Aromatase inhibitors (AIs) were launched over 2 decades ago, but even with the introduction of the CDK4/6i class, there has been little innovation in endocrine therapies (ETs) since.1-3
Endocrine therapy backbones really have seen little innovation in over two decades . . . but to help address resistance mechanisms, novel endocrine therapy agents must be developed and further integrated into treatment paradigms.
– Erika P. Hamilton, MD
Director, Breast Cancer Research
Sarah Cannon Research Institute
Evolving cancer demands rethinking our approach to the 1L endocrine therapy backbone1,3
The goal: Extend patients’ time on 1L3-9
1L treatment response is key as outcomes worsen in later lines. A key goal in HR+/HER2- metastatic breast cancer (mBC) is to prolong the time patients have on 1L ET.
AI use may limit ET efficacy in 1L3,10,11
Despite the effectiveness of AIs + CDK4/6i as the SOC in 1L mBC, AIs leave the ER intact, enabling the potential for self-activation and downstream cancer growth. This may lead to endocrine resistance.
Emerging research in ET approaches
Emerging therapies may show potential advancements in ER degradation in the hope of supporting patients' time on 1L.
How might modernizing our understanding of 1L treatment approaches affect patients’ time on ET?1-3
1L=first line; CDK4/6i=cyclin-dependent kinase 4/6 inhibitor; ER=estrogen receptor; HER2-=human epidermal growth factor receptor 2-negative; HR+=hormone receptor-positive; SERD=selective estrogen receptor degrader; SOC=standard of care.
- Raheem F, Karikalan SA, Batalini F, El Masry A, Mina L. Metastatic ER+ breast cancer: mechanisms of resistance and future therapeutic approaches. Int J Mol Sci. 2023;24(22):16198. doi:10.3390/ijms242216198
- Zanotti G, Hunger M, Perkins JJ, Horblyuk R, Martin M. Treatment patterns and real world clinical outcomes in ER+/HER2- post-menopausal metastatic breast cancer patients in the United States. BMC Cancer. 2017;17(1):393. doi:10.1186/s12885-017-3379-1
- Hanker AB, Sudhan DR, Arteaga CL. Overcoming endocrine resistance in breast cancer. Cancer Cell. 2020;37(4):496-513. doi:10.1016/j.ccell.2020.03.009
- Yamamura J, Kamigaki S, Tsujie M, et al. Response to first-line recurrence treatment influences survival in hormone receptor-positive, HER2-negative breast cancer: a multicenter study. In Vivo. 2019;33(1):281-287. doi:10.21873/invivo.11473
- Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019;321(3):288-300. doi:10.1001/jama.2018.19323
- Mayer EL, Ren Y, Wagle N, et al. PACE: a randomized phase II study of fulvestrant, palbociclib, and avelumab after progression on cyclin-dependent kinase 4/6 inhibitor and aromatase inhibitor for hormone receptor-positive/human epidermal growth factor receptor-negative metastatic breast cancer. J Clin Oncol. 2024;42(17):2050-2060. doi:10.1200/JCO.23.01940
- Llombart-Cussac A, Harper-Wynne C, Perello A, et al. Second-line endocrine therapy (ET) with or without palbociclib (P) maintenance in patients (pts) with hormone receptor-positive (HR[+])/human epidermal growth factor receptor 2-negative (HER2[-]) advanced breast cancer (ABC): PALMIRA trial. J Clin Oncol. 2023;41(16_suppl):1001. doi:10.1200/JCO.2023.41.16_suppl.1001
- Kalinsky K, Bianchini G, Hamilton E, et al. Abemaciclib plus fulvestrant in advanced breast cancer after progression on CDK4/6 inhibition: results from the phase 3 postMONARCH trial. J Clin Oncol. 2025;43(9):1101-1112. doi:10.1200/JCO-24-02086
- Turner NC, Oliveira M, Howell SJ, et al. Capivasertib in hormone receptor-positive advanced breast cancer. N Engl J Med. 2023;388(22):2058-2070. doi:10.1056/NEJMoa2214131
- Chen S, Masri S, Wang X, Phung S, Yuan YC, Wu X. What do we know about the mechanisms of aromatase inhibitor resistance? J Steroid Biochem Mol Biol. 2006;102(1-5):232-240. doi:10.1016/j.jsbmb.2006.09.012
- Will M, Liang J, Metcalfe C, Chandarlapaty S. Therapeutic resistance to anti-oestrogen therapy in breast cancer. Nat Rev Cancer. 2023;23(10):673-685. doi:10.1038/s41568-023-00604-3
