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HR+, HER2- Metastatic Breast Cancer

ESR1m

ESR1 Mutations Lead to Resistance to ET

Multiple mechanisms lead to resistance to endocrine therapy (ET) ± cyclin-dependent kinase 4/6 inhibitors (CDK4/6i)^1-5; up to 50% of patients with endocrine resistance harbor the ESR1 mutation.⁶

Approximately 20-40% of patients who have received an aromatase inhibitor (AI) for advanced breast cancer (ABC) develop ESR1 mutations⁶
ESR1 mutations induce ligand-independent activation, causing resistance to ET⁶
All ESR1 mutations form in the ligand-binding domain and decrease the binding affinity for selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs)⁶
Constitutive activity is a method by which ESR1 mutations produce resistance. The ESR1-mutated estrogen receptor (ER) auto activates, even in the absence of estrogen, leading to constitutive ER signaling⁶
In addition to constitutive activity, ESR1 mutations may also gain neomorphic and hypermorphic activity⁶

Side-by-side depiction of wildtype ER and ESR1-mutated ER. — *ESR1*-mutated ER auto activates even in the absence of estrogen, leading to constitutive ER signaling.⁶

When and How to Test for ESR1 Mutations

Guidelines recommend routine testing for emerging ESR1 mutations at recurrence or progression on ET in ER-positive (ER+), human epidermal growth factor receptor 2–negative (HER2-) ABC to help identify the appropriate next line of therapy.^1,7,8 Upon disease recurrence in the adjuvant setting, patients should be tested for ESR1 mutations.⁷ Patients who still have ESR1 wildtype on second-line and greater treatment should be retested at subsequent disease progression(s).⁷

Adjuvant therapy

Disease Recurrence
Test at disease recurrence

ABC 1L

Disease Progression
Test at disease progression

ABC 2L

Disease Progression
Retest at subsequent disease progression(s) in patients who remain ESR1 wildtype

ABC 3L+

ESR1 mutations emerge while on treatment (typically AI) and are not usually detected before treatment.^1,7,8 ESR1 mutations are best detected by blood-based, circulating-tumor DNA analyses, which have greater sensitivity and are less invasive than tissue-based testing.^1,7-9

Doctor discussing ESR1-mutation testing with a patient.

Guidelines recommend routine testing for emerging ESR1 mutations at recurrence or progression on ET in ER+, HER2- ABC.

As healthcare providers, understanding when and how to test for ESR1 mutations may help identify the appropriate next line of therapy for patients with metastatic disease. See resources below for more information on ESR1 mutations in the ABC setting.

Related Resources

Downloadable PDFs

DECK: ESR1 Biomarker Testing in Metastatic Breast Cancer

This slide deck provides an overview of the importance of testing for ESR1 mutations in metastatic breast cancer.

INFOGRAPHIC: ESR1_Resistance to Endocrine Therapy

Infographic regarding the role of ESR1m in mediating resistance to estrogen therapy in ER+, HER2- Advanced Breast Cancer

INFOGRAPHIC: ESR1 Testing and Treatement

Infographic regarding the guideline recommendations and appropriate testing methodologies for identifying ESR1m in ER+, HER2- advanced breast cancer

INFOGRAPHIC: Mechanism of Resistance to ETs, ESR1 Mutations and Testing in ER+, HER2-, ABC

This infographic provides an overview of resistance mechanisms against ET; highlighting ESR1 mutations, including when and how to test for these mutations in ER+, HER2-, ABC

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.

(00:00) Light music and animation

(00:10) Lower thirds title animates on as speaker responds to title card prompt. Music fades.

A common clinical challenge in the treatment of hormone receptor–positive (HR+), HER2–negative (HER2-) metastatic breast cancer (MBC) is really the emergence of resistance to endocrine therapy (ET), either alone or in combination with CDK4/6 inhibitors (CDK4/6i). Over 25% of our patients do not respond to ET at first use or develop resistance within 2 years after an initial response. And mechanisms of resistance are really not very well understood and may include many different pathways, including loss of estrogen receptor (ER) expression, emergence of ESR1 mutations, alterations in the expression of genes encoding for aromatase, kinases, and transcription factors, epigenetic modifications, and activation of compensatory signaling pathways. Mutations in the ESR1 gene that encodes the ER may impact efficacy of ETs in patients with HR+, HER2- MBC. And it is really important to understand the mechanisms of endocrine resistance and how that may impact the treatment outcomes after first-line (1L) CDK4/6i therapy in combination with ET.

