Introduction
Treatment
Design and created by Guideline Central in participation with the American Society of Clinical Oncology.
HR-Positive, HER2-Negative Metastatic Breast Cancer
Endocrine Treatment and Targeted Therapy
American Society of Clinical Oncology
Publication Date: May 3, 2024
Introduction
- The purpose of this guideline is to update recommendations of the American Society of Clinical Oncology (ASCO) systemic therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) guideline.a
- Specifically, it:
- provides new recommendations for the use of alpelisib and capivasertib in the treatment of patients with hormone receptor-positive metastatic breast cancer
- addresses the role of biomarkers in treatment selection for this patient population
- adds two new biomarkers — AKT1, and inactivation of PTEN,b and
- amends prior recommendations concerning the use of CDK4/6 inhibitors in the treatment of these patients.
- Note that this guideline provides recommendations for endocrine therapy and targeted therapy, including CDK 4/6 and PI3 kinase inhibition for hormone receptor-positive metastatic breast cancer patients. A companion guidelinec provides recommendations for use of chemo-and targeted therapy for patients with HER2-negative metastatic breast cancer that is either endocrine-pretreated or hormone receptor-negative
a Rugo HS, et al. J Clin Oncol 34:3069-103, 2016.
b Burstein HJ, et al. J Clin Oncol. doi: 10.1200/JCO.24.00248
c Moy B et al. J Clin Oncol. 39(35):3938-3958, 2021.
b Burstein HJ, et al. J Clin Oncol. doi: 10.1200/JCO.24.00248
c Moy B et al. J Clin Oncol. 39(35):3938-3958, 2021.
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.
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.
Table 1. Treatment Options According to Prior Endocrine Therapy
| Line of Therapy | Tumor Genomic Findings Tumor genomic testingb | Prior Endocrine Therapya | |
|---|---|---|---|
| None, tamoxifen only, or no prior recent AI therapy (anastrozole, exemestane, letrozole) | Recurrence on or within recent exposure to AI therapy | ||
| First-line treatment | AI + CDK4/6 inhibitor | Fulvestrant + CDK4/6 inhibitor | |
| Second-line treatment | No targetable mutation | Fulvestrant or fulvestrant + everolimu | Fulvestrant + everolimus, or chemotherapy |
| Second-line treatment | ESR1 mutation | Elacestrant, or fulvestrant + everolimus | Elacestrant |
| Second-line treatment | PIK3CA mutation | Fulvestrant + capivasertib, fulvestrant + alpelisib,d or fulvestrant | Fulvestrant + capivasertib, or fulvestrant + alpelisibd |
| Second-line treatment | AKT1 mutation or PTEN inactivation | Fulvestrant + capivasertib, or fulvestrant | Fulvestrant + capivasertib |
| Third-line treatment and beyondc | No targetable mutations or targeted therapy already given | Chemotherapy or further endocrine-based treatments | Chemotherapy or further endocrine-based treatments |
| Third-line treatment and beyondc | ESR1 mutation | Elacestrante or chemotherapy | Elacestrante or chemotherapy |
| Third-line treatment and beyondc | PIK3CA mutation | Fulvestrant + capivasertib,e or fulvestrant + alpelisib,d,e or chemotherapy | Fulvestrant + capivasertib,e or fulvestrant + alpelisib,d,e or chemotherapy |
| Third-line treatment and beyondc | AKT1 mutation or PTEN inactivation | Fulvestrant + capivasertib,e or chemotherapy | Fulvestrant + capivasertib,e or chemotherapy |
- a All contemporary studies for ER-positive advanced breast cancer have been based on outcomes in postmenopausal women or women who were premenopausal at the time of diagnosis of advanced cancer and then underwent medically induced menopause. For premenopausal women diagnosed with advanced, ER-positive breast cancer, ovarian function suppression should be initiated and then treatment proceeds as in the Table.
- b Tumor genomic testing includes sequencing for targetable mutations, accomplished through large panel tumor genomic testing in a CLIA-certified laboratory performed on tissue or plasma obtained either at the time of progression or from archival tissue. In addition to selecting patients whose tumors have increased PIK3CA or AKT1 activity because of the presence of activating mutations, it is also important to identify those whose tumors have inactivation of PTEN protein. PTEN inactivation can be identified based on the presence of premature stop codons, frameshift alterations, splice site mutations, PTEN homozygous deletion, PTEN rearrangements that disrupt protein function, or specific missense mutations (C124R, C124S, G129E, G129V, G129R, R130Q, R130G, R130L, R130P, C136R, C136Y, S170R, and R173C) on next-generation sequencing.
