Biomarkers for Systemic Therapy in Metastatic Breast Cancer Guideline and Rapid Update

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.

2022 Guideline Abstract

Published online before print June 27, 2022, DOI: 10.1200/JCO.22.01063

N. Lynn Henry, Mark R. Somerfield, Zoneddy Dayao, Anthony Elias, Kevin Kalinsky, Lisa M. McShane, Beverly Moy, MD, Ben Ho Park, Kelly M. Shanahan, Priyanka Sharma, Rebecca Shatsky, Erica Stringer-Reasor, Melinda Telli, Nicholas C. Turner, MD, and Angela DeMichele.

Purpose

To update the ASCO Biomarkers to Guide Systemic Therapy for Metastatic Breast Cancer (MBC) guideline.

Methods

An Expert Panel conducted a systematic review to identify randomized clinical trials and prospectiveretrospective studies from January 2015 to January 2022

Results

The search identified 19 studies informing the evidence base.

Recommendations

Candidates for a regimen with a phosphatidylinositol 3-kinase inhibitor and hormonal therapy should undergo testing for PIK3CA mutations using next-generation sequencing of tumor tissue or circulating tumor DNA (ctDNA) in plasma to determine eligibility for alpelisib plus fulvestrant. If no mutation is found in ctDNA, testing in tumor tissue, if available, should be used. Patients who are candidates for poly (ADP-ribose) polymerase (PARP) inhibitor therapy should undergo testing for germline BRCA1 and BRCA2 pathogenic or likely pathogenic mutations to determine eligibility for a PARP inhibitor. There is insufficient evidence for or against testing for a germline PALB2 pathogenic variant to determine eligibility for PARP inhibitor therapy in the metastatic setting. Candidates for immune checkpoint inhibitor therapy should undergo testing for expression of programmed cell death ligand-1 in the tumor and immune cells to determine eligibility for treatment with pembrolizumab plus chemotherapy. Candidates for an immune checkpoint inhibitor should also undergo testing for deficient mismatch repair/microsatellite instability-high to determine eligibility for dostarlimab-gxly or pembrolizumab, as well as testing for tumor mutational burden. Clinicians may test for NTRK fusions to determine eligibility for TRK inhibitors. There are insufficient data to recommend routine testing of tumors for ESR1 mutations, for homologous recombination deficiency, or for TROP2 expression to guide MBC therapy selection. There are insufficient data to recommend routine use of ctDNA or circulating tumor cells to monitor response to therapy among patients with MBC.

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The clinical practice guidelines and other guidance published herein are provided by the American Society of Clinical Oncology, Inc. ("ASCO") to assist practitioners in clinical decision making. The information therein should not be relied upon as being complete or accurate, nor should it be considered as inclusive of all proper treatments or methods of care or as a statement of the standard of care. With the rapid development of scientific knowledge, new evidence may emerge between the time information is developed and when it is published or read. The information is not continually updated and may not reflect the most recent evidence. The information addresses only the topics specifically identified therein and is not applicable to other interventions, diseases, or stages of diseases. This information does not mandate any particular course of medical care. Further, the information is not intended to substitute for the independent professional judgment of the treating physician, as the information does not account for individual variation among patients. Recommendations reflect high, moderate or low confidence that the recommendation reflects the net effect of a given course of action. The use of words like "must," "must not," "should," and "should not" indicate that a course of action is recommended or not recommended for either most or many patients, but there is latitude for the treating physician to select other courses of action in individual cases. In all cases, the selected course of action should be considered by the treating physician in the context of treating the individual patient. Use of the information is voluntary. ASCO provides this information on an "as is" basis, and makes no warranty, express or implied, regarding the information. ASCO specifically disclaims any warranties of merchantability or fitness for a particular use or purpose. ASCO assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of this information or for any errors or omissions.