HR+, HER2- Metastatic Breast Cancer
Unmet Needs and 2L Treatment
Endocrine therapy (ET) + cyclin-depending kinase 4/6 inhibitor (CDK4/6i) is the first-line (1L) standard of care in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) metastatic breast cancer (MBC)1; however, despite efficacy in treatment, disease progression inevitably occurs. There are multiple mechanisms of resistance to ET ± CDK4/6i.2,3
ET resistance may be due to amplification of FGFR1, activation of PI3K/AKT/mTOR pathway, and/or mutated ESR1; kinase resistance may be due to CDK4/6 activation and/or CDK6 amplification, retinoblastoma gene loss of function, activation and overexpression of TK1, or activation of cyclin E-CDK2 axis and/or overexpression of CCNE1, 2, or CDK2.4
Lack of Consensus on Treatment Upon Disease Progression
After disease progression or recurrence on 1L ET ± CDK4/6i, no consensus on an optimal treatment strategy for HR+, HER2- MBC has been reached.1-3 Treatments utilized in the clinic include ETs, targeted therapies, and nontargeted agents.1-3,5
Treatments for patients with HR-positive, HER2-negative MBC who progress on ET alone, or in combination with CDK4/6i, include ETs, targeted therapies, and nontargeted agents. ETs include aromatase inhibitors, selective estrogen receptor modulators, and selective estrogen receptor degraders; targeted therapies include AKT inhibitors, CDK4/6i, mTOR inhibitors, PARP inhibitors, and PI3K inhibitors; and nontargeted therapies include antibody-drug conjugates and chemotherapy.1-3,5
Several Limitations Exist for All 3 Classes of Approved Therapies
Let’s review the limitations associated with ETs, targeted therapies, and nontargeted therapies in the second-line (2L) setting. The efficacy of ET is impacted by prior ET and limited in the contemporary therapeutic landscape.6-8 Targeted therapies are subject to tolerability concerns and the efficacy is dependent on treatment history.1,3,5 In addition, the use of targeted therapies is limited by a lack of universal access to genomic testing and may be restricted to specific biomarker-selected subgroups.3 Nontargeted agents have significant toxicities, and poor quality of life is associated with chemotherapy.1,5,9
Limitations of ET
Although ET is a tolerable strategy targeting the primary driver of HR+, HER2- MBC, limitations exist.1,3,4,6,8,10-15 Novel therapeutic approaches are needed to overcome limitations of current ET options.
Limitations associated with AIs, SERMs, and SERDs1,3,4,6,8,10-15:
- Exposure leads to ESR1 mutations: AIs
- ESR1 mutation impacts efficacy: AIs, SERMs, SERDs (Intramuscular injection [IM])
- Partial ER agonism: SERMs
- Fluctuations in oral drug absorption due to gastrointestinal (GI) physiology, possibly resulting in transient autocrine ER signaling: AIs, SERMs, SERDs
- Inferior pharmacokinetics (PK) and additional clinic visits: SERDs (IM)
- Additional toxicities and resistance mechanisms when combined with targeted therapies: AIs, SERMs, SERDs (IM)
Unmet Needs for Patients With HR+, HER2- MBC
The treatment goal for patients with HR+, HER2- MBC is to extend survival, alleviate symptoms, and improve quality of life.1 Despite the utility of 1L treatment, patients still experience progression.1-3
Novel therapeutic approaches are needed to overcome limitations of current therapies, and research is ongoing. Additional information can be found in the resources below.
References
- Gradishar WJ, et al. J Natl Compr Cancer Netw. 2023;21(6):594-608.
- Chen YS, et al. Expert Opin Investig Drugs. 2023;31(6):515-529.
- Zhou FH, et al. Front Cell Dev Biol. 2023;11:1148792.
- Al-Qasem AJ, et al. Cancers (Basel). 2021;13(21):5397.
- https://www.cancer.org/cancer/types/breast-cancer/treatment.html.. (Accessed April 19, 2024).
- Patel R, et a. NP J Breast Cancer. 2023;9(20). doi: 10.1038/s41523-023-00523-4
- Kaminska K, et al. Breast Cancer Res. 2021;23:26.
- Brett JO, et al. Breast Cancer Res. 2021;23(1):85.
- Mayer EL. Am Soc Clin Oncol Educ Book. 2013;9-14. doi:10.14694/EdBook_AM.2013.33.9
- Vareslija D, et al. Clin Cancer Res. 2016;22(11):2765-2777.
- Allouchery V, et al. Breast Cancer Res. 2018;20(1):40.
- Clatot F, et al. Oncotarget. 2016;7(46):74448-74459.
- Patel HK, Bihani T. Pharmacol Ther. 2018;186:1-24.
- Yu J, et al. Pharmcol Ther. 2022:236:108108. Wardell SE, et al.
- Wardell SE, et al. Breast Cancer Res Treat. 2020;179(1):67-77.
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