HER2-low disease demands a different approach from that of HER2-negative disease.
Breast cancer is the most common cancer in the United States in women and the secondleading cause of cancer-related deaths. Treatment selection for breast cancer depends on multiple factors and can be complicated, with early- and latestage breast cancers requiring different management goals and different options to meet those goals. Upon receiving a diagnosis, approximately 5% of patients with breast cancer have stage IV disease, with an overall survival (OS) of 30% and an average survival of 18 to 24 months. Additionally, approximately 20% to 30% of patients with breast cancer have overexpression of HER2.1 In the management of metastatic breast cancer (MBC), treatment options have recently been updated regarding HER2 status.
HER2-Low Breast Cancer
HER2-low disease is defined as an immunohistochemistry (IHC) score of 1+ or 2+ with a negative in situ hybridization (ISH) result and is seen in approximately 60% of patients with MBC. Historically, HER2- low disease was managed as HER2-negative (HER2–) disease, resulting in limited treatment options. Most of the treatments to date have been ineffective, but a recent phase 3 trial shed light on a potential treatment showing significant survival benefit.2
The DESTINY-Breast04 trial (NCT03734029) is a phase 3 trial that looked at patients with HER2-low metastatic breast cancer who had received 1 or 2 lines of chemotherapy. Patients received either standard singleagent chemotherapy, such as capecitabine (Xeloda; Genentech), eribulin mesylate (Halaven; Eisai, Merck), gemcitabine (Gemzar; Eli Lilly), paclitaxel (Taxol; Bristol Myers Squibb), or nab-paclitaxel (Abraxane; Bristol Myers Squibb), or they received fam-trastuzumab deruxtecan-nxki (Enhertu; AstraZeneca, Daiichi Sankyo). The primary end point was progression-free survival (PFS). In patients with HR-positive (HR+) breast cancer, the median PFS was 10.1 months in the fam-trastuzumab deruxtecan-nxki group vs 5.4 months in the chemotherapy group. Median PFS was 9.9 months in the fam-trastuzumab deruxtecan-nxki group vs 5.1 months in the chemotherapy group (P < .01), with both showing statistical significance. Common adverse effects (AEs) for fam-trastuzumab deruxtecan-nxki were nausea, fatigue, alopecia, vomiting, and neutropenia. These data confirmed the use of fam-trastuzumab deruxtecan-nxki in previously managed metastatic HER2-low breast cancer.3
As previously noted, several drugs have been studied in HER2-low breast cancer, but some respond differently to the degree of HER2 positivity seen in IHC and ISH assays. In metastatic HER2-low breast cancer, fam-trastuzumab deruxtecan-nxki is the preferred option after patients fail to respond to 1 or 2 lines of chemotherapy.4
HER2-positive (HER2+) disease accounts for approximately 15% of MBC and typically has a worse prognosis due to tumor aggressiveness. Ado-trastuzumab emtansine (Kadcyla; Genentech) has been approved in this population based on the results of the EMILIA trial (NCT00829166). Approximately half of patients who do not have brain metastases at the time of diagnosis will develop them at some point. After first-line chemotherapy, second-line options apart from ado-trastuzumab emtansine now include fam-trastuzumab deruxtecannxki, and third-line options include tucatinib (Tukysa; Seagen) combined with capecitabine and trastuzumab.2
Tucatinib is a reversible tyrosine kinase inhibitor that targets HER2 disease and was studied in the HER2CLIMB trial (NCT02614794) in patients with HER2+ MBC who had been previously treated with trastuzumab, pertuzumab (Perjeta; Genentech), and TDM-1. The agent was found to have some PFS and OS benefit when added to trastuzumab and capecitabine as a third-line option. Diarrhea and hepatotoxicity were the most common AEs of tucatinib.5
DESTINY-Breast01 (NCT03248492) was an open-label, single-group, phase 2 study in which fam-trastuzumab deruxtecan-nxki was investigated in the treatment of patients with HER2+ MBC who had been previously treated with ado-trastuzumab emtansine. Although the first part of the study focused mainly on safety and efficacy, the primary end points were met. Study results showed an overall response rate of 61%, median PFS of 19.4 months, and OS of 24.6 months, with neutropenia, anemia, and nausea being the most common AEs. This led to its approval in patients with HER2+ MBC who had previously been treated with 2 or more anti-HER2–based regimens.6
Margetuximab-cmkb (Margenza; MacroGenics) is a fragment crystallizable–engineered, anti-HER2 IgG monoclonal antibody. It has similar targets to those of trastuzumab, with some differences. It was designed to have a tighter binding affinity than trastuzumab. The phase 3 SOPHIA trial (NCT02492711) demonstrated both PFS and OS. This led to its approval in patients with HER2+ MBC who had received more than 2 anti-HER2 regimens in the third line.7
Sacituzumab govitecan-hziy (Trodelvy; Gilead Sciences) is a monoclonal antibody agent that has activity against TROP2, a calcium signal transducer that is overexpressed in approximately 80% of patients with triple-negative breast cancer (TNBC). Based on results from the phase 3 ASCENT trial (NCT02574455), sacituzumab govitecanhziy showed some benefit.
