AMCP Market Insights: Managed care approaches to ESR1-mutated advanced breast cancer

Abstract

A mutation in the estrogen receptor alpha gene (ESR1m) following first-line treatment with endocrine therapy in hormone receptor–positive metastatic breast cancer occurs in nearly half of patients. Detection of this mutation prior to radiologic progression using circulating tumor DNA (ctDNA)–based monitoring is an emerging practice that may allow an early switch to a more effective therapy. To discuss approaches to managing ESR1m advanced breast cancer (aBC) including ctDNA-based monitoring, AMCP Market Insights virtually convened an expert panel of managed care stakeholders in February 2026. This article provides a qualitative summary of the panel discussion along with key insights and suggested payer practices meant to support informed coverage decisions and guide future work. Key insights include that community oncologists and patients may benefit from support, for example, with treatment pathways and patient navigators. Additionally, patients care about survival outcomes when combined with sustained quality of life and want monitoring practices that take patient-specific considerations into account. A primary consideration of payers related to aBC is that the optimal biomarker testing parameters, including ctDNA-based monitoring for ESR1m aBC, are uncertain, which leads to inconsistent testing practices and the need for management that promotes consistency while mitigating delays in care. Payers acknowledge that the role of next-generation selective estrogen receptor degraders is evolving based on current data and ongoing clinical trials. Suggested payer practices involve care delivery, coverage, and system advancements including engaging in multistakeholder conversations and advocating for or participating in evidence generation.

Plain language summary

Many patients develop changes in their disease expression from therapy for a common type of breast cancer. There is interest in finding a specific gene change as early as possible. Finding it earlier means treatment could be switched to one that works better for this change. This article describes a discussion among managed care professionals about how this change can be found and other issues in managing this type of breast cancer.

Implications for managed care pharmacy

The biomarker testing and treatment paradigm in advanced hormone receptor–positive breast cancer is evolving. This article provides key insights and suggested payer practices from an expert managed care panel discussion on approaches to managing advanced hormone receptor–positive breast cancer including circulating tumor DNA monitoring for early detection of the ESR1m and the role of next-generation selective estrogen receptor degraders.

Breast cancer is the most common cancer diagnosed in women in the United States, affecting approximately 1 in 8 women (13.1%) and causing death in 1 in 43 (2.3%).¹ The incidence of breast cancer has increased 1% annually from 2012 to 2021.¹ Its etiology is due to the interaction between various modifiable and nonmodifiable risk factors including genetic, environmental, nutritional, hormonal, and heritable elements.²

Breast cancer is a heterogeneous disease and is commonly grouped into 1 of 4 subtypes, which are characterized by hormone receptor (HR; includes estrogen and progesterone receptors) and human epidermal growth factor receptor 2 (HER2) status, and level of the cell proliferation marker Ki67 (Table 1).^3,4 The breast cancer subtype, determined via biomarker testing, often has diagnostic and prognostic relevance and, particularly in the case of HER2 status, drives treatment decisions (Figure 1).^3,4

TABLE 1.

Breast Cancer Subtypes^3,4,22

Subtype	HR		HER2	Ki67	Incidence/ 100,000	5-Year relative survival
	ER	PR				Local	Regional	Distant
Luminal A	Either or both +		-	Low	91.3	100%	90.8%	36.5%
Luminal B	Either or both +		-	High
	Either or both +		+	Any	12.3	99.5%	91.0%	46.7%
HER2+	-	-	+	n/a	5.1	97.7%	85.4%	40.8%
Triple-negative	-	-	-	n/a	13.9	92.4%	67.5%	14.9%

ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; HR = hormone receptor; Ki67 = cell proliferation marker; PR = progesterone receptor.

FIGURE 1.

Fundamentals of Biomarker Testing in Oncology^18–21

Adapted from Biomarker Testing: Breaking Down the Terminology and Cancer Biomarkers - Emerging Trends and Clinical Implications for personalized treatment, Table 1.

ctDNA = circulating tumor DNA; FISH = fluorescence in situ hybridization; GEP = gene expression profiling; IHC = immunohistochemistry; NGS = next-generation sequencing; PCR = polymerase chain reaction.

