In ER+/HER2- metastatic breast cancer (mBC)

COULD ADVANCEMENTS IN ENDOCRINE THERAPY UNLOCK A BRIGHTER PATH FORWARD?

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Endocrine therapies (Els) have advanced the care of patients with ER+/HER2- mBC, yet due to

complex tumor mechanisms and endocrine resistance, progression still persists.1-3

Currently, -50% of ER+/HER2- mBC patients that are treated with ETs develop resistance or don’t respond to initial ET.4,5

• The majority of patients with ER+ mBC acquire resistance within 2 to 3 years of starting endocrine therapy4

• Endocrine resistance is a key reason patients progress and ultimately need chemotherapy1

Almost all patients with metastatic disease will experience disease progression eventually.6

A wide range of mechanisms have been implicated in ET resistance.4

Addressing complex tumor mechanisms may further delay disease progression in patients with mBC.1,2,8

• Findings suggest that resistance to endocrine therapy is complex and may differ between patients and therapy types4

The ER pathway and its mutations are a key mechanism of ET resistance.4

~40% of patients who have developed ET resistance have ESR1 mutations.9,10 Research into different strategies for ER inhibition and degradation may show promise in delaying disease progression for these patients 2,7,8

• Mutations such as ESR1 are associated with worsened PFS and OS, and are a potential predictive biomarker to inform optimal therapeutic strategy7

Better insight into the underlying mechanisms of resistance may open opportunity for the

improvement of treatment strategies.4

Ongoing studies suggest that a greater understanding of the biology behind treatment-resistant mechanisms may allow for advancements in ET. Could advancements in ET unlock more possibilities by helping to delay disease progression for mBC patients?1,2,7,8

Explore further discussion at UnlockmBC.com.

References: 1. Brufsky AM, Dickier MN. Estrogen receptor-positive breast cancer: exploiting signaling pathways implicated in endocrine resistance. The Oncologist. 2018;23(5):528-539. doi:10.1634/theoncologist.2017-0423 2. Patel HK, Bihani T. Selective estrogen receptor modulators (SERMs) and selectiveestrogen receptor degraders (SERDs) in cancer treatment. Pharmacol Ther. 2018;186:1-24. doi:10.1016/j.pharmthera.2017.12.012 3. Osbourne CK, Schiff R. Mechanisms of endocrine resistance in breast cancer. Annu Rev Med. 2011;62:233-247. doi:10.1146/annurev-med-070909-182917 4. Dixon JM. Endocrineresistance in breast cancer. New Journal of Science. 2014;2014:1-27. doi: 10.1155/2014/390618 5. Higgins MJ, Base!ga J. Targeted therapies for breast

cancer. J Clin Invest. 2011;121(10):3797-3803. doi:10.1172/JCl57152 6. Burstein HJ. Systemic therapy for estrogen receptor-positive, HER2-negative breast cancer. N Engl J Med. 2020;383:2557-2570. doi:10.1056/NEJMra1307118 7. Reinert T, Saad ED, Barrios CH, Bines J. Clinical implications of ESR1 mutations in hormone receptor-positive advanced breast cancer. Front Oncol. 2017;7(26):1-9. doi:10.3389/fonc.2017.00026 8. El-Ahmad Y, Tabart M, Halley F, et al. Discovery of 6 (2,4-Dichlorophenyl)-5-14-l(3S) 1-(3-fluoropropyl)pyrrolidin-3-ylJoxyphenyl]-8,9-dihydro 7H benzo[7]annu!ene-2-carboxylic acid (SAR439859), a potent and selective estrogen receptor degrader (SER□) for the treatment of estrogen-receptor-positive breast cancer. J Med Chem. 2020;63(2):512-528. doi:10.1021/acs.jmedchem.9b01293 9. De Santo I, McCartney A, Migliaccio I, Di Leo A, Malorni L. The emerging role of ESR1 mutations in luminal breast cancer as a prognostic and predictive biomarker of response to endocrine therapy. Cancers. 2019;11(12):1894. doi:10.3390/cancers11121894 10. Spoerke JM, Gendreau S, Walter K, et al. Heterogeneity and clinical significance of ESR1 mutations in ER-positive metastatic breast cancer patients receiving fulvestrant. Nat Commun. 2016;7:11579. doi:10.1038/ncomms11579

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