ER Progression and Resistance: Causes, Consequences, and Hope
Episode Notes
About 80% of breast cancers are ER+, meaning that the cancer cells have estrogen receptors, and estrogen is likely to make them grow. Here’s the good news/bad news story for ER+ MBC patients. First, the good news: there are a number of effective medications that either reduce available systemic estrogen or block its ability to stimulate cancer growth. The bad news: over time, ER+ cancers develop resistance to these medications, resulting in cancer progression and signaling the need for a new treatment. For many of us with ER+ MBC, that means a repeating cycle of high stakes scans, biopsies, and blood tests—and the ever present fear that we will run out of treatment options.
Fortunately, there is more good news: the best minds in cancer research are on the case. In this episode, the Our MBC Life team hears from two dynamic MSK oncologists on treatment strategies and the latest research around the problem of endocrine resistance
Dr. Pedram Razavi and Dr. Komal Jhaveri will review recent advances in delineating mechanisms of resistance to endocrine therapies and potential strategies to overcome such resistance including the molecular tumor board that meets regularly at MSK
Subjects and Terms Included in This Episode
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They are chemical substances known as hormones. Like all natural hormones they are produced and stored by glands of the endocrine system (In this case ovaries) and are secreted directly into blood in response to a signal from the brain. Hormones act as messengers that help control and coordinate how our body works and responds to the environment.
In addition to their normal functions, estrogen and progesterone promote the growth of hormone-sensitive (or hormone-receptor-positive) breast cancers
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Every cell in our body is exposed to hormones circulating in the bloodstream, but only the cells, which have proteins called receptors for that hormone, are activated. estrogen receptor or ER is a receptor for estrogen, progesterone receptor or PR is a receptor for progesterone. Approximately 67%–80% of breast cancers in women are ER positive. Approximately 90% of breast cancers in men are ER positive and approximately 80% are PR positive
The activated receptors cause changes in the expression of specific genes, which can stimulate cell growth.They can act at any point along this hormone signaling pathway.
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Hormone therapy(aka hormonal therapy, hormone treatment, or endocrine therapy) slows or stops the growth of hormone-sensitive tumors by blocking the body’s ability to produce hormones or by interfering with effects of hormones on breast cancer cells.
Several types of hormone therapies are approved to treat metastatic breast cancer.
Aromatase inhibitors are used to block the activity of an enzyme called aromatase. This enzyme is used to make estrogen in the ovaries and in other tissues.
Several types of drugs interfere with estrogen’s ability to stimulate the growth of breast cancer cells. Selective estrogen receptor modulators (SERMs) bind to estrogen receptors, preventing estrogen from binding. Other anti estrogen drugs, known as SERDs or selective estrogen receptor degraders work in a somewhat different way to block estrogen’s effects. Like SERMs, a SERD binds to the estrogen receptor. when a SERD binds to the estrogen receptor, the receptor is targeted for destruction. In addition, targeted therapies are used in treating HR positive MBC in a combination with hormone therapy. Targeted therapies like CDK4/6 inhibitors or cyclin-dependent-kinase-inhibitors. Kinases are proteins in cells that normally relay signals (such as telling the cell to grow). Drugs that block kinases are called kinase inhibitors. A CDK4/6 inhibitor inhibits two cyclin-dependent kinases (CDK4 and CDK6) that appear to promote the growth of HR-positive breast cancer cells.
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Even though traditional tumor biopsy is still considered the gold standard in diagnostic oncology, the invasive nature of this technique is one of its main limits. On the other hand, body fluids can be easily obtained in a non-invasive way, and thus liquid biopsy is a great alternative approach. Tumor cells release to the bloodstream DNA of different forms, such as cell-free DNA (cfDNA), circulating tumor DNA (ctDNA), micro RNAs (miRNAs), and more. These sources could be used for rapid and effective tumor molecular profiling and have the potential to overcome several practical issues with tissue biopsy such as often inaccessible metastatic sites like lungs and bones, the impossibility of serial sampling and inadequate or insufficient material for molecular analysis. Liquid biopsy among other things will potentially be able to intercept the onset of disease recurrence, treatment resistance, and even predict response and prognosis.
In addition, because ctDNA levels are associated with tumor burden they may represent an indirect measure of treatment response and predict clinical outcome.
