New Targets in Endocrine-Resistant Hormone Receptor–Positive Breast Cancer Laura C. Kennedy, MD, PhD, and Ingrid A. Mayer, MD, MSCI Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee Corresponding author: Abstract: Endocrine-based treatments are the backbone of initial Ingrid Mayer, MD therapy for advanced hormone receptor–positive breast cancers. Professor of Medicine Developing new therapeutic strategies to address resistance to Vanderbilt University Medical Center/ endocrine therapy is an area of active research. In this review, we Vanderbilt-Ingram Cancer Center 2220 Pierce Ave 777 PRB discuss targeted therapies that are currently the standard of care, Nashville, TN 37232 as well as agents that are at present under investigation as potential Tel: (615) 936-2033 treatments for advanced hormone receptor–positive breast cancer. Email: [email protected] Introduction Hormone receptor–positive (HR+) breast cancers are the most com- monly identified subtype of breast cancer, accounting for about 70% of early and de novo metastatic breast cancer diagnoses.1,2 Estrogen is the main driver of cancer cell proliferation in HR+ breast cancer. Upon binding with estrogen, the estrogen receptor (ER) acts as both a direct transcription factor and a regulator of other transcription factors to drive cell proliferation.3 Therefore, a key component in the initial treatment of metastatic HR+ breast cancer is estrogen depriva- tion. In the treatment-naive state, most advanced HR+ breast cancers are sensitive to estrogen blockade with either an aromatase inhibitor (AI; eg, letrozole, anastrozole, or exemestane) for postmenopausal women or an AI plus ovarian suppression for premenopausal women. Resistance to endocrine therapy is an inevitable development, however, and may be acquired or primary. Acquired resistance is defined as disease progression beyond 2 years of adjuvant endocrine therapy or after at least 6 months of endocrine therapy in the setting of advanced breast cancer; primary resistance is defined as disease progression within 2 years of adjuvant endocrine therapy or after less than 6 months of endocrine therapy in the advanced setting.4 In acquired resistance, mutations or genomic alterations develop owing to therapy selection pressures that favor continued cancer cell proliferation despite the loss of primary estrogen signaling. In pri- mary resistance, which affects a smaller pool of patients, mutations or genomic alterations are present in the untreated breast cancer.5 Examples of acquired genomic alterations leading to endocrine therapy resistance include mutations in the estrogen receptor alpha Keywords (ESR1) gene and mutations or alterations leading to an increased acti- Endocrine resistance, hormone receptor–positive vation of growth factor pathways, such as phosphoinositide 3-kinase breast cancer, targeted therapy (PI3K). Primary genomic alterations include loss of p16, fibroblast Clinical Advances in Hematology & Oncology Volume 19, Issue 8 August 2021 511 KENNEDY AND MAYER growth factor receptor (FGFR) gene amplifications, and growth and contributing to endocrine resistance.8,10 The MYC amplification or overexpression.5-8 addition of specific inhibitors of CDK4/6 (palbociclib In this review, we discuss the development of current [Ibrance, Pfizer], ribociclib [Kisqali, Novartis], abemac- and investigational targeted therapies for patients with iclib [Verzenio, Lilly], and dalpiciclib [SHR6390]) to advanced HR+ breast cancer. an endocrine backbone (an AI or fulvestrant) prolongs endocrine sensitivity, and CDK4/6 inhibitors are now Standard-of-Care Strategies to Address recommended as part of first-line therapy for patients Endocrine Resistance with metastatic HR+ disease. Palbociclib, ribociclib, abe- maciclib, and dalpiciclib all prolong progression-free sur- Genomic Alterations in HR+ Breast Cancer vival (PFS) in the first- or second-line setting,11-15 and an Resistance to endocrine therapy can be related to a vari- overall survival (OS) benefit has been shown in the first- ety of genomic alterations in several different pathways line setting for premenopausal women,12 although it has (Figure). One of the challenges of addressing the genomic not yet been reported in postmenopausal women.11,16,17 alterations in advanced HR+ breast cancer is the diversity In the second-line setting, the combination of either of mutations that can be implicated in treatment resis- fulvestrant and abemaciclib or fulvestrant and ribociclib tance. Several breast cancer cell pathways can be altered prolonged OS in the intention-to-treat population and to favor cancer progression and carcinogenesis, and many in patients with endocrine-resistant disease.14,18 Although of the genomic alterations that are seen in advanced