- c There are few data on the value of older ET options after therapy with modern treatment regimens such as AIs, SERDs, CDK4/6 inhibitors, and/or other targeted agents. In select patients—typically those with indolent cancers, limited disease burden or symptoms, and demonstrated clinical benefit from prior ETs—therapies such as tamoxifen, megestrol acetate, or reintroduction of previously administered treatments may be of clinical value.
- Alpelisib is an option for patients with tumors harboring PIK3CA-activating mutations but not AKT1-activating mutations or PTEN inactivation.
- e If not previously given
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, H, B, S )
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, H, B, S )
Recommendations from 2021 Focused Guideline Update
Recommendation 1.1
Alpelisib in combination with endocrine therapy should be offered to postmenopausal patients in combination with fulvestrant, and to male patients, with HR-positive, HER2-negative, PIK3CA-mutated, advanced or metastatic breast cancer following prior endocrine therapy including an aromatase inhibitor, with or without a CDK4/6 inhibitor. Careful screening for and management of common toxicities are required. ( EB, H, B, M )
Recommendation 2.1
To guide the decision to use alpelisib in combination with fulvestrant in postmenopausal patients, and in male patients, with HR-positive metastatic breast cancer, clinicians should use next generation sequencing in tumor tissue or cell-free DNA in plasma to detect PIK3CA mutations. If no mutation is found in cell free DNA, testing in tumor tissue, if available, should be used as this will detect a small number of additional patients with PIK3CA mutations. ( EB, H, B, S )
Recommendation 2.3
Patients with metastatic HR-positive but HER2-negative breast cancer with germline BRCA1 or 2 mutations who are no longer benefiting from endocrine therapy may be offered an oral PARP inhibitor in the first- through to third-line setting rather than chemotherapy. ( EB, I, B, S )
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 mutation carriers and somatic BRCA 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.
Recommendation 3.1
A nonsteroidal AI and a CDK4/6 inhibitor should be offered to postmenopausal patients and to premenopausal patients combined with chemical ovarian function suppression, and to male patients (with a gonadotropin-releasing hormone analog), with treatment-naïve HR-positive MBC. ( EB, H, B, S )
Recommendation 3.2
Fulvestrant and a CDK4/6 inhibitor should be offered to patients with progressive disease during treatment with AIs (or who develop a recurrence within one year of adjuvant AI therapy) with or without one line of prior chemotherapy for metastatic disease, or as first-line therapy. Treatment should be limited to those without prior exposure to CDK4/6 inhibitors in the metastatic setting. ( EB, H, B, S )
Recommendations Unchanged from 2016 Guideline
Postmenopausal women with metastatic, HR-positive breast cancer should be offered AIs as first-line endocrine therapy.
Combination hormone therapy with fulvestrant with a loading dose followed by 500 mg every 28 days combined with a nonsteroidal aromatase inhibitor may be offered for patients with metastatic breast cancer without prior exposure to adjuvant endocrine therapy.
Premenopausal women with metastatic hormone receptor positive breast cancer should be offered ovarian suppression/ablation in combination with hormonal therapy. Ovarian suppression with either gonadotropin releasing hormone (GnRH) agonists or ablation with oophorectomy appears to achieve similar results in metastatic breast cancer. For most patients, clinicians should use guidelines for postmenopausal women to guide the choice of hormone treatment, although sequential therapy can also be considered. Patients without exposure to prior hormone therapy can also be treated with tamoxifen or ovarian suppression/ablation alone although combination therapy is preferred. Treatment should be based on the biology of the tumor and the menopausal status of the patient with careful attention paid to production of ovarian estrogen.
Treatment should take into account the biology of the tumor and the menopausal status of the patient with careful attention paid to ovarian production of estrogen.
The choice of second-line hormonal therapy should take into account prior treatment exposure and response to previous endocrine therapy.
Sequential hormonal therapy should be offered to patients with endocrine responsive disease.
Fulvestrant should be administered using the 500 mg dose and with a loading schedule.
Exemestane and everolimus may be offered to postmenopausal women with hormone receptor positive metastatic breast cancer progressing on prior treatment with non-steroidal AIs, either before or after treatment with fulvestrant, as PFS but not OS is improved compared to exemestane alone. This combination should not be offered as first-line therapy for patients who relapse more than 12 months from prior nonsteroidal AI therapy or for those who are naïve to hormonal therapy.
