Endocrine Treatment and Targeted Therapy for HR-Positive, HER2-Negative Metastatic Breast Cancer Guideline and Rapid Update
Guideline Status: Current
Published Online: February 6, 2024
Last Updated: September 20, 2024
Rapid Recommendation Update
Published online February 6, 2024
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 (Evidence quality: High; Strength of recommendation: Strong).
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 (Evidence quality: Low; Strength of recommendation: Weak).
Qualifying statement for Recommendations 1.1 and 1.2. 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). 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.
A more detailed manuscript has been submitted to the Journal of Clinical Oncology (JCO).
Rapid Recommendation Update
Published online March 23, 2023
Updated Recommendations:
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 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;5 blood-based ctDNA is preferred owing to greater sensitivity.6 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.
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 monotherapy, other older ET options such as tamoxifen, 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.
This rapid recommendation provides timely guidance on elacestrant for patients with previously treated estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, including patients with ESR1-mutated tumors.
2021 Guideline Abstract
Purpose
To update recommendations of the ASCO systemic therapy for hormone receptor (HR)-positive metastatic breast cancer (MBC) guideline.
Methods
An Expert Panel conducted a systematic review to identify new, potentially practice-changing data. RESULTS Fifty-one articles met eligibility criteria and form the evidentiary basis for the recommendations.
Recomendations
Alpelisib in combination with endocrine therapy (ET) should be offered to postmenopausal patients, and to male patients, with HR-positive, human epidermal growth factor receptor 2 (HER2)-negative, PIK3CA-mutated, ABC, or MBC following prior endocrine therapy with or without a cyclin-dependent kinase (CDK) 4/ 6 inhibitor. 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. There are insufficient data at present to recommend routine testing for ESR1 mutations to guide therapy for HR-positive, HER2-negative MBC. For BRCA1 or BRCA2 mutation carriers with metastatic HER2-negative breast cancer, olaparib or talazoparib should be offered in the 1st-line through 3rd-line setting. A nonsteroidal aromatase inhibitor (AI) and a CDK4/6 inhibitor should be offered to postmenopausal women with treatment-naive HR-positive MBC. Fulvestrant and a CDK4/6 inhibitor should be offered to patients with progressive disease during treatment with AIs (or who develop a recurrence within 1 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.
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