Lliquid biopsy as a source of material for assaying ctDNAs for genetic/genomic marker alterations is now widely used. Working in tandem liquid biopsy and ctDNA analysis are beginning to pave the way to a growingly individualized cancer care.
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A tumor that responds to immunotherapy is called “hot”, one that doesn’t respond is called “cold”. ER+ tumors are typically cold, they have not responded to immunotherapy. One therapeutic goal is to make the ER+ tumor hotter so that immunotherapy might be a little more effective
Envatinib
Example: Lenvatinib is a tyrosine kinase inhibitor combined with pembrolizumab – brand name is Keytruda
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Inhibition of ER activity by endocrine treatments is an effective and safe treatment strategy for patients harboring ER+ breast cancer. However, some patients with metastatic breast cancer do not respond to any form of endocrine treatment (de novo resistance), and virtually all patients who initially respond eventually develop endocrine resistance (acquired resistance). The scientists have identified mutations in the ER ligand-binding domain (LBD) that mimic the activated ligand (or hormone ) bound receptor and serve as a novel mechanism of resistance to endocrine therapy These activating mutations were identified in up to 39% of heavily pretreated patients with metastatic breast cancer. The analysis of PALOMA clinical trials and accumulated clinical and laboratory data, indicated shortened progression free-survival of patients with tumors harboring LBD mutations and noted an association between the presence of these mutations and increased frequency of liver mets
These data suggest that breast cancers harboring these LBD-activating mutations may constitute a new subgroup of breast cancers, characterized by increased invasiveness translating into a more aggressive clinical behavior.
A possible candidate mediating aggressive behavior of ER+ breast cancer cells is the PI3K-AKT-mTOR pathway. Activating mutations in this pathway occur in over 40% of ER+ breast cancers and activation of this pathway has been linked to endocrine-resistant breast cancer Accordingly, inhibition of mTOR by everolimus is an effective strategy to overcome endocrine resistance in patients Activation of the PI3K-AKT-mTOR pathway may be associated not only with endocrine resistance but also with a more aggressive disease behavior However, the interaction between the presence of LBD mutations and activation of the PI3K-AKT-mTOR has not been characterized yet.
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ESR1 mutation – a change in the endocrine receptor molecule that allows the receptor to become active without the need to bind estrogen thereby the drug that blocks the receptor is no longer effective. When this occurs, the AI’s letrozole, anastrazole and exemestane no longer work.
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PIK3CA/AKT/mTOR pathway: upregulation of growth factor receptor pathway. A tumor that has a PIK3CA mutation should be responsive to alpelisib (Piqray).
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ctDNA: circulating tumor DNA, found in the blood ( liquid biopsy)
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A selective estrogen receptor degrader or downregulator (SERD) is a type of drug which binds to the estrogen receptor (ER) and, in the process of doing so, causes the ER to be degraded and thus downregulated. They are used to treat estrogen receptor-sensitive or progesterone receptor-sensitive breast cancer, along with older classes of drugs like selective estrogen receptor modulators (SERMs) and aromatase inhibitors.
As of 2016 the only marketed SERD was fulvestrant (brand name Faslodex). The new type of SERDs under development are oral SERDs. They include brilanestrant and elacestrant and others. Elacestrant is the closest to being approved an is in Phase 3 Trial
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A drug that acts like estrogen on some tissues but blocks the effect of estrogen on other tissues. Tamoxifen and raloxifene are selective estrogen receptor modulators. Also called SERM.
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MAPK (also known as MAP2K, MEK, MAPKK) kinases are important mediators of signal transduction and play a key role in the regulation of many cellular processes, such as cell growth and proliferation, differentiation, and apoptosis.
Abnormal MAPK signaling may lead to increased or uncontrolled cell proliferation and resistance to apoptosis. Research into the MAPK pathway has shown it to be important in breast cancer
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The Cyclin D/Cdk4 complex is a multi-protein structure consisting of the proteins Cyclin D and cyclin-dependent kinase 4, or Cdk4, a serine-threonine kinase. This complex is one of many cyclin/cyclin-dependent kinase complexes that are the "hearts of the cell-cycle control system" and govern the cell cycle and its progression. The Cyclin D/Cdk4 complex is integral for the progression of the cell from the Growth 1 phase to the Synthesis phase of the cell cycle, for the Start or G1/S checkpoint.
