) resistance in TNBC, hypothesizing that AR/TIL classification using pretreatment biopsies can identify NAC-resistant subgroups and improve the understanding of apocrine differentiation. This retrospective study included 156 consecutive patients with TNBC treated with NAC. AR immunostaining was defined positive if ≥ 1% of the tumor cell nuclei were stained. Stromal TIL levels were assessed, with high levels defined as ≥ 50%. Apocrine differentiation was detected using an anti-15-PGDH antibody. The pathological response to NAC was evaluated. Overall, 36% (n = 56) of the patients achieved a pathological complete response (pCR). AR+ /TILlow tumors had a high non-pCR rate (76%, 42/55) and were resistant to NAC. Kaplan-Meier plots showed significant differences in overall survival (OS) and distant metastasis-free survival (DMFS) among the four AR/TIL subgroups (OS: p = 0.013; DMFS: p = 0.0016). All 11 cases with some degree of apocrine differentiation were AR+ /TILlow , 15-PGDH-positive, and NAC-resistant. AR+ /TILlow status was significantly associated with a high likelihood of non-pCR (OR = 0.26, p = 0.009). Multivariate analysis confirmed pCR as an independent predictor of better prognosis (OS, HR = 0.13, p = 0.006; DMFS, HR = 0.15, p = 0.002), whereas AR+ /TILlow status was not significantly associated with OS or DMFS. AR/TIL classification using pretreatment biopsies identified TNBC subgroups with distinct NAC responses and prognoses. AR+ /TILlow TNBC, including apocrine differentiation cases, were NAC-resistant, highlighting the need for alternative therapies. © 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society. Ushigusa Takeshi T 0000-0002-5946-3742 Department of Pathology, St. Luke's International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo, 1048560, Japan. taushig@luke.ac.jp. Hirakawa Nami N Department of Pathology, St. Luke's International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo, 1048560, Japan. Kajiura Yuka Y Department of Breast Surgery, St. Luke's International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo, 1048560, Japan. Yoshida Atsushi A 0000-0001-5536-132X Department of Breast Surgery, St. Luke's International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo, 1048560, Japan. Yamauchi Hideko H University of Hawai'i Cancer Center, 701 Ilalo Street, Honolulu, HI, 96813, USA. Kanomata Naoki N 0000-0002-0172-4524 Department of Pathology, St. Luke's International Hospital, 9-1, Akashi-cho, Chuo-ku, Tokyo, 1048560, Japan. eng 22H04343 Japan Society for the Promotion of Science ZK2022-04 St. Luke's Health Science Research Fund Journal Article 2024 12 27 Japan Breast Cancer 100888201 1340-6868 IM 15-prostaglandin dehydrogenase Androgen receptor Apocrine Triple-negative breast cancer Tumor-infiltrating lymphocytes Declarations. Conflict of interest: The authors declare that they have no conflicts of interest related to this article. Ethical approval: The study was approved by the Institutional Review Board (22R010). All procedures performed in studies involving human participants adhered to the ethical standards of the institutional research committee, the 1964 Helsinki Declaration, and its later amendments or comparable ethical standards. Patient consent: Informed consent was obtained from all participants in the study. 2024 12 27 12 20 2024 12 27 12 20 2024 6 17 2024 12 20 2024 12 27 11 16 aheadofprint 39729292 10.1007/s12282-024-01662-7 10.1007/s12282-024-01662-7 Cortazar P, Zhang L, Untch M, Mehta K, Costantino JP, Wolmark N, et al. Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet. 2014;384:164–72. https://doi.org/10.1016/s0140-6736(13)62422-8 . 10.1016/s0140-6736(13)62422-8 24529560 Liedtke C, Mazouni C, Hess KR, André F, Tordai A, Mejia JA, et al. Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol. 2023;41:1809–15. https://doi.org/10.1200/jco.22.02572 . 10.1200/jco.22.02572 36989609 Gerratana L, Basile D, Buono G, De Placido S, Giuliano M, Minichillo S, et al. Androgen receptor in triple negative breast cancer: a potential target for the targetless subtype. Cancer Treat Rev. 2018;68:102–10. https://doi.org/10.1016/j.ctrv.2018.06.005 . 10.1016/j.ctrv.2018.06.005 29940524 Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, et al. Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest. 2011;121:2750–67. https://doi.org/10.1172/JCI45014 . 10.1172/JCI45014 21633166 3127435 Thompson KJ, Leon-Ferre RA, Sinnwell JP, Zahrieh DM, Suman VJ, Metzger FO, et al. Luminal androgen receptor breast cancer subtype and investigation of the microenvironment and neoadjuvant chemotherapy response. NAR Cancer. 2022. https://doi.org/10.1093/narcan/zcac018 . 10.1093/narcan/zcac018 35734391 9204893 Masuda H, Baggerly KA, Wang Y, Zhang Y, Gonzalez-Angulo AM, Meric-Bernstam F, et al. Differential response to neoadjuvant chemotherapy among 7 triple-negative breast cancer molecular subtypes. Clin Cancer Res. 2013;19:5533–40. https://doi.org/10.1158/1078-0432.Ccr-13-0799 . 10.1158/1078-0432.Ccr-13-0799 23948975 Salgado R, Denkert C, Demaria S, Sirtaine N, Klauschen F, Pruneri G, et al. The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014. Ann Oncol. 2015;26:259–71. https://doi.org/10.1093/annonc/mdu450 . 10.1093/annonc/mdu450 25214542 Denkert C, von Minckwitz G, Darb-Esfahani S, Lederer B, Heppner BI, Weber KE, et al. Tumour-infiltrating lymphocytes and prognosis in different subtypes of breast cancer: a pooled analysis of 3771 patients treated with neoadjuvant therapy. Lancet Oncol. 2018;19:40–50. https://doi.org/10.1016/s1470-2045(17)30904-x . 10.1016/s1470-2045(17)30904-x 29233559 El Bairi K, Haynes HR, Blackley E, Fineberg S, Shear J, Turner S, et al. The tale of TILs in breast cancer: a report from the international immuno-oncology biomarker working group. NPJ Breast Cancer. 2021;7:150. https://doi.org/10.1038/s41523-021-00346-1 . 10.1038/s41523-021-00346-1 34853355 8636568 Gatalica Z, Kuzmova N, Rose I, Ulamec M, Peric-Balja M, Skenderi F, et al. The assessment of tumor-infiltrating lymphocytes in invasive apocrine carcinoma of the breast in relation to the HER2 status. Biomol Biomed. 2024;24:256–61. https://doi.org/10.17305/bb.2023.9868 . 10.17305/bb.2023.9868 37782562 10950344 Sun X, Zuo K, Yao Q, Zhou S, Shui R, Xu X, et al. Invasive apocrine carcinoma of the breast: clinicopathologic features and comprehensive genomic profiling of 18 pure triple-negative apocrine carcinomas. Mod Pathol. 2020;33:2473–82. https://doi.org/10.1038/s41379-020-0589-x . 10.1038/s41379-020-0589-x 32504034 Board WCoTE. Breast tumours. World Health Organization classification of tumours. 5th ed. Lyon: International Agency for Research on Cancer; 2019. Schwartz CJ, Ruiz J, Bean GR, Sirohi D, Joseph NM, Hosfield EM, et al. Triple-negative apocrine carcinomas: toward a unified group with shared molecular features and clinical behavior. Mod Pathol. 2023;36:100125. https://doi.org/10.1016/j.modpat.2023.100125 . 10.1016/j.modpat.2023.100125 36870308 Wolff AC, Somerfield MR, Dowsett M, Hammond MEH, Hayes DF, McShane LM, et al. Human epidermal growth factor receptor 2 testing in breast cancer: ASCO–College of American pathologists guideline update. J Clin Oncol. 2023;41:3867–72. https://doi.org/10.1200/jco.22.02864 . 10.1200/jco.22.02864 37284804 Hammond ME, Hayes DF, Dowsett M, Allred DC, Hagerty KL, Badve S, et al. American society of clinical oncology/College of American pathologists guideline recommendations for immunohistochemical testing of estrogen and progesterone receptors in breast cancer. J Clin Oncol. 2010;28:2784–95. https://doi.org/10.1200/jco.2009.25.6529 . 10.1200/jco.2009.25.6529 20404251 2881855 (UICC) UfICC. TNM classification of malignant tumours. 8th ed. Oxford: Wiley-Blackwell; 2017. Celis JE, Cabezón T, Moreira JM, Gromov P, Gromova I, Timmermans-Wielenga V, et al. Molecular characterization of apocrine carcinoma of the breast: validation of an apocrine protein signature in a well-defined cohort. Mol Oncol. 2009;3:220–37. https://doi.org/10.1016/j.molonc.2009.01.005 . 10.1016/j.molonc.2009.01.005 19393583 5527852 Hanamura T, Kitano S, Kagamu H, Yamashita M, Terao M, Okamura T, et al. Expression of hormone receptors is associated with specific immunological profiles of the breast cancer microenvironment. Breast Cancer Res. 2023;25:13. https://doi.org/10.1186/s13058-023-01606-7 . 10.1186/s13058-023-01606-7 36721218 9887885 Leon-Ferre RA, Jonas SF, Salgado R, Loi S, De Jong V, Carter JM, et al. Tumor-infiltrating lymphocytes in triple-negative breast cancer. JAMA. 2024;331:1135–44. https://doi.org/10.1001/jama.2024.3056 . 10.1001/jama.2024.3056 38563834 10988354 Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, et al. Phase II trial of bicalutamide in patients with androgen receptor–positive, estrogen receptor–negative metastatic breast cancer. Clin Cancer Res. 2013;19:5505–12. https://doi.org/10.1158/1078-0432.Ccr-12-3327 . 10.1158/1078-0432.Ccr-12-3327 23965901 4086643 Traina TA, Miller K, Yardley DA, Eakle J, Schwartzberg LS, O’Shaughnessy J, et al. Enzalutamide for the treatment of androgen receptor–expressing triple-negative breast cancer. J Clin Oncol. 2018;36:884–90. https://doi.org/10.1200/jco.2016.71.3495 . 10.1200/jco.2016.71.3495 29373071 5858523 Bonnefoi H, Grellety T, Tredan O, Saghatchian M, Dalenc F, Mailliez A, et al. A phase II trial of abiraterone acetate plus prednisone in patients with triple-negative androgen receptor positive locally advanced or metastatic breast cancer (UCBG 12–1). Ann Oncol. 2016;27:812–8. https://doi.org/10.1093/annonc/mdw067 . 10.1093/annonc/mdw067 27052658 Jiang Y-Z, Liu Y, Xiao Y, Hu X, Jiang L, Zuo W-J, et al. Molecular subtyping and genomic profiling expand precision medicine in refractory metastatic triple-negative breast cancer: the FUTURE trial. Cell Res. 2021;31:178–86. https://doi.org/10.1038/s41422-020-0375-9 . 10.1038/s41422-020-0375-9 32719455 Hu T, Liu Y, Wu J, Hu XL, Zhao G, Liang B, et al. Triple-negative apocrine breast carcinoma has better prognosis despite poor response to neoadjuvant chemotherapy. J Clin Med. 2022;11:1607. https://doi.org/10.3390/jcm11061607 . 