Can Patients with HER2-Low Breast Cancer Benefit from Anti-HER2 Therapies? A Review

References

• Sung H, Ferlay J, Siegel RL, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209–249. doi:10.3322/caac.21660
   PubMed Web of Science ®Google Scholar
• Dawood S, Broglio K, Buzdar AU, Hortobagyi GN, Giordano SH. Prognosis of women with metastatic breast cancer by HER2 status and trastuzumab treatment: an institutional-based review. J Clin Oncol. 2010;28(1):92–98. doi:10.1200/jco.2008.19.9844
   PubMed Web of Science ®Google Scholar
• Ishii K, Morii N, Yamashiro H. Pertuzumab in the treatment of HER2-positive breast cancer: an evidence-based review of its safety, efficacy, and place in therapy. Core Evid. 2019;14:51–70. doi:10.2147/ce.S217848
   PubMed Web of Science ®Google Scholar
• Swain SM, Miles D, Kim SB, et al. Pertuzumab, trastuzumab, and docetaxel for HER2-positive metastatic breast cancer (CLEOPATRA): end-of-study results from a double-blind, randomised, placebo-controlled, Phase 3 study. Lancet Oncol. 2020;21(4):519–530. doi:10.1016/s1470-2045(19)30863-0
   PubMed Web of Science ®Google Scholar
• Diéras V, Miles D, Verma S, et al. Trastuzumab emtansine versus capecitabine plus lapatinib in patients with previously treated HER2-positive advanced breast cancer (EMILIA): a descriptive analysis of final overall survival results from a randomised, open-label, phase 3 trial. Lancet Oncol. 2017;18(6):732–742. doi:10.1016/s1470-2045(17)30312-1
   PubMed Web of Science ®Google Scholar
• Keam SJ. Trastuzumab deruxtecan: first approval. Drugs. 2020;80(5):501–508. doi:10.1007/s40265-020-01281-4
   PubMed Web of Science ®Google Scholar
• Fehrenbacher L, Cecchini RS, Geyer CE, et al. NSABP B-47/NRG oncology phase III randomized trial comparing adjuvant chemotherapy with or without trastuzumab in high-risk invasive breast cancer negative for HER2 by FISH and with IHC 1+ or 2. J Clin Oncol. 2020;38(5):444–453. doi:10.1200/jco.19.01455
   PubMed Web of Science ®Google Scholar
• Ahn S, Woo JW, Lee K, Park SY. HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation. Jptm. 2019;54(1):34–44. doi:10.4132/jptm.2019.11.03
   Web of Science ®Google Scholar
• Schettini F, Chic N, Brasó-Maristany F, et al. Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer. Npj Breast Cancer. 2021;7(1):1. doi:10.1038/s41523-020-00208-2
   PubMed Web of Science ®Google Scholar
• Marchiò C, Annaratone L, Marques A, Casorzo L, Berrino E, Sapino A. Evolving concepts in HER2 evaluation in breast cancer: heterogeneity, HER2-low carcinomas and beyond. Semin Cancer Biol. 2021;72:123–135. doi:10.1016/j.semcancer.2020.02.016
   PubMed Web of Science ®Google Scholar
• Gordian-Arroyo AM, Zynger DL, Tozbikian GH. Impact of the 2018 ASCO/CAP HER2 guideline focused update. Am J Clin Pathol. 2019;152(1):17–26. doi:10.1093/ajcp/aqz012
   PubMed Web of Science ®Google Scholar
• Cardoso F, Kyriakides S, Ohno S, et al. Early breast cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up†. Ann Oncol. 2019;30(8):1194–1220. doi:10.1093/annonc/mdz173
   PubMed Web of Science ®Google Scholar
• Li X, Yang J, Peng L, et al. Triple-negative breast cancer has worse overall survival and cause-specific survival than non-triple-negative breast cancer. Breast Cancer Res Treat. 2017;161(2):279–287. doi:10.1007/s10549-016-4059-6
   PubMed Web of Science ®Google Scholar
• Berrino E, Annaratone L, Bellomo SE, et al. Integrative genomic and transcriptomic analyses illuminate the ontology of HER2-low breast carcinomas. Genome Med. 2022;14(1):98. doi:10.1186/s13073-022-01104-z
   PubMed Web of Science ®Google Scholar
• Horisawa N, Adachi Y, Takatsuka D, et al. 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. 2022;29(2):234–241. doi:10.1007/s12282-021-01303-3
   PubMed Web of Science ®Google Scholar
• Denkert C, Seither F, Schneeweiss A, et al. Clinical and molecular characteristics of HER2-low-positive breast cancer: pooled analysis of individual patient data from four prospective, neoadjuvant clinical trials. Lancet Oncol. 2021;22(8):1151–1161. doi:10.1016/s1470-2045(21)00301-6
   PubMed Web of Science ®Google Scholar
• van den Ende NS, Smid M, Timmermans A, et al. HER2-low breast cancer shows a lower immune response compared to HER2-negative cases. Sci Rep. 2022;12(1):12974. doi:10.1038/s41598-022-16898-6
   PubMed Web of Science ®Google Scholar
• Clarke R, Liu MC, Bouker KB, et al. Antiestrogen resistance in breast cancer and the role of estrogen receptor signaling. Oncogene. 2003;22(47):7316–7339. doi:10.1038/sj.onc.1206937
   PubMed Web of Science ®Google Scholar
• Gianni L, Lladó A, Bianchi G, et al. Open-label, phase II, multicenter, randomized study of the efficacy and safety of two dose levels of Pertuzumab, a human epidermal growth factor receptor 2 dimerization inhibitor, in patients with human epidermal growth factor receptor 2-negative metastatic breast cancer. J Clin Oncol. 2010;28(7):1131–1137. doi:10.1200/jco.2009.24.1661
   PubMed Web of Science ®Google Scholar
• Ramić S, Asić K, Balja MP, Paić F, Benković V, KneŽEviĆ F. Correlation of phosphorylated HER2 with clinicopathological characteristics and efficacy of trastuzumab treatment for breast cancer. Anticancer Res. 2013;33(6):2509.
