HER2-low metastatic breast cancer: molecular insights and therapeutic strategies

Abstract

The identification of HER2-low metastatic breast cancer as a novel subgroup with therapeutic implications underscores the intricacies in breast cancer classification. This subset, comprising 45%-60% of breast cancer cases, presents a challenge due to its heterogeneous nature, characterized by varying HER2 protein expression levels. This heterogeneity complicates diagnosis and treatment decisions. The advent of trastuzumab deruxtecan (T-DXd), a second-generation antibody-drug conjugate (ADC), instills renewed hope for HER2-low breast cancer patients, having demonstrated effectiveness in clinical trials. The article also explores the evolution of HER2 testing guidelines, notably the 2023 ASCO/CAP guidelines that acknowledge the potential benefits of HER2-targeted therapies for this subgroup. In summary, this article emphasizes the significance of collaborative efforts between Pathologists and Oncologists in the era of precision medicine. It also highlights the potential for innovative, tailored therapies for HER2-low breast cancer, promising enhanced treatment outcomes and a broader range of therapeutic options.

Keywords

HER2-low breast cancer / heterogeneity / trastuzumab deruxtecan (T-DXd) / HER2 testing guidelines / precision medicine / therapeutic strategies / immunohistochemistry / in situ hybridization.

References

[1] Schechter AL,Vaidyanathan L.The neu gene: an erbB-homologous gene distinct from and unlinked to the gene encoding the EGF receptor.Science1985;229:976-8

[2] Coussens L,Liao YC.Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene.Science1985;230:1132-9

[3] Holmes WE,Akita RW.Identification of heregulin, a specific activator of p185^erbB2.Science1992;256:1205-10

[4] Slamon DJ,Wong SG,Ullrich A.Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene.Science1987;235:177-82

[5] Pritchard KI,O'Malley FP.National Cancer Institute of Canada Clinical Trials GroupHER2 and responsiveness of breast cancer to adjuvant chemotherapy.N Engl J Med2006;354:2103-11

[6] King CR,Aaronson SA.Amplification of a novel v-erbB-related gene in a human mammary carcinoma.Science1985;229:974-6

[7] Baselga J,Mendelsohn J.Phase II study of weekly intravenous trastuzumab (Herceptin) in patients with HER2/neu-overexpressing metastatic breast cancer.Semin Oncol1999;26:78-83

[8] Slamon DJ,Shak S.Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.N Engl J Med2001;344:783-92

[9] Nahta R.Herceptin: mechanisms of action and resistance.Cancer Lett2006;232:123-38

[10] Emens LA,Beresford M.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 Oncol2020;21:1283-95

[11] Esteva FJ,Hagan MK.An open-label safety study of lapatinib plus trastuzumab plus paclitaxel in first-line HER2-positive metastatic breast cancer.Oncologist2013;18:661-6 PMCID:PMC4063391

[12] Morrow PK,Ensor J.Phase I/II study of trastuzumab in combination with everolimus (RAD001) in patients with HER2-overexpressing metastatic breast cancer who progressed on trastuzumab-based therapy.J Clin Oncol2011;29:3126-32 PMCID:PMC3157979

[13] Nahta R,Du Y.Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling.Mol Cancer Ther2007;6:667-74

[14] Stebbing J,Baryash V.CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial.Lancet Oncol2017;18:917-28

[15] Esteva FJ,Tang J.Immunotherapy and targeted therapy combinations in metastatic breast cancer.Lancet Oncol2019;20:e175-86

[16] He X,Esteva FJ.A new paradigm for classifying and treating HER2-positive breast cancer.Cancer Rep2023;6:e1841 PMCID:PMC10432420

[17] Hess KR.Effect of HER2 status on distant recurrence in early stage breast cancer.Breast Cancer Res Treat2013;137:449-55 PMCID:PMC3544467

[18] Ye F,Li Y.Advancements in clinical aspects of targeted therapy and immunotherapy in breast cancer.Mol Cancer2023;22:105 PMCID:PMC10324146

[19] Modi S,Yamashita T.DESTINY-Breast04 Trial InvestigatorsTrastuzumab deruxtecan in previously treated HER2-low advanced breast cancer.N Engl J Med2022;387:9-20

[20] Wolff AC,Hicks DG.American Society of Clinical OncologyCollege of American PathologistsRecommendations 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 Oncol2013;31:3997-4013

[21] Wolff AC,Allison KH.Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update.J Clin Oncol2018;36:2105-22

[22] Check DK,Reeder-Hayes KE.Characteristics, healthcare utilization, and outcomes of patients with HER2-low breast cancer. Breast Cancer Res Treat 2023.

[23] Gaudio M,Benvenuti C.Unveiling the HER2-low phenomenon: exploring immunohistochemistry and gene expression to characterise HR-positive HER2-negative early breast cancer. Breast Cancer Res Treat 2023.

[24] Molinelli C,Agostinetto E.Prognostic value of HER2-low status in breast cancer: a systematic review and meta-analysis.ESMO Open2023;8:101592 PMCID:PMC10485402

[25] Fehrenbacher L,Geyer CE Jr.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 Oncol2020;38:444-53

[26] Doi T,Naito Y.Safety, pharmacokinetics, and antitumour activity of trastuzumab deruxtecan (DS-8201), a HER2-targeting antibody-drug conjugate, in patients with advanced breast and gastric or gastro-oesophageal tumours: a phase 1 dose-escalation study.Lancet Oncol2017;18:1512-22

[27] Modi S,Yamashita T.DESTINY-Breast01 InvestigatorsTrastuzumab deruxtecan in previously treated HER2-positive breast cancer.N Engl J Med2020;382:610-21

[28] Modi S,Murthy RK.Antitumor activity and safety of trastuzumab deruxtecan in patients with HER2-low-expressing advanced breast cancer: results from a phase ib study.J Clin Oncol2020;38:1887-96 PMCID:PMC7280051

[29] Mosele F,Lusque A.Trastuzumab deruxtecan in metastatic breast cancer with variable HER2 expression: the phase 2 DAISY trial.Nat Med2023;29:2110-20 PMCID:PMC10427426

[30] Venetis K,Sajjadi E.HER2 low, ultra-low, and novel complementary biomarkers: expanding the spectrum of HER2 positivity in breast cancer.Front Mol Biosci2022;9:834651 PMCID:PMC8965450

[31] Fernandez AI,Bellizzi A.Examination of low ERBB2 protein expression in breast cancer tissue.JAMA Oncol2022;8:1-4 PMCID:PMC8814969

[32] Mantrala S,Mitkari A.Concordance in breast cancer grading by artificial intelligence on whole slide images compares with a multi-institutional cohort of breast pathologists.Arch Pathol Lab Med2022;146:1369-77

[33] Paige answers call to better identify breast cancer patients with low expression of HER2. 2022. Avaliable from: https://www.businesswire.com/news/home/20220623005253/en/Paige-Answers-Call-to-Better-Identify-Breast-Cancer-Patients-with-Low-Expression-of-HER2 [Last accessed on 1 Dec 2023]

[34] Uzunparmak B,Raso G.HER2-low expression in patients with advanced or metastatic solid tumors.Ann Oncol2023;34:1035-46