10.3390/jcm11061607 35329934 8949126 Ogiya A, Horii R, Osako T, Ito Y, Iwase T, Eishi Y, et al. Apocrine metaplasia of breast cancer: clinicopathological features and predicting response. Breast Cancer. 2010;17:290–7. https://doi.org/10.1007/s12282-009-0178-9 . 10.1007/s12282-009-0178-9 19789945 Celis JE, Gromov P, Cabezón T, Moreira JM, Friis E, Jirström K, et al. 15-prostaglandin dehydrogenase expression alone or in combination with ACSM1 defines a subgroup of the apocrine molecular subtype of breast carcinoma. Mol Cell Proteomics. 2008;7:1795–809. https://doi.org/10.1074/mcp.R800011-MCP200 . 10.1074/mcp.R800011-MCP200 18632593 Tai H-H. Prostaglandin catabolic enzymes as tumor suppressors. Cancer Metastasis Rev. 2011;30:409–17. https://doi.org/10.1007/s10555-011-9314-z . 10.1007/s10555-011-9314-z 22020925 Asano Y, Kashiwagi S, Onoda N, Kurata K, Morisaki T, Noda S, et al. Clinical verification of sensitivity to preoperative chemotherapy in cases of androgen receptor-expressing positive breast cancer. Br J Cancer. 2016;114:14–20. https://doi.org/10.1038/bjc.2015.434 . 10.1038/bjc.2015.434 26757422 4716546 Zuo T, Wilson P, Cicek AF, Harigopal M. Androgen receptor expression is a favorable prognostic factor in triple-negative breast cancers. Hum Pathol. 2018;80:239–45. https://doi.org/10.1016/j.humpath.2018.06.003 . 10.1016/j.humpath.2018.06.003 29902579 Astvatsaturyan K, Yue Y, Walts AE, Bose S. Androgen receptor positive triple negative breast cancer: clinicopathologic, prognostic, and predictive features. PLoS ONE. 2018;13:e0197827. https://doi.org/10.1371/journal.pone.0197827 . 10.1371/journal.pone.0197827 29883487 5993259 Sridhar N, Glisch C, Jawa Z, Chaudhary LN, Kamaraju S, Burfeind J, et al. Androgen receptor expression in patients with triple negative breast cancer treated with neoadjuvant chemotherapy: a single institution study. J Cancer. 2022;13:2472–6. https://doi.org/10.7150/jca.67536 . 10.7150/jca.67536 35711833 9174868 Choi JE, Kang SH, Lee SJ, Bae YK. Androgen receptor expression predicts decreased survival in early stage triple-negative breast cancer. Ann Surg Oncol. 2015;22:82–9. https://doi.org/10.1245/s10434-014-3984-z . 10.1245/s10434-014-3984-z 25145503 Thike AA, Chong LY-Z, Cheok PY, Li HH, Wai-Cheong Yip G, Huat Bay B, et al. Loss of androgen receptor expression predicts early recurrence in triple-negative and basal-like breast cancer. Mod Pathol. 2014;27:352–60. https://doi.org/10.1038/modpathol.2013.145 . 10.1038/modpathol.2013.145 23929266 Mangia A, Saponaro C, Vagheggini A, Opinto G, Centonze M, Vicenti C, et al. Should tumor infiltrating lymphocytes, androgen receptor, and FOXA1 expression predict the clinical outcome in triple negative breast cancer patients? Cancers. 2019;11:1393. https://doi.org/10.3390/cancers11091393 . 10.3390/cancers11091393 31540486 6769726 Asano Y, Kashiwagi S, Goto W, Tanaka S, Morisaki T, Takashima T, et al. Expression and clinical significance of androgen receptor in triple-negative breast cancer. Cancers. 2017;9:4. https://doi.org/10.3390/cancers9010004 . 10.3390/cancers9010004 28067809 5295775 39729291 2024 12 27 1880-4233 2024 Dec 27 Breast cancer (Tokyo, Japan) Breast Cancer Identifying subgroups of ypN1 breast cancer patients who may exempt from axillary lymph node dissection after neoadjuvant chemotherapy: insights from a large cohort study. 10.1007/s12282-024-01663-6 In patients with breast cancer staged ypN1 after neoadjuvant chemotherapy (NAC), there is limited evidence-based guidance regarding exemption from axillary lymph node dissection (ALND). This study analyzed ypN1 breast cancer patients post-NAC from the Surveillance, Epidemiology, and End Results databases. Patients were categorized into the breast-conserving surgery (BCS) group and the total mastectomy (TM) group, and further divided by the number of positive lymph nodes (LNs). The effects of three axillary management strategies, ALND, sentinel lymph node biopsy combined with radiotherapy (SLNB + RT), and ALND + RT were compared. The overall survival (OS) and breast cancer-specific survival (BCSS) of all subgroups and their independent risk factors were analyzed. Independent prognostic factors selected from multivariate Cox analysis were utilized to create nomograms for predicting OS and BCSS. A total of 3641 patients were involved, with 1331 in the BCS group and 2310 in the TM group. In the TM group, patients with 3 residual positive LNs exhibited significant improvements in OS and BCSS when treated with ALND + RT. For patients with 1 or 2 residual positive LNs in the TM group and all BCS patients, no significant survival differences in survival outcomes were observed among the three axillary management methods. The accuracy of the nomograms was validated via calibration curves, receiver operating characteristic curves, and decision curve analysis curves. For TM group patients with 3 residual positive LNs after NAC, ALND + RT is recommended. For other subgroups of ypN1 patients, SLNB + RT can be considered an alternative to ALND. The nomogram developed to predict OS and BCSS in ypN1 breast cancer patients demonstrated excellent predictive ability. © 2024. The Author(s), under exclusive licence to The Japanese Breast Cancer Society. Liu Peinan P The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. Liu Dandan D The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. Zhao Changying C Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. Wei Yumeng Y The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. Liu Xingyu X The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. Cui Hanxiao H The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. Zhao Xuyan X The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. Chang Lidan L The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. Lin Shuai S The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. Wu Hao H School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases of Ministry of Education, Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China. Ma Xiaobin X The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. Kang Huafeng H The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. kanghuafeng1973@126.com. Wang Meng M 0000-0002-7417-9192 The Comprehensive Breast Care Center, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, China. wmeng0308@126.com. eng 2020YJ (ZYTS)625 Xi'an Jiaotong University Journal Article 2024 12 27 Japan Breast Cancer 100888201 1340-6868 IM Axillary lymph node dissection Breast cancer Neoadjuvant chemotherapy Sentinel lymph node biopsy Declarations. Conflict of interest: All authors declare that they have no conflicts of interest to disclose. Ethical approval and informed consent. As the SEER database used in this study does not contain personally identifiable information, patient informed consent is not needed. The study received an exemption from the Ethics Committee of the Second Affiliated Hospital of Xi'an Jiaotong University. Consent for publication: All the authors declare that this manuscript is original work and has not been published previously, nor is it under consideration for publication elsewhere. All sources of funding and potential conflicts of interest have been disclosed. 2024 12 27 12 20 2024 12 27 12 20 2024 10 9 2024 12 20 2024 12 27 11 16 aheadofprint 39729291 10.1007/s12282-024-01663-6 10.1007/s12282-024-01663-6 Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. Ca-a Cancer J Clin. 2024;74:229–63. https://doi.org/10.3322/caac.21834 . 10.3322/caac.21834 Veronesi U, et al. A randomized comparison of sentinel-node biopsy with routine axillary dissection in breast cancer. N Engl J Med. 2003;349:546–53. https://doi.org/10.1056/NEJMoa012782 . 10.1056/NEJMoa012782 12904519 Caudle AS, et al. Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer using selective evaluation of clipped nodes: implementation of targeted axillary dissection. J Clin Oncol. 2016;34:1072–8. https://doi.org/10.1200/JCO.2015.64.0094 . 10.1200/JCO.2015.64.0094 26811528 4933133 Fleissig A, et al. Post-operative arm morbidity and quality of life. Results of the ALMANAC randomised trial comparing sentinel node biopsy with standard axillary treatment in the management of patients with early breast cancer. Breast Cancer Res Treatment. 2006. https://doi.org/10.1007/s10549-005-9025-7 . 10.1007/s10549-005-9025-7 Mansel RE, et al. Randomized multicenter trial of sentinel node biopsy versus standard axillary treatment in operable breast cancer: The ALMANAC trial. J Natl Cancer Inst. 2006;98:599–609. https://doi.org/10.1093/jnci/djj158 . 10.1093/jnci/djj158 16670385 Land SR, et al. Patient-reported outcomes in sentinel node-negative adjuvant breast cancer patients receiving sentinel-node biopsy or axillary dissection: National Surgical Adjuvant Breast and Bowel Project phase III protocol B-32. J Clin Oncol. 2010;28:3929–36. https://doi.org/10.1200/JCO.2010.28.2491 . 10.1200/JCO.2010.28.2491 20679600 2940391 Giuliano AE, et al. Locoregional recurrence after sentinel lymph node dissection with or without axillary dissection in patients with sentinel lymph node metastases: long-term follow-up from the american college of surgeons oncology group (alliance) acosog z0011 randomized trial. Ann Surg. 2016;264:413–20. https://doi.org/10.1097/SLA.0000000000001863 . 10.1097/SLA.0000000000001863 27513155 Giuliano AE, et al. Effect of axillary dissection vs no axillary dissection on 10-year overall survival among women with invasive breast cancer and sentinel node metastasis the ACOSOG Z0011 (Alliance) randomized clinical trial. Jama-J the Am Med Assoc. 2017;318:918–26. https://doi.org/10.1001/jama.2017.11470 . 10.1001/jama.2017.11470 Donker M, et al. Radiotherapy or surgery of the axilla after a positive sentinel node in breast cancer (EORTC 10981–22023 AMAROS): a randomised, multicentre, open-label, phase 3 non-inferiority trial. Lancet Oncol. 2014;15:1303–10. https://doi.org/10.1016/s1470-2045(14)70460-7 . 10.1016/s1470-2045(14)70460-7 25439688 4291166 Tinterri C, et al. Preservation of axillary lymph nodes compared with complete dissection in t1–2 breast cancer patients presenting one or two metastatic sentinel lymph nodes: the sinodar-one multicenter randomized clinical trial. Ann Surg Oncol. 2022;29:5732–44. https://doi.org/10.1245/s10434-022-11866-w . 10.1245/s10434-022-11866-w 35552930 Frei E. Clinical cancer-research - an embattled species. Cancer. 1982;50:1979–92. 10.1002/1097-0142(19821115)50:10<1979::AID-CNCR2820501002>3.0.CO;2-D 7127245 Shien T, Iwata H. Adjuvant and neoadjuvant therapy for breast cancer. Jpn J Clin Oncol. 2020;50:225–9. https://doi.org/10.1093/jjco/hyz213 . 10.1093/jjco/hyz213 32147701 Rastogi P, et al. Preoperative chemotherapy: updates of national surgical adjuvant breast and bowel project protocols B-18 and B-27. J Clin Oncol. 2008;26:778–85. https://doi.org/10.1200/jco.2007.15.0235 . 10.1200/jco.2007.15.0235 18258986 van der Hage JA, et al. Preoperative chemotherapy in primary operable breast cancer: results from the european organization for research and treatment of cancer trial 10902. J Clin Oncol. 2001;19:4224–37. https://doi.org/10.1200/jco.2001.19.22.4224 . 10.1200/jco.2001.19.22.4224 11709566 Boughey JC, et al. Sentinel lymph node surgery after neoadjuvant chemotherapy in patients with node-positive breast cancer the ACOSOG Z1071 (Alliance) clinical trial. Jama-J Am Med Assoc. 2013;310:1455–61. https://doi.org/10.1001/jama.2013.278932 . 10.1001/jama.2013.278932 Heidinger M, Knauer M, Tausch C, Weber WP. Tailored axillary surgery - A novel concept for clinically node positive breast cancer. Breast. 2023;69:281–9. https://doi.org/10.1016/j.breast.2023.03.005 . 10.1016/j.breast.2023.03.005 36922305 10034500 Kunkler IH, Canney P, van Tienhoven G, Russell NS. Elucidating the role of chest wall irradiation in “intermediate-risk” breast cancer: the MRC/EORTC SUPREMO trial. Clin Oncol (R Coll Radiol). 2008;20:31–4. 10.1016/j.clon.2007.10.004 18345543 Pilewskie M, Morrow M. Axillary nodal management following neoadjuvant chemotherapy: a review. JAMA Oncol. 2017;3:549–55. https://doi.org/10.1001/jamaoncol.2016.4163 . 10.1001/jamaoncol.2016.4163 27918753 5580251 Giuliano AE, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. Arch Surg. 2011;146:980–980. EBCTCG. Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 2018. https://doi.org/10.1016/S1470-2045(17)30777-5 . 10.1016/S1470-2045(17)30777-5 Barrio AV, et al. Nodal recurrence in patients with node-positive breast cancer treated with sentinel node biopsy alone after neoadjuvant chemotherapy-a rare event. JAMA Oncol. 2021;7:1851–5. https://doi.org/10.1001/jamaoncol.2021.4394 . 10.1001/jamaoncol.2021.4394 34617979 Kuehn T, et al. Sentinel-lymph-node biopsy in patients with breast cancer before and after neoadjuvant chemotherapy (SENTINA): a prospective, multicentre cohort study. Lancet Oncology. 2013;14:609–18. https://doi.org/10.1016/s1470-2045(13)70166-9 . 10.1016/s1470-2045(13)70166-9 23683750 Boileau J-F, et al. Sentinel node biopsy after neoadjuvant chemotherapy in biopsy-proven node-positive breast cancer: the SN FNAC study. J Clin Oncol. 2015;33:258-U150. https://doi.org/10.1200/jco.2014.55.7827 . 10.1200/jco.2014.55.7827 25452445 Classe J-M, et al. Sentinel lymph node biopsy without axillary lymphadenectomy after neoadjuvant chemotherapy is accurate and safe for selected patients: the GANEA 2 study. Breast Cancer Res Treat. 2019;173:343–52. https://doi.org/10.1007/s10549-018-5004-7 . 10.1007/s10549-018-5004-7 30343457 Montagna G, et al. Omission of axillary dissection following nodal downstaging with neoadjuvant chemotherapy. JAMA Oncol. 2024;10:831–2. https://doi.org/10.1001/jamaoncol.2024.0578 . 10.1001/jamaoncol.2024.0578 Magnoni F, et al. Axillary surgery in breast cancer: An updated historical perspective. Semin Oncol. 2020;47:341–52. https://doi.org/10.1053/j.seminoncol.2020.09.001 . 10.1053/j.seminoncol.2020.09.001 33131896 Beck AC, Morrow M. Axillary lymph node dissection: Dead or still alive? Breast. 2023;69:469–75. https://doi.org/10.1016/j.breast.2023.01.009 . 10.1016/j.breast.2023.01.009 36702672 10300611 Gerber B, et al. Axillary lymph node dissection in early-stage invasive breast cancer: is it still standard today? Breast Cancer Res Treat. 2011;128:613–24. https://doi.org/10.1007/s10549-011-1532-0 . 10.1007/s10549-011-1532-0 21523451 Harlow SP, et al. Prerandomization surgical training for the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-32 trial - A randomized phase III clinical trial to compare sentinel node resection to conventional axillary dissection in clinically node-negative breast cancer. Ann Surg. 2005;241:48–54. https://doi.org/10.1097/01.sla.0000149429.39656.94 . 10.1097/01.sla.0000149429.39656.94 15621990 1356845 Galimberti V, et al. Axillary dissection versus no axillary dissection in patients with sentinel-node micrometastases (IBCSG 23–01): a phase 3 randomised controlled trial. Lancet Oncology. 2013;14:297–305. https://doi.org/10.1016/s1470-2045(13)70035-4 . 10.1016/s1470-2045(13)70035-4 23491275 Tinterri C, et al. Sentinel lymph node biopsy versus axillary lymph node dissection in breast cancer patients undergoing mastectomy with one to two metastatic sentinel lymph nodes: sub-analysis of the SINODAR-ONE multicentre randomized clinical trial and reopening of enrolment. Br J Surg. 2023;110:1143–52. https://doi.org/10.1093/bjs/znad215 . 10.1093/bjs/znad215 37471574 10492188 Cao S, et al. Feasibility and reliability of sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer patients with positive axillary nodes at initial diagnosis: An up-to-date meta-analysis of 3,578 patients. Breast (Edinburgh, Scotland). 2021;59:256–69. https://doi.org/10.1016/j.breast.2021.07.015 . 10.1016/j.breast.2021.07.015 34325383 Swarnkar PK, Tayeh S, Michell MJ, Mokbel K. The Evolving role of marked lymph node biopsy (MLNB) and targeted axillary dissection (TAD) after neoadjuvant chemotherapy (NACT) for node-positive breast cancer: systematic review and pooled analysis. Cancers (Basel). 2021. https://doi.org/10.3390/cancers13071539 . 10.3390/cancers13071539 33810544 Gasparri ML, et al. Axillary surgery after neoadjuvant therapy in initially node-positive breast cancer: international EUBREAST survey. Br J Surg. 2022;109:857–63. https://doi.org/10.1093/bjs/znac217 . 10.1093/bjs/znac217 35766257 Choy N, et al. Initial results with preoperative tattooing of biopsied axillary lymph nodes and correlation to sentinel lymph nodes in breast cancer patients. Ann Surg Oncol. 2015;22:377–82. https://doi.org/10.1245/s10434-014-4034-6 . 10.1245/s10434-014-4034-6 25164040 Caudle AS, et al. Improved axillary evaluation following neoadjuvant therapy for patients with node-positive breast cancer using selective evaluation of clipped nodes: implementation of targeted axillary dissection. J Clin Oncol. 2016. https://doi.org/10.1200/jco.2015.64.0094 . 10.1200/jco.2015.64.0094 26811528 4933133 Diego EJ, et al. Axillary staging after neoadjuvant chemotherapy for breast cancer: a pilot study combining sentinel lymph node biopsy with radioactive seed localization of pre-treatment positive axillary lymph nodes. Ann Surg Oncol. 2016;23:1549–53. https://doi.org/10.1245/s10434-015-5052-8 . 10.1245/s10434-015-5052-8 26727919 Ling DC, Iarrobino NA, Champ CE, Soran A, Beriwal S. Regional recurrence rates with or without complete axillary dissection for breast cancer patients with node-positive disease on sentinel lymph node biopsy after neoadjuvant chemotherapy. Adv Radiat Oncol. 2020;5:163–70. https://doi.org/10.1016/j.adro.2019.09.006 . 10.1016/j.adro.2019.09.006 32280815 Almahariq MF, et al. Omission of axillary lymph node dissection is associated with inferior survival in breast cancer patients with residual n1 nodal disease following neoadjuvant chemotherapy. Ann Surg Oncol. 2021;28:930–40. https://doi.org/10.1245/s10434-020-08928-2 . 10.1245/s10434-020-08928-2 32712895 Zhu T, et al. Multifactor artificial intelligence model assists axillary lymph node surgery in breast cancer after neoadjuvant chemotherapy: multicenter retrospective cohort study. Int J Surg. 2023;109:3383–94. https://doi.org/10.1097/js9.0000000000000621 . 10.1097/js9.0000000000000621 37830943 10651262 39729247 2024 12 27 1432-1335 151 1 2024 Dec 27 Journal of cancer research and clinical oncology J Cancer Res Clin Oncol Clinicopathological characteristics and long-term prognosis of triple-negative breast cancer patients with HER2-Low expression: a retrospective propensity score-matched cohort study. 24 24 10.1007/s00432-024-06069-7 The objective of the current research was to assess the clinicopathological characteristics and long-term prognosis of triple-negative breast cancer (TNBC) patients with human epidermal growth factor receptor 2 (HER2)-low status following breast surgery. A total of 202 TNBC patients treated at Qingdao Central Hospital from January 2010 to December 2019 were included, comprising 71 HER2-low and 131 HER2-zero patients. Propensity score matching (PSM) was applied to minimize differences between the cohorts. HER2-low TNBC patients had lower histological grade, lower Ki-67 expression levels, and a higher prevalence of hypertension compared to HER2-zero TNBC patients. Before and after PSM, the HER2-low group consistently exhibited a lower recurrence rate and longer RFS compared to HER2-zero TNBC patients. HER2-low status was validated as an independent low-risk factor for RFS both pre-PSM (HR 0.354, 95% CI 0.178-0.706, p = 0.003) and post-PSM (HR 0.405, 95% CI 0.185-0.886, p = 0.024). No statistically significant differences in mortality rate and OS were observed, both before and after PSM. HER2-low and HER2-zero TNBC patients show significant clinicopathological differences. Compared to HER2-zero, HER2-low status is linked to better long-term prognosis and serves as an independent low-risk factor for RFS in TNBC patients. © 2024. The Author(s). Liu Xin X Qingdao Medical College, Qingdao University, Qingdao, 266071, Shandong, China. Department of Breast Surgery, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Hospital), Qingdao, 266042, Shandong, China. Zhao Kaihua K Department of Breast Surgery, Qingdao Central Hospital, University of Health and Rehabilitation Sciences (Qingdao Central Hospital), Qingdao, 266042, Shandong, China. Zhang Ziyan Z Department of Breast Surgery, Women and Children's Hospital, Qingdao University, Qingdao, 266034, Shandong, China. Liu Meiyan M Qingdao Medical College, Qingdao University, Qingdao, 266071, Shandong, China. Chu Hongwu H Guangdong Provincial Key Laboratory of Digestive Cancer Research, The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, 518107, Guangdong, China. chuhw5@mail2.sysu.edu.cn. Zou Xiao X Department of Breast Surgery, Xiangdong Hospital Affiliated to Hunan Normal University, Liling, 412200, Hunan, China. 