HR+ the combination of fulvestrant and palbociclib did not breast cancer occur in 10% or fewer of patients.5,7 result in a significant OS difference in the intention- The major steps in the ER pathway include estrogen to-treat population, it did appear to increase OS in the binding to the ER with signaling through cyclin-depen- patients with endocrine-sensitive breast cancer on sub- dent kinases 4 and 6 (CDK4/6) and cyclin D, leading group analysis.13 to the phosphorylation of retinoblastoma protein (Rb). Evidence suggests that patients with HR+ breast Phosphorylation of Rb releases the E2F transcription fac- cancer that has progressed during endocrine therapy and tor and triggers progression from G1 to S in the cell cycle, CDK4/6 inhibitor treatment could still benefit from an leading to cancer cell proliferation and tumor growth. endocrine-based regimen if the correct resistance mecha- Multiple pathways and proteins other than direct binding nism were addressed. In a small study looking at patients with the ER route through CDK4/6 and lead to Rb phos- treated with letrozole/palbociclib, new ESR1 mutations phorylation.. These include alterations such as inactiva- developed over the course of treatment.19 Another tion of p16, which inhibits CDK4/6, a common finding correlative study (PALOMA-3) looking at the cell-free in breast cancer9; mutations in PIK3CA and TP53, which circulating tumor DNA of patients treated with fulves- are found in about 40% of patients with metastatic HR+ trant/palbociclib found that 30% of them had acquired breast cancer; and alterations in proteins such as PTEN, new mutations in genes such as ESR1, PI3KCA, ERBB2, ERBB2, MYC, and ARID1A, which occur in 10% or FGFR, and Rb over the course of treatment.20 Interestingly, fewer patients but still drive cell proliferation.5,7 the mutational profile of patients treated with fulvestrant These alterations ultimately favor the development was the same as that of the patients treated with fulves- of endocrine therapy resistance (ie, continued cellular trant/palbociclib except for the presence of Rb mutations, proliferation despite endocrine blockade). Some of the which developed in 5% of patients after treatment with propensities to resistance are present in untreated pri- fulvestrant/palbociclib but not in those treated with mary HR+ breast cancer, such as genomic alterations fulvestrant alone. This finding suggests that treatment in PIK3CA, HER2, AKT, and FGFR,5,7 whereas others is pressuring both the development of mutations such develop through selection pressure with endocrine treat- as those in ESR1 that will directly evade the endocrine ment. Mutations in ESR1 are one of the more common backbone and alterations in other pathways that drive treatment-acquired alterations. ESR1 mutations are pres- breast cancer proliferation, rather than that the breast ent in only 3% of untreated HR+ breast cancers, but in cancer is developing independence from estrogen-based 25% of AI-treated HR+ breast cancers.7 Selective estrogen signaling. With continued tumor dependence on estrogen receptor downregulators (SERDs) such as fulvestrant were signaling, it is reasonable to posit that additional endo- subsequently developed to address ESR1 mutations. crine-based treatments could be effective if paired with the correct adjunct treatment to address the resistant CDK4/6 Inhibitors pathway. This idea was supported by the results of the Inactivation of p16 and modifications in the Rb/CDK4/ BOLERO-2 randomized phase 3 trial, which showed that CDK6/cyclin D pathway are present in approximately the combination of everolimus, a mammalian target of 50% of primary HR+ breast cancers, driving cancer cell rapamycin (mTOR) inhibitor, plus exemestane improved 512 Clinical Advances in Hematology & Oncology Volume 19, Issue 8 August 2021 ENDOCRINE-RESISTANT HORMONE RECEPTOR–POSITIVE BREAST CANCER Estrogen signaling IGFR-1 IGFR-2 HER2 HER3 ESR1 mutation Downregulation of ERα expression p16 FGFR Inactivation of p16 Loss of p16 binding owing to CDK4 mutation PI3K CDK4/6 ↑ CDK4 ↑ Cyclin D PTEN Cyclin D Alterations noted in untreated ER+ BC Alterations noted in treated ER+ BC AKT mTORC P Rb PTEN inactivation Rb PIK3CA mutations E2F Nucleus AKT1 mutations AKT2 and AKT3 amplications Aurora Cell cycle A Functional loss of Rb progression E2F and cell growth Figure. Estrogen receptor signaling in HR+ breast cancer. AKT, RAC-alpha serine/threonine protein kinase; BC, breast cancer; CDK4/6, cyclin-dependent kinases 4 and 6; ER+, estrogen receptor–positive; ERα, estrogen receptor alpha; ESR1, estrogen receptor alpha gene; FGFR, fibroblast growth factor receptor; HER2, human epidermal growth factor receptor 2; IGFR-1, insulin-like growth factor receptor 1; mTORC, mammalian