IN ER+/HER2- METASTATIC BREAST CANCER (mBC)

CAN IMPROVING ER ANTAGONISM AND DEGRADATION UNLOCK A BRIGHTER FUTURE?

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ER ACTIVATION

ER+/HER2- tumor cells depend on different kinds of signaling activity to drive activation1,2

The growth, proliferation, and metastasis of these tumors are largely driven by signals that are triggered by estrogen’s
effects on the estrogen receptor (ER)1-3

ER Activity Is Pervasive

79% OF BREAST CANCER PATIENTS ARE ER+ AT DIAGNOSIS4

~90%of resistant mBC tumors rely on
ER-dependent activity5

~50%of patients do not respond to
initial endocrine therapy6,7

>300 proteins interact with one or more receptor types, including the ER8

ER+ Tumors Adapt to Resist Treatment

In response to endocrine therapies, ER+ tumors may utilize different escape mechanisms that either rely on estrogen receptors or circumvent them entirely9

Some key mechanisms of ER-dependent resistance:

  • Mutations that allow the ER to remain active in the presence of ER antagonism10
  • Activation of the ER by growth factors11

Both of these types of resistance depend on the presence of ER10,11

Some key mechanisms of ER-independent resistance:

  • Reduction of ER levels in the cell12
  • Amplification of signals downstream of the ER11

Resistance to Therapy Is Inevitable in the Metastatic Setting

Despite the benefits of endocrine therapy, the majority of patients with mBC will eventually acquire resistance and progress1,5,13

  • To combat the possibility that the ER will continue to conduct growth signaling, strategies that degrade the receptor and improve ER antagonism may have the potential to overcome resistance
Can improving ER antagonism and degradation unlock a brighter future?
HER2=human epidermal growth factor receptor 2.

See how advancements in ER antagonism and degradation can
reveal something more for patients

ADVANCES IN ER RESEARCH

Improving ER antagonism and degradation can offer more potential

Endocrine resistance is common and may lead to disease recurrence, metastases, and eventually death3,11,14

Optimizing Approaches

The established role of ER-dependent mechanisms in driving endocrine resistance suggests there is a need to optimize antagonism and degradation of the ER pathway5

Addressing Treatment Resistance

Alternating endocrine therapies is a common approach to treatment resistance. Tumors that have developed resistance to one endocrine therapy, but continue to rely on ER-mediated signaling, often respond to an alternative endocrine therapy1,2

However, ER-dependent tumors can adapt to develop escape pathways, which can lead to progressively shorter response times with subsequent lines of therapy. Following exposure to certain targeted therapies, cross resistance may also occur in patients5,8

Achieving ER Antagonism Through Degradation

Research suggests that the level of antagonistic effects in ER-dependent pathways may be tied to the level of degradation that occurs in the pathway3,5,8

Strong ER degradation may deliver an increase in maximal growth inhibition of the tumor cells, but the clinical significance of these findings is under investigation3,5

Advancing Science

Researchers are continuing to investigate approaches to improve antagonism and degradation of estrogen receptors, including:

  • Identifying molecules that more effectively inhibit or degrade the receptor5,15
  • Finding molecules that more efficiently travel to the tumor, allowing the drug to reach the tumor cells in higher concentrations16
Can advancements in ER antagonism and degradation brighten the path forward?

Explore the underlying disease mechanisms further

ABOUT SANOFI GENZYME

Driven by our commitment to patients, we strive to develop strong relationships with our patient communities, listening to their perspectives so that we can truly understand their needs.

We recognize the incredible burden that breast cancer places on individuals and the people who care for them. Their stories motivate and inspire us in our mission to develop novel treatment options, expand access to therapies, provide patient support services, and partner with patient organizations around the world to fully understand both patient and caregiver needs.

Determined for patients around
the world

References: 1. Haque MM, Desai KV. Pathways to endocrine therapy resistance in breast cancer. Front Endocrinol (Lausanne). 2019;10:573. 2. Roy SS, Vadlamudi RK. Role of estrogen receptor signaling in breast cancer metastasis. Int J Breast Cancer. 2012. doi:10.1155/2012/654698 3. Jeffreys SA, Powter B, Balakrishnar B, et al. Endocrine resistance in breast cancer: the role of estrogen receptor stability. Cells. 2020. doi:10.3390/cells9092077 4. DeSantis CE, Ma J, Gaudet MM, et al. Breast cancer statistics, 2019. CA Cancer J Clin. 2019;69(6):438-451. 5. Lin X, Xiang H, Luo G. Targeting estrogen receptor α for degradation with PROTACs: A promising approach to overcome endocrine resistance. Eur J Med Chem. 2020. doi:10.1016/j.ejmech.2020.112689 6. Ibrance [prescribing information]. New York, NY: Pfizer, Inc., 2019. 7. Kisqali [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corp; 2020. 8. McDonnell DP, Wardell SE. The molecular mechanisms underlying the pharmacological actions of ER modulators: implications for new drug discovery in breast cancer. Curr Opin Pharmacol. 2010;10(6):620-628. 9. Babayan A, Hannemann J, Spötter J, Müller V, Pantel K, Joosse SA. Heterogeneity of estrogen receptor expression in circulating tumor cells from metastatic breast cancer patients. PLoS One. 2013;8(9). doi:10.1371/journal.pone.0075038 10. Katzenellenbogen JA, Mayne CG, Katzenellenbogen BS, Greene GL, Chandarlapaty S. Structural underpinnings of oestrogen receptor mutations in endocrine therapy resistance. Nat Rev Cancer. 2018;18(6):377-388. 11. Osborne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011; 62:233-247. 12. Rani A, Stebbing J, Giamas G, Murphy J. Endocrine resistance in hormone receptor positive breast cancer–from mechanism to therapy. Front Endocrinol (Lausanne). 2019;10. doi:10.3389/fendo.2019.00245 13. Dixon JM. Endocrine resistance in breast cancer. New J Sci. 2014;2014:1-27. 14. Lei JT, Anurag M, Haricharan S, Gou X, Ellis MJ. Endocrine therapy resistance: new insights. Breast. 2019;48 Suppl 1(Suppl 1):S26-S30. 15. Shagufta, Ahmad I, Mathew S, Rahman S. Recent progress in selective estrogen receptor downregulators (SERDs) for the treatment of breast cancer. RSC Med Chem. 2020;11(4):438-454. 16. Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) in cancer treatment. Pharmacol Ther. 2018;186:1-24.