18660229101@qq.com. eng Journal Article 2024 12 27 Germany J Cancer Res Clin Oncol 7902060 0171-5216 IM Clinicopathological characteristics HER2-Low Long-term prognosis Triple-negative breast cancer Declarations. Ethical approval: The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of Qingdao Central Hospital. Written informed consent requirement was waived by the Ethics Committee. Consent to publish: Not applicable. Competing interests: The authors declare no competing interests. 2024 12 27 12 20 2024 12 27 12 20 2024 11 13 2024 12 17 2024 12 27 11 14 epublish 39729247 10.1007/s00432-024-06069-7 10.1007/s00432-024-06069-7 Allison KH, Hammond MEH, Dowsett M, McKernin SE, Carey LA, Fitzgibbons PL et al (2020) Estrogen and progesterone receptor testing in breast Cancer: ASCO/CAP Guideline Update. J Clin Oncol 38(12):1346–1366. https://doi.org/10.1200/jco.19.02309 10.1200/jco.19.02309 31928404 Almstedt K, Heimes AS, Kappenberg F, Battista MJ, Lehr HA, Krajnak S et al (2022) Long-term prognostic significance of HER2-low and HER2-zero in node-negative breast cancer. Eur J Cancer 173:10–19. https://doi.org/10.1016/j.ejca.2022.06.012 10.1016/j.ejca.2022.06.012 35839597 Berrino E, Annaratone L, Bellomo SE, Ferrero G, Gagliardi A, Bragoni A et al (2022) Integrative genomic and transcriptomic analyses illuminate the ontology of HER2-low breast carcinomas. Genome Med 14(1):98. https://doi.org/10.1186/s13073-022-01104-z 10.1186/s13073-022-01104-z 36038884 9426037 Bianchini G, De Angelis C, Licata L, Gianni L (2022) Treatment landscape of triple-negative breast cancer - expanded options, evolving needs. Nat Rev Clin Oncol 19(2):91–113. https://doi.org/10.1038/s41571-021-00565-2 10.1038/s41571-021-00565-2 34754128 Bray F, Laversanne M, Sung H, Ferlay J, Siegel RL, Soerjomataram I et al (2024) Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 74(3):229–263. https://doi.org/10.3322/caac.21834 10.3322/caac.21834 38572751 Chen L, Liu CC, Zhu SY, Ge JY, Chen YF, Ma D et al (2023) Multiomics of HER2-low triple-negative breast cancer identifies a receptor tyrosine kinase-relevant subgroup with therapeutic prospects. JCI Insight 8(22). https://doi.org/10.1172/jci.insight.172366 Corti C, Giugliano F, Nicolò E, Tarantino P, Criscitiello C, Curigliano G (2023) HER2-Low breast Cancer: a New Subtype? Curr Treat Options Oncol 24(5):468–478. https://doi.org/10.1007/s11864-023-01068-1 10.1007/s11864-023-01068-1 36971965 Dai LJ, Ma D, Xu YZ, Li M, Li YW, Xiao Y et al (2023) Molecular features and clinical implications of the heterogeneity in Chinese patients with HER2-low breast cancer. Nat Commun 14(1):5112. https://doi.org/10.1038/s41467-023-40715-x 10.1038/s41467-023-40715-x 37607916 10444861 Denkert C, Seither F, Schneeweiss A, Link T, Blohmer JU, Just M et al (2021) Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol 22(8):1151–1161. https://doi.org/10.1016/s1470-2045(21)00301-6 10.1016/s1470-2045(21)00301-6 34252375 Dent R, Trudeau M, Pritchard KI, Hanna WM, Kahn HK, Sawka CA et al (2007) Triple-negative breast cancer: clinical features and patterns of recurrence. Clin Cancer Res 13(15 Pt 1):4429–4434. https://doi.org/10.1158/1078-0432.Ccr-06-3045 10.1158/1078-0432.Ccr-06-3045 17671126 Gampenrieder SP, Dezentjé V, Lambertini M, de Nonneville A, Marhold M, Le Du F et al (2023) Influence of HER2 expression on prognosis in metastatic triple-negative breast cancer-results from an international, multicenter analysis coordinated by the AGMT Study Group. ESMO Open 8(1):100747. https://doi.org/10.1016/j.esmoop.2022.100747 10.1016/j.esmoop.2022.100747 36563519 Giuliano AE, Edge SB, Hortobagyi GN (2018) Eighth Edition of the AJCC Cancer staging Manual: breast Cancer. Ann Surg Oncol 25(7):1–3. https://doi.org/10.3389/fonc.2023.1157789 10.3389/fonc.2023.1157789 Han BY, Chen C, Luo H, Lin CJ, Han XC, Nasir J et al (2024) Clinical sequencing defines the somatic and germline mutation landscapes of Chinese HER2-Low breast Cancer. Cancer Lett 588:216763. https://doi.org/10.1016/j.canlet.2024.216763 10.1016/j.canlet.2024.216763 38403109 Horisawa N, Adachi Y, Takatsuka D, Nozawa K, Endo Y, Ozaki Y et al (2022) The frequency of low HER2 expression in breast cancer and a comparison of prognosis between patients with HER2-low and HER2-negative breast cancer by HR status. Breast Cancer 29(2):234–241. https://doi.org/10.1007/s12282-021-01303-3 10.1007/s12282-021-01303-3 34622383 Hu XE, Yang P, Chen S, Wei G, Yuan L, Yang Z et al (2023) Clinical and biological heterogeneities in triple-negative breast cancer reveals a non-negligible role of HER2-low. Breast Cancer Res 25(1):34. https://doi.org/10.1186/s13058-023-01639-y 10.1186/s13058-023-01639-y 36998014 10061837 Jin J, Li B, Cao J, Li T, Zhang J, Cao J et al (2023) Analysis of clinical features, genomic landscapes and survival outcomes in HER2-low breast cancer. J Transl Med 21(1):360. https://doi.org/10.1186/s12967-023-04076-9 10.1186/s12967-023-04076-9 37264417 10236705 Li Y, Sun Y, Kulke M, Hechler T, Van der Jeught K, Dong T et al (2021) Targeted immunotherapy for HER2-low breast cancer with 17p loss. Sci Transl Med 13(580). https://doi.org/10.1126/scitranslmed.abc6894 Li Y, Zhang H, Merkher Y, Chen L, Liu N, Leonov S et al (2022) Recent advances in therapeutic strategies for triple-negative breast cancer. J Hematol Oncol 15(1):121. https://doi.org/10.1186/s13045-022-01341-0 10.1186/s13045-022-01341-0 36038913 9422136 Li Y, Tsang JY, Tam F, Loong T, Tse GM (2023) Comprehensive characterization of HER2-low breast cancers: implications in prognosis and treatment. EBioMedicine 91:104571. https://doi.org/10.1016/j.ebiom.2023.104571 10.1016/j.ebiom.2023.104571 37068349 10130469 Li H, Plichta JK, Li K, Jin Y, Thomas SM, Ma F et al (2024) Impact of HER2-low status for patients with early-stage breast cancer and non-pCR after neoadjuvant chemotherapy: a National Cancer Database Analysis. Breast Cancer Res Treat 204(1):89–105. https://doi.org/10.1007/s10549-023-07171-z 10.1007/s10549-023-07171-z 38066250 Liu Y, Hu Y, Xue J, Li J, Yi J, Bu J et al (2023) Advances in immunotherapy for triple-negative breast cancer. Mol Cancer 22(1):145. https://doi.org/10.1186/s12943-023-01850-7 10.1186/s12943-023-01850-7 37660039 10474743 Löb S, Linsmeier E, Herbert SL, Schlaiß T, Kiesel M, Wischhusen J et al (2023) Prognostic effect of HER2 evolution from primary breast cancer to breast cancer metastases. J Cancer Res Clin Oncol 149(8):5417–5428. https://doi.org/10.1007/s00432-022-04486-0 10.1007/s00432-022-04486-0 36451043 Miglietta F, Griguolo G, Bottosso M, Giarratano T, Lo Mele M, Fassan M et al (2021) Evolution of HER2-low expression from primary to recurrent breast cancer. NPJ Breast Cancer 7(1):137. https://doi.org/10.1038/s41523-021-00343-4 10.1038/s41523-021-00343-4 34642348 8511010 Modi S, Jacot W, Yamashita T, Sohn J, Vidal M, Tokunaga E et al (2022) Trastuzumab Deruxtecan in previously treated HER2-Low advanced breast Cancer. N Engl J Med 387(1):9–20. https://doi.org/10.1056/NEJMoa2203690 10.1056/NEJMoa2203690 35665782 10561652 Peiffer DS, Zhao F, Chen N, Hahn OM, Nanda R, Olopade OI et al (2023) Clinicopathologic characteristics and prognosis of ERBB2-Low breast Cancer among patients in the National Cancer Database. JAMA Oncol 9(4):500–510. https://doi.org/10.1001/jamaoncol.2022.7476 10.1001/jamaoncol.2022.7476 36821125 9951099 Sanomachi T, Okuma HS, Kitadai R, Kawachi A, Yazaki S, Tokura M et al (2023) Low HER2 expression is a predictor of poor prognosis in stage I triple-negative breast cancer. Front Oncol 13:1157789. https://doi.org/10.3389/fonc.2023.1157789 10.3389/fonc.2023.1157789 37051545 10083471 Schettini F, Chic N, Brasó-Maristany F, Paré L, Pascual T, Conte B et al (2021) Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. NPJ Breast Cancer 7(1):1. https://doi.org/10.1038/s41523-020-00208-2 10.1038/s41523-020-00208-2 33397968 7782714 Schettini F, Blondeaux E, Molinelli C, Bas R, Kim HJ, Di Meglio A et al (2024) Characterization of HER2-low breast cancer in young women with germline BRCA1/2 pathogenetic variants: results of a large international retrospective cohort study. Cancer 130(16):2746–2762. https://doi.org/10.1002/cncr.35323 10.1002/cncr.35323 38752572 Shao Y, Guan H, Luo Z, Yu Y, He Y, Chen Q et al (2024) Clinicopathological characteristics and value of HER2-low expression evolution in breast cancer receiving neoadjuvant chemotherapy. Breast 73:103666. https://doi.org/10.1016/j.breast.2023.103666 10.1016/j.breast.2023.103666 38159433 Shi Z, Liu Y, Fang X, Liu X, Meng J, Zhang J (2024) Efficacy and prognosis of HER2-Low and HER2-Zero in triple-negative breast cancer after neoadjuvant chemotherapy. Sci Rep 14(1):16899. https://doi.org/10.1038/s41598-024-67795-z 10.1038/s41598-024-67795-z 39043756 11266405 So JY, Ohm J, Lipkowitz S, Yang L (2022) Triple negative breast cancer (TNBC): non-genetic tumor heterogeneity and immune microenvironment: emerging treatment options. Pharmacol Ther 237:108253. https://doi.org/10.1016/j.pharmthera.2022.108253 