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HR+, HER2- Metastatic Breast Cancer

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Overview

1L Treatment

Unmet Needs

ESR1m

ET Advancements

Unmet Needs and 2L Treatment

Mechanisms of Resistance to 1L Treatment for Patients With HR+, HER2- MBC

Endocrine therapy (ET) + cyclin-depending kinase 4/6 inhibitor (CDK4/6i) is the first-line (1L) standard of care in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2-) metastatic breast cancer (MBC)1; however, despite efficacy in treatment, disease progression inevitably occurs. There are multiple mechanisms of resistance to ET ± CDK4/6i.2,3

Pathways for ET resistance and kinase resistance for patients with estrogen receptor-positive, HER2-negative MBC. Pathways for ET resistance and kinase resistance for patients with estrogen receptor-positive, HER2-negative MBC.

ET resistance may be due to amplification of FGFR1, activation of PI3K/AKT/mTOR pathway, and/or mutated ESR1; kinase resistance may be due to CDK4/6 activation and/or CDK6 amplification, retinoblastoma gene loss of function, activation and overexpression of TK1, or activation of cyclin E-CDK2 axis and/or overexpression of CCNE1, 2, or CDK2.4

Lack of Consensus on Treatment Upon Disease Progression

After disease progression or recurrence on 1L ET ± CDK4/6i, no consensus on an optimal treatment strategy for HR+, HER2- MBC has been reached.1-3 Treatments utilized in the clinic include ETs, targeted therapies, and nontargeted agents.1-3,5

Three treatment classes for patients with HR-positive, HER2-negative MBC who progress on ET alone, or in combination with CDK4/6i. Three treatment classes for patients with HR-positive, HER2-negative MBC who progress on ET alone, or in combination with CDK4/6i.

Treatments for patients with HR-positive, HER2-negative MBC who progress on ET alone, or in combination with CDK4/6i, include ETs, targeted therapies, and nontargeted agents. ETs include aromatase inhibitors, selective estrogen receptor modulators, and selective estrogen receptor degraders; targeted therapies include AKT inhibitors, CDK4/6i, mTOR inhibitors, PARP inhibitors, and PI3K inhibitors; and nontargeted therapies include antibody-drug conjugates and chemotherapy.1-3,5

Several Limitations Exist for All 3 Classes of Approved Therapies

Let’s review the limitations associated with ETs, targeted therapies, and nontargeted therapies in the second-line (2L) setting. The efficacy of ET is impacted by prior ET and limited in the contemporary therapeutic landscape.6-8 Targeted therapies are subject to tolerability concerns and the efficacy is dependent on treatment history.1,3,5 In addition, the use of targeted therapies is limited by a lack of universal access to genomic testing and may be restricted to specific biomarker-selected subgroups.3 Nontargeted agents have significant toxicities, and poor quality of life is associated with chemotherapy.1,5,9


Limitations of ET

Although ET is a tolerable strategy targeting the primary driver of HR+, HER2- MBC, limitations exist.1,3,4,6,8,10-15 Novel therapeutic approaches are needed to overcome limitations of current ET options.

Table displaying limitations associated with AIs, SERMs, and SERDs. Table displaying limitations associated with AIs, SERMs, and SERDs.

Limitations associated with AIs, SERMs, and SERDs1,3,4,6,8,10-15:

  • Exposure leads to ESR1 mutations: AIs
  • ESR1 mutation impacts efficacy: AIs, SERMs, SERDs (Intramuscular injection [IM])
  • Partial ER agonism: SERMs
  • Fluctuations in oral drug absorption due to gastrointestinal (GI) physiology, possibly resulting in transient autocrine ER signaling: AIs, SERMs, SERDs
  • Inferior pharmacokinetics (PK) and additional clinic visits: SERDs (IM)
  • Additional toxicities and resistance mechanisms when combined with targeted therapies: AIs, SERMs, SERDs (IM)

