Metastatic Breast Cancer With ESR1 Mutation: Clinical Management Considerations From the Molecular and Precision Medicine (MAP) Tumor Board at Massachusetts General Hospital

Abstract

: The last decade in oncology has witnessed impressive response rates with targeted therapies, largely because of collaborative efforts at understanding tumor biology and careful patient selection based on molecular fingerprinting of the tumor. Consequently, there has been a push toward routine molecular genotyping of tumors, and large precision medicine-based clinical trials have been launched to match therapy to the molecular alteration seen in a tumor. However, selecting the "right drug" for an individual patient in clinic is a complex decision-making process, including analytical interpretation of the report, consideration of the importance of the molecular alteration in driving growth of the tumor, tumor heterogeneity, the availability of a matched targeted therapy, efficacy and toxicity considerations of the targeted therapy (compared with standard therapy), and reimbursement issues. In this article, we review the key considerations involved in clinical decision making while reviewing a molecular genotyping report. We present the case of a 67-year-old postmenopausal female with metastatic estrogen receptor-positive (ER+) breast cancer, whose tumor progressed on multiple endocrine therapies. Molecular genotyping of the metastatic lesion revealed the presence of an ESR1 mutation (encoding p.Tyr537Asn), which was absent in the primary tumor. The same ESR1 mutation was also detected in circulating tumor DNA (ctDNA) extracted from her blood. The general approach for interpretation of genotyping results, the clinical significance of the specific mutation in the particular cancer, potential strategies to target the pathway, and implications for clinical practice are reviewed in this article.

Key points: ER+ breast tumors are known to undergo genomic evolution during treatment with the acquisition of new mutations that confer resistance to treatment.ESR1 mutations in the ligand-binding domain of ER can lead to a ligand-independent, constitutively active form of ER and mediate resistance to aromatase inhibitors.ESR1 mutations may be detected by genomic sequencing of tissue biopsies of the metastatic tumor or by sequencing the circulating tumor cells or tumor DNA (ctDNA).Sequencing results may lead to a therapeutic "match" with an existing FDA-approved drug or match with an experimental agent that fits the clinical setting.

Figure 1.

Tumor genotyping results from tissue and blood, respectively. (A): Screenshot of the ESR1 mutation visualized in JBrowse. Upper: The hg19 reference genome sequence (and corresponding amino acid translation) for ESR1 codons 533–541. The horizontal gray rows indicate individual reads (i.e., individual molecules) sequenced in the forward direction. The small green bars indicate a nucleotide change (single nucleotide variant [SNV]) from the reference nucleotide T to A. The yellow vertical line marks the ESR1 nucleotides at position 1,609 in the coding sequence where an SNV was detected. Labeled arrow is pointing to an example of the presence of thymidine (T) as compared with adenine (A). (B): Droplet digital polymerase chain reaction analysis demonstrating an ESR1 p.Tyr537Asn mutation in circulating tumor DNA isolated from the patient described in this article. Blