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Review
. 2023 Jun 5:15:17588359231175440.
doi: 10.1177/17588359231175440. eCollection 2023.

Targeting HER2-low in metastatic breast cancer: an evolving treatment paradigm

Charlie Yang  1 , Christine Brezden-Masley  2 , Anil Abraham Joy  3 , Sandeep Sehdev  4 , Shanu Modi  5 , Christine Simmons  6 , Jan-Willem Henning  7
Affiliations
Review

Targeting HER2-low in metastatic breast cancer: an evolving treatment paradigm

Charlie Yang et al. Ther Adv Med Oncol. .

Abstract

The results of the Phase III DESTINY-Breast04 trial of trastuzumab deruxtecan (T-DXd) are leading to a shift in both the classification and treatment of human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer. In this trial, T-DXd was associated with a substantial survival benefit among patients with hormone receptor-positive and hormone receptor-negative disease and low expression of HER2, a biomarker previously considered unactionable in this treatment setting. Herein, we discuss the evolving therapeutic pathway for HER2-low disease, ongoing clinical trials, and the potential challenges and evidence gaps arising with treatment of this patient population.

Keywords: HER2-low; HER2-targeted therapy; chemotherapy; metastatic breast cancer; sacituzumab govitecan; trastuzumab deruxtecan; treatment sequencing.

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Conflict of interest statement

CY had no conflicts to disclose. CB-M reports serving in a consultancy or advisory role and receiving honoraria from Amgen, AstraZeneca, BMS, Eli Lilly, Gilead, Knight Therapeutics, Mylan, Novartis, Pfizer, Roche, Seagen, and Taiho and has received research funding from Eli Lilly and AstraZeneca. AAJ has served in a consultancy or advisory role and has received honoraria from AstraZeneca, BMS, Eli Lilly, Gilead, Knight Therapeutics, Mylan, Novartis, Pfizer, Roche, and Teva. SS reports participating in advisory boards and/or receiving speaker fees from AstraZeneca, Gilead, Roche, Novartis, and Merck. SM has been a scientific advisor for AstraZeneca, Daiichi Sankyo, Eli Lilly, Genentech, Gilead, GlaxoSmithKline, Macrogenics, Puma Biotechnology, Seagen, and Zymeworks. SM also reports attending speaking engagements for AstraZeneca, Daiichi Sankyo, Genentech, Novartis, and Seagen and being a primary investigator on trials for AstraZeneca, Daiichi Sankyo, Genentech, and Seagen. CS has served in a consultancy or advisory role and received honoraria from Eli Lilly, Mylan, Pfizer, and Roche, and CS has received research funding from AstraZeneca Global, Knight Therapeutics, Roche, Pfizer, and Viatris. J-WH reports serving in a consultancy or advisory role and receiving honoraria from AstraZeneca, Eli Lilly, Knight Therapeutics, Mylan, Novartis, Pfizer, Roche, and Seagen. J-WH also reports having speaking arrangements with Gilead and receiving research grant support from AstraZeneca, Novartis, and Pfizer.

Figures

Figure 1.
Figure 1.
Evolving classification of mBC according to HER2 status. HER2, human epidermal growth factor receptor 2; IHC, immunohistochemistry; ISH, in situ hybridization; mBC, metastatic breast cancer.
Figure 2.
Figure 2.
Mechanism of action of T-DXd. Source: Figure 1 from Swain et al. Creative Commons license and disclaimer available from https://creativecommons.org/licenses/by-nc-nd/4.0/. ADC, antibody–drug conjugate; HER2, human epidermal growth factor receptor 2; T-DXd, trastuzumab deruxtecan.
Figure 3.
Figure 3.
DESTINY-Breast04: Kaplan–Meier analysis of survival outcomes associated with T-DXd versus physician’s choice chemotherapy among patients with HR-positive (a, b) and HR-negative (c, d) HER2-low mBC. Source: Figures compiled from Modi et al. Permission for use granted by the authors. CI, confidence interval; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; mBC, metastatic breast cancer; mo, months; NE, not estimable; OS, overall survival; PFS, progression-free survival; T-DXd, trastuzumab deruxtecan; TPC, physician’s choice chemotherapy.
Figure 4.
Figure 4.
Current and evolving treatment paradigms for HER2-negative mBC, including HER2-low disease. (a) Chemotherapy to be used among patients with imminent organ failure. (b) Rechallenge with ET monotherapy. (c) Option if not received in 1L. (d) Option for PD-L1-positive patients. (e) PARPi preferred over chemotherapy for appropriate patients. (f) SG preferred over chemotherapy. (g) Optimal sequencing of T-DXd and SG in HER2-low disease has yet to be determined. Standard chemotherapies (2L and beyond) may include taxanes, platinum agents, capecitabine, gemcitabine, anthracyclines, eribulin, and vinorelbine. Patients receiving 1L or 2L CDK4/6i therapy may not be eligible for funding of subsequent therapy with everolimus + exemestane, alpelisib + fulvestrant, single-agent fulvestrant or elacestrant, or PARPi in some countries (e.g., Canada). 1L/2L/3L/4L/5L, first/second/third/four/fifth line of therapy; CDK4/6i, cyclin-dependent kinase 4/6 inhibitor; ET, endocrine therapy; HER2, human epidermal growth factor receptor 2; HR, hormone receptor; IO, immunotherapy; mBC, metastatic breast cancer; PARPi, poly(adenosine diphosphate-ribose) polymerase inhibitor; PD-L1, programmed death-ligand 1; SG, sacituzumab govitecan; T-DXd, trastuzumab deruxtecan.
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