   PubMed Web of Science ®Google Scholar
• Onsum MD, Geretti E, Paragas V, et al. Single-cell quantitative HER2 measurement identifies heterogeneity and distinct subgroups within traditionally defined HER2-positive patients. Am J Pathol. 2013;183(5):1446–1460. doi:10.1016/j.ajpath.2013.07.015
   PubMed Web of Science ®Google Scholar
• Rugo HS, Im S-A, Wright GLS, et al. SOPHIA primary analysis: a phase 3 (P3) study of margetuximab (M) + chemotherapy (C) versus trastuzumab (T) + C in patients (pts) with HER2+ metastatic (met) breast cancer (MBC) after prior anti-HER2 therapies (Tx). J Clin Oncol. 2019;37(15_suppl):1000. doi:10.1200/JCO.2019.37.15_suppl.1000
   Web of Science ®Google Scholar
• Nordstrom JL, Gorlatov S, Zhang W, et al. Anti-tumor activity and toxicokinetics analysis of MGAH22, an anti-HER2 monoclonal antibody with enhanced Fcγ receptor binding properties. Breast Cancer Res. 2011;13(6):R123. doi:10.1186/bcr3069
   PubMed Web of Science ®Google Scholar
• Im S-A, Cardoso F, Cortes J, et al. Abstract PS10-12: integrated safety summary of single agent and combination margetuximab in Phase 1, 2, and 3 studies of HER2-positive advanced cancers and metastatic breast cancer (MBC). Cancer Res. 2021;81(4_Supplement):PS10-12-PS10-12. doi:10.1158/1538-7445.Sabcs20-ps10-12
   Web of Science ®Google Scholar
• Catenacci DVT, Kang Y-K, Park H, et al. Margetuximab plus pembrolizumab in patients with previously treated, HER2-positive gastro-oesophageal adenocarcinoma (CP-MGAH22–05): a single-arm, phase 1b–2 trial. Lancet Oncol. 2020;21(8):1066–1076. doi:10.1016/S1470-2045(20)30326-0
   PubMed Web of Science ®Google Scholar
• 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(1):93. doi:10.1038/s41392-022-00947-7
   PubMed Web of Science ®Google Scholar
• Beck A, Goetsch L, Dumontet C, Corvaïa N. Strategies and challenges for the next generation of antibody–drug conjugates. Nat Rev Drug Discov. 2017;16(5):315–337. doi:10.1038/nrd.2016.268
   PubMed Web of Science ®Google Scholar
• Kovtun YV, Audette CA, Ye Y, et al. Antibody-drug conjugates designed to eradicate tumors with homogeneous and heterogeneous expression of the target antigen. Cancer Res. 2006;66(6):3214–3221. doi:10.1158/0008-5472.Can-05-3973
   PubMed Web of Science ®Google Scholar
• Lambert JM, Chari RV. Ado-trastuzumab Emtansine (T-DM1): an antibody-drug conjugate (ADC) for HER2-positive breast cancer. J Med Chem. 2014;57(16):6949–6964. doi:10.1021/jm500766w
   PubMed Web of Science ®Google Scholar
• Burris HA, Rugo HS, Vukelja SJ, et al. Phase II study of the antibody drug conjugate trastuzumab-DM1 for the treatment of human epidermal growth factor receptor 2 (HER2)-positive breast cancer after prior HER2-directed therapy. J Clin Oncol. 2011;29(4):398–405. doi:10.1200/jco.2010.29.5865
   PubMed Web of Science ®Google Scholar
• Krop IE, LoRusso P, Miller KD, et al. A Phase II study of trastuzumab emtansine in patients with human epidermal growth factor receptor 2–positive metastatic breast cancer who were previously treated with trastuzumab, lapatinib, an anthracycline, a taxane, and capecitabine. J Clin Oncol. 2012;30(26):3234–3241. doi:10.1200/JCO.2011.40.5902
   PubMed Web of Science ®Google Scholar
• Xu Z, Guo D, Jiang Z, et al. Novel HER2-targeting antibody-drug conjugates of trastuzumab beyond T-DM1 in breast cancer: trastuzumab deruxtecan (DS-8201a) and (Vic-)trastuzumab duocarmazine (SYD985). Eur J Med Chem. 2019;183:111682. doi:10.1016/j.ejmech.2019.111682
   PubMed Web of Science ®Google Scholar
• Indini A, Rijavec E, Grossi F. Trastuzumab deruxtecan: changing the destiny of HER2 expressing solid tumors. Int J Mol Sci. 2021;22(9):4774.
