Biomarkers for Systemic Therapy in Metastatic Breast Cancer
Publication Date: March 13, 2024
Last Updated: May 3, 2024
Treatment
Recommendations from 2024 Rapid Recommendation Update
Recommendation 1.1
The Expert Panel recommends multiple lines of endocrine treatment (ET), frequently paired with targeted agents, with choices informed by prior treatments and by routine testing for activating mutations in ESR1, PIK3CA, or AKT1, or inactivation of PTEN (Table 1). Panelists recommend inclusion of CDK4/6 inhibitor therapy with ET in the first line. Second- and third-line therapies reflect targeted options based on tumor genomics. Combining ET with the AKT pathway inhibitor capivasertib is appropriate for tumors harboring PIK3CA or AKT1 mutations or PTEN inactivation while ET combined with the PI3 kinase inhibitor alpelisib is an option for tumors harboring PIK3CA mutations, but not AKT1 mutations. Other options include ET with mTOR inhibitor everolimus irrespective of tumor genomics (Table 1). Monotherapy with the oral selective estrogen receptor degrader (SERD) elacestrant is an option for tumors with ESR1 mutation. (, , H , S )
Qualifying statement for Recommendations 1.1 and 1.2.
Both capivasertib and alpelisb can cause rash and/or diarrhea. Grade 3 or greater AEs included diarrhea (9.3% capivasertib vs 6.7% alpelisib), rash (12.1% capivasertib vs 9.9% alpelisib), and hyperglycemia (2.3% capivasertib vs 36.6% alpelisib). Clinicians may mitigate symptoms with antihistamines, anti-diarrheal agents, or other supportive measures. Most patients with estrogen receptor (ER)-positive, HER2-negative breast cancers will be candidates for multiple lines of ET and/or targeted agents prior to chemotherapy or antibody-drug conjugate therapy. While newer agents have been added to the armamentarium, there remain few studies on the optimal timing or sequence of treatments, comparisons of targeted agents within a class, or studies that compare one class of agents against another. Such trials are an important clinical priority, as are studies to mitigate side effects of these agents.
Both capivasertib and alpelisb can cause rash and/or diarrhea. Grade 3 or greater AEs included diarrhea (9.3% capivasertib vs 6.7% alpelisib), rash (12.1% capivasertib vs 9.9% alpelisib), and hyperglycemia (2.3% capivasertib vs 36.6% alpelisib). Clinicians may mitigate symptoms with antihistamines, anti-diarrheal agents, or other supportive measures. Most patients with estrogen receptor (ER)-positive, HER2-negative breast cancers will be candidates for multiple lines of ET and/or targeted agents prior to chemotherapy or antibody-drug conjugate therapy. While newer agents have been added to the armamentarium, there remain few studies on the optimal timing or sequence of treatments, comparisons of targeted agents within a class, or studies that compare one class of agents against another. Such trials are an important clinical priority, as are studies to mitigate side effects of these agents.
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Recommendation 1.2
There are no comparative efficacy data for choosing a PIK3CA targeted option for those who are potential candidates for capivasertib or alpelisib treatment. For such patients, the Panel recommends selecting the targeted agent based on perceived risk-benefit considerations such as hyperglycemia, diarrhea, or treatment discontinuation for AEs. (, , L , W )
Qualifying statement for Recommendations 1.1 and 1.2.
Both capivasertib and alpelisb can cause rash and/or diarrhea. Grade 3 or greater AEs included diarrhea (9.3% capivasertib vs 6.7% alpelisib), rash (12.1% capivasertib vs 9.9% alpelisib), and hyperglycemia (2.3% capivasertib vs 36.6% alpelisib). Clinicians may mitigate symptoms with antihistamines, anti-diarrheal agents, or other supportive measures. Most patients with estrogen receptor (ER)-positive, HER2-negative breast cancers will be candidates for multiple lines of ET and/or targeted agents prior to chemotherapy or antibody-drug conjugate therapy. While newer agents have been added to the armamentarium, there remain few studies on the optimal timing or sequence of treatments, comparisons of targeted agents within a class, or studies that compare one class of agents against another. Such trials are an important clinical priority, as are studies to mitigate side effects of these agents.