(01:27) Full-screen graphic. Question moves to Lower Third position. Reveals speaker. Question fades away.

So, as we were discussing, one of the mechanisms of endocrine resistance is the emergence of ESR1 mutations, and we know that point mutations and amplifications in the ligand-binding domain of the ER leads to constitutive activation of this receptor. These mutations stabilize the active conformation of the receptor in the absence of estrogen, resulting in constitutive activity and enhancing cancer growth. ESR1 mutations are not commonly observed in treatment-naïve patients, but they really seem to be acquired due to selective pressure after exposure to 1L aromatase inhibitor therapy.6 In fact, the frequency of ESR1 mutation[s] really rises the longer the patients receive these ETs, with an incidence of up to 50% in patients who are exposed to ET. Growing knowledge of ESR1 mutations has truly motivated the development of novel ETs that might be effective in patients with these mutations.

(02:30) Full-screen graphic. Question moves to Lower Third position. Reveals speaker. Question fades away.

Testing of ESR1 mutations is really critical as identification of these mutations now has therapeutic implications. The ASCO guidelines really recommend routine testing for [the] emergence of ESR1 mutations at recurrence or progression on ET, regardless of the use of CDK4/6i for patients with HR+, HER2- MBC. Detection of ESR1 mutations could be performed on plasma or tissue samples that are obtained at the time of progression. Patients who test negative for ESR1 mutations may be retested at subsequent progressions. A blood-based, circulating tumor DNA assay is preferred for testing of ESR1 mutations because it is noninvasive and certainly has greater sensitivity as compared with tissue-based testing. Disadvantages of tissue-based testing really include that it can be impractical to repeat, it has a longer turnaround time, and [it] may not really reveal tumor heterogeneity. Additionally, sites of metastases may be very difficult to biopsy.

Resistance Mechanisms to ET, Including ESR1 Mutations in HR+, HER2- MBC

In this video, renowned oncologist Dr. Komal Jhaveri discusses mechanisms of endocrine resistance, including an overview of ESR1 mutations and recommendations for testing.

(00:00)
[Light intro music and animation].

(0:12)
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JHAVERI: For patients with HR-positive, HER2-negative metastatic breast cancer, the current standard first-line treatment is endocrine therapy in combination with a CDK4/6 inhibitor. However, despite prolonged survival observed with this treatment, disease progression is inevitable, largely due to endocrine resistance. Now, in this video, we will review mechanisms leading to resistance to standard-of-care therapies for these patients and highlight the pote ntial value ofnovel, newer endocrine agents.

(0:43)
[Divider soft fades on and off to reveal speaker. Text animates on].

JHAVERI: Hormone receptors play a key role in breast cancer pathogenesis and have prognostic implications. Nearly 80% of all breast cancers are ER-positive, and aberrant ER expression and deregulation promotes breast cancer initiation and progression. Endocrine therapy is the backbone treatment for patients with HR-positive breast cancer. However, despite tremendous strides that have been made in the development of endocrine therapies, HR-positive, HER2-negative metastatic breast cancer remains incurable. And for these patients, endocrine resistance inevitably leads to disease progression and death.
In the metastatic setting, there are 2 categories of endocrine resistance. Primary endocrine resistance, which is defined as progression of disease within the first 6 months of first-line endocrine therapy, and secondary or acquired resistance, which is defined as progression of disease after 6 months of initiating endocrine therapy.