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Next-generation sequencing (NGS) is a technology for determining the sequence of DNA or RNA to study genetic variation associated with diseases or other biological phenomena. Introduced for commercial use in 2005, this method was initially called “massively-parallel sequencing”, because it enabled the sequencing of many DNA strands at the same time, instead of one at a time as with traditional Sanger sequencing by capillary electrophoresis (CE).
Each of these technologies has utility in today’s genetic analysis environment. Sanger sequencing is best for analyzing small numbers of gene targets and samples and can be accomplished in a single day. It is also considered the gold-standard sequencing technology, so NGS results are often verified using Sanger sequencing. NGS enables the interrogation of hundreds to thousands of genes at one time in multiple samples, as well as discovery and analysis of different types of genomic features in a single sequencing run, from single nucleotide variants (SNVs), to copy number and structural variants, and even RNA fusions. NGS provides the ideal throughput per run, and studies can be performed quickly and cost-effectively. Additional advantages of NGS include lower sample input requirements, higher accuracy.
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A series of recent studies have demonstrated that the retinoblastoma tumor suppressor (RB) pathway plays a critical role in multiple clinically relevant aspects of breast cancer biology, spanning early stage lesions to targeted treatment of metastatic disease. Invasive breast cancers are treated in distinct fashions, and heterogeneity within the RB pathway relates to prognosis and response to commonly used therapeutics. Luminal B breast cancers that have a poor prognosis amongst estrogen receptor-positive disease are defined based on the expression of RB-regulated genes. Such findings have led to clinical interventions that directly target the RB pathway through CDK4/6 inhibition which have promise in both estrogen receptor-positive and Her2-positive disease. In contrast, RB loss results in improved response to chemotherapy in triple-negative breast cancer, where ongoing research is attempting to define intrinsic vulnerabilities for targeted intervention. These findings support a wide-reaching impact of the RB pathway on disease that could be harnessed for improved clinical interventions.
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Approximately 40% of patients with HR-positive/HER2-negative advanced breast cancer have a PIK3CA driver mutation. The presence of PIK3CA mutations is associated with a poor prognosis and can contribute to endocrine therapy resistance.
In May 2019, the FDA approved alpelisib plus fulvestrant as a treatment for postmenopausal patients with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen.
The BYLieve trial assessed the utility of combining alpelisib with additional endocrine therapies in patients with HR-positive/HER2-negative advanced breast cancer harboring a PIK3CA mutation in tumor tissue or blood. Prior lines of treatment were required to include a CDK4/6 inhibitor plus endocrine therapy, systemic chemotherapy, or endocrine therapy alone.
Moreover, patients needed ECOG performance status no greater than 2, plus measurable disease per the RECIST v1.1 criteria, or at least 1 predominantly lytic bone lesion.
Cohort A featured patients who received a CDK4/6 inhibitor plus an aromatase inhibitor as immediate prior treatment. This cohort received alpelisib plus fulvestrant
Cohort B included patients who received a CDK4/6 inhibitor plus fulvestrant as immediate prior treatment. These patients received alpelisib plus letrozole.
Cohort C evaluated patients whose disease progressed on or after treatment with an aromatase inhibitor and then received chemotherapy or endocrine therapy as immediate prior treatment). These patients received the same dosing of alpelisib and fulvestrant as cohort A.
The combination of alpelisib (Piqray) plus endocrine therapy elicited a clinical benefit across all subgroups according to data from a subgroup analysis of the phase 2 BYLieve trial (NCT03056755) presented in a poster at the European Society for Medical Oncology Breast Cancer Congress 2022. Across 3 cohorts, progression-free survival (PFS) ranged from 5.1 to 16.6 months in subgroups classified by menopausal status
Novel Therapies Mentioned in the Episode
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Lenvatinib is a kinase inhibitor used to treat certain types of cancer. Kinase inhibitors are enzyme inhibitors that blocks the action of one or more protein kinases. Lenvatinib is currently used to treat thyroid cancer.
“And so we have an investigator initiated trial with Merck that we have currently, , working through our system so that we can get that approved and open for our patients. We are trying to study the combination of Lenvatinib, which is Tyrosine Kinase inhibitor for multiple tyrosine kinases, including FGFR receptor VEGF receptor, PDGF amongst others in combination with pembrolizumab, the checkpoint inhibitor, that's already approved for triple negative breast cancer and Fulvestrant.