   PubMed Web of Science ®Google Scholar
• 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(7):1039–1046. doi:10.1111/cas.12966
   PubMed Web of Science ®Google Scholar
• Modi S, Saura C, Yamashita T, et al. Abstract PD3-06: updated results from DESTINY-breast01, a Phase 2 trial of trastuzumab deruxtecan (T-DXd) in HER2 positive metastatic breast cancer. Cancer Res. 2021;81(4_Supplement):PD3-06-PD3-06. doi:10.1158/1538-7445.Sabcs20-pd3-06
   Web of Science ®Google Scholar
• Modi S, Park H, Murthy RK, et al. Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-Low-expressing advanced breast cancer: results from a Phase Ib study. J Clin Oncol. 2020;38(17):1887–1896. doi:10.1200/jco.19.02318
   PubMed Web of Science ®Google Scholar
• Modi S, Tsurutani J, Takahashi S, et al. Abstract PD3-07: safety and efficacy results from a phase 1 study of DS-8201a in patients with HER2 expressing breast cancers. Cancer Res. 2018;78(4_Supplement):PD3-07-PD3-07. doi:10.1158/1538-7445.Sabcs17-pd3-07
   Web of Science ®Google Scholar
• Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan (T-DXd) versus treatment of physician’s choice (TPC) in patients (pts) with HER2-low unresectable and/or metastatic breast cancer (mBC): results of DESTINY-Breast04, a randomized, phase 3 study. J Clin Oncol. 2022;40(17_suppl):LBA3–LBA3. doi:10.1200/JCO.2022.40.17_suppl.LBA3
   Web of Science ®Google Scholar
• Ueno NT, Jacot W, Yamashita T, et al. 217O Patient-reported outcomes (PROs) from DESTINY-Breast04, a randomized phase III study of trastuzumab deruxtecan (T-DXd) vs treatment of physician’s choice (TPC) in patients (pts) with HER2-low metastatic breast cancer (MBC). Ann Oncol. 2022;33:S632–S633. doi:10.1016/j.annonc.2022.07.256
   Web of Science ®Google Scholar
• Kabraji S, Ni J, Sammons S, et al. Preclinical and clinical efficacy of trastuzumab deruxtecan in breast cancer brain metastases. Clin Cancer Res. 2022. doi:10.1158/1078-0432.Ccr-22-1138
   Web of Science ®Google Scholar
• Batista MV, Cortez P, Ruiz M, et al. Abstract PD4-06: trastuzumab deruxtecan in patients with HER2[+] or HER2-low-expressing advanced breast cancer and central nervous system involvement: preliminary results from the DEBBRAH phase 2 study. Cancer Res. 2022;82(4_Supplement):PD4-06-PD4-06. doi:10.1158/1538-7445.Sabcs21-pd4-06
   Web of Science ®Google Scholar
• Bardia A, Barrios C, Dent R, et al. Abstract OT-03-09: trastuzumab deruxtecan (T-DXd; DS-8201) vs investigator’s choice of chemotherapy in patients with hormone receptor-positive (HR+), HER2 low metastatic breast cancer whose disease has progressed on endocrine therapy in the metastatic setting: a randomized, global phase 3 trial (DESTINY-Breast06). Cancer Res. 2021;81(4_Supplement):OT-03-09-OT-03-09. doi:10.1158/1538-7445.Sabcs20-ot-03-09
   Web of Science ®Google Scholar
• Jhaveri K, Hamilton E, Loi S, et al. Abstract OT-03-05: trastuzumab deruxtecan (T-DXd; DS-8201) in combination with other anticancer agents in patients with HER2-low metastatic breast cancer: a phase 1b, open-label, multicenter, dose-finding and dose-expansion study (DESTINY-Breast08). Cancer Res. 2021;81(4_Supplement):OT-03-05-OT-03-05. doi:10.1158/1538-7445.Sabcs20-ot-03-05
   PubMed Web of Science ®Google Scholar
• Hurvitz SA, Peddi PF, Tetef ML, 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. 2021;39(15_suppl):TPS603. doi:10.1200/JCO.2021.39.15_suppl.TPS603
   Web of Science ®Google Scholar
• Hurvitz SA, Wang LS, Chan D, 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;40(16_suppl):TPS623. doi:10.1200/JCO.2022.40.16_suppl.TPS623
   Web of Science ®Google Scholar
• Elgersma RC, Coumans RG, Huijbregts T, et al. Design, synthesis, and evaluation of linker-duocarmycin payloads: toward selection of HER2-targeting antibody-drug conjugate SYD985. Mol Pharm. 2015;12(6):1813–1835. doi:10.1021/mp500781a
   PubMedGoogle Scholar