10.1016/j.pharmthera.2022.108253 35872332 9378710 Tan R, Ong WS, Lee KH, Lim AH, Park S, Park YH et al (2022) HER2 expression, copy number variation and survival outcomes in HER2-low non-metastatic breast cancer: an international multicentre cohort study and TCGA-METABRIC analysis. BMC Med 20(1):105. https://doi.org/10.1186/s12916-022-02284-6 10.1186/s12916-022-02284-6 35296300 8928638 Tang Y, Shen G, Xin Y, Li Z, Zheng Y, Wang M et al (2023) The association between HER2-low expression and prognosis of breast cancer: a systematic review and meta-analysis. Ther Adv Med Oncol 15:17588359231156669. https://doi.org/10.1177/17588359231156669 10.1177/17588359231156669 36872948 9983100 Tarantino P, Hamilton E, Tolaney SM, Cortes J, Morganti S, Ferraro E et al (2020) HER2-Low breast Cancer: pathological and clinical Landscape. J Clin Oncol 38(17):1951–1962. https://doi.org/10.1200/jco.19.02488 10.1200/jco.19.02488 32330069 Tarantino P, Gandini S, Nicolò E, Trillo P, Giugliano F, Zagami P et al (2022) Evolution of low HER2 expression between early and advanced-stage breast cancer. Eur J Cancer 163:35–43. https://doi.org/10.1016/j.ejca.2021.12.022 10.1016/j.ejca.2021.12.022 35032815 Tarantino P, Viale G, Press MF, Hu X, Penault-Llorca F, Bardia A et al (2023) ESMO expert consensus statements (ECS) on the definition, diagnosis, and management of HER2-low breast cancer. Ann Oncol 34(8):645–659. https://doi.org/10.1016/j.annonc.2023.05.008 10.1016/j.annonc.2023.05.008 37269905 Tuluhong D, Li X, Gao H, Zhu Y, Li Q, Wang S (2023) Molecular characteristics and prognosis of breast cancer patients with different level of HER2 positivity after adjuvant and neoadjuvant chemotherapy. Eur J Cancer Prev 32(4):377–387. https://doi.org/10.1097/cej.0000000000000813 10.1097/cej.0000000000000813 37302017 Weng L, Zhou J, Guo S, Xu N, Ma R (2024) The molecular subtyping and precision medicine in triple-negative breast cancer—based on Fudan TNBC classification. Cancer Cell Int 24(1):120. https://doi.org/10.1186/s12935-024-03261-0 10.1186/s12935-024-03261-0 38555429 10981301 Wolff AC, Somerfield MR, Dowsett M, Hammond MEH, Hayes DF, McShane LM et al (2023) Human epidermal growth factor receptor 2 testing in breast Cancer: ASCO-College of American Pathologists Guideline Update. J Clin Oncol 41(22):3867–3872. https://doi.org/10.1200/jco.22.02864 10.1200/jco.22.02864 37284804 Won HS, Ahn J, Kim Y, Kim JS, Song JY, Kim HK et al (2022) Clinical significance of HER2-low expression in early breast cancer: a nationwide study from the Korean breast Cancer Society. Breast Cancer Res 24(1):22. https://doi.org/10.1186/s13058-022-01519-x 10.1186/s13058-022-01519-x 35307014 8935777 Zhang H, Katerji H, Turner BM, Audeh W, Hicks DG (2022a) HER2-low breast cancers: incidence, HER2 staining patterns, clinicopathologic features, MammaPrint and BluePrint genomic profiles. Mod Pathol 35(8):1075–1082. https://doi.org/10.1038/s41379-022-01019-5 10.1038/s41379-022-01019-5 35184150 Zhang G, Ren C, Li C, Wang Y, Chen B, Wen L et al (2022b) Distinct clinical and somatic mutational features of breast tumors with high-, low-, or non-expressing human epidermal growth factor receptor 2 status. BMC Med 20(1):142. https://doi.org/10.1186/s12916-022-02346-9 10.1186/s12916-022-02346-9 35484593 9052533 Zheng L, Zhang Y, Wang Z, Wang H, Hao C, Li C et al (2023) Comparisons of clinical characteristics, prognosis, epidemiological factors, and genetic susceptibility between HER2-low and HER2-zero breast cancer among Chinese females. Cancer Med 12(14):14937–14948. https://doi.org/10.1002/cam4.6129 10.1002/cam4.6129 37387469 10417066 Zhou S, Liu T, Kuang X, Zhen T, Shi H, Lin Y et al (2023) Comparison of clinicopathological characteristics and response to neoadjuvant chemotherapy between HER2-low and HER2-zero breast cancer. Breast 67:1–7. https://doi.org/10.1016/j.breast.2022.12.006 10.1016/j.breast.2022.12.006 36535072 39729236 2024 12 27 2730-6011 15 1 2024 Dec 27 Discover oncology Discov Oncol Advancements in research and clinical management of interstitial lung injury associated with ADC drugs administration in breast cancer. 843 843 10.1007/s12672-024-01705-7 Antibody-drug conjugates (ADCs) represent a novel class of targeted anti-tumor medications that utilize the covalent linkage between monoclonal antibodies and cytotoxic agents. This unique mechanism combines the cytotoxic potency of drugs with the targeting specificity conferred by antigen recognition. However, it is essential to recognize that many ADCs still face challenges related to off-target toxicity akin to cytotoxic payloads, as well as targeted toxicity and other potential life-threatening adverse effects, such as treatment-induced interstitial lung injury. Currently, of the four approved ADC drugs for breast cancer, several reports have documented post-treatment lung injury-related fatalities. As a result, treatment-induced interstitial lung injury due to ADC drugs has become a clinical concern. In this review article, we delve into the factors associated with ADC-induced interstitial lung injury in patients with advanced-stage breast cancer and highlight strategies expected to decrease the incidence of ADC-related interstitial lung injury in the years ahead. These efforts are directed at enhancing treatment outcomes in both advanced and early-stage cancer patients while also providing insights into the development and innovation of ADC drugs and bolstering clinicians' understanding of the diagnosis and management of ADC-associated interstitial lung injury. © 2024. The Author(s). Zhu Jia-Yu JY Department of Graduate Student, Zhejiang Chinese Medical University, NO.548, Binwen Road, Binjiang District, Hangzhou, 310000, Zhejiang, China. Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China. Jiang Rui-Yuan RY Department of Graduate Student, Zhejiang Chinese Medical University, NO.548, Binwen Road, Binjiang District, Hangzhou, 310000, Zhejiang, China. Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China. Zhang Huan-Ping HP Department of Graduate Student, Zhejiang Chinese Medical University, NO.548, Binwen Road, Binjiang District, Hangzhou, 310000, Zhejiang, China. Department of Graduate Student, Wenzhou Medical University, No. 270, Xueyuan West Road, Lucheng District, Wenzhou, 325027, Zhejiang, China. Fang Zi-Ru ZR Department of Graduate Student, Zhejiang Chinese Medical University, NO.548, Binwen Road, Binjiang District, Hangzhou, 310000, Zhejiang, China. Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China. Zhou Huan-Huan HH Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China. Wei Qing Q Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China. Weiqingmd@163.com. Wang Xiaojia X Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, 310022, Zhejiang, China. wxiaojia0803@163.com. eng 2012C13019-1 Major Science and Technology Projects of Zhejiang Province 2021RC043 Science and Technology Program offered by the Health Bureau of Zhejiang Province Y-pierrefabre202101-0126 Beijing Xisike Clinical Oncology Research Foundation Journal Article Review 2024 12 27 United States Discov Oncol 101775142 2730-6011 Adverse reaction Antibody–drug conjugate Breast cancer Drug-induced interstitial lung injury Targeted therapy Declarations. Ethics approval and consent to participate: Not applicable. Consent for publication: All authors consent to the publication of this work in Discover Oncology. Competing interests: The authors declare no competing interests. 2024 12 27 12 21 2024 12 27 12 20 2024 8 26 2024 12 13 2024 12 27 11 14 epublish 39729236 10.1007/s12672-024-01705-7 10.1007/s12672-024-01705-7 Bray F, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2024;74:229–63. https://doi.org/10.3322/caac.21834 . 10.3322/caac.21834 38572751 Huppert LA, Gumusay O, Idossa D, Rugo HS. Systemic therapy for hormone receptor-positive/human epidermal growth factor receptor 2-negative early stage and metastatic breast cancer. CA Cancer J Clin. 2023. https://doi.org/10.3322/caac.21777 . 10.3322/caac.21777 36939293 Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019;321:288–300. https://doi.org/10.1001/jama.2018.19323 . 10.1001/jama.2018.19323 30667505 Breast cancer. Nat Rev Dis Primers 2019;5:67. https://doi.org/10.1038/s41572-019-0122-z . Yin L, Duan J-J, Bian X-W, Yu S-C. Triple-negative breast cancer molecular subtyping and treatment progress. Breast Cancer Res. 2020;22:61. https://doi.org/10.1186/s13058-020-01296-5 . 10.1186/s13058-020-01296-5 32517735 7285581 Haque R, et al. Impact of breast cancer subtypes and treatment on survival: an analysis spanning two decades. Cancer Epidemiol Biomarkers Prev. 2012;21:1848–55. https://doi.org/10.1158/1055-9965.EPI-12-0474 . 10.1158/1055-9965.EPI-12-0474 22989461 3467337 Waks AG, Winer EP. Breast cancer treatment. JAMA. 2019;321:316–316. https://doi.org/10.1001/jama.2018.20751 . 10.1001/jama.2018.20751 30667503 Lau KH, Tan AM, Shi Y. New and emerging targeted therapies for advanced breast cancer. Int J Mol Sci. 2022;23(4):2288. 10.3390/ijms23042288 35216405 8874375 Kunte S, Abraham J, Montero AJ. Novel HER2-targeted therapies for HER2-positive metastatic breast cancer. Cancer. 2020;126:4278–88. https://doi.org/10.1002/cncr.33102 . 10.1002/cncr.33102 32721042 Swain SM, Shastry M, Hamilton ET. Targeting HER2-positive breast cancer: advances and future directions. Nat Rev Drug Discov. 2023;22:101–26. https://doi.org/10.1038/s41573-022-00579-0 . 10.1038/s41573-022-00579-0 36344672 Slamon DJ, et al. Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science. 1989;244:707–12. https://doi.org/10.1126/science.2470152 . 10.1126/science.2470152 2470152 Oh D-Y, Bang Y-J. HER2-targeted therapies — a role beyond breast cancer. Nat Rev Clin Oncol. 2020;17:33–48. https://doi.org/10.1038/s41571-019-0268-3 . 10.1038/s41571-019-0268-3 31548601 Fu Z, Li S, Han S, Shi C, Zhang Y. Antibody drug conjugate: the “biological missile” for targeted cancer therapy. Signal Transduct Target Ther. 2022;7:93. https://doi.org/10.1038/s41392-022-00947-7 . 