For the most common subtype, HR+/HER2−, the current standard first-line regimen for metastatic disease is combination treatment with a cyclin-dependent kinase (CDK) 4/6 inhibitor and endocrine therapy (ET) with an aromatase inhibitor, a selective estrogen receptor degrader (SERD), or a selective estrogen receptor modulator (Table 2).^5–8 Appropriate second-line treatment for HR+/HER2− metastatic breast cancer is less straightforward. Planning for management of advanced disease generally focuses on maximizing benefit, minimizing toxicity, and preserving future options.^5,6 This requires integration of clinical trial and real-world data, previous response and duration of response to adjuvant and first-line therapy, comorbidities, patient status, and patient needs.^5,6

TABLE 2.

Commonly Used FDA-Approved Therapies in ER+/HER2− Metastatic or Advanced Breast Cancer^23,24

Drug classa	Mechanism of action	Generic (brand)	Route of administration	Select potential adverse events
Aromatase inhibitorsb	Prevents the conversion of androgens to estrogens, resulting in a reduction of estrogen biosynthesis in all tissues.	Anastrozole (Arimidex)	Oral	Hot flashes, nausea, asthenia, pain, headache, back pain, bone pain, cough, dyspnea, pharyngitis, peripheral edema
		Exemestane (Aromasin)	Oral	Hot flashes, nausea, fatigue, sweating, increased appetite
		Letrozole (Femara)	Oral	Hot flashes, flushing, asthenia, edema, arthralgia, headache, dizziness, hypercholesterolemia, sweating, bone pain, musculoskeletal pain
CDK 4/6 inhibitors	Inhibits CDK 4 and 6, and thus progression of the cell cycle from G1 into S phase, resulting in decreased proliferation of ER-positive breast cancer cell lines.	Abemaciclib (Verzenio)	Oral	Diarrhea, neutropenia, nausea, abdominal pain, infections, fatigue, anemia, leukopenia, decreased appetite, vomiting, headache, alopecia, thrombocytopenia
		Palbociclib (Ibrance)	Oral	Leukopenia, neutropenia, elevated CK, anemia, thrombocytopenia, infections, transaminitis, fatigue, nausea, stomatitis, diarrhea, alopecia
		Ribociclib (Kisqali)	Oral	Leukopenia, neutropenia, anemia, lymphopenia, transaminitis, elevated GGT, infections, nausea, elevated CK, fatigue, thrombocytopenia, diarrhea, vomiting, headache, constipation, alopecia, cough, rash, back pain, hypoglycemia
GnRH agonists	Inhibits gonadotropin secretion, leading to a decrease in serum estradiol and regression of hormone-responsive tumors.	Goserelin (Zoladex)	Subcutaneous implant	Hot flashes, headache, sweating, acne, emotional lability, depression, decreased libido, vaginitis, breast atrophy, seborrhea, peripheral edema
		Leuprolide (Lupron)	Intramuscular/ subcutaneous injection	Hot flashes/sweats, headache/migraine, vaginitis, depression/emotional lability, general pain, weight gain/loss, nausea/vomiting, decreased libido, dizziness
		Triptorelin (Trelstar, Triptodur)	Intramuscular injection	Hot flashes, skeletal pain, headache, leg edema, leg pain, erectile dysfunction, testicular atrophy. injection site reactions, vaginal bleeding, cough, infections
HER2-neu inhibitors	Inhibits phosphorylation of HER2/HER3, resulting in inhibition of downstream MAPK and AKT signaling and cell proliferation.	Capivasertib (Truqap)	Oral	Diarrhea, cutaneous reactions, hyperglycemia, lymphopenia, anemia, nausea, fatigue, leukopenia, hypertriglyceridemia, neutropenia, elevated CK, vomiting, stomatitis
		Lapatinib (Tykerb)	Oral	Diarrhea, palmar-plantar erythrodysesthesia, nausea, rash, vomiting, fatigue
		Neratinib (Nerlynx)	Oral	Diarrhea, nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, muscle spasms, dyspepsia, transaminitis, nail disorder, dry skin, abdominal distention, epistaxis, weight decreased, urinary tract infection
		Tucatinib (Tukysa)	Oral	Diarrhea, palmar-plantar erythrodysesthesia, nausea, hepatotoxicity, vomiting, stomatitis, decreased appetite, anemia, rash, fatigue, abdominal pain, pyrexia