(1:53)
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JHAVERI: Resistance to endocrine therapy may develop due to changes in the tumor microenvironment, epigenetic changes, or somatic alterations. Some somatic alterations commonly observed in the metastatic breast cancer associated with endocrine resistance include PIK3CA mutations, ESR1 mutations, FGFR1 amplification, PTEN mutations, or PTEN deletions. Frequency of these alterations in metastatic breast cancer ranges from 10% to approximately 40%. Recent research findings have established a significant role that ESR1 mutations have on endocrine resistance, bringing the ESR1 gene to the forefront of clinical efforts. Mutations in ESR1 gene lead to activation of the ER pathway even in the absence of the estrogen ligand and decrease the binding affinity for drugs such as selective estrogen receptor modulators and selective estrogen receptor degraders.
Notably, the prevalence of these ESR1 mutations in patients with metastatic breast cancer is shown to be affected by prior duration of endocrine therapy, and whether it was received in the neoadjuvant versus adjuvant setting. For patients who have not received any endocrine therapy, the prevalence of ESR1 mutation is less than 1%. Resistance is usually acquired upon exposure to endocrine therapies, particularly aromatase inhibitors. For patients with prior aromatase inhibitor therapy, the prevalence of ESR1 mutation has increased in the order of about 40% to 50%. This is particularly in the metastatic setting.
With an understanding of the therapeutic consequences that ESR1 mutations may have on the treatment efficacy for patients with HR-positive, HER2-negative metastatic breast cancer, guidelines now recommend routine testing for emerging ESR1 mutations at recurrence or progression on endocrine therapy. To determine if ESR1 mutations have emerged, patients whose tumor or ctDNA tests remain ESR1 wild type should be retested at subsequent progression. In addition, tests should be performed on blood or tissue samples obtained at the time of progression, with blood-based ctDNA preferred owing to greater sensitivity.

(4:47)
[Divider soft fades on and off to reveal speaker].

JHAVERI: To summarize, understanding mechanisms by which resistance occurs and how it may impact treatment outcomes is vital for the optimization of treatment plans and development of therapies.8 And to that end, for patients with HR- positive, HER2-negative metastatic breast cancer who recur or progress on endocrine therapy and develop ESR1 mutations, novel endocrine-based regimens are really desired. These therapies aim to provide an efficacy benefit with minimal impact on patients’ quality of life, as well as delaying the time to chemotherapy, including antibody-drug conjugates.

(05:33)
[Light outro music and animation].

Establishing the Unmet Needs for Patients with ESR1 Mutations with Dr. Jhaveri

In this video, Dr. Komal Jhaveri reviews the mechanisms leading to resistance to standard-of-care therapies for patients with HR-positive, HER2-negative metastatic breast cancer and highlights the potential value of novel, newer endocrine targets.

00:00-00:03
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00:03-00:15
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CAPTION: Interpretation of ESR1 mutations in mBC presented by Doctor Virginia Kaklamani.
00:15-00:31
DOCTOR KAKLAMANI: Hello. My name is Virginia Kaklamani.
[Previous graphics fade off screen. Speaker appears on screen. Speaker name in blue text and white background fades onto screen, red line slides up into screen from bottom]
DOCTOR KAKLAMANI: I’m a professor of medicine at University of Texas Health Science Center in San Antonio. I’m the leader of the breast program at UT, and I have been treating breast cancer patients for more than 20 years.
00:31-00:39
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CAPTION: What is the role of somatic mutation testing in metastatic breast cancer?
00:39-01:09
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DOCTOR KAKLAMANI: Somatic testing is considered standard of care for patients with metastatic HR+ and triple negative breast cancer. The reason for that is the presence of genomic alternations which can help determine the best therapeutic approach. Specifically in HR+ breast cancer the presence of a PIK3CA mutation can select patients for treatment with PIK3CA-selective agents, and the emergence of ESR1 mutations can also help select patients for treatment with oral SERDs.
01:09-01:15
[Ambient music continues to play in the background. Speaker, and graphics fade off screen. Question text fades onto screen, red line slides up from bottom to align horizontally with text]
CAPTION: What are the clinical implications of an ESR1 mutation?
01:15-01:39
[Ambient music continues to play in the background. Previous question fades off screen, speaker fades back onto screen with white right-aligned box. ESR1 domains appear at top with zoom on the ligand-binding domain branches down. Vertical lines wipe down (stopping at the end of the end of the anchors below Ligand-binding domain). Mutations (E380Q, Y537S/N/C, and D538G) fade onto screen and appear all at one time.]
CAPTION: ~90% of all identified ESR1 mutations.
DOCTOR KAKLAMANI: ESR1 mutations are mutations that alter the ligand binding domain of the estrogen receptor. These mutations render the ER constitutively active meaning that the pathway does not need estrogen to become activated. Therefore, aromatase inhibitors and tamoxifen are less effective in patients with ESR1 mutated tumors. Patients with tumors that have ESR1 mutations tend to have a shorter PFS.
01:39-01:45
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CAPTION: How and when do you test for ESR1 mutations?
01:45-01:57
[Ambient music continues to play in the background. Previous question fades off screen, speaker fades back onto screen with white right-aligned box. Treatment DNA Icons appear. Top DNA Icon; Treatment text + arrow wipes from top; Bottom DNA icon with Treatment-resistant mutation text.]
DOCTOR KAKLAMANI: ESR1 mutations are subclonal mutations. This means that they develop over time as a tumor is exposed to antiestrogens and becomes resistant to them.
01:57-02:22
[Ambient music continues to play in the background. Previous graphic fades off screen. Body silhouette fades onto screen. Top line fades onto screen. Tissue biopsy icons and text appear simultaneously following red line. Bottom line fades onto screen. Liquid biopsy icons and text appear simultaneously following red line.]
DOCTOR KAKLAMANI: My typical approach is that I will get a tissue biopsy at time of diagnosis of metastatic disease and then at the time of disease progression after first-line endocrine therapy I would perform a liquid biopsy to determine ESR1 mutation status. I may also perform additional liquid biopsies at the time of subsequent progressions if I think the patient is still a candidate for endocrine therapy.
02:22-02:27
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CAPTION: How should I interpret variant allele frequency (VAF)?
02:27-03:03
DOCTOR KAKLAMANI:
[Ambient music continues to play in the background. Previous question fades off screen, speaker fades back onto screen with white right-aligned box. DNA bubbles and Germline mutation, and Somatic Mutation headers appear.]
DOCTOR KAKLAMANI: The variant allele frequency, or VAF, measures the proportion of a variant allele in a genomic locus.