10.1038/s41392-022-00947-7 35318309 8941077 Ye F, et al. Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer. Mol Cancer. 2023;22:105. https://doi.org/10.1186/s12943-023-01805-y . 10.1186/s12943-023-01805-y 37415164 10324146 Smolarz B, Nowak AZ, Romanowicz H. Breast cancer-epidemiology, classification, pathogenesis and treatment (review of literature). Cancers. 2022;14(10):2569. 10.3390/cancers14102569 35626173 9139759 Planes-Laine G, et al. PD-1/PD-L1 targeting in breast cancer: the first clinical evidences are emerging—a literature review. Cancers. 2019;11(7):1033. 10.3390/cancers11071033 31336685 6679223 Keam SJ. Trastuzumab deruxtecan: first approval. Drugs. 2020;80:501–8. https://doi.org/10.1007/s40265-020-01281-4 . 10.1007/s40265-020-01281-4 32144719 Indini A, Rijavec E, Grossi F. Trastuzumab deruxtecan: changing the destiny of HER2 expressing solid tumors. Int J Mol Sci. 2021;22(9):4774. https://doi.org/10.3390/ijms22094774 . 10.3390/ijms22094774 33946310 8125530 American Association for Cancer Research. SG improves OS in HR+/HER2− breast cancer. Cancer Discov. 2022;12:2714–5. https://doi.org/10.1158/2159-8290.Cd-nb2022-0061 . 10.1158/2159-8290.Cd-nb2022-0061 Yang H, Ganguly A, Cabral F. Inhibition of cell migration and cell division correlates with distinct effects of microtubule inhibiting drugs. J Biol Chem. 2010;285:32242–50. https://doi.org/10.1074/jbc.M110.160820 . 10.1074/jbc.M110.160820 20696757 2952225 Birrer MJ, Moore KN, Betella I, Bates RC. Antibody-drug conjugate-based therapeutics: state of the science. J Natl Cancer Inst. 2019;111:538–49. https://doi.org/10.1093/jnci/djz035 . 10.1093/jnci/djz035 30859213 Jin Y, Schladetsch MA, Huang X, Balunas MJ, Wiemer AJ. Stepping forward in antibody-drug conjugate development. Pharmacol Ther. 2022;229:107917. https://doi.org/10.1016/j.pharmthera.2021.107917 . 10.1016/j.pharmthera.2021.107917 34171334 Khongorzul P, Ling CJ, Khan FU, Ihsan AU, Zhang J. Antibody-drug conjugates: a comprehensive review. Mol Cancer Res. 2020;18:3–19. https://doi.org/10.1158/1541-7786.MCR-19-0582 . 10.1158/1541-7786.MCR-19-0582 31659006 Yaghoubi S, et al. Potential drugs used in the antibody-drug conjugate (ADC) architecture for cancer therapy. J Cell Physiol. 2020;235:31–64. https://doi.org/10.1002/jcp.28967 . 10.1002/jcp.28967 31215038 Staudacher AH, Brown MP. Antibody drug conjugates and bystander killing: is antigen-dependent internalisation required? Br J Cancer. 2017;117:1736–42. https://doi.org/10.1038/bjc.2017.367 . 10.1038/bjc.2017.367 29065110 5729478 Green DR, Ferguson T, Zitvogel L, Kroemer G. Immunogenic and tolerogenic cell death. Nat Rev Immunol. 2009;9:353–63. https://doi.org/10.1038/nri2545 . 10.1038/nri2545 19365408 2818721 Kepp O, Tesniere A, Zitvogel L, Kroemer G. The immunogenicity of tumor cell death. Curr Opin Oncol. 2009;21:71–6. https://doi.org/10.1097/CCO.0b013e32831bc375 . 10.1097/CCO.0b013e32831bc375 19125021 Nagata S, Tanaka MP. Programmed cell death and the immune system. Nat Rev Immunol. 2017;17:333–40. https://doi.org/10.1038/nri.2016.153 . 10.1038/nri.2016.153 28163302 Obeid M, et al. Calreticulin exposure dictates the immunogenicity of cancer cell death. Nat Med. 2007;13:54–61. https://doi.org/10.1038/nm1523 . 10.1038/nm1523 17187072 Clarke C, Smyth MJ. Calreticulin exposure increases cancer immunogenicity. Nat Biotechnol. 2007;25:192–3. https://doi.org/10.1038/nbt0207-192 . 10.1038/nbt0207-192 17287754 Garg AD, et al. A novel pathway combining calreticulin exposure and ATP secretion in immunogenic cancer cell death. EMBO J. 2012;31:1062–79. https://doi.org/10.1038/emboj.2011.497 . 10.1038/emboj.2011.497 22252128 3298003 Rios-Doria J, et al. Antibody-drug conjugates bearing pyrrolobenzodiazepine or tubulysin payloads are immunomodulatory and synergize with multiple immunotherapies. Cancer Res. 2017;77:2686–98. https://doi.org/10.1158/0008-5472.Can-16-2854 . 10.1158/0008-5472.Can-16-2854 28283653 Iwata TN, et al. A HER2-targeting antibody-drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model. Mol Cancer Ther. 2018;17:1494–503. https://doi.org/10.1158/1535-7163.Mct-17-0749 . 10.1158/1535-7163.Mct-17-0749 29703841 Zammarchi F, et al. CD25-targeted antibody-drug conjugate depletes regulatory T cells and eliminates established syngeneic tumors via antitumor immunity. J Immunother Cancer. 2020. https://doi.org/10.1136/jitc-2020-000860 . 10.1136/jitc-2020-000860 32912922 7482493 Vivier E, et al. Innate or adaptive immunity? The example of natural killer cells. Science. 2011;331:44–9. https://doi.org/10.1126/science.1198687 . 10.1126/science.1198687 21212348 3089969 Nucera S, Conti C, Martorana F, Wilson B, Genta S. Antibody-drug conjugates to promote immune surveillance: lessons learned from breast cancer. Biomedicines. 2024;12:1491. 10.3390/biomedicines12071491 39062065 11274676 D’Amico L, et al. A novel anti-HER2 anthracycline-based antibody-drug conjugate induces adaptive anti-tumor immunity and potentiates PD-1 blockade in breast cancer. J Immunother Cancer. 2019;7:16. https://doi.org/10.1186/s40425-018-0464-1 . 10.1186/s40425-018-0464-1 30665463 6341578 Natsume A, Niwa R, Satoh M. Improving effector functions of antibodies for cancer treatment: enhancing ADCC and CDC. Drug Design Dev Ther. 2009;3:7–16. https://doi.org/10.2147/DDDT.S4378 . 10.2147/DDDT.S4378 Radocha J, van de Donk N, Weisel K. Monoclonal antibodies and antibody drug conjugates in multiple myeloma. Cancers. 2021. https://doi.org/10.3390/cancers13071571 . 10.3390/cancers13071571 33805481 8037134 Tai YT, et al. Novel anti-B-cell maturation antigen antibody-drug conjugate (GSK2857916) selectively induces killing of multiple myeloma. Blood. 2014;123:3128–38. https://doi.org/10.1182/blood-2013-10-535088 . 10.1182/blood-2013-10-535088 24569262 4023420 Mahalingaiah PK, et al. Potential mechanisms of target-independent uptake and toxicity of antibody-drug conjugates. Pharmacol Ther. 2019;200:110–25. https://doi.org/10.1016/j.pharmthera.2019.04.008 . 10.1016/j.pharmthera.2019.04.008 31028836 Hafeez U, Parakh S, Gan HK, Scott AM. Antibody-drug conjugates for cancer therapy. Molecules. 2020. https://doi.org/10.3390/molecules25204764 . 10.3390/molecules25204764 33081383 7587605 Donaghy H. Effects of antibody, drug and linker on the preclinical and clinical toxicities of antibody-drug conjugates. MAbs. 2016;8:659–71. https://doi.org/10.1080/19420862.2016.1156829 . 10.1080/19420862.2016.1156829 27045800 4966843 Li L, et al. Antibody-drug conjugates in HER2-positive breast cancer. Chin Med J. 2021;135:261–7. https://doi.org/10.1097/cm9.0000000000001932 . 10.1097/cm9.0000000000001932 34935688 8812658 Wolska-Washer A, Robak T. Safety and tolerability of antibody-drug conjugates in cancer. Drug Saf. 2019;42:295–314. https://doi.org/10.1007/s40264-018-0775-7 . 10.1007/s40264-018-0775-7 30649747 6399172 Lu J, Jiang F, Lu A, Zhang G. Linkers having a crucial role in antibody–drug conjugates. Int J Mol Sci. 2016;17(4):561. 10.3390/ijms17040561 27089329 4849017 Tsuchikama K, An Z. Antibody-drug conjugates: recent advances in conjugation and linker chemistries. Protein Cell. 2018;9:33–46. https://doi.org/10.1007/s13238-016-0323-0 . 10.1007/s13238-016-0323-0 27743348 Masters JC, Nickens DJ, Xuan D, Shazer RL, Amantea M. Clinical toxicity of antibody drug conjugates: a meta-analysis of payloads. Invest New Drugs. 2018;36:121–35. https://doi.org/10.1007/s10637-017-0520-6 . 10.1007/s10637-017-0520-6 29027591 Hinrichs MJ, Dixit R. Antibody drug conjugates: nonclinical safety considerations. AAPS J. 2015;17:1055–64. https://doi.org/10.1208/s12248-015-9790-0 . 10.1208/s12248-015-9790-0 26024656 4540738 Ogitani Y, Hagihara K, Oitate M, Naito H, Agatsuma T. Bystander killing effect of DS-8201a, a novel anti-human epidermal growth factor receptor 2 antibody-drug conjugate, in tumors with human epidermal growth factor receptor 2 heterogeneity. Cancer Sci. 2016;107:1039–46. https://doi.org/10.1111/cas.12966 . 10.1111/cas.12966 27166974 4946713 Menderes G, et al. SYD985, a novel duocarmycin-based HER2-targeting antibody-drug conjugate, shows antitumor activity in uterine and ovarian carcinosarcoma with HER2/Neu expression. Clin Cancer Res. 2017;23:5836–45. https://doi.org/10.1158/1078-0432.CCR-16-2862 . 10.1158/1078-0432.CCR-16-2862 28679774 5626613 Ogitani Y, et al. DS-8201a, a novel HER2-targeting ADC with a novel DNA topoisomerase I inhibitor, demonstrates a promising antitumor efficacy with differentiation from T-DM1. Clin Cancer Res. 2016;22:5097–108. https://doi.org/10.1158/1078-0432.Ccr-15-2822 . 10.1158/1078-0432.Ccr-15-2822 27026201 Saber H, Leighton JK. An FDA oncology analysis of antibody-drug conjugates. Regulat Toxicol Pharmacol. 2015;71:444–52. https://doi.org/10.1016/j.yrtph.2015.01.014 . 10.1016/j.yrtph.2015.01.014 Nessler I, Menezes B, Thurber GM. Key metrics to expanding the pipeline of successful antibody-drug conjugates. Trends Pharmacol Sci. 2021;42:803–12. https://doi.org/10.1016/j.tips.2021.07.005 . 10.1016/j.tips.2021.07.005 34456094 8519343 Adams GP, et al. High affinity restricts the localization and tumor penetration of single-chain fv antibody molecules. Can Res. 2001;61:4750–5. Cilliers C, Menezes B, Nessler I, Linderman J, Thurber GM. Improved tumor penetration and single-cell targeting of antibody-drug conjugates increases anticancer efficacy and host survival. Can Res. 2018;78:758–68. https://doi.org/10.1158/0008-5472.Can-17-1638 . 10.1158/0008-5472.Can-17-1638 Modi S, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610–21. https://doi.org/10.1056/NEJMoa1914510 . 10.1056/NEJMoa1914510 31825192 Banerji U, et al. 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;20:1124–35. https://doi.org/10.1016/S1470-2045(19)30328-6 . 10.1016/S1470-2045(19)30328-6 31257177 Zhang J, et al. Phase I trial of a novel anti-HER2 antibody-drug conjugate, ARX788, for the treatment of HER2-positive metastatic breast cancer. Clin Cancer Res. 2022;28:4212–21. https://doi.org/10.1158/1078-0432.CCR-22-0456 . 