• Dokter W, Ubink R, van der Lee M, et al. Preclinical profile of the HER2-targeting ADC SYD983/SYD985: introduction of a new duocarmycin-based linker-drug platform. Mol Cancer Ther. 2014;13(11):2618–2629. doi:10.1158/1535-7163.Mct-14-0040-t
   PubMed Web of Science ®Google Scholar
• Saura C, Thistlethwaite F, Banerji U, et al. A phase I expansion cohorts study of SYD985 in heavily pretreated patients with HER2-positive or HER2-low metastatic breast cancer. J Clin Oncol. 2018;36(15_suppl):1014. doi:10.1200/JCO.2018.36.15_suppl.1014
   Web of Science ®Google Scholar
• Li H, Zhang X, Xu Z, et al. Preclinical evaluation of MRG002, a novel HER2-targeting antibody-drug conjugate with potent antitumor activity against HER2-positive solid tumors. Antib Ther. 2021;4(3):175–184. doi:10.1093/abt/tbab017
   PubMedGoogle Scholar
• Jiang Z, Sun T, Wang X, et al. A multiple center, open-label, single-arm, phase II clinical trial of MRG002, an HER2-targeted antibody-drug conjugate, in patients with HER2-low expressing advanced or metastatic breast cancer. J Clin Oncol. 2022;40(16_suppl):1102. doi:10.1200/JCO.2022.40.16_suppl.1102
   PubMed Web of Science ®Google Scholar
• Liu Y, Lian W, Zhao X, et al. A first in-human study of A166 in patients with locally advanced/metastatic solid tumors which are HER2-positive or HER2-amplified who did not respond or stopped responding to approved therapies. J Clin Oncol. 2020;38(15_suppl):1049. doi:10.1200/JCO.2020.38.15_suppl.1049
   Web of Science ®Google Scholar
• Graziani EI, Sung M, Ma D, et al. PF-06804103, A site-specific anti-HER2 antibody–drug conjugate for the treatment of HER2-expressing breast, gastric, and lung cancers. Mol Cancer Ther. 2020;19(10):2068–2078. doi:10.1158/1535-7163.Mct-20-0237
   PubMed Web of Science ®Google Scholar
• Meric-Bernstam F, Calvo E, Moreno V, et al. A phase I dose escalation study evaluating the safety and tolerability of a novel anti-HER2 antibody-drug conjugate (PF-06804103) in patients with HER2-positive solid tumors. J Clin Oncol. 2020;38(15_suppl):1039. doi:10.1200/JCO.2020.38.15_suppl.1039
   Web of Science ®Google Scholar
• Wang J, Liu Y, Zhang Q, et al. RC48-ADC, a HER2-targeting antibody-drug conjugate, in patients with HER2-positive and HER2-low expressing advanced or metastatic breast cancer: a pooled analysis of two studies. J Clin Oncol. 2021;39(15_suppl):1022. doi:10.1200/JCO.2021.39.15_suppl.1022
   Web of Science ®Google Scholar
• Kontermann RE, Brinkmann U. Bispecific antibodies. Drug Discov Today. 2015;20(7):838–847. doi:10.1016/j.drudis.2015.02.008
   PubMed Web of Science ®Google Scholar
• Weisser N, Wickman G, Davies R, Rowse G. Abstract 31: preclinical development of a novel biparatopic HER2 antibody with activity in low to high HER2 expressing cancers. Cancer Res. 2017;77(13_Supplement):31. doi:10.1158/1538-7445.Am2017-31
   Google Scholar
• Hamblett K, Barnscher S, Davies R, et al. Abstract P6-17-13: ZW49, a HER2 targeted biparatopic antibody drug conjugate for the treatment of HER2 expressing cancers. Cancer Res. 2019;79(4_Supplement):P6-17-13-P6-17-13. doi:10.1158/1538-7445.Sabcs18-p6-17-13
   Web of Science ®Google Scholar
• Vaught DB, Stanford JC, Young C, et al. HER3 is required for HER2-induced preneoplastic changes to the breast epithelium and tumor formation. Cancer Res. 2012;72(10):2672–2682. doi:10.1158/0008-5472.Can-11-3594
   PubMed Web of Science ®Google Scholar
• Lee-Hoeflich ST, Crocker L, Yao E, et al. A central role for HER3 in HER2-amplified breast cancer: implications for targeted therapy. Cancer Res. 2008;68(14):5878–5887. doi:10.1158/0008-5472.Can-08-0380
   PubMed Web of Science ®Google Scholar
• Lazrek Y, Dubreuil O, Garambois V, et al. Anti-HER3 domain 1 and 3 antibodies reduce tumor growth by hindering HER2/HER3 dimerization and AKT-induced MDM2, XIAP, and FoxO1 phosphorylation. Neoplasia. 2013;15(3):335–IN40. doi:10.1593/neo.121960