Both capivasertib and alpelisb can cause rash and/or diarrhea. Grade 3 or greater AEs included diarrhea (9.3% capivasertib vs 6.7% alpelisib), rash (12.1% capivasertib vs 9.9% alpelisib), and hyperglycemia (2.3% capivasertib vs 36.6% alpelisib). Clinicians may mitigate symptoms with antihistamines, anti-diarrheal agents, or other supportive measures. Most patients with estrogen receptor (ER)-positive, HER2-negative breast cancers will be candidates for multiple lines of ET and/or targeted agents prior to chemotherapy or antibody-drug conjugate therapy. While newer agents have been added to the armamentarium, there remain few studies on the optimal timing or sequence of treatments, comparisons of targeted agents within a class, or studies that compare one class of agents against another. Such trials are an important clinical priority, as are studies to mitigate side effects of these agents.
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Recommendations from 2023 Rapid Recommendation Update
To aid in treatment selection, the Expert Panel recommends routine testing for emergence of ESR1 mutations at recurrence or progression on ET (with or without CDK4/6 inhibitor) in patients with ER-positive, HER2-negative MBC. Testing with a CLIA-certified assay should be performed on blood or tissue obtained at the time of progression, as ESR1 mutations develop in response to selection pressure during treatment and are typically undetectable in the primary tumor; blood-based ctDNA is preferred owing to greater sensitivity. If not performed earlier, testing for PIK3CA mutations should also be performed to guide further therapy. Patients whose tumor or ctDNA tests remain ESR1 wildtype may warrant retesting at subsequent progression(s) to determine if an ESR1 mutation has arisen. ( EB , B , H , S )
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Patients previously treated with ET and a CDK4/6 inhibitor for advanced breast cancer have several therapeutic options if choosing to continue endocrine-based approaches. For patients with prior CDK4/6 inhibitor treatment and ESR1 wildtype tumors, appropriate subsequent ET options include fulvestrant, aromatase inhibitor, or tamoxifen monotherapy, or ET in combination with targeted agents such as alpelisib (for PIK3CA mutated tumors), or everolimus. For patients with prior CDK4/6 inhibitor treatment and a detectable ESR1 mutation, options include elacestrant or other ET either alone or in combination with targeted agents such as alpelisib (for PIK3CA-mutated tumors) or everolimus. Elacestrant has comparable or greater activity than SOC ET monotherapy. Currently, there are no data on safety or clinical efficacy to support the use of elacestrant in combination with targeted agents. ( EB , B , H , S )
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Recommendations from 2022 Focused Guideline Update
Recommendation 1.1
Patients with locally recurrent unresectable or metastatic hormone receptor-positive and human epidermal growth factor receptor 2 (HER2) -negative breast cancer who are candidates for a treatment regimen that includes a PI3K inhibitor and a hormonal therapy, should undergo testing for PIK3CA mutations using next-generation sequencing of tumor tissue or ctDNA in plasma to determine their eligibility for treatment with the PI3K inhibitor alpelisib plus fulvestrant. If no mutation is found in ctDNA, testing in tumor tissue, if available, should be used since this will detect a small number of additional patients with PIK3CA mutations. ( EB , B , H , S )
Note: See J Clin Oncol 39:3959-3977, 2021 for the corresponding recommendation concerning the use of alpelisib in patients with PIK3CA-mutated, advanced or metastatic breast cancer: https://ascopubs.org/doi/full/10.1200/JCO.21.01392.
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Recommendation 3.1
Patients with metastatic HER2-negative breast cancer who are candidates for treatment with a poly [ADP-ribose] polymerase (PARP) inhibitor should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine their eligibility for treatment with the PARP inhibitors olaparib or talazoparib. ( EB , B , H , S )
Note: See: J Clin Oncol 39:3959-3977, 2021 for the corresponding recommendation concerning the use of the use of PARP inhibitors in the treatment of patients with HER2-negative metastatic breast cancer: https://ascopubs.org/doi/full/10.1200/JCO.21.01392
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Recommendation 3.2
There is insufficient evidence to support a recommendation either for or against testing for a germline PALB2 pathogenic variant for the purpose of determining eligibility for treatment with PARP inhibitor therapy in the metastatic setting. This recommendation is independent of the indication for testing to assess cancer risk. ( IC , , L , M )
Qualifying Statements: Small single-arm studies show that oral PARP inhibitor therapy demonstrates high response rates in metastatic breast cancer encoding DNA repair defects, such as germline PALB2 pathogenic variants and somatic BRCA1/2 mutations. It should also be noted that the randomized PARP inhibitor trials made no direct comparison with taxanes, anthracyclines, or platinums. Comparative efficacy against these compounds is unknown.
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Recommendation 4.1
There are insufficient data at present to recommend routine testing of tumors for homologous recombination deficiency (HRD) to guide therapy for metastatic breast cancer. ( IC , , L , M )
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Recommendation 5.1
Patients with locally recurrent unresectable or metastatic hormone receptor-negative and HER2-negative breast cancer who are candidates for a treatment regimen that includes an immune checkpoint inhibitor should undergo testing for expression of PD-L1 in the tumor and immune cells with an FDA-approved test to determine eligibility for treatment with the immune checkpoint inhibitor pembrolizumab plus chemotherapy. ( EB , B , I , S )
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Recommendation 6.1
Patients with metastatic cancer who are candidates for a treatment regimen that includes an immune checkpoint inhibitor should undergo testing for dMMR/microsatellite instability-high (MSI-H) to determine eligibility for dostarlimab-gxly or pembrolizumab. ( IC , , L , M )
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Recommendation 7.1
Patients with metastatic cancer who are candidates for treatment with an immune checkpoint inhibitor should undergo testing for TMB to determine eligibility for pembrolizumab monotherapy. ( IC , , L , M )
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Recommendation 8.1
Clinicians may test for NTRK fusions in patients with metastatic cancer who are candidates for a treatment regimen that includes a tyrosine receptor kinase (TRK) inhibitor to determine eligibility for larotrectinib or entrectinib. ( IC , , L , M )
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Recommendation 9.1
There are insufficient data to recommend routine testing of tumors for TROP2 expression to guide therapy with an anti-TROP2 antibody-drug conjugate for hormone receptor-negative, HER2-negative metastatic breast cancer. ( IC , , L , M )
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Recommendation 10.1
There are insufficient data to recommend routine use of ctDNA to monitor response to therapy among patients with metastatic breast cancer. ( IC , , L , M )
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Recommendation 11.1
There are insufficient data to recommend routine use of CTCs to monitor response to therapy among patients with metastatic breast cancer. ( IC , , I , M )
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Recommendations Unchanged From 2015 Guideline
At initial presentation of metastasis from breast cancer, it is standard of care to biopsy an accessible lesion to confirm metastatic breast cancer. When evaluating the metastatic site(s), it is important to note that the results of estrogren receptor (ER), progesterone receptor (PR), and/or HER2 status may have changed from the primary tumor, and these results may inform treatment decisions. Therefore, this Panel recommends retesting for ER, PR, and HER2 on ≥ one metastasis with careful attention to assay performance, particularly for bone metastases. However, for patients with documented changes in these biomarkers, data are lacking to determine whether outcomes from systemic therapy are altered when guided by biomarker test results from the metastases. The Panel informal consensus for the management of care when there is discordance of ER, PR, or HER2 results between primary and metastatic tissues is to use the ER, PR, or HER2 status from the metastasis to direct therapy, if supported by the clinical scenario and the patient’s goals for care. (Moderate recommendation; EB-Ins for biomarker change from primary to metastasis, but no evidence to demonstrate that systemic therapy choices affect health outcomes when biomarker change occurs.) ( EB , , Ins , M )
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Recommendation for Tissue Biomarkers
In patients who are already receiving systemic therapy for metastatic breast cancer, decisions on changing to a new drug or regimen or discontinuing treatment should be based on the patient’s goals for care and clinical evaluation and judgment of disease progression or response, given that there is no evidence at this time that changing therapy solely on the basis of biomarker results beyond ER, PR, and HER2 improves health outcome, quality of life, or cost effectiveness. ( EB , , L , M )
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Recommendations for Circulating Tumor Markers
In patients already receiving systemic therapy for metastatic breast cancer, decisions on changing to a new drug or regimen or discontinuing treatment should be based on clinical evaluation, judgment of disease progression or response, and the patient’s goals for care. There is no evidence at this time that changing therapy based solely on circulating biomarker results improves health outcomes, quality of life, or cost effectiveness. ( EB , , I , M )
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Carcinoembryonic antigen (CEA), cancer antigen (CA) 15-3, and CA 27-29 may be used as adjunctive assessments to contribute to decisions regarding therapy for metastatic breast cancer. Data are insufficient to recommend use of CEA, CA 15-3, and CA 27-29 alone for monitoring response to treatment. The Panel acknowledges the lack of evidence of clinical utility in support of use of these circulating biomarkers; biochemical assessments of CEA, CA 15-3, and CA 27-29 were developed before the present standards for measuring clinical utility. The recommendation for use is based on clinical experience and Panel informal consensus in the absence of studies designed to evaluate the clinical utility of the markers. As such, it is also reasonable for clinicians to not use these markers as adjunctive assessments. ( IC , , Ins , M )
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At-A-Glance Guide to ASCO Biomarker Testing in Metastatic Breast Cancer Recommendations
Biomarker Tests Recommended by the ASCO Expert Panel
Having trouble viewing table?
| Test | Type of Recommendation | Quality of Evidence | Strength of Recommendation |
|---|---|---|---|
| PIK3CA | Evidence-based | High | Strong |
| Germline BRCA1 and BRCA2 | Evidence-based | High | Strong |
| PD-L1 | Evidence-based | Intermediate | Strong |
| dMMR/MSI-H | Informal consensus-based | Low | Moderate |
| TMB | Informal consensus-based | Low | Moderate |
| NTRK fusions | Informal consensus-based | Low | Moderate |
Biomarker Tests Not Recommended by the ASCO Expert Panel
Having trouble viewing table?
| Test | Type of Recommendation | Quality of Evidence | Strength of Recommendation |
|---|---|---|---|
| ESR1 | Evidence-based | Insufficient | Moderate |
| PALB2 | Evidence-based | Low | Moderate |
| HRD | Informal consensus-based | Low | Moderate |
| TROP2 expression | Informal consensus-based | Low | Moderate |
| ctDNA | Informal consensus-based | Low | Moderate |
| CTCs | Informal consensus-based | Low | Moderate |
Recommendation Grading
Overview
Title
Biomarkers for Systemic Therapy in Metastatic Breast Cancer
Authoring Organization
American Society of Clinical Oncology
Publication Month/Year
March 13, 2024
Last Updated Month/Year
May 3, 2024
Supplemental Implementation Tools
Document Type
Guideline
Country of Publication
US
Target Patient Population
Women with metastatic breast cancer being considered for systemic therapy or for changes in the drug or regimen they are receiving.
Target Provider Population
Medical, surgical, and radiation oncologists
Inclusion Criteria
Female, Adult, Older adult
Health Care Settings
Ambulatory, Hospital, Outpatient
Intended Users
Nurse, nurse practitioner, physician, physician assistant
Scope
Diagnosis
Diseases/Conditions (MeSH)
D001943 - Breast Neoplasms, D009362 - Neoplasm Metastasis, D015415 - Biomarkers
Keywords
breast cancer, biomarkers, metastatic, BRCA1, BRCA2, PIK3CA, PD-L1, dMMR/MSI-H, TMB, NTRK
Source Citation
Burstein HJ, et al., Endocrine and Targeted Therapy for Hormone Receptor–Positive, Human Epidermal Growth Factor Receptor 2–Negative Metastatic Breast Cancer—Capivasertib-Fulvestrant: ASCO Rapid Recommendation Update. J Clin Oncol. 2024 March 13 doi:10.1200/JCO.24.00248
Henry NL, Somerfield MR, Dayao Z, et al. Biomarkers for Systemic Therapy in Metastatic Breast Cancer: ASCO Guideline Update. J Clin Oncol. 2022 June 27. doi: 10.1200/JCO.22.01063.
Burstein HJ, et al. Testing for ESR1 Mutations to Guide Therapy for HR-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update. J Clin Oncol. 2023 May 17 doi: 10.1200/JCO.23.00638.
Supplemental Methodology Resources
Methodology
Number of Source Documents
103
Literature Search Start Date
December 31, 2014
Literature Search End Date
December 31, 2021