mTOR inhibitors	Inhibits mTOR downstream of the PI3K/AKT pathway, leading to decreased cell proliferation.	Everolimus (Afinitor, Afinitor DISPERZ)	Oral	Stomatitis, infections, rash, fatigue, diarrhea, edema, abdominal pain, nausea, fever, asthenia, cough, headache, decreased appetite
PARP inhibitors	Inhibits PARP enzymes, resulting in DNA damage, decreased cell proliferation, and apoptosis.	Olaparib (Lynparza)	Oral	Nausea, fatigue/asthenia, anemia, vomiting, diarrhea, decreased appetite, headache, dysgeusia, cough, neutropenia, dyspnea, dizziness, dyspepsia, leukopenia, thrombocytopenia
		Talazoparib (Talzenna)	Oral	Anemia, neutropenia, lymphopenia, thrombocytopenia, fatigue, hyperglycemia, transaminitis, elevated ALP, hypocalcemia, nausea, headache, vomiting, alopecia, diarrhea, decreased appetite
PD-1/PD-L1-blocking antibody	Blocks the PD-1/PD-L1 pathway, which inhibits T-cell proliferation and cytokine production.	Pembrolizumab (Keytruda)	Intravenous infusion/ subcutaneous injection	Fatigue, musculoskeletal pain, rash, diarrhea, pyrexia, cough, decreased appetite, pruritus, dyspnea, constipation, pain, abdominal pain, nausea, hypothyroidism
PI3K inhibitor	Inhibits PI3K, leading to reduced cellular proliferation, and apoptosis in PIK3 catalytic alpha-mutated breast cancer cell lines.	Alpelisib (Piqray)	Oral	Hyper-/hypoglycemia, elevated CK, diarrhea, rash, lymphopenia, elevated GGT, nausea, transaminitis, fatigue, anemia, hyperlipasemia, decreased appetite, stomatitis, vomiting, weight decreased, hypocalcemia, prolonged aPTT, alopecia
		Inavolisib (Itovebi)	Oral	Neutropenia, anemia, hyperglycemia, thrombocytopenia, lymphopenia, stomatitis, diarrhea, hypocalcemia, fatigue, hypokalemia, elevated CK, transaminitis, nausea, hyponatremia, hypomagnesemia, rash, decreased appetite, COVID-19 infection, headache
Progestogen	Enhances estrogen metabolism, lowering plasma estrogen concentrations and suppressing estrogen-dependent tumors.	Megestrol	Oral	Nausea, diarrhea, erectile dysfunction, rash, flatulence, hypertension, asthenia
Selective ER degradersb	Binds to ER-alpha, inhibiting 17-beta-estradiol-mediated cell proliferation in ER-positive, HER2-negative breast cancer cells.	Elacestrant (Orserdu)	Oral	Musculoskeletal pain, nausea, vomiting, dyspepsia, hypercholesterolemia, transaminitis, anemia, hypertriglyceridemia, fatigue, hyponatremia, elevated CK, decreased appetite, diarrhea, headache, constipation, abdominal pain, hot flashes
		Imlunestrant (Inluriyo)	Oral	Anemia, musculoskeletal pain, hypocalcemia, neutropenia, transaminitis, fatigue, diarrhea, hypertriglyceridemia, nausea, thrombocytopenia, constipation, hypercholesterolemia, abdominal pain
		Fulvestrant (Faslodex)	Intramuscular injection	Injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot flash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, constipation
Selective ER modulatorsb	Competes with estrogen for binding sites in cancer cells, thereby blocking the growth-stimulating effects of estrogen in the tumor.	Tamoxifen	Oral	Hot flashes, fluid retention, vaginal discharge, nausea, irregular menses, weight loss
		Toremifene (Fareston)	Oral	Hot flashes, sweating, nausea, vaginal discharge
Trop-2-directed antibody and topoisomerase inhibitor conjugate	Binds to Trop-2-expressing cancer cells and prevents the re-ligation of topoisomerase I-induced single-strand DNA breaks, leading to apoptosis and cell death.	Datopotamab deruxtecan (Datroway)	Intravenous infusion	Stomatitis, nausea, fatigue, leukopenia, hypocalcemia, alopecia, lymphopenia, anemia, constipation, neutropenia, dry eye, vomiting, transaminitis, keratitis, elevated ALP
		Sacituzumab govitecan (Trodelvy)	Intravenous infusion	Leukopenia, neutropenia, anemia, diarrhea, nausea, lymphopenia, fatigue, alopecia, constipation, hyperglycemia, hypoalbuminemia, vomiting, decreased appetite, decreased CrCl, elevated ALP, hypomagnesemia, hypokalemia, hyponatremia

^a As listed in the Clinical Pharmacology drug database.