And so the idea is, is there something lenvatinib does to the tumor micro environment that makes the tumor microenvironment really conducive to get better prepped and have more neoantigens and more immunomodulatory changes. So that pembrolizumab will eventually work in the triplet might work even for ER-positive disease. “ Komal Jhaveri
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Approximately 67%–80% of breast cancers in women are ER positive. Approximately 90% of breast cancers in men are ER positive and approximately 80% are PR positive Currently only medicines that block estrogen are approved, meaning that progesterone signaling continues in those patients receiving anti-estrogen therapy. ONA-XR from Context Therapeutics is an investigational medicine that prevents progesterone signaling by blocking the interaction between progesterone and its binding partner, progesterone receptor. Onapristone is the only known full PR antagonist. Under normal conditions, progesterone is primarily responsible for the development of sex organs and for regulating the menstrual cycle. Cancer cells hijack progesterone to stimulate cancer cell proliferation, metastases, regeneration, and immune evasion - thus, leading to worse outcomes.e
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Elacestrant (developmental code names RAD-1901, ER-306323) is a nonsteroidal combined selective estrogen receptor modulator (SERM) and selective estrogen receptor degrader (SERD) (described as a "SERM/SERD hybrid (SSH)") that was discovered by Eisai and is under development by Radius Health and Takeda for the treatment estrogen receptor (ER)-positive advanced breast cancer. Unlike the SERD fulvestrant, elacestrant is able to readily cross the blood-brain-barrier into the central nervous system, where it can target breast cancer metastases in the brain, and is orally bioavailable and does not require intramuscular injection.
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Lasofoxifene, sold under the brand name Fablyn, is a nonsteroidal selective estrogen receptor modulator (SERM) which is marketed by Pfizer in Lithuania and Portugal for the prevention and treatment of osteoporosis and for the treatment of vaginal atrophy,
In studies of breast cancer prevention, lasofoxifene showed a 79% reduction in breast cancer incidence and an 83% reduction specific incidence of estrogen receptor-positive breast cancers, which is significantly higher than reductions found with the related SERMs tamoxifen and raloxifene.In accordance, a network meta-analysis of SERMs for breast cancer prevention found the highest reduction in risk with lasofoxifene of all the drugs.The reduction was even greater than that observed with aromatase inhibitors, which have generally been found to confer a greater risk reduction than SERMs.[6]It also has shown promise in ESR1 mutant patients with 'approximately 40% of patients harboring this mutation'.
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Bazedoxifene, used as bazedoxifene acetate, is a medication for bone problems and possibly (pending more study) for cancer.It is a third-generation selective estrogen receptor modulator (SERM). Since late 2013 it has had U.S. FDA approval for bazedoxifene as part of the combination drug Duavee in the prevention (not treatment) of postmenopausal osteoporosis. It is also being studied for possible treatment of breast cancer and pancreatic cancer.
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Arvinas is developing ARV-471, an oral estrogen receptor (ER)-targeting PROTAC® protein degrader for the potential treatment of patients with locally advanced or metastatic ER positive / HER2 negative breast cancer. Arvinas and Pfizer have a global collaboration to co-develop and co-commercialize ARV-471.
While approved treatments have produced some success in this patient population, many ER+ breast cancers become resistant to therapy. Today, fulvestrant (Faslodex®)—a selective estrogen receptor degrader (SERD)—is the standard of care for ER+ metastatic breast cancer after anti-estrogen therapy. While fulvestrant has validated the importance of ER degradation as a therapeutic intervention, up to 50% of ER can remain when compared to baseline levels after six months of treatment with fulvestrant. Unlike fulvestrant, which is administered via intramuscular injection, Arvinas’ ER-directed PROTAC protein degrader, ARV-471, is an oral therapy under development for the treatment of women with ER+ metastatic breast cancer.
Clinical Trials
Clinical Trials Investigated by Dr. Jhaveri and Dr. Razavi
A Phase IA Study of PF-06873600 in Patients with Advanced Breast Cancer
A Phase II Study of Neratinib in Patients with Solid Tumors Containing Mutated HER2
Clinical Trials Investigated by Dr. Ezra Rosen
Research and Publications
The Genomic Landscape of Endocrine-Resistant Advanced Breast Cancers.
