A key goal in 1L HR+/HER2- metastatic breast cancer (mBC) is to maximize the time patients have on endocrine therapy (ET).2-4 This time can be shortened due to the emergence of endocrine resistance mechanisms, which can originate at the level of the estrogen receptor (ER).1,5,6

Aromatase inhibitors (AIs) leave the estrogen receptor intact, which may lead to estrogen-independent activation3,7,8

AROMATASE INHIBITORS USE A SINGLE-ACTION MECHANISM TO BLOCK CONVERSION TO ESTROGEN3,8

Without AI treatment3,8

Without Aromatase Inhibitors Treatment Without Aromatase Inhibitors Treatment
  • In ER+ tumors, estrogen activates the ER, leading to gene transcription and tumor growth3,8,9

How AIs work3,8

With Aromatase Inhibitors Treatment With Aromatase Inhibitors Treatment
  • AIs use a single-action mechanism to block the androgen-to-estrogen conversion, causing deprivation of estrogen, the ligand needed to activate the ER3,8,9

Estrogen receptor can become self-activated through mechanisms of endocrine resistance1,3,7

Self-activation after AI use

Self Activation of Estrogen ReceptorSelf Activation of Estrogen Receptor
  • As mBC adapts to estrogen deprivation, it triggers alternative signaling pathways that can begin the onset of endocrine resistance—enabling ER self-activation and downstream cancer proliferation

AI exposure can lead to endocrine RESISTANCE — progression may occur6,7,10,11

Emergence of ESR1m may be detectable 3-6 months before clinical disease progression

Rise of Aromatase Inhibitors ResistanceRise of Aromatase Inhibitors Resistance
  • Intervening at the earliest molecular sign of resistance, such as ESR1m, may help limit the emergence of resistant clones and improve outcomes.10

Start icon of quoteWe know despite the fact that aromatase inhibitors are effective in the first line, inevitably, resistance develops for many patients.End icon of quote

– Erika P. Hamilton, MD
Director, Breast Cancer Research
Sarah Cannon Research Institute

Early signals, such as ESR1m, can indicate emerging endocrine resistance7,10,11

Without timely intervention, this can lead to progression and limit patients' time on treatment.6,10

High prevalence

UP TO 40%

of patients with mBC develop ESR1m upon exposure to AIs12

Endocrine resistance mechanisms like ESR1m have been associated with7,11:

Increased risk

3x GREATER RISK

for disease progression 6 months after the mutation emerges in patients with mBC

Poor response

83%

of mBC patients with ESR1m experienced a poorer response to ET versus nonmutated

First Line Icon

To maximize patients’ time on 1L, how can we innovate our thinking TO INTERCEPT endocrine resistance at its earliest emergence?

Time to rethink 1L approach

1L=first line; ER+=estrogen receptor-positive; ERα=estrogen receptor alpha; ESR1=estrogen receptor 1; HER2-=human epidermal growth factor receptor 2-negative; HR+=hormone receptor-positive.

  1. 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
  2. Waks AG, Winer EP. Breast cancer treatment: a review. JAMA. 2019;321(3):288-300. doi:10.1001/jama.2018.19323
  3. 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
  4. Başaran GA, Twelves C, Diéras V, Cortés J, Awada A. Ongoing unmet needs in treating estrogen receptor-positive/HER2-negative metastatic breast cancer. Cancer Treat Rev. 2018;63:144-155. doi:10.1016/j.ctrv.2017.12.002
  5. 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
  6. Ma CX, Reinert T, Chmielewska I, Ellis MJ. Mechanisms of aromatase inhibitor resistance. Nat Rev Cancer. 2015;15(5):261-275. doi:10.1038/nrc3920
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  8. Hernando C, Ortega-Morillo B, Tapia M, et al. Oral selective estrogen receptor degraders (SERDs) as a novel breast cancer therapy: present and future from a clinical perspective. Int J Mol Sci. 2021;22(15):7812. doi:10.3390/ijms22157812
  9. Clusan L, Ferrière F, Flouriot G, Pakdel F. A basic review on estrogen receptor signaling pathways in breast cancer. Int J Mol Sci. 2023;24(7):6834. doi:10.3390/ijms24076834
  10. Grinshpun A, Chen V, Sandusky ZM, Fanning SW, Jeselsohn R. ESR1 activating mutations: from structure to clinical application. Biochim Biophys Acta Rev Cancer. 2023;1878(1):188830. doi:10.1016/j.bbcan.2022.188830
  11. Clatot F, Perdrix A, Beaussire L, et al. Risk of early progression according to circulating ESR1 mutation, CA-15.3 and cfDNA increases under first-line anti-aromatase treatment in metastatic breast cancer. Breast Cancer Res. 2020;22(1):56. doi:10.1186/s13058-020-01290-x
  12. Brett JO, Spring LM, Bardia A, Wander SA. ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer. Breast Cancer Res. 2021;23(1):85. doi:10.1186/s13058-021-01462-3