   PubMed Web of Science ®Google Scholar
• Arpino G, Wiechmann L, Osborne CK, Schiff R. Crosstalk between the estrogen receptor and the HER tyrosine kinase receptor family: molecular mechanism and clinical implications for endocrine therapy resistance. Endocr Rev. 2008;29(2):217–233. doi:10.1210/er.2006-0045
   PubMed Web of Science ®Google Scholar
• Collins D, Jacob W, Cejalvo JM, et al. Direct estrogen receptor (ER) / HER family crosstalk mediating sensitivity to lumretuzumab and pertuzumab in ER+ breast cancer. PLoS One. 2017;12(5):e0177331. doi:10.1371/journal.pone.0177331
   PubMed Web of Science ®Google Scholar
• Schneeweiss A, Park-Simon T-W, Albanell J, et al. Phase Ib study evaluating safety and clinical activity of the anti-HER3 antibody lumretuzumab combined with the anti-HER2 antibody pertuzumab and paclitaxel in HER3-positive, HER2-low metastatic breast cancer. Invest New Drugs. 2018;36(5):848–859. doi:10.1007/s10637-018-0562-4
   PubMed Web of Science ®Google Scholar
• Geuijen CAW, De Nardis C, Maussang D, et al. Unbiased combinatorial screening identifies a bispecific IgG1 that potently inhibits HER3 signaling via HER2-guided ligand blockade. Cancer Cell. 2018;33(5):922–936.e10. doi:10.1016/j.ccell.2018.04.003
   PubMed Web of Science ®Google Scholar
• Pistilli B, Wildiers H, Hamilton EP, et al. Clinical activity of MCLA-128 (zenocutuzumab) in combination with endocrine therapy (ET) in ER+/HER2-low, non-amplified metastatic breast cancer (MBC) patients (pts) with ET-resistant disease who had progressed on a CDK4/6 inhibitor (CDK4/6i). J Clin Oncol. 2020;38(15_suppl):1037. doi:10.1200/JCO.2020.38.15_suppl.1037
   Google Scholar
• Hurvitz SA, Chaves J, Brufsky A, et al. Abstract OT1-14-01: zanidatamab in combination with ALX148 in advanced human epidermal growth factor receptor 2 (HER2)-expressing cancers, including breast cancer: a phase 1b/2, multicenter, open-label, dose-finding and cohort-expansion study (ZWI-ZW25-204). Cancer Res. 2022;82(4_Supplement):OT1-14-01-OT1-14-01. doi:10.1158/1538-7445.Sabcs21-ot1-14-01
   Web of Science ®Google Scholar
• Sha W, Vadde S, Song Z, et al. Abstract 1825: SAR443216, a novel trispecific T cell engager with potent T cell-dependent cytotoxicity for HER2-low tumors. Cancer Res. 2021;81(13_Supplement):1825. doi:10.1158/1538-7445.Am2021-1825
   Web of Science ®Google Scholar
• Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity. 2013;39(1):1–10. doi:10.1016/j.immuni.2013.07.012
   PubMed Web of Science ®Google Scholar
• Alexandrov LB, Nik-Zainal S, Wedge DC, et al. Signatures of mutational processes in human cancer. Nature. 2013;500(7463):415–421. doi:10.1038/nature12477
   PubMed Web of Science ®Google Scholar
• Brigham & Women’s Hospital & Harvard Medical School Chin Lynda 9 11 Park Peter J. 12 Kucherlapati Raju 13, Genome data analysis: Baylor College of Medicine Creighton Chad J. 22 23 Donehower Lawrence A. 22 23 24 25, Institute for Systems Biology Reynolds Sheila 31 Kreisberg Richard B. 31 Bernard Brady 31 Bressler Ryan 31 Erkkila Timo 32 Lin Jake 31 Thorsson Vesteinn 31 Zhang Wei 33 Shmulevich Ilya 31, Oregon Health & Science University Anur Pavana 37 Spellman Paul T. 37. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70. doi:10.1038/nature11412
   PubMed Web of Science ®Google Scholar
• Bianchini G, De Angelis C, Licata L, Gianni L. Treatment landscape of triple-negative breast cancer — expanded options, evolving needs. Nat Rev Clin Oncol. 2022;19(2):91–113. doi:10.1038/s41571-021-00565-2
   PubMed Web of Science ®Google Scholar
• Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ. 2014;21(1):15–25. doi:10.1038/cdd.2013.67
   PubMed Web of Science ®Google Scholar