If the VAF is high such as 50% or more, it typically means that the mutation is a germline mutation.
[Peach = 50% text and graphic appear as correlating bubbles pulse.]
DOCTOR KAKLAMANI: However, a low VAF doesn’t have any negative implications for treatment selection. Therefore, if a tumor has both a PIK3CA and an ESR1 mutation I will not pick an agent based on the VAF of each mutation, but instead I will choose the therapy I believe most appropriate for the patient.
[Navy = 33% text and graphic appear as correlating bubbles pulse. Light Blue = 8% text and graphic appear as correlating bubbles pulse.]
03:03-03:09
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CAPTION: If there is no ESR1 alteration should testing be repeated? What is the frequency of repeat testing?
03:09-03:46
[Ambient music continues to play in the background. Previous question fades off screen, speaker fades back onto screen with white right-aligned box. Navy arrow graphic slides down onto screen from top. Each label (Disease Recurrence or Metastasis; Disease Progression 1; Disease Progression 2; Disease Progression 3) appears by row starting from top with biopsy icons.]
DOCTOR KAKLAMANI: This is a very important point. ESR1 mutations develop over time as a tumor becomes endocrine resistant. Studies have shown that at the time of the detection of metastatic disease only 5% of HR positive breast cancers have ESR1 mutations. But at progression the rate of ESR1 mutations increases to 30-40%, and even higher if we perform serial testing. I personally perform liquid biopsies at the time of recurrence or progression as long as I think the patient is a candidate for endocrine therapy, which is supported by the international treatment guidelines.
03:46-03:55
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ESR1 Biomarker Testing in mBC with Dr. Kaklamani

Dr. Kaklamani shares clinical implications for why testing for ESR1 mutations in metastatic breast cancer is important, and practical considerations for testing and interpreting results.

References

Al-Qasem AJ, et al. Cancers (Basel). 2021;13(21):5397.
Lindstrom LS, et al. J Clin Oncol. 2012;30(21):2601-2608.
Hanker AB, et al. Cancer Cell. 2020;37(4):496-513.
Clarke R, et al. Mol Cell Endocrinol. 2015;418(03):220-234.
Patel HK, Bihani T. Pharmacol Ther. 2018;186:1-24.
Brett JO, et al. Breast Cancer Res. 2021;23(1):85.
Burstein HJ, et al. J Clin Oncol. 2023;31(18):3423-3425.
Clatot F, et al. Oncotarget. 2016;7(46):74448-74459.
Lone SN, et al. Mol Cancer. 2022;18;21(1):79.

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