Blog | Dec. 07, 2022
Most common cancer diagnosed in women worldwide
Breast cancer (BC) is the most common cancer diagnosed in women worldwide, having recently surpassed lung cancer, and accounts for more than 25% of new cancer diagnoses.1,2 It is also the leading cause of death among cancers in women.2 According to the CDC, BC care in the U.S. cost the country 16.5 billion USD annually in 2010, and has the highest treatment cost of any cancer.3
Among BCs, more than 70% are classified as estrogen receptor positive (ER+). This classification is based on the ER expression determined by immunohistochemistry in at least 1% of tumor cells. Estrogen receptor alpha (ERα) and its natural ligand, estrogen, are major drivers of tumor development and disease progression in BCs. Targeting ERα has led to several highly successful BC therapeutics that are widely utilized in both early stage BC and metastatic BC.4 In 1997, the selective estrogen receptor modulator Tamoxifen was approved for use in combatting BC, and it still represents the standard of care for adjuvant treatment of early stage BC.5 Tamoxifen is especially useful in postmenopausal patients, though use of aromatase inhibitors (AIs) that inhibit biosynthesis of estrogen are often utilized in adjuvant treatment and represent the standard of care in advanced metastatic breast cancer in postmenopausal patients.6,7
Intrinsic and acquired resistance to breast cancer therapies
Even though these various anti-hormonal therapies have proven effective at combatting BC, intrinsic and acquired resistance to these therapies is and remains a persistent problem. The issue is especially apparent when it comes to ER+ metastatic breast cancer (MBC), where up to half of patients will demonstrate intrinsic resistance and no benefit from these therapies, and eventually all the ER+ MBC patients will develop acquired resistance.7 Patients who grow resistant to the first-line treatments experience a drop in progression-free survival (PFS) when they move onto second-line therapies.8 A mechanism of acquired resistance that has come into focus is the mutation of the ligand binding domain (LBD) of Estrogen Receptor 1 (ESR1), and it has been intensely studied over the last decade plus to elucidate its role in therapy resistance and to guide selection of appropriate treatments and therapeutic vulnerabilities.9
The first ESR1 mutations were discovered in 1997,10 however, their role in BC resistance to first line therapies was not firmly established until 2013 with genomic sequencing of MBCs.11 The prevalence of ESR1 mutations has since been measured among BC patients and is dependent on prior duration and setting of hormonal therapy. ESR1 mutations in ER+ BC occur almost exclusively after AI therapy in the metastatic setting, and among patients who have received AIs, approximately 20-40% have mutations in ESR1.9,11,12
The simplest mechanism through which ESR1 mutations result in resistance to hormone therapy is constitutive activity. Wild-type ESR1 requires estrogen in order to function and the mutations can remove the need for estrogen to bind to ESR1 before assuming its active conformation. Thus, therapies that rely on depleting the amount of estrogen in the system to deactivate ESR1 are no longer effective. Alternatively, ESR1 mutations can result in relative resistance to ER-targeted therapies like Tamoxifen and Fulvestrant, a selective estrogen receptor degrader. ESR1 mutants have demonstrated up to 30-fold decreased binding affinity for Tamoxifen and up to 40-fold decreased binding affinity for Fulvestrant (varying by specific mutation) requiring higher dosages in order to elicit therapeutic effects.14,15,16
In addition to the general resistance mechanisms, there are mutation-specific and context-specific mutations to ESR1 that effect therapeutic options for treatment of BC and MBC. For example, among two of the most commonly observed mutations, Y537S, has greater resistance to estrogen deprivation, Tamoxifen, Fulvestrant, and several novel drugs; and D538G results in greater metastatic potential, especially to the liver.12,13,15,16
Clinical utility of mutation detection
These mutations may bear out their effects not just in a pre-clinical theoretical setting, but also in clinical practice, however, the results of how ESR1 mutations manifest in clinical practice are mixed. In the plasmaMATCH trial, it was found that Fulvestrant monotherapy may not be effective for patients in the late-line setting with ESR1 mutations.17 However, in the PALOMA-3 trial, it was found that ESR1 mutations in general do not result in resistance to Fulvestrant plus a CDK4/6 inhibitor, but the Y537S mutation deserves further study as it may have an effect on treatment.18,19,20
There is a glaring need to elucidate further the effects of specific mutations of ESR1 on BC and MBC. The effects of mutations can potentially be used for therapy selection as well as monitoring of response to therapy. With technologies like Plasma-Safe-SeqS (PSS) we are able to detect mutations to ESR1 with great specificity and sensitivity.21 This type of monitoring will allow for further study of ESR1 mutations and can also be useful in the clinical application of findings concerning ESR1 mutations and how they affect the clinical application of cancer treatment.
- Wild, C. P., Weiderpass, E. & Stewart, B. W. (eds) World Cancer Report: Cancer Research for Cancer Prevention (IARC, 2020).
- Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. International journal of cancer Journal international du cancer. 2015;136(5):E359–86. Epub 2014/09/16.
- Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. Projections of the cost of cancer care in the United States: 2010–2020. J Natl Cancer Inst. 2011;103(2):117–128.
- Ariazi, E. A., Ariazi, J. L., Cordera, F. & Jordan, V. C. Estrogen receptors as therapeutic targets in breast cancer. Curr. Top. Med. Chem. 6, 181–202 (2006).
- Osborne, C. K. Tamoxifen in the treatment of breast cancer. N. Engl. J. Med. 339, 1609–1618 (1998)
- Burstein, H. J. et al. Adjuvant endocrine therapy for women with hormone receptor-positive breast cancer: american society of clinical oncology clinical practice guideline focused update. J. Clin. Oncol. 32, 2255–2269 (2014).
- Nardone, A., De Angelis, C., Trivedi, M. V., Osborne, C. K. & Schiff, R. The changing role of ER in endocrine resistance. Breast 24, S60–S66 (2015).
- Nagaraj G, Ma CX. Clinical challenges in the management of hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: a literature review. Adv Ther. 2021;38:109–36.
- Hermida-Prado F, Jeselsohn R. The ESR1 mutations: from bedside to bench to bedside. Cancer Res. 2021;81:537–8.
- Zhang QX, Borg A, Wolf DM, Oesterreich S, Fuqua SA. An estrogen receptor mutant with strong hormone-independent activity from a metastatic breast cancer. Cancer Res. 1997;57:1244–9.
- Li S, et al. Endocrine-therapy-resistant ESR1 variants revealed by genomic characterization of breast-cancer-derived xenografts. Cell Rep. 2013;4:1116–30.
- Toy W, et al. ESR1 ligand-binding domain mutations in hormone-resistant breast cancer. Nat Genet. 2013;45:1439–45.
- Merenbakh-Lamin K, et al. D538G mutation in estrogen receptor-α: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 2013;73:6856–64.
- Jeselsohn R, et al. Emergence of constitutively active estrogen receptor-α mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res Off J Am Assoc Cancer Res. 2014;20:1757–67.
- Fanning SW, et al. Estrogen receptor alpha somatic mutations Y537S and D538G confer breast cancer endocrine resistance by stabilizing the activating function-2 binding conformation. Elife. 2016;5:e12792.
- Bahreini A, et al. Mutation site and context dependent effects of ESR1 mutation in genome-edited breast cancer cell models. Breast Cancer Res BCR. 2017;19:60.
- Turner NC, et al. Circulating tumour DNA analysis to direct therapy in advanced breast cancer (plasmaMATCH): a multicentre, multicohort, phase 2a, platform trial. Lancet Oncol. 2020;21:1296–308.
- Fribbens C, et al. Plasma ESR1 mutations and the treatment of estrogen receptor-positive advanced breast cancer. J Clin Oncol Off J Am Soc Clin Oncol. 2016;34:2961
- O’Leary B, et al. The genetic landscape and clonal evolution of breast cancer resistance to palbociclib plus fulvestrant in the PALOMA-3 trial. Cancer Discov. 2018;8:1390–403.
- O’Leary B, et al. Early circulating tumor DNA dynamics and clonal selection with palbociclib and fulvestrant for breast cancer. Nat Commun. 2018;9:896.
- Rodriguez; Córdoba; Aranda; Álvarez; Vicioso; Pérez; Hernando; Bermejo; Parreño; Lluch; et al. Detection of TP53 and PIK3CA Mutations in Circulating Tumor DNA Using Next-Generation Sequencing in the Screening Process for Early Breast Cancer Diagnosis. JCM 2019, 8 (8), 1183.