Razavi P, Chang MT, Xu G, Bandlamudi C, Ross DS, Vasan N, Cai Y, Bielski CM, Donoghue MTA, Jonsson P, Penson A, Shen R, Pareja F, Kundra R, Middha S, Cheng ML, Zehir A, Kandoth C, Patel R, Huberman K, Smyth LM, Jhaveri K, Modi S, Traina TA, Dang C, Zhang W, Weigelt B, Li BT, Ladanyi M, Hyman DM, Schultz N, Robson ME, Hudis C, Brogi E, Viale A, Norton L, Dickler MN, Berger MF, Iacobuzio-Donahue CA, Chandarlapaty S, Scaltriti M, Reis-Filho JS, Solit DB, Taylor BS, Baselga J.Cancer Cell. 2018 Sep 10;34(3):427-438.e6. doi: 10.1016
Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors.
Vasan N, Razavi P, Johnson JL, Shao H, Shah H, Antoine A, Ladewig E, Gorelick A, Lin TY, Toska E, Xu G, Kazmi A, Chang MT, Taylor BS, Dickler MN, Jhaveri K, Chandarlapaty S, Rabadan R, Reznik E, Smith ML, Sebra R, Schimmoller F, Wilson TR, Friedman LS, Cantley LC, Scaltriti M, Baselga J.Science. 2019 Nov 8;366(6466):714-723. doi: 10.1126/science.aaw9032.
Alterations in PTEN and ESR1 promote clinical resistance to alpelisib plus aromatase inhibitors.
Razavi P, Dickler MN, Shah PD, Toy W, Brown DN, Won HH, Li BT, Shen R, Vasan N, Modi S, Jhaveri K, Caravella BA, Patil S, Selenica P, Zamora S, Cowan AM, Comen E, Singh A, Covey A, Berger MF, Hudis CA, Norton L, Nagy RJ, Odegaard JI, Lanman RB, Solit DB, Robson ME, Lacouture ME, Brogi E, Reis-Filho JS, Moynahan ME, Scaltriti M, Chandarlapaty S.
Selective AKT kinase inhibitor capivasertib in combination with fulvestrant in PTEN-mutant ER-positive metastatic breast cancer.Smyth LM, Batist G, Meric-Bernstam F, Kabos P, Spanggaard I, Lluch A, Jhaveri K, Varga A, Wong A, Schram AM, Ambrose H, Carr TH, de Bruin EC, Salinas-Souza C, Foxley A, Hauser J, Lindemann JPO, Maudsley R, McEwen R, Moschetta M, Nikolaou M, Schiavon G, Razavi P, Banerji U, Baselga J, Hyman DM, Chandarlapaty S.
Hamilton EP, Patel MR, Armstrong AC, Baird RD, Jhaveri K, Hoch M, Klinowska T, Lindemann JPO, Morgan SR, Schiavon G, Weir HM, Im SA.
Paoletti C, Schiavon G, Dolce EM, Darga EP, Carr TH, Geradts J, Hoch M, Klinowska T, Lindemann J, Marshall G, Morgan S, Patel P, Rowlands V, Sathiyayogan N, Aung K, Hamilton E, Patel M, Armstrong A, Jhaveri K, Im SA, Iqbal N, Butt F, Dive C, Harrington EA, Barrett JC, Baird R, Hayes DF.
Activating ESR1 Mutations Differentially Affect the Efficacy of ER Antagonists.Toy W, Weir H, Razavi P, Lawson M, Goeppert AU, Mazzola AM, Smith A, Wilson J, Morrow C, Wong WL, De Stanchina E, Carlson KE, Martin TS, Uddin S, Li Z, Fanning S, Katzenellenbogen JA, Greene G, Baselga J, Chandarlapaty S.
Rose Brannon A, Jayakumaran G, Diosdado M, Patel J, Razumova A, Hu Y, Meng F, Haque M, Sadowska J, Murphy BJ, Baldi T, Johnson I, Ptashkin R, Hasan M, Srinivasan P, Rema AB, Rijo I, Agarunov A, Won H, Perera D, Brown DN, Samoila A, Jing X, Gedvilaite E, Yang JL, Stephens DP, Dix JM, DeGroat N, Nafa K, Syed A, Li A, Lebow ES, Bowman AS, Ferguson DC, Liu Y, Mata DA, Sharma R, Yang SR, Bale T, Benhamida JK, Chang JC, Dogan S, Hameed MR, Hechtman JF, Moung C, Ross DS, Vakiani E, Vanderbilt CM, Yao J, Razavi P, Smyth LM, Chandarlapaty S, Iyer G, Abida W, Harding JJ, Krantz B, O'Reilly E, Yu HA, Li BT, Rudin CM, Diaz L, Solit DB, Arcila ME, Ladanyi M, Loomis B, Tsui D, Berger MF, Zehir A, Benayed R.Nat Commun. 2021 Jun 18;12(1):3770. doi: 10.1038/s41467-021-24109-5.