Unmet Needs for Patients With HR+, HER2- MBC

The treatment goal for patients with HR+, HER2- MBC is to extend survival, alleviate symptoms, and improve quality of life.1 Despite the utility of 1L treatment, patients still experience progression.1-3

HR+, HER2- MBC Unmet Needs
Medical notebook
Despite the utility of 1L treatment, patients still experience progression
Map with location pinned
There are limitations with 2L therapies and no defined treatment strategy
Magnifying glass
Within the incurable disease setting of MBC, research is ongoing
Doctor discussing 2L therapeutic approaches with a patient.
As healthcare providers, it is important to understand the unmet needs that exist for patients with HR+, HER2- MBC who have progressed on 1L standard of care.

Novel therapeutic approaches are needed to overcome limitations of current therapies, and research is ongoing. Additional information can be found in the resources below.

Related Resources

Downloadable PDFs

Download PDF Medical Answer PDF Document Created with Sketch. DECK: Overview of ER+, HER2-, ABC including ER-Targeted Therapies

This slide deck provides an overview of the ER+, HER2- advanced breast cancer landscape, including information on ER targeted therapies, mechanisms of resistance to ET ± CDK4/6 inhibitors, & scientific advancements in the form of next-generation ETs.

Download PDF Medical Answer PDF Document Created with Sketch. INFOGRAPHIC: Navigating Treatments After ET + CDK4/6is and ET Limitations in ER+ HER2- ABC

This infographic summarizes the complex treatment landscape after progression or recurrence on ET+ CKD4/6 inhibitors in ER+, HER2-, ABC and the limitations for the 3 main classes of approved ETs.

Download PDF Medical Answer PDF Document Created with Sketch. INFOGRAPHIC: Bridging the Gap: Unmet Needs for Patients in 2L HR+, HER2- MBC

This infographic summarizes the unmet needs for patients with HR+, HER2- MBC who progress on 1L SOC.



(00:00) Light music and animation

(00:15) Lower thirds title animates on as speaker responds to title card prompt. Music fades.

For hormone receptor–positive (HR+), HER2-negative (HER2-) metastatic breast cancer (MBC) patients in the first-line (1L) setting, the standard clinical practice is to use a CDK4/6 inhibitor (CDK4/6i) in combination with endocrine therapy (ET). In the second-line (2L) setting, once a patient's disease progresses, the selection of 2L treatment options is more nuanced and depends on several factors.

(00:37) Music swells. Question animates on screen. Drops to reveal speaker.

Once patients' HR+, HER2- MBC progresses on 1L treatment, which is usually a CDK4/6i plus ET, the choice in the 2L setting is based on the patient's overall health, on their prior ET agent, and their response to prior treatments, among other factors. For patients with HR+, HER2- MBC with visceral crisis, chemotherapy is recommended, but for other patients, cytotoxic chemotherapy is deferred to later lines until we've really exhausted all other ET options.

(01:19) Music swells. Question animates on screen. Drops to reveal speaker.

When patients with HR+, HER2- MBC disease progresses on their 1L CDK4/6i plus ET, the treatment decision around what to recommend in the 2L setting should be based on biomarker testing. For example, it's very important that we have a biopsy in the metastatic setting, if at all possible, to have [the patient] checked for HR status and HER2 expression. I think it's also very important at that juncture to send tissue, as well as circulating tumor DNA, for next-generation sequencing to look for actionable mutations, such as an ESR1 mutation or a PIK3CA, PTEN, or AKT mutation, germline and somatic BRCA1/2 mutations, as well as others. With molecular information in hand about the HR+, HER2- MBC patient whose disease has progressed on 1L CDK4/6i therapy plus ET, we have a range of options now that opens up to the patient. Some of the key ones are a SERD, intramuscular or oral, an inhibitor of the PI3K/AKT/PTEN pathway, or potentially for some patients, a CDK4/6i, if it has not been already used in the 1L setting. Importantly, current guidelines recommend at least 3 sequential ET regimens in the metastatic setting before giving consideration to cytotoxic therapies.