10.1158/1078-0432.CCR-22-0456 Hamilton E, et al. Abstract PD3-07: Trastuzumab deruxtecan (T-DXd; DS-8201) with nivolumab in patients with HER2-expressing, advanced breast cancer: A 2-part, phase 1b, multicenter, open-label study. Cancer Res. 2021. https://doi.org/10.1158/1538-7445.SABCS20-PD3-07 . 10.1158/1538-7445.SABCS20-PD3-07 Wei Q, et al. The promise and challenges of combination therapies with antibody-drug conjugates in solid tumors. J Hematol Oncol. 2024;17(1):1. https://doi.org/10.1186/s13045-023-01509-2 . 10.1186/s13045-023-01509-2 38178200 10768262 Martin M, et al. Trastuzumab emtansine (T-DM1) plus docetaxel with or without pertuzumab in patients with HER2-positive locally advanced or metastatic breast cancer: results from a phase Ib/IIa study. Ann Oncol. 2016;27:1249–56. https://doi.org/10.1093/annonc/mdw157 . 10.1093/annonc/mdw157 27052654 Levy B, et al. MA13.07 TROPION-Lung 02: initial results for datopotamab deruxtecan plus pembrolizumab and platinum chemotherapy in advanced NSCLC. J Thorac Oncol. 2022;17:S91. https://doi.org/10.1016/j.jtho.2022.07.152 . 10.1016/j.jtho.2022.07.152 Janjigian YY, et al. Dose-escalation and dose-expansion study of trastuzumab deruxtecan (T-DXd) monotherapy and combinations in patients (pts) with advanced/metastatic HER2+ gastric cancer (GC)/gastroesophageal junction adenocarcinoma (GEJA): DESTINY-Gastric03. J Clin Oncol. 2022;40:295–295. https://doi.org/10.1200/JCO.2022.40.4_suppl.295 . 10.1200/JCO.2022.40.4_suppl.295 Mamounas EP, et al. Adjuvant T-DM1 versus trastuzumab in patients with residual invasive disease after neoadjuvant therapy for HER2-positive breast cancer: subgroup analyses from KATHERINE. Ann Oncol. 2021;32:1005–14. https://doi.org/10.1016/j.annonc.2021.04.011 . 10.1016/j.annonc.2021.04.011 33932503 Hurvitz SA, et al. TRIO-US B-12 TALENT: Phase II neoadjuvant trial evaluating trastuzumab deruxtecan with or without anastrozole for HER2-low, HR+ early-stage breast cancer. J Clin Oncol. 2022. https://doi.org/10.1200/JCO.2022.40.16_suppl.TPS623 . 10.1200/JCO.2022.40.16_suppl.TPS623 Schmid P, et al. 166MO Datopotamab deruxtecan (Dato-DXd) + durvalumab (D) as first-line (1L) treatment for unresectable locally advanced/metastatic triple-negative breast cancer (a/mTNBC): initial results from BEGONIA, a phase Ib/II study. Ann Oncol. 2022;33:199. https://doi.org/10.1016/j.annonc.2022.03.185 . 10.1016/j.annonc.2022.03.185 Patel JD, et al. Sacituzumab govitecan (SG) + pembrolizumab (pembro) in first-line (1L) metastatic non-small cell lung cancer (mNSCLC) with PD-L1 ≥ 50%: cohort A of EVOKE-02. J Clin Oncol. 2024;42:8592–8592. https://doi.org/10.1200/JCO.2024.42.16_suppl.8592 . 10.1200/JCO.2024.42.16_suppl.8592 Zhu Z, et al. Incidence of antibody-drug conjugates-related pneumonitis in patients with solid tumors: a systematic review and meta-analysis. Crit Rev Oncol Hematol. 2023;184:103960. https://doi.org/10.1016/j.critrevonc.2023.103960 . 10.1016/j.critrevonc.2023.103960 36907365 André F, et al. Trastuzumab deruxtecan versus treatment of physician’s choice in patients with HER2-positive metastatic breast cancer (DESTINY-Breast02): a randomised, open-label, multicentre, phase 3 trial. Lancet. 2023;401:1773–85. https://doi.org/10.1016/s0140-6736(23)00725-0 . 10.1016/s0140-6736(23)00725-0 37086745 Tarantino P, et al. Interstitial lung disease induced by anti-ERBB2 antibody-drug conjugates: a review. JAMA Oncol. 2021;7:1873–81. https://doi.org/10.1001/jamaoncol.2021.3595 . 10.1001/jamaoncol.2021.3595 34647966 Mathur R, Weiner GJ. Picking the optimal target for antibody-drug conjugates. Am Soc Clin Oncol Educ Book. 2013. https://doi.org/10.14694/EdBook_AM.2013.33.e103 . 10.14694/EdBook_AM.2013.33.e103 23714470 Ritchie M, Tchistiakova L, Scott N. Implications of receptor-mediated endocytosis and intracellular trafficking dynamics in the development of antibody drug conjugates. MAbs. 2013;5(1):13–21. https://doi.org/10.4161/mabs.22854 . 10.4161/mabs.22854 23221464 3564878 Saber H, Leighton JK. An FDA oncology analysis of antibody-drug conjugates. Regul Toxicol Pharmacol. 2015;71:444–52. https://doi.org/10.1016/j.yrtph.2015.01.014 . 10.1016/j.yrtph.2015.01.014 25661711 Beck A, Goetsch L, Dumontet C, Corvaïa NS. Strategies and challenges for the next generation of antibody-drug conjugates. Nat Rev Drug Discov. 2017;16:315–37. https://doi.org/10.1038/nrd.2016.268 . 10.1038/nrd.2016.268 28303026 Kumagai K, et al. Interstitial pneumonitis related to trastuzumab deruxtecan, a human epidermal growth factor receptor 2-targeting Ab-drug conjugate, in monkeys. Cancer Sci. 2020;111:4636–45. https://doi.org/10.1111/cas.14686 . 10.1111/cas.14686 33051938 7734153 Zhao H, et al. Inhibition of megakaryocyte differentiation by antibody-drug conjugates (ADCs) is mediated by macropinocytosis: implications for ADC-induced thrombocytopenia. Mol Cancer Ther. 2017;16:1877–86. https://doi.org/10.1158/1535-7163.Mct-16-0710 . 10.1158/1535-7163.Mct-16-0710 28655784 Aoyama M, Tada M, Yokoo H, Demizu Y, Ishii-Watabe A. Fcγ receptor-dependent internalization and off-target cytotoxicity of antibody-drug conjugate aggregates. Pharm Res. 2022;39:89–103. https://doi.org/10.1007/s11095-021-03158-x . 10.1007/s11095-021-03158-x 34961908 Ahmadi M, et al. Small amounts of sub-visible aggregates enhance the immunogenic potential of monoclonal antibody therapeutics. Pharm Res. 2015;32:1383–94. https://doi.org/10.1007/s11095-014-1541-x . 10.1007/s11095-014-1541-x 25319104 Tada M, Aoyama M, Ishii-Watabe A. Fcγ receptor activation by human monoclonal antibody aggregates. J Pharm Sci. 2020;109:576–83. https://doi.org/10.1016/j.xphs.2019.10.046 . 10.1016/j.xphs.2019.10.046 31676270 Nguyen TD, Bordeau BM, Balthasar JP. Mechanisms of ADC toxicity and strategies to increase ADC tolerability. Cancers. 2023;15(3):713. 10.3390/cancers15030713 36765668 9913659 Bruggeman CW, et al. Tissue-specific expression of IgG receptors by human macrophages ex vivo. PLoS ONE. 2019;14:e0223264. https://doi.org/10.1371/journal.pone.0223264 . 10.1371/journal.pone.0223264 31613876 6793881 Aegerter H, Lambrecht BN, Jakubzick CV. Biology of lung macrophages in health and disease. Immunity. 2022;55:1564–80. https://doi.org/10.1016/j.immuni.2022.08.010 . 10.1016/j.immuni.2022.08.010 36103853 9533769 Silver RF, et al. Diversity of human and macaque airway immune cells at baseline and during tuberculosis infection. Am J Respir Cell Mol Biol. 2016;55:899–908. https://doi.org/10.1165/rcmb.2016-0122OC . 10.1165/rcmb.2016-0122OC 27509488 5248955 Barletta KE, et al. Leukocyte compartments in the mouse lung: distinguishing between marginated, interstitial, and alveolar cells in response to injury. J Immunol Methods. 2012;375:100–10. https://doi.org/10.1016/j.jim.2011.09.013 . 10.1016/j.jim.2011.09.013 21996427 Schneider C, et al. Induction of the nuclear receptor PPAR-γ by the cytokine GM-CSF is critical for the differentiation of fetal monocytes into alveolar macrophages. Nat Immunol. 2014;15:1026–37. https://doi.org/10.1038/ni.3005 . 10.1038/ni.3005 25263125 Roberts AW, et al. Tissue-resident macrophages are locally programmed for silent clearance of apoptotic cells. Immunity. 2017;47:913-927.e916. https://doi.org/10.1016/j.immuni.2017.10.006 . 10.1016/j.immuni.2017.10.006 29150239 5728676 Zhou X, Liu X, Huang L. Macrophage-mediated tumor cell phagocytosis: opportunity for nanomedicine intervention. Adv Funct Mater. 2021;31:2006220. https://doi.org/10.1002/adfm.202006220 . 10.1002/adfm.202006220 33692665 Conner SD, Schmid SL. Regulated portals of entry into the cell. Nature. 2003;422:37–44. https://doi.org/10.1038/nature01451 . 10.1038/nature01451 12621426 Lin JH. Pharmacokinetics of biotech drugs: peptides, proteins and monoclonal antibodies. Curr Drug Metab. 2009;10:661–91. https://doi.org/10.2174/138920009789895499 . 10.2174/138920009789895499 19702530 Muro S, Koval M, Muzykantov V. Endothelial endocytic pathways: gates for vascular drug delivery. Curr Vasc Pharmacol. 2004;2:281–99. https://doi.org/10.2174/1570161043385736 . 10.2174/1570161043385736 15320826 Doherty GJ, McMahon HT. Mechanisms of endocytosis. Annu Rev Biochem. 2009;78:857–902. https://doi.org/10.1146/annurev.biochem.78.081307.110540 . 10.1146/annurev.biochem.78.081307.110540 19317650 Koganemaru S, et al. Potential mechanisms of interstitial lung disease induced by antibody-drug conjugates based on quantitative analysis of drug distribution. Mol Cancer Ther. 2024. https://doi.org/10.1158/1535-7163.Mct-24-0267 . 10.1158/1535-7163.Mct-24-0267 39450538 Freites-Martinez A, Santana N, Arias-Santiago S, Viera A. Using the common terminology criteria for adverse events (CTCAE - Version 5.0) to evaluate the severity of adverse events of anticancer therapies. Actas dermo-sifiliograficas. 2021;112:90–2. https://doi.org/10.1016/j.ad.2019.05.009 . 10.1016/j.ad.2019.05.009 32891586 Skeoch S, et al. Drug-induced interstitial lung disease: a systematic review. J Clin Med. 2018. https://doi.org/10.3390/jcm7100356 . 10.3390/jcm7100356 30326612 6209877 Abuhelwa Z, Alloghbi A, Alqahtani A, Nagasaka M. Trastuzumab deruxtecan-induced interstitial lung disease/pneumonitis in ERBB2-positive advanced solid malignancies: a systematic review. Drugs. 2022;82:979–87. https://doi.org/10.1007/s40265-022-01736-w . 10.1007/s40265-022-01736-w 35759121 9276583 Jian Z, et al. criteria for the management of targeted drug-induced interstitial lung disease in solid tumors. China Oncol. 2021;31:241–9. https://doi.org/10.19401/j.cnki.1007-3639.2021.04.001 . 10.19401/j.cnki.1007-3639.2021.04.001 Bardia A, et al. Clinical practices and institutional protocols on prophylaxis, monitoring, and management of selected adverse events associated with trastuzumab deruxtecan. Oncologist. 2022;27:637–45. https://doi.org/10.1093/oncolo/oyac107 . 10.1093/oncolo/oyac107 35642907 9355822 中国医师协会肿瘤医师分会乳腺癌学组 & 中国抗癌协会国际医疗交流分会. 中国乳腺癌抗体药物偶联物安全性管理专家共识. 