^b Endocrine therapies.

AKT = a serine/threonine protein kinase; ALP = alkaline phosphatase; aPTT = activated partial thromboplastin time; CDK = cyclin-dependent kinase; CK = creatinine kinase; CrCl = creatinine clearance; DNA = deoxyribonucleic acid; ER = estrogen receptor; FDA = US Food and Drug Administration; GGT = gamma glutamyl transferase; GnRH = gonadotropin releasing hormone; HER = human epidermal growth factor receptor; MAPK = mitogen-activated protein kinase; mTOR = mammalian target of rapamycin; PARP = poly-ADP ribose polymerase; PD = programmed death; PD-L = programmed death ligand; PI3K = phosphatidylinositol-3 kinase; Trop = trophoblast cell-surface antigen 2.

Although some patients may benefit from continuing a CDK4/6 inhibitor following radiologic progression, biomarker-guided therapy is becoming more common.^5,6 An important element of biomarker testing following radiologic progression on first-line therapy is to determine the presence of acquired resistance to ET.^6–9 One relatively common mechanism of resistance is mutation of the estrogen receptor alpha gene (ESR1m), which, according to a recent retrospective cohort study, occurred in 45% (686/1511) of patients.¹⁰ Recommended treatment for patients with ESR1m advanced breast cancer (aBC) following at least 1 line of ET is a second-generation SERD (elacestrant, imlunestrant), as they have demonstrated efficacy in the presence of this mutation.^7,9,11,12

Given these advances, there is increasing interest in methods of detecting the ESR1m earlier—prior to radiologic evidence of progression—allowing a switch to a more effective ET while maintaining CDK 4/6 inhibition, thus delaying progression and treatment with a more toxic antibody drug conjugate or chemotherapy (Table 2).¹³ A phase 3, randomized trial (PADA-1), for example, assessed the clinical validity of serial, real-time monitoring of ESR1m in circulating tumor DNA (ctDNA).^13,14 The PADA-1 trial demonstrated that early switching to the US Food and Drug Administration (FDA)–approved, first-generation SERD fulvestrant plus the CDK 4/6 inhibitor palbociclib upon detection of a newly emergent or rising ESR1m resulted in a significant improvement in progression-free survival (PFS) vs continued aromatase inhibitor plus palbociclib (median [m] PFS = 11.9 vs 5.7 months; hazard ratio [HR] = 0.61, P = 0.0040) and vs switching to fulvestrant plus palbociclib upon evidence of disease progression (mPFS = 3.5 months).^13,14

Building on the findings from PADA-1, the phase 3 SERENA-6 trial was designed to assess the clinical utility of ctDNA-based monitoring for the detection of emerging ESR1m in patients on standard therapy (aromatase inhibitor plus CDK 4/6 inhibitor for at least 6 months) and evaluate the benefit of early ET modification to the investigational, next-generation SERD, camizestrant.^13,15 The ctDNA-guided treatment modification significantly improved PFS compared with continued standard therapy (mPFS = 16 vs 9.2 months; HR = 0.44, P < 0.0001) and a delayed deterioration of patient-reported global health status and quality of life (median time to deterioration = 23 vs 6.4 months; HR = 0.53).^13,15 However, questions remain regarding the broader applicability and optimization of this approach, and more data such as long-term outcomes and cost-effectiveness analyses are necessary to support its integration into routine practice.¹³

Panel Description

To discuss approaches to managing ESR1m aBC including ctDNA-based monitoring, AMCP Market Insights virtually convened an expert panel of managed care stakeholders in February 2026. Market Insights panels comprise at least 1 practicing clinician and several executive managed care pharmacy decision-makers. All panelists are recruited by AMCP based on their relevant experience. This panel included an oncologist/hematologist with a focus on treating breast cancer, a board-certified oncology pharmacist working in a community oncology practice, an individual with breast cancer who also leads a patient advocacy organization, and representatives from health plans (n = 2), pharmacy benefit managers (n = 2), an integrated delivery network, and a digital prior authorization solution for payers.

In the moderated 4-hour panel discussion, panelists examined unmet needs from both the clinician and patient perspective in HR+/HER2− metastatic breast cancer, the value of biomarker testing including routine biomarker monitoring in advanced HR+ breast cancer, and recent clinical advancements with SERDs including the PADA-1 and SERENA-6 trials. Panelists reviewed presentations on each topic, which were followed by discussions prompted by polling questions and a structured discussion guide. All program materials were developed in advance by AMCP.