• Loi S, Giobbe-Hurder A, Gombos A, et al. Abstract GS2-06: Phase Ib/II study evaluating safety and efficacy of pembrolizumab and trastuzumab in patients with trastuzumab-resistant HER2-positive metastatic breast cancer: results from the PANACEA (IBCSG 45-13/BIG 4-13/KEYNOTE-014) study. Cancer Res. 2018;78(4_Supplement):GS2-06-GS2-06. doi:10.1158/1538-7445.Sabcs17-gs2-06
   Web of Science ®Google Scholar
• Loi S, Giobbie-Hurder A, Gombos A, et al. Pembrolizumab plus trastuzumab in trastuzumab-resistant, advanced, HER2-positive breast cancer (PANACEA): a single-arm, multicentre, phase 1b–2 trial. Lancet Oncol. 2019;20(3):371–382. doi:10.1016/S1470-2045(18)30812-X
   PubMed Web of Science ®Google Scholar
• Kitai Y, Kawasaki T, Sueyoshi T, et al. DNA-containing exosomes derived from cancer cells treated with topotecan activate a STING-dependent pathway and reinforce antitumor immunity. J Immunol. 2017;198(4):1649–1659. doi:10.4049/jimmunol.1601694
   PubMed Web of Science ®Google Scholar
• Iwata TN, Ishii C, Ishida S, Ogitani Y, Wada T, Agatsuma T. A HER2-targeting antibody–drug conjugate, trastuzumab deruxtecan (DS-8201a), enhances antitumor immunity in a mouse model. Mol Cancer Ther. 2018;17(7):1494–1503. doi:10.1158/1535-7163.Mct-17-0749
   PubMed Web of Science ®Google Scholar
• Zerdes I, Matikas A, Bergh J, Rassidakis GZ, Foukakis T. Genetic, transcriptional and post-translational regulation of the programmed death protein ligand 1 in cancer: biology and clinical correlations. Oncogene. 2018;37(34):4639–4661. doi:10.1038/s41388-018-0303-3
   PubMed Web of Science ®Google Scholar
• Hamilton EP, Shapiro CL, Boni V, et al. 162O primary analysis from DS8201-A-U105: a 2-part, open label, phase Ib trial assessing trastuzumab deruxtecan (T-DXd) with nivolumab (nivo) in patients (pts) with HER2-expressing advanced breast cancer. Ann Oncol. 2022;33:S196. doi:10.1016/j.annonc.2022.03.181
   Web of Science ®Google Scholar
• Borghaei H, Besse B, Bardia A, et al. Trastuzumab deruxtecan (T-DXd; DS-8201) in combination with pembrolizumab in patients with advanced/metastatic breast or non-small cell lung cancer (NSCLC): a phase Ib, multicenter, study. J Clin Oncol. 2020;38(15_suppl):TPS1100. doi:10.1200/JCO.2020.38.15_suppl.TPS1100
   Web of Science ®Google Scholar
• Stewart R, Morrow M, Hammond SA, et al. Identification and characterization of MEDI4736, an antagonistic anti-PD-L1 monoclonal antibody. Cancer Immunol Res. 2015;3(9):1052–1062. doi:10.1158/2326-6066.Cir-14-0191
   PubMed Web of Science ®Google Scholar
• Schmid P, Im S-A, Armstrong A, et al. BEGONIA: Phase 1b/2 study of durvalumab (D) combinations in locally advanced/metastatic triple-negative breast cancer (TNBC)—Initial results from arm 1, d+paclitaxel (P), and arm 6, d+trastuzumab deruxtecan (T-DXd). J Clin Oncol. 2021;39(15_suppl):1023. doi:10.1200/JCO.2021.39.15_suppl.1023
   Web of Science ®Google Scholar
• Andre F, Hamilton EP, Loi S, et al. Dose-finding and -expansion studies of trastuzumab deruxtecan in combination with other anti-cancer agents in patients (pts) with advanced/metastatic HER2+ (DESTINY-Breast07 [DB-07]) and HER2-low (DESTINY-Breast08 [DB-08]) breast cancer (BC). J Clin Oncol. 2022;40(16_suppl):3025. doi:10.1200/JCO.2022.40.16_suppl.3025
   Web of Science ®Google Scholar
• Emens LA, Esteva FJ, Beresford M, et al. Trastuzumab emtansine plus atezolizumab versus trastuzumab emtansine plus placebo in previously treated, HER2-positive advanced breast cancer (KATE2): a phase 2, multicentre, randomised, double-blind trial. Lancet Oncol. 2020;21(10):1283–1295. doi:10.1016/S1470-2045(20)30465-4
   PubMed Web of Science ®Google Scholar
• Diamond JR, Henry JT, Falchook GS, et al. Abstract CT249: first-in-human study of TAK-500, a novel STING agonist immune stimulating antibody conjugate (ISAC), alone and in combination with pembrolizumab in patients with select advanced solid tumors. Cancer Res. 2022;82(12_Supplement):CT249. doi:10.1158/1538-7445.Am2022-ct249