中华肿瘤杂志 2022;44:913–27. Johkoh T, et al. Chest CT diagnosis and clinical management of drug-related pneumonitis in patients receiving molecular targeting agents and immune checkpoint inhibitors: a position paper from the Fleischner Society. Radiology. 2021;298:550–66. https://doi.org/10.1148/radiol.2021203427 . 10.1148/radiol.2021203427 33434111 Verheijden G, et al. Toward clinical development of SYD985, a novel HER2-targeting antibody-drug conjugate (ADC). J Clin Oncol. 2014;32:626–626. https://doi.org/10.1200/jco.2014.32.15_suppl.626 . 10.1200/jco.2014.32.15_suppl.626 Manich CS, et al. LBA15 Primary outcome of the phase III SYD985.002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. Ann Oncol. 2021;32(5):1288–9. 10.1016/j.annonc.2021.08.2088 Kuhlman JE. The role of chest computed tomography in the diagnosis of drug-related reactions. J Thorac Imaging. 1991;6:52–61. https://doi.org/10.1097/00005382-199101000-00008 . 10.1097/00005382-199101000-00008 1703580 Nishino M, et al. Trastuzumab deruxtecan-related interstitial lung disease/pneumonitis: computed tomography imaging patterns to guide diagnosis and management. JCO Precis Oncol. 2023;7:e2300391. https://doi.org/10.1200/PO.23.00391 . 10.1200/PO.23.00391 38061008 Chugh K, Jatwani S. Transbronchial biopsy vs bronchoalveolar lavage in interstitial lung disease. Curr Opin Pulmonary Med. 2022;28:3–8. https://doi.org/10.1097/mcp.0000000000000847 . 10.1097/mcp.0000000000000847 Costabel U, Uzaslan E, Guzman J. Bronchoalveolar lavage in drug-induced lung disease. Clin Chest Med. 2004;25:25–35. https://doi.org/10.1016/S0272-5231(03)00143-6 . 10.1016/S0272-5231(03)00143-6 15062594 Hutchinson JP, Fogarty AW, McKeever TM, Hubbard RB. In-hospital mortality after surgical lung biopsy for interstitial lung disease in the United States 2000 to 2011. Am J Respir Crit Care Med. 2016;193:1161–7. https://doi.org/10.1164/rccm.201508-1632OC . 10.1164/rccm.201508-1632OC 26646481 Yamakawa H, et al. Anti-inflammatory and/or anti-fibrotic treatment of MPO-ANCA-positive interstitial lung disease: a short review. J Clin Med. 2022;11(13):3835. https://doi.org/10.3390/jcm11133835 . 10.3390/jcm11133835 35807120 9267459 Yang S, et al. Serum oncomarkers in patients with MPO-ANCA-positive vasculitis: diagnostic and prognostic predictive values for interstitial lung disease. Lung. 2022;200:331–8. https://doi.org/10.1007/s00408-022-00532-3 . 10.1007/s00408-022-00532-3 35426513 Zhang T, Shen P, Duan C, Gao L. KL-6 as an immunological biomarker predicts the severity, progression, acute exacerbation, and poor outcomes of interstitial lung disease: a systematic review and meta-analysis. Front Immunol. 2021;12:745233. https://doi.org/10.3389/fimmu.2021.745233 . 10.3389/fimmu.2021.745233 34956179 8699527 Kobayashi J, Kitamura S. KL-6: a serum marker for interstitial pneumonia. Chest. 1995;108:311–5. https://doi.org/10.1378/chest.108.2.311 . 10.1378/chest.108.2.311 7634858 Ohnishi H, et al. Circulating KL-6 levels in patients with drug induced pneumonitis. Thorax. 2003;58:872–5. https://doi.org/10.1136/thorax.58.10.872 . 10.1136/thorax.58.10.872 14514942 1746480 Hackshaw MD, et al. Incidence of pneumonitis/interstitial lung disease induced by HER2-targeting therapy for HER2-positive metastatic breast cancer. Breast Cancer Res Treat. 2020;183:23–39. https://doi.org/10.1007/s10549-020-05754-8 . 10.1007/s10549-020-05754-8 32591987 7376509 Swain SM, et al. Multidisciplinary clinical guidance on trastuzumab deruxtecan (T-DXd)-related interstitial lung disease/pneumonitis-Focus on proactive monitoring, diagnosis, and management. Cancer Treatment Rev. 2022;106:102378. https://doi.org/10.1016/j.ctrv.2022.102378 . 10.1016/j.ctrv.2022.102378 Yong WP, et al. Clinical best practices in optimal monitoring, early diagnosis, and effective management of antibody–drug conjugate-induced interstitial lung disease or pneumonitis: a multidisciplinary team approach in Singapore. Expert Opin Drug Metab Toxicol. 2022;18:805–15. https://doi.org/10.1080/17425255.2022.2162383 . 10.1080/17425255.2022.2162383 36636012 Xu C, et al. Clinical best practices in interdisciplinary management of human epidermal growth factor receptor 2 antibody-drug conjugates-induced interstitial lung disease/pneumonitis: an expert consensus in China. Cancer. 2024;130:3054–66. https://doi.org/10.1002/cncr.35475 . 10.1002/cncr.35475 39092590 von Minckwitz G, et al. Trastuzumab emtansine for residual invasive HER2-positive breast cancer. N Engl J Med. 2019;380:617–28. https://doi.org/10.1056/NEJMoa1814017 . 10.1056/NEJMoa1814017 Krop IE, et al. Trastuzumab emtansine versus treatment of physician’s choice in patients with previously treated HER2-positive metastatic breast cancer (TH3RESA): final overall survival results from a randomised open-label phase 3 trial. Lancet Oncol. 2017;18:743–54. https://doi.org/10.1016/s1470-2045(17)30313-3 . 10.1016/s1470-2045(17)30313-3 28526538 Wuerstlein R, et al. Final results of the global and Asia cohorts of KAMILLA, a phase IIIB safety trial of trastuzumab emtansine in patients with HER2-positive advanced breast cancer. ESMO Open. 2022;7:100561. https://doi.org/10.1016/j.esmoop.2022.100561 . 10.1016/j.esmoop.2022.100561 36084395 9588895 Beeram M, et al. A phase 1 study of weekly dosing of trastuzumab emtansine (T-DM1) in patients with advanced human epidermal growth factor 2-positive breast cancer. Cancer. 2012;118:5733–40. https://doi.org/10.1002/cncr.27622 . 10.1002/cncr.27622 22648179 Hurvitz SA, et al. Trastuzumab deruxtecan versus trastuzumab emtansine in patients with HER2-positive metastatic breast cancer: updated results from DESTINY-Breast03, a randomised, open-label, phase 3 trial. Lancet. 2023;401:105–17. https://doi.org/10.1016/s0140-6736(22)02420-5 . 10.1016/s0140-6736(22)02420-5 36495879 Modi S, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387:9–20. https://doi.org/10.1056/NEJMoa2203690 . 10.1056/NEJMoa2203690 35665782 10561652 Tsurutani J, et al. Targeting HER2 with trastuzumab deruxtecan: a dose-expansion, phase I study in multiple advanced solid tumors. Cancer Discov. 2020;10:688–701. https://doi.org/10.1158/2159-8290.Cd-19-1014 . 10.1158/2159-8290.Cd-19-1014 32213540 8292921 Meric-Bernstam F, et al. Efficacy and safety of trastuzumab deruxtecan (T-DXd) in patients (pts) with HER2-expressing solid tumors: DESTINY-PanTumor02 (DP-02) interim results. J Clin Oncol. 2023;41:LBA3000. https://doi.org/10.1200/JCO.2023.41.17_suppl.LBA3000 . 10.1200/JCO.2023.41.17_suppl.LBA3000 Xu Y, et al. Phase I study of the recombinant humanized anti-HER2 monoclonal antibody-MMAE conjugate RC48-ADC in patients with HER2-positive advanced solid tumors. Gastric Cancer. 2021;24:913–25. https://doi.org/10.1007/s10120-021-01168-7 . 10.1007/s10120-021-01168-7 33945049 8205919 Zhang J, et al. Phase I trial of a novel anti-HER2 antibody-drug conjugate, ARX788, for the treatment of HER2-positive metastatic breast cancer. Clin Cancer Res. 2022. https://doi.org/10.1158/1078-0432.ccr-22-0456 . 10.1158/1078-0432.ccr-22-0456 36260524 9890931 Saura Manich C, et al. LBA15 Primary outcome of the phase III SYD985002/TULIP trial comparing [vic-]trastuzumab duocarmazine to physician’s choice treatment in patients with pre-treated HER2-positive locally advanced or metastatic breast cancer. Ann Oncol. 2021;32:S1288. https://doi.org/10.1016/j.annonc.2021.08.2088 . 10.1016/j.annonc.2021.08.2088 Banerji UT, et al. Trastuzumab duocarmazine in locally advanced and metastatic solid tumours and HER2-expressing breast cancer: a phase 1 dose-escalation and dose-expansion study. Lanct Oncol. 2019;20:1124–35. https://doi.org/10.1016/s1470-2045(19)30328-6 . 10.1016/s1470-2045(19)30328-6 trying2...
The relationship between high ratios of CD4/FOXP3 and CD8/CD163 and the improved survivability of metastatic triple-negative breast cancer patients: a multicenter cohort study. | LitMetric
Background : Triple-negative breast cancer (TNBC) has been documented as the most aggressive subtype of breast cancer. This study aimed to analyze antitumor and protumor immune activities, and their ratios as significant prognostic biomarkers in metastatic TNBC (mTNBC).Methods : A multicenter cohort study was conducted among 103 de novo mTNBC patients. The expression of CD8 and CD163 was evaluated using immunohistochemistry staining, CD4 and FOXP3 using double-staining immunohistochemistry, and PD-L1 using immunohistochemistry and RT-PCR.Results : Multivariate analysis revealed that high CD4/FOXP3 (HR 1.857; 95% CI 1.049-3.288; p = 0.034) and the CD8/CD163 ratio (HR 2.089; 95% CI 1.174-3.717; p = 0.012) yield significantly improved 1 year overall survival (OS). Kaplan-Meier analysis showed that high levels of CD4 (p = 0.023), CD8 (p = 0.043), CD4/FOXP3 (p = 0.016), CD8/FOXP3 (p = 0.005), CD8/CD163 (p = 0.005) ratios were significantly associated with higher rate of 1 year OS. Furthermore, 1 year OS was directly correlated with antitumor CD4 (R = 0.233; p = 0.018) and CD8 (R = 0.219; p = 0.026) and was indirectly correlated with protumor CD163 and FOXP3 through CD4/FOXP3 (R = 0.282; p = 0.006), CD4/CD163 (R = 0.239; p = 0.015), CD8/FOXP3 (R = 0.260; p = 0.008), and CD8/CD163 (R = 0.258; p = 0.009).Conclusion : This is the first study to demonstrate that high levels of CD4/FOXP3 and CD8/CD163 significantly improved the 1 year OS in de novo mTNBC patients. Thus, we recommend the application of these markers as prognosis determination and individual treatment decision.
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Background : Triple-negative breast cancer (TNBC) is a serious disease with limited treatment options. We explored the significance of androgen receptor (AR) expression and tumor-infiltrating lymphocytes (TILs) in predicting neoadjuvant chemotherapy (NAC) resistance in TNBC, hypothesizing that AR/TIL classification using pretreatment biopsies can identify NAC-resistant subgroups and improve the understanding of apocrine differentiation.Methods : This retrospective study included 156 consecutive patients with TNBC treated with NAC.
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