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 J Clin Oncol. 2023 May 17. IF: 50.717 Testing for ESR1 Mutations to Guide Therapy for Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Metastatic Breast Cancer: ASCO Guideline Rapid Recommendation Update. Burstein HJ, DeMichele A, Somerfield MR, Henry NL; Biomarker Testing and Endocrine and Targeted Therapy in Metastatic Breast Cancer Expert Panels. Dana Farber Cancer Institute, Boston, MA; University of Pennsylvania, Philadelphia, PA; American Society of Clinical Oncology, Alexandria, VA; University of Michigan, Ann Arbor, MI. BACKGROUND: Two previous ASCO guidelines discussed the role of testing in activating gain-of-function mutations in the estrogen receptor gene ligand-binding domain (ESR1 mutation) to guide therapy for hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative metastatic breast cancer (MBC) and concluded that data were insufficient to recommend routine testing. The EMERALD trial, an international, open-label, randomized phase III trial that evaluated the efficacy and safety of the oral selective estrogen receptor degrader, elacestrant, versus endocrine monotherapy (standard-of-care [SOC]) in patients with previously treated estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, including patients with ESR1-mutated tumors, provides a strong signal for updating previous ASCO MBC guidelines. METHODS: A targeted electronic literature search was conducted to identify any additional phase III randomized controlled trials in this patient population. No additional randomized controlled trials were identified. The original guideline Expert Panels reconvened to review evidence from EMERALD and to review and approve the revised recommendations. EVIDENCE REVIEW: EMERALD randomly assigned postmenopausal women or men with advanced breast cancer to either elacestrant 345 mg orally once daily (n = 239) or physician's choice SOC endocrine therapy (ET) with fulvestrant, anastrozole, letrozole, or exemestane monotherapy (n = 238); the SOC control arm permitted reintroduction of previous therapy and did not permit combination therapy with targeted agents such as alpelisib or everolimus. Eligible patients had cancer progression after first- or second-line ET and had received a CDK4/6 inhibitor in combination with ET as part of their previous therapy. The coprimary end points were progression-free survival (PFS) in all patients (N = 477) and in patients with detectable ESR1 mutations in circulating tumor DNA (ctDNA; n = 228). Compared with SOC, there was improved PFS with elacestrant in both the overall study population (hazard ratio [HR], 0.70; 95% CI, 0.55 to 0.88; P = 0.002) and patients with ESR1 mutations in ctDNA (HR, 0.55; 95% CI, 0.39 to 0.77; P = 0.0005). In cases with ESR1 mutations, the median PFS was 3.8 months for elacestrant and 1.9 months for SOC, and 6-month PFS rates were 41% and 19% for elacestrant and SOC, respectively. Among patients without detectable ESR1 mutations, there was no significant improvement in PFS with elacestrant compared with SOC ET (HR, 0.86; 95% CI, 0.63 to 1.19; P = 0.308). Objective response rates were 4% in each arm in the overall population and were not statistically significantly different between elacestrant and SOC ET in those with detectable ESR1 mutations (7.1% v 4.7%; P = 0.455). Elacestrant therapy was associated with more toxicity than SOC ET including nausea and vomiting. Appraisal of the trial report using the GRADE instrument was performed as per ASCO's methodology and found a high certainty of the evidence. UPDATED RECOMMENDATIONS: To aid in treatment selection, the Expert Panel recommends routine testing for emergence of ESR1 mutations at recurrence or progression on ET (given with or without CDK4/6 inhibitor) in patients with ER-positive, HER2-negative MBC. Testing with a Clinical Laboratory Improvement Amendments-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 wild-type may warrant retesting at subsequent progression(s) to determine if an ESR1 mutation has arisen (Type: Evidence-based, benefits outweigh harms; Evidence quality: High; Strength of recommendation: Strong). 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 wild-type 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. While elacestrant has comparable or greater activity than SOC ET monotherapy, there are at present no data on the safety or clinical efficacy to support its use in combination with targeted agents. PMID: 37196213 DOI: 10.1200/JCO.23.00638 |
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