The panel session was recorded and transcribed, and polling question results were documented. These were manually analyzed for themes and relevant examples and actions. This article provides a qualitative summary of the panel discussion including key insights (Figure 2) and suggested payer practices (Table 3). Consensus was not sought, and where perspectives differed, it is noted in the text. All authors, including panelists who elected to be authors (n = 8), reviewed the findings.

FIGURE 2.

Key Insights From the AMCP Market Insights Panel

aBC = advanced breast cancer; ctDNA = circulating tumor DNA; ESR1m = estrogen receptor alpha gene mutated; SERDs = selective estrogen receptor degraders.

TABLE 3.

Payer Practices in ESR1-Mutated Advanced Breast Cancer Suggested by the AMCP Market Insights Panel

Action	Description
Care delivery
Develop an advocacy list to empower patients	This should include a list of questions patients need answered to gather the information that is most useful to them along each stage of the cancer care journey (eg, diagnosis, prognosis, treatment, monitoring). It could be developed, for example, through a collaboration between organizations (eg, professional organizations, patient advocacy organizations). Patient tools such as this should be unbranded and generalizable to the extent possible and should take SDOH into account.
Provide care coordinators	Patient navigators or other care coordinators can support patients and help overcome care fragmentation. These individuals should be engaged as an integral part of the care team such as by ensuring they attend all meetings or discussions covering individual patient care issues.
Coverage
Implement treatment pathways	Treatment pathways help support community oncology practice including equitable, financially sustainable biomarker testing. Consider incorporating guidance from external sources (eg, treatment guideline developers, practicing clinicians, biopharmaceutical manufacturers, partner organizations) to develop treatment pathways.
Consider real-world evidence in decision-making	Real-world evidence may be particularly useful when outcomes can be confirmed within a specific payer population and to provide total cost-of-care information. Collaborating with biopharmaceutical manufacturers who have experience with methodologies to analyze data can be helpful.
Align medical, laboratory testing, and pharmacy coverage policies	Alignment aids consistency and can prevent delays in care. It requires collaboration between internal payer teams and with relevant external stakeholders (eg, laboratory benefit managers, specialty pharmacies) and patient navigators or other care coordinators.
Streamline prior authorization processes	For example, creating a checklist of information necessary for coverage review, implementing auto-approvals, extending authorization duration (eg, from 12 to 24 months), and allowing gold carding.
System advancements
Engage in multistakeholder conversations	This could be through an advisory group or other forum and can increase understanding of other perspectives, help surface challenges, and offer an opportunity to develop solutions.
Advocate for, or participate in, evidence generation	Examples discussed include data to guide dose reductions to alleviate toxicities for patients and evidence for the applicability, optimal cadence, and additional cost of ctDNA-based monitoring.

ctDNA = circulating tumor DNA; ESR1 = estrogen receptor alpha gene; SDOH = social determinants of health.

These findings are intended to support informed coverage decisions and offer practical actions for payers. Although they may be used to inform future work, they should not be construed as original empirical research.

Care Delivery in HR+/HER2− Advanced Breast Cancer

Key insight: Community oncologists must treat multiple cancer types and may benefit from support such as treatment pathways and improved information flow with payers.

Participants emphasized that community oncologists must treat multiple cancer types, which requires staying current with a rapidly expanding clinical evidence base, including increasingly sophisticated and specific guidance for biomarker-driven treatment. Education comes from multiple sources including biopharmaceutical manufacturers, professional organizations, clinical treatment and biomarker testing guidelines, and conferences. However, micro-level knowledge specific to a particular cancer type, such as resistance biology and sequencing logic in HR+/HER2− aBC, is more commonly concentrated among specialized oncologists compared with generalists. Participants suggested payers can be partners in the support of community oncologists by implementing evidence-based treatment pathways—protocols for delivering cancer care—which bring together a range of clinical and evidentiary sources and provide a blueprint for appropriate use of resources.¹⁶

Participants also discussed that information flow between clinicians and payers is a challenge and contributes to delays in care. Clinicians, for example, expend resources to manage prior authorization requests, which requires navigating each payer’s coverage criteria over multiple benefits, including medical, laboratory, and pharmacy benefits, as well as dispensing via multiple specialty pharmacies. Payers generally do not have access to the patient-level data needed to review prior authorization requests but must rely on clinical staff to send correct, timely information.

Participants suggested payers can create a checklist of information necessary for coverage review to streamline the authorization process. They also indicated that many payers are already working to reduce prior authorization burden through practices such as auto-approvals (eg, for requests in concordance with biomarker testing guidelines), extending authorization duration (eg, from 12 to 24 months), and allowing gold carding, which relaxes prior authorization requirements for providers who have a demonstrated history of complying with coverage criteria.¹⁷

Collaboration between stakeholders including payers and employer groups, clinicians, and other organizations to share data, knowledge, and best practices was also recommended by participants to mitigate delays in care. Advisory groups or other forums for multistakeholder conversations can increase understanding of other perspectives, help surface challenges, and offer an opportunity to develop solutions. Knowledge sharing may also be facilitated by compiling available data into a dossier, which offers biopharmaceutical manufacturers a framework for presenting data to formulary decision-makers.

Key insight: Patients care about survival outcomes when combined with sustained quality of life, and they want monitoring practices that take patient-specific considerations into account.

The oncologist and patient participants indicated that current regimens, especially aromatase inhibitors, provide survival gains for many patients with HR+/HER2− breast cancer but are associated with toxicities, affecting both mental and physical health and, ultimately, quality of life. Although payers often value survival outcomes as the gold standard for oncology treatments, patients and clinicians emphasize the importance of survival outcomes when combined with sustained quality of life, including the ability to participate in major life milestones. Other outcomes of particular interest to patients are those related to making them feel or look sick, for example, time to pain or time to chemotherapy initiation.

Participants discussed that toxicities are often accepted as an expected outcome of treatment in oncology. They encouraged challenging this perspective as unmanaged toxicities not only impact patient quality of life but also contribute to discontinuation and progression risk. Participants additionally advocated for more data to guide dose reductions in aBC treatments to alleviate toxicities while maintaining efficacy.

Participants also discussed that routine monitoring is most often done with a standard cadence of radiologic scans and that biomarker testing also generally follows a standard protocol such as once at baseline and once upon evidence of radiologic progression. The patient participant underscored that radiologic scans are burdensome to patients and can cause distress during the wait for results or when areas to watch appear; therefore, some patients may prefer less burdensome monitoring such as ctDNA-based monitoring with a liquid biopsy that can be done at regular appointments. Some patients may also prefer more frequent monitoring, for example, to have more information about how their disease may be changing. Still, many clinicians continue to follow standard monitoring protocols vs considering individual patient needs or preferences even at large, certified cancer centers.

Key insight: Patients need accessible, actionable information and support to participate more fully in shared decision-making and overcome care fragmentation.

The oncologist participant emphasized that, ideally, there would be an informed discussion with each patient regarding their treatment and monitoring plan as part of shared decision-making. This discussion might include, for example, the purpose, evidence, and risks and benefits for different monitoring practices and why more frequent monitoring is appropriate for some patients and not for others. According to the patient participant, patients struggle with accessing and synthesizing the knowledge they need to fully participate in shared decision-making. Many organizations have information available, but navigating that information may not be feasible for every patient. For example, it requires collecting large amounts of complicated, often technical information from multiple sources, not all of which may be relevant to the individual.

Participants suggested empowering patients with an advocacy list of questions they need answered to gather the information that is most useful to them along each stage of the care journey (eg, diagnosis, prognosis, treatment, monitoring). This could be developed, for example, through a collaboration between organizations including professional organizations representing oncologists, pharmacy, and nursing, and patient advocacy organizations. Participants emphasized that patient tools such as this should be organizationally agnostic and generalizable to the extent possible and should take social determinants of health into account.

Participants also discussed that patients need additional support from within the health care system such as with a patient navigator or other care coordinator to overcome care fragmentation. One participant organization, for example, offers a pharmacy concierge team who provides white glove service to assist patients with navigating all aspects of their cancer care journey, especially issues that arise. The patient participant underscored that organizations should work to make care coordinators such as these more effective given that different organizations and types of stakeholders have their own infrastructure and practices that must be navigated. Participants suggested this may be accomplished by engaging care coordinators as an integral part of the care team such as ensuring they attend cross-functional status meetings or other similar discussions covering individual patient care issues.

Payer Considerations for Coverage of Biomarker Testing in Advanced HR+ Breast Cancer

Key insight: A primary consideration of payers in aBC is that the optimal biomarker testing parameters are uncertain, which leads to inconsistent testing practices and the need for management that promotes consistency while mitigating delays in care such as via treatment pathways.

Payer participants noted a primary consideration in aBC is that optimal biomarker testing parameters are uncertain and suggested that treatment pathways can improve consistency in biomarker testing practices, which may help ensure appropriate testing that is equitable and financially sustainable. Creating useful treatment pathways that maintain the flexibility to address patient-specific needs requires evidence and expertise. Because of limited internal resources and the need for synthesis of a large amount of evolving clinical evidence in oncology, payer participants indicated they often seek guidance from external sources to assist with developing treatment pathways and coverage policies and maintaining evidence-based formularies. External sources may include clinical treatment guideline developers, practicing clinicians, and biopharmaceutical manufacturers, for example. Some payers may also enlist assistance from partner organizations such as those who specialize in pathway development or provide other cancer care management services.

Participants discussed the role of real-word evidence in developing treatment pathways and coverage policies. In general, they indicated that payers often consider it as part of the body of evidence but that it may not drive decision-making. Payer participants acknowledged that the ability to confirm real-world outcomes within their own population provides greater confidence in the data; however, many biomarker outcomes do not have specific diagnostic codes and may represent a relatively small number of patients, which makes this challenging. Collaborating with biopharmaceutical manufacturers who have experience with methodologies to analyze data can be helpful, according to participants. Outcomes of interest include, for example, time to progression, quality-of-life duration, exposure to ineffective therapies and their toxicities, time to chemotherapy initiation, and complications and hospitalizations.

Participants also highlighted the need for alignment between medical, laboratory testing, and pharmacy policies to promote consistency while mitigating delays in care. This requires collaboration and coordination between the internal payer teams developing the policies and with relevant external stakeholders such as laboratory benefit managers and specialty pharmacies. Additionally, participants recommended that patient navigators or other care coordinators need to be involved to bring the provider and patient together with the health plan and other benefit managers.

Key insight: Although early switching guided by ctDNA-based monitoring for ESR1m aBC shows promise, there remains uncertainty regarding the applicability, optimal cadence, and additional cost of this approach.

Participants discussed that clinically, biomarker testing is useful at baseline to make decisions regarding unchangeable disease characteristics and again at some point later in the disease course, for example, following evidence of radiologic progression to determine the presence of ET resistance mechanisms (eg, ESR1m) to guide treatment switching. Currently, this is a typical approach supported by biomarker testing guidelines.⁷ The emerging practice of ctDNA-based monitoring to detect changes and switch to a more effective treatment earlier offers potential clinical and cost-of-care benefits if it results in improved PFS and delaying treatment with more toxic therapies. However, there remains uncertainty regarding the applicability, optimal cadence, and additional cost of this approach.

Payer participants expressed concern with regular, potentially costly testing if it does not result in actionable information for making treatment decisions. Considerations specific to the applicability of ctDNA-based monitoring include whether ctDNA is the best marker to predict progression and how to identify the appropriate patient population to receive it, such as those who may be at higher risk of ET resistance or rapid progression. Additionally, the optimal frequency of testing is unclear. Because some providers may do more testing than others, participants agree setting limits is reasonable but that they need a biological or clinical rationale and the current data are not sufficient to support specific parameters (eg, testing frequency or number of tests in a given period).

Participants also recognized that although the cost of additional biomarker testing may not be realized by the provider or patient, it could be a cost-of-care consideration for payers including employer groups. Payer participants, therefore, see value in confirming the impact of this intervention on total cost of care with real-world evidence, especially in oncology, where there is already considerable sensitivity to cost. They underscored the need to not only analyze the cost of additional testing but also compare the total cost of current and emerging testing and treatment paradigms including any cost savings or cost avoidance achieved, as well as the potential impact of high-cost therapies in the therapeutic pipeline.

The Role of Next-Generation SERDs in HR+ Advanced Breast Cancer

Key insight: The role of next-generation SERDs is evolving. The current data for early switching in ESR1m aBC are promising, but gaps remain. There are also ongoing clinical trials evaluating next-generation SERDs in the adjuvant and first-line settings.

Clinical treatment guidelines currently recommend next-generation SERDs for ESR1m aBC following progression on first-line therapy; however, participants discussed that their role is evolving.⁷ The available data for early switching in ESR1m aBC are promising, but gaps remain. For example, although early switching in the SERENA-6 trial demonstrated both a PFS benefit and a quality-of-life benefit, the trial did not evaluate early switching vs switching at radiologic progression like the PADA-1 trial, and overall survival data are still immature. There are also uncertainties about optimal monitoring for early switching using ctDNA as discussed above.

Additionally, there are ongoing clinical trials evaluating next-generation SERDs in the adjuvant and first-line settings without regard for ESR1m status. From the clinician participant perspective, these data—for example, the positive toxicity profile of next-generation SERDs vs aromatase inhibitors—will likely result in shifting the place in therapy of the next-generation SERDs to the standard of care. From the payer participant perspective, evidence is the foundation of decision-making. They require evidence of safety and efficacy—ideally overall survival coupled with PFS or recurrence-free or disease-free survival—as well as tolerability. The evolution of clinical treatment guidelines is also important to support a place in therapy change.

Most payer participants indicated that in the current treatment paradigm, all SERDs are likely to be on the formulary with coverage criteria that aligns with the clinical trial inclusion/exclusion criteria and product labeling to ensure use in the appropriate patient population. Approval will likely require, for example, documentation of diagnostics and presence of an appropriate biomarker, documentation of outcomes on any prior therapies, and evidence of progression at the time of switch, if relevant. As more SERDs come to market, payers may begin to consider other strategies such as contracting and preferencing, for example, based on approved indications and indirect comparison, and requiring access through specialty pharmacies.

Summary

Detection of the ESR1m prior to radiologic progression using ctDNA-based monitoring is an emerging practice that may allow an early switch to a more effective therapy. This AMCP Market Insights article describes a discussion among an expert panel of managed care stakeholders on approaches to managing ESR1m aBC including ctDNA-based monitoring. Key insights relate to patient and provider support in advanced HR+ breast cancer, and payer considerations regarding biomarker testing coverage and the evolving role of next-generation SERDs.

Opportunities suggested by participants include interventions to support community oncologists with treatment pathways and to empower and support patients with tools and care coordinators. Other suggested practices for payers are to consider real-world evidence in decision-making, align coverage policies across benefits, and streamline prior authorization processes. Payers can also engage in multistakeholder conversations such as advisory groups and advocate for, or participate in, evidence generation.

Although panel-based insights such as these are associated with limitations, for example, because of their small sample size and subjectivity, these findings can support informed coverage decisions and guide future work.

Disclosures

Dr Flavin discloses payment from AMCP for the preparation of this manuscript and employment at University of Florida College of Pharmacy. Dr Tweed discloses consulting fees from AstraZeneca and participation in the US Steering Committee for camizestrant. Dr Evans discloses honoraria from AMCP and Impact Education, LLC. Dr Fleszar discloses honoraria from AMCP and an unpaid role in developing a manuscript in collaboration with the Hematology/Oncology Pharmacy Association. Dr Hanna discloses honorarium from AMCP and employment as an associate editor for the Journal of the Advanced Practitioner in Oncology. Dr Richardson discloses payment to Impact Education, LLC, from AMCP for support of this program. Dr Wolff discloses payment from AMCP for moderating this Market Insights. Drs Gandhi, Haumschild, and O’Shea and Ms Valbh disclose honoraria from AMCP for participation in this program.

AMCP conducted this Market Insights and conceptualized this supplement with funding provided by AstraZeneca. AstraZeneca manufactures and/or markets capivasertib (Truqap), datopotamab deruxtecan (Datroway), fulvestrant (Faslodex), goserelin acetate implant (Zoladex), olaparib (Lynparza), and trastuzumab deruxtecan (Enhertu), which are currently FDA approved for breast cancer. AstraZeneca is also developing camizestrant, a next-generation selective estrogen receptor degrader, and saruparib, a poly-ADP ribose polymerase inhibitor, for treatment of breast cancer.

AMCP Market Insights is a nonpromotional, sponsor-supported initiative designed to support informed clinical and coverage decisions across a range of disease states and therapeutic areas. AMCP independently recruits participants who represent multiple perspectives, which may include those of health plans, integrated delivery networks, pharmacy benefit managers, employer benefit consultants, specialty pharmacies, and patient advocacy organizations, among others. AMCP independently manages all aspects of program execution and deliverables to ensure unbiased, balanced content. Sponsors participate in the initial planning to define program objectives and potential participants.