   Web of Science ®Google Scholar
• Ackerman SE, Pearson CI, Gregorio JD, et al. Immune-stimulating antibody conjugates elicit robust myeloid activation and durable antitumor immunity. Nat Cancer. 2021;2(1):18–33. doi:10.1038/s43018-020-00136-x
   PubMedGoogle Scholar
• Dumbrava EI, Sharma MR, Carvajal RD, et al. Abstract OT-03-02: Phase 1/2 study of a novel HER2 targeting TLR7/8 immune-stimulating antibody conjugate (ISAC), BDC-1001, as a single agent and in combination with an immune checkpoint inhibitor in patients with advanced HER2-expressing solid tumors. Cancer Res. 2021;81(4_Supplement):OT-03-02-OT-03-02. doi:10.1158/1538-7445.Sabcs20-ot-03-02
   Web of Science ®Google Scholar
• Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer. 2014;14(2):135–146. doi:10.1038/nrc3670
   PubMed Web of Science ®Google Scholar
• McCarthy PM, Clifton GT, Vreeland TJ, Adams AM, O’Shea AE, Peoples GE. AE37: a HER2-targeted vaccine for the prevention of breast cancer recurrence. Expert Opin Investig Drugs. 2021;30(1):5–11. doi:10.1080/13543784.2021.1849140
   PubMed Web of Science ®Google Scholar
• Benavides LC, Gates JD, Carmichael MG, et al. The impact of HER2/neu expression level on response to the E75 vaccine: from U.S. Military Cancer Institute Clinical Trials Group Study I-01 and I-02. Clin Cancer Res. 2009;15(8):2895–2904. doi:10.1158/1078-0432.Ccr-08-1126
   PubMed Web of Science ®Google Scholar
• Mittendorf EA, Lu B, Melisko M, et al. Efficacy and safety analysis of nelipepimut-S vaccine to prevent breast cancer recurrence: a randomized, multicenter, Phase III clinical trial. Clin Cancer Res. 2019;25(14):4248–4254. doi:10.1158/1078-0432.Ccr-18-2867
   PubMed Web of Science ®Google Scholar
• Clifton GT, Hale D, Vreeland TJ, et al. Results of a randomized Phase IIb trial of nelipepimut-S + trastuzumab versus trastuzumab to prevent recurrences in patients with high-risk HER2 low-expressing breast cancer. Clin Cancer Res. 2020;26(11):2515–2523. doi:10.1158/1078-0432.Ccr-19-2741
   PubMed Web of Science ®Google Scholar
• Chick RC, Clifton GT, Hale DF, et al. Subgroup analysis of nelipepimut-S plus GM-CSF combined with trastuzumab versus trastuzumab alone to prevent recurrences in patients with high-risk, HER2 low-expressing breast cancer. Clin Immunol. 2021;225:108679. doi:10.1016/j.clim.2021.108679
   PubMed Web of Science ®Google Scholar
• Mittendorf EA, Ardavanis A, Symanowski J, et al. Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide AE37 vaccine in breast cancer patients to prevent recurrence. Ann Oncol. 2016;27(7):1241–1248. doi:10.1093/annonc/mdw150
   PubMed Web of Science ®Google Scholar
• Witkiewicz AK, Cox D, Knudsen ES. CDK4/6 inhibition provides a potent adjunct to Her2-targeted therapies in preclinical breast cancer models. Genes Cancer. 2014;5(7–8):261–272. doi:10.18632/genesandcancer.24
   PubMedGoogle Scholar
• Scirocchi F, Scagnoli S, Botticelli A, et al. Immune effects of CDK4/6 inhibitors in patients with HR+/HER2− metastatic breast cancer: relief from immunosuppression is associated with clinical response. eBioMedicine. 2022;79:104010. doi:10.1016/j.ebiom.2022.104010
   PubMed Web of Science ®Google Scholar
• Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471–475. doi:10.1038/nature23465
   PubMed Web of Science ®Google Scholar
• Gianni L, Colleoni M, Bisagni G, et al. Effects of neoadjuvant trastuzumab, pertuzumab and palbociclib on Ki67 in HER2 and ER-positive breast cancer. NPJ Breast Cancer. 2022;8(1):1. doi:10.1038/s41523-021-00377-8
   PubMed Web of Science ®Google Scholar
• Carlino F, Diana A, Ventriglia A, et al. HER2-low status does not affect survival outcomes of patients with Metastatic Breast Cancer (MBC) undergoing first-line treatment with endocrine therapy plus palbociclib: results of a multicenter, retrospective cohort study. Cancers. 2022;14(20):4981.