Hormonal therapy should be offered to patients whose tumors express any level of estrogen and/or progesterone receptors.
Treatment recommendations should be offered based on the type of adjuvant treatment, disease free interval and extent of disease at the time of recurrence. A specific hormone agent may be used again if recurrence occurs >12 months from last treatment.
Endocrine therapy should be recommended as initial treatment for patients with HR-positive, metastatic breast cancer except in patients with immediately life-threatening disease or in those with rapid visceral recurrence on adjuvant endocrine therapy.
The use of combined endocrine therapy and chemotherapy is not recommended.
Treatment should be given until there is unequivocal evidence of disease progression as documented by imaging, clinical examination or disease-related symptoms. Tumor markers or circulating tumor cells should not be used as the sole criteria for determining progression.
The addition of HER2 targeted therapy to first-line AIs should be offered to patients with hormone receptor positive, HER2 positive metastatic breast cancer in whom chemotherapy is not immediately indicated.The addition of HER2 targeted therapy to first-line AIs improves PFS without a demonstrated improvement in OS. HER2 targeted therapy combined with chemotherapy has resulted in improvement in OS, and is the preferred first-line approach in most cases.
Patients should be encouraged to consider enrolling in clinical trials, including those receiving treatment in the first-line setting. Multiple clinical trials are ongoing or planned, with a focus on improving response to hormonal therapy in metastatic disease.
Figure 1. Algorithm for Endocrine Treatment and Targeted Therapy for HR-Positive, HER2-Negative Metastatic Breast Cancer
Please refer to Table 1 footnotes.
Table 2. At-A-Glance Guide to ASCO Biomarker Testing in Metastatic Breast Cancer Recommendations - Biomarker Tests Recommended by the ASCO Expert Panel
| Test | Recommendation grade |
|---|---|
| AKT1 | Strong recommendation;H |
| PTEN inactivation | Weak recommendation; L |
| ESR1 | Strong recommendation; EB-B-H |
| PIK3CA | Strong recommendation; EB-B-H |
| Germline BRCA1 and BRCA2 | Strong recommendation; EB-B-H |
| PD-L1 | Strong recommendation; EB-B-I |
| dMMR/MSI-H | Moderate recommendation; IC-L |
| TMB | Moderate recommendation; IC-L |
| NTRK fusions | Moderate recommendation; IC-L |
Table 2. At-A-Glance Guide to ASCO Biomarker Testing in Metastatic Breast Cancer Recommendations - Biomarker Tests Not Recommended by the ASCO Expert Panel
| Test | Recommendation grade |
|---|---|
| PALB2 | Moderate recommendation; EB-L |
| HRD | Moderate recommendation; IC-L |
| TROP2 expression | Moderate recommendation; IC-L |
| ctDNA | Moderate recommendation; IC-L |
| CTCs | Moderate recommendation; IC-L |
ASCO believes that cancer clinical trials are vital to inform medical decisions and improve cancer care and that all patients should have the opportunity to participate.
Additional information, which may include data supplements, slide sets, and other clinical tools and resources, is available at www.asco.org/breast-cancer-guidelines .
Additional information, which may include data supplements, slide sets, and other clinical tools and resources, is available at www.asco.org/breast-cancer-guidelines .
Grading Table
| Type | Benefit/harm | Evidence Quality | Strength of Recommendation | ||||
|---|---|---|---|---|---|---|---|
| EB | Evidence-based | B | Benefits outweigh harms | H | High | Strong | |
| CB | Consensus-based | H | Harms outweigh benefits | I | Intermediate | Moderate | |
| IC | Informal consensus | B/H | Relative balance of benefits and harms | L | Low | Weak | |
| U | Unknown | Ins | Insufficient | ||||
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
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.
Burstein HJ et al. Endocrine Treatment and Targeted Therapy for HR-Positive, HER2-Negative Metastatic Breast Cancer: ASCO Guideline Update. J Clin Oncol. 2021 July 29 doi: 10.1200/JCO.21.01392.
Disclaimer
This pocket guide attempts to define principles of practice that should produce high-quality patient care. It is applicable to specialists, primary care, and providers at all levels. This pocket guide should not be considered exclusive of other methods of care reasonably directed at obtaining the same results. The ultimate judgment concerning the propriety of any course of conduct must be made by the clinician after consideration of each individual patient situation. Neither IGC, the medical associations, nor the authors endorse any product or service associated with the distributor of this clinical reference tool.
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