Scientists are learning how estrogen receptor-positive breast cancer evolves to thwart hormonal therapies and are developing ways to stop it. (65 kB)
Want more?
For an introduction to resistance and progression, we suggest that you listen to this episode with Dr. Stephanie Graff, Director of the Breast Oncology Program at Lifespan Cancer Institute and co-leader of the Breast Cancer Translational Research Disease Group at Brown University in Rhode Island.
Meet the Guests of this Episode
Komal Jhaveri, MD, FACP
Dr. Jhaveri is an Associate Attending Physician and the Section Head for the Endocrine Therapy Research Program within the Breast Medicine Service and the Clinical Director for the Early Drug Development Service at MSKCC. She is an Assistant Professor in the Department of Medicine at Weill Cornell Medicine in NYC. She earned her medical degree followed by a training in nuclear medicine from the University of Mumbai. She completed her Internal Medicine residency from Icahn School of Medicine at Mount Sinai in New York and her Medical Oncology and Hematology fellowship at MSKCC.
Dr. Jhaveri’s primary research interests focus on the development of improved She conducts companion translational research in collaboration with her laboratory and imaging colleagues and is focused on identifying and understanding the biomarkers of response and/or resistance to novel therapies through acquired cfDNA and tissue samples or imaging analyses. She has led the development of many targeted therapies including and not limited to PI3K/Akt inhibitors, FGFR inhibitors, ERBB2 inhibitors, oral SERD’s, Antibody-drug conjugates, amongst others.
Dr. Jhaveri is a member of the Alliance Breast Committee and the Co-Chair for the Endocrine Resistance working group within the TBCRC. Her work has been presented at annual scientific meetings of the ASCO, AACR, ESMO, and the SABCS and has been published widely in many reputable journals.
Twitter: @jhaveri_komal
Pedram Razavi, MD, PhD
Dr. Razavi is a medical oncologist and a physician-scientist focused on personalized care in breast cancer at MSKCC. He is the Director of MSK Breast Molecular Tumor Board, Breast Liquid Biopsy Program and Translational Platform and Associate Director of MSK Biomarker Development Program. He obtained his medical degree from Tehran University of Medical Sciences. He has a PhD in cancer epidemiology with a focus on population genetics at the University of Southern California followed by a postdoctoral fellowship at Channing Laboratory in Boston. He did his internal medicine residency training at the University of Southern California and completed his medical oncology fellowship at Memorial Sloan Kettering Cancer Center where he was also a postdoctoral fellow at the Laboratory of Dr. Jose Baselga. He joined MSK faculty in 2016 as a breast oncologist.
His research efforts have been focused on two major areas: 1) integrative clinicogenomic studies to guide hypothesis-based translational research in breast cancer, and 2) the development and validation of circulating tumor biomarkers such as circulating ctDNA, methylomes . He serves as the PI of multiple large-scale genomic studies in breast cancer to devise and optimize computational and analytical pipelines based on statistical methods and machine learning algorithms to identify the biomarkers of response and resistance to systemic therapy and to predict outcomes. These efforts have led to the identification of novel mechanisms of resistance to major targeted therapies modalities in breast cancer including endocrine therapy, CDK4/6 inhibitors and PI3K inhibitors and shed light on new potentially druggable genomic drivers of breast cancer.
Twitter: @PedramRazaviMD
Over the last 20 years, advances in HER2 targeting treatments, antibody-drug conjugates (ADCs), immune checkpoint inhibitors (ICIs), and cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6is) have prolonged survival and changed the breast cancer treatment landscape. Success leads to more questions about optimal drug sequencing, mechanisms of resistance, and how to overcome that resistance. Let’s ask Dr. Stephanie Graff to help us tackle these topics and more.