   PubMed Web of Science ®Google Scholar
• An R, Li Y-Q, Lin Y-L, Xu F, Li M-M, Liu Z. EZH1/2 as targets for cancer therapy. Cancer Gene Ther. 2022. doi:10.1038/s41417-022-00555-1
   Web of Science ®Google Scholar
• Lee Shuet S, Li Z, Wu Z, et al. Context-specific regulation of NF-κB target gene expression by EZH2 in breast cancers. Mol Cell. 2011;43(5):798–810. doi:10.1016/j.molcel.2011.08.011
   PubMed Web of Science ®Google Scholar
• Ulrich L, Okines AFC. Treating advanced unresectable or metastatic HER2-positive breast cancer: a spotlight on tucatinib. Breast Cancer. 2021;13:361–381. doi:10.2147/bctt.S268451
   PubMed Web of Science ®Google Scholar
• Collins D, O’Donovan N, Mahgoub T, et al. Trastuzumab (T) and pertuzumab (P)-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) in tyrosine kinase inhibitor (TKI)-treated breast cancer (BC) cell lines.. J Clin Oncol. 2014;32(15_suppl):643. doi:10.1200/jco.2014.32.15_suppl.643
   Web of Science ®Google Scholar
• Roßwag S, Cotarelo CL, Pantel K, et al. Functional characterization of Circulating Tumor Cells (CTCs) from metastatic ER+/HER2− breast cancer reveals dependence on HER2 and FOXM1 for endocrine therapy resistance and tumor cell survival: implications for treatment of ER+/HER2− breast cancer. Cancers. 2021;13(8):1810. doi:10.3390/cancers13081810
   PubMed Web of Science ®Google Scholar
• Bartlett JMS, Ahmed I, Regan MM, et al. HER2 status predicts for upfront AI benefit: a TRANS-AIOG meta-analysis of 12,129 patients from ATAC, BIG 1–98 and TEAM with centrally determined HER2. Eur J Cancer. 2017;79:129–138. doi:10.1016/j.ejca.2017.03.033
   PubMed Web of Science ®Google Scholar
• Bussolati G, Annaratone L, Maletta F. The pre-analytical phase in surgical pathology. Recent Results Cancer Res. 2015;199:1–13. doi:10.1007/978-3-319-13957-9_1
   PubMedGoogle Scholar
• Nitta H, Kelly BD, Allred C, et al. The assessment of HER2 status in breast cancer: the past, the present, and the future. Pathol Int. 2016;66(6):313–324. doi:10.1111/pin.12407
   PubMed Web of Science ®Google Scholar
• Holten-Rossing H, Møller Talman M-L, Kristensson M, Vainer B. Optimizing HER2 assessment in breast cancer: application of automated image analysis. Breast Cancer Res Treat. 2015;152(2):367–375. doi:10.1007/s10549-015-3475-3
   PubMed Web of Science ®Google Scholar
• Otsuji K, Sasaki T, Tanaka A, et al. Use of droplet digital PCR for quantitative and automatic analysis of the HER2 status in breast cancer patients. Breast Cancer Res Treat. 2017;162(1):11–18. doi:10.1007/s10549-016-4092-5
   PubMed Web of Science ®Google Scholar
• Tarantino P, Hamilton E, Tolaney SM, et al. HER2-low breast cancer: pathological and clinical landscape. J Clin Oncol. 2020;38(17):1951–1962. doi:10.1200/jco.19.02488
   PubMed Web of Science ®Google Scholar
• Miglietta F, Griguolo G, Bottosso M, et al. HER2-low-positive breast cancer: evolution from primary tumor to residual disease after neoadjuvant treatment. NPJ Breast Cancer. 2022;8(1):66. doi:10.1038/s41523-022-00434-w
   PubMed Web of Science ®Google Scholar
• Miglietta F, Griguolo G, Bottosso M, et al. Evolution of HER2-low expression from primary to recurrent breast cancer. NPJ Breast Cancer. 2021;7(1):137. doi:10.1038/s41523-021-00343-4
   PubMed Web of Science ®Google Scholar