Because sacituzumab govitecan-hziy targets TROP2, it was compared with chemotherapy during the trial. ASCENT is a randomized, double-blind study investigating sacituzumab vs single-agent chemotherapy commonly used for patients with metastatic TNBC who have experienced relapse from multiple lines of chemotherapy.
The data showed the sacituzumab govitecan-hziy group had an OS benefit of 12.1 months and PFS benefit of 5.6 months, whereas the chemotherapy group (who received eribulin, vinorelbine [Navelbine; Burroughs Wellcome], capecitabine, or gemcitabine) had an OS of 6.7 months and a PFS of 1.7 months. Furthermore, AEs including neutropenia, leukopenia, diarrhea, anemia, and febrile neutropenia were higher in the sacituzumab govitecan-hziy group. Results from the study showed a significant survival benefit with sacituzumab govitecan-hziy in patients with triple-negative MBC who had failed to respond to at least 2 prior lines of chemotherapy and did not have brain metastases. These results led to the FDA approval of sacituzumab govitecan-hziy on April 7, 2021.8
HR+/HER2– disease is one of the most common types of breast cancers (approximately 70% of cases) and has always shown a high expression of TROP2. Initial management of HR+/HER2– MBC includes hormonedriven treatment. However, additional treatment after this initial treatment has not shown positive responses.
The open-label, randomized, phase 2 TROPiCS-02 trial (NCT03901339) looked at sacituzumab govitecanhziy vs standard single-agent chemotherapy for MBC and included patients who had failed to respond to 2 or more lines of chemotherapy. OS was 14.4 months with sacituzumab govitecan-hziy vs 11.2 months (P = .02) with chemotherapy, and diarrhea was the most common AE. Based on these results, sacituzumab govitecan-hziy is an agent that should be considered in HR+/HER2– MBC after patients fail to respond to 2 or more lines of therapy.9
Although advances have been made in the management of MBC and new drugs with increased survival benefits have become available, there is still room for further investigation to advance treatment options for patients with HER2-low MBC.
1. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 4.2022. Accessed January 6, 2023. https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf
2. Armitage M. Novel therapies for the treatment of metastatic breast cancer. NCCN Pharmacy Updates webinar [live]. October 22, 2022. Accessed October 22, 2022.
3. Modi S, Jacot W, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-low advanced breast cancer. N Engl J Med. 2022;387(1):9-20. doi:10.1056/NEJMoa2203690
4. Lai HZ, Han JR, Fu X, Ren YF, Li ZH, You FM. Targeted approaches to HER2-low breast cancer: current practice and future directions. Cancers (Basel). 2022;14(15):3774. doi:10.3390/cancers14153774
5. Murthy RK, Loi S, Okines A, et al. Tucatinib, trastuzumab, and capecitabine for HER2-positive metastatic breast cancer. N Engl J Med. 2020;382(7):597-609. doi:10.1056/NEJMoa1914609
6. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382(7):610-621. doi:10.1056/NEJMoa1914510
7. Rugo HS, Im SA, Cardoso F, et al. Margetuximab versus trastuzumab in patients with previously treated HER2-positive advanced breast cancer (SOPHIA): final overall survival results from a randomized phase 3 trial. J Clin Oncol. 2023;41(2):198-205. doi:10.1200/JCO.21.02937
8. Bardia A, Hurvitz SA, Tolaney SM, et al. Sacituzumab govitecan in metastatic triple-negative breast cancer. N Engl J Med. 2021;384(16):1529-1541. doi:10.1056/NEJMoa2028485
9. Rugo HS, Bardia A, Marmé F, et al. Primary results from TROPiCS-02: a randomized phase 3 study of sacituzumab govitecan (SG) versus treatment of physician’s choice (TPC) in patients (Pts) with hormone receptor-positive/HER2-negative (HR+/HER2-) advanced breast cancer. J Clin Oncol. 2022;40(suppl 17):LBA1001. doi:10.1200/JCO.2022.40.17_suppl.LBA1001
About the Author
Sonia Amin Thomas, PharmD, BCOP, is an associate professor of pharmacy practice in oncology at the Philadelphia School of Osteopathic Medicine School of Pharmacy, in Suwanee, a clinical oncology specialist and clinical pharmacist at Wellstar North Fulton Regional Hospital in Roswell, and an integrative nutrition health coach, all in Georgia.