(02:53) Music swells. Question animates on screen. Drops to reveal speaker.

MBC, unfortunately, remains incurable and thus patients need effective therapies in the 2L setting and beyond. It's important to consider the patient's quality of life, so it's highly desirable to develop new therapies that have minimal adverse event burden. There's a need for better treatment strategies that can prolong the time on ET before the use of cytotoxic chemotherapy is considered.

(03:24) Music swells. Question animates on screen. Drops to reveal speaker.

Fulvestrant was the first approved SERD and has benefited patients for over 20 years. Fulvestrant, while providing benefits to patients, has certain limitations. Poor solubility requires intramuscular administration by a healthcare professional at a medical office. Over the years, we've learned that fulvestrant's efficacy is dose dependent. Due to its formulation, there's a limit to how much fulvestrant can be administered. While there was research interest in developing fulvestrant in the adjuvant setting, it was ultimately seen as impractical to give a monthly injection in the adjuvant setting. Oral SERDS are beginning to enter our practice as they provide consistent pharmacokinetics and favorable drug-like properties.

(04:13) Music swells. Question animates on screen. Drops to reveal speaker.

There are patients with HR+, HER2- MBC whose disease has progressed on 1L CDK4/6i and ET where we find, on circulating tumor DNA, an ESR1 mutation. ESR1 mutations are clearly a resistance marker for aromatase inhibitors (AIs), particularly in the metastatic setting, but also some patients who have adjuvant AIs will also be found to have ESR1 mutations in the metastatic setting. It's very important that we have therapeutic options that directly inhibit that mutant ESR1 because for some patients, it can be a surrogate marker for ET sensitivity. This has translated into our practice with the approval of the first oral SERD in a biomarker-selected population. Oral SERDs are being studied in ET-sensitive as well as ET-resistant MBC as monotherapy as well as in a variety of combinations. Oral SERDs may also have potential in the early-stage setting and may eventually provide an alternative treatment, a more effective treatment, over our current standards, but may also provide an alternative for patients who are intolerant to AIs. Oral SERDs are being investigated to provide consistent and optimal bioavailability and to offer convenient administration.

Treatment Options in Patients Who Progress on 1L Therapy

Dr Joyce O’Shaughnessy reviews the 2L treatment options for patients with HR+, HER2- MBC and factors that influence treatment decisions.

References

  1. Gradishar WJ, et al. J Natl Compr Cancer Netw. 2023;21(6):594-608.
  2. Chen YS, et al. Expert Opin Investig Drugs. 2023;31(6):515-529.
  3. Zhou FH, et al. Front Cell Dev Biol. 2023;11:1148792.
  4. Al-Qasem AJ, et al. Cancers (Basel). 2021;13(21):5397.
  5. https://www.cancer.org/cancer/types/breast-cancer/treatment.html.. (Accessed April 19, 2024).
  6. Patel R, et a. NP J Breast Cancer. 2023;9(20). doi: 10.1038/s41523-023-00523-4
  7. Kaminska K, et al. Breast Cancer Res. 2021;23:26.
  8. Brett JO, et al. Breast Cancer Res. 2021;23(1):85.
  9. Mayer EL. Am Soc Clin Oncol Educ Book. 2013;9-14. doi:10.14694/EdBook_AM.2013.33.9
  10. Vareslija D, et al. Clin Cancer Res. 2016;22(11):2765-2777.
  11. Allouchery V, et al. Breast Cancer Res. 2018;20(1):40.
  12. Clatot F, et al. Oncotarget. 2016;7(46):74448-74459.
  13. Patel HK, Bihani T. Pharmacol Ther. 2018;186:1-24.
  14. Yu J, et al. Pharmcol Ther. 2022:236:108108. Wardell SE, et al.
  15. Wardell SE, et al. Breast Cancer Res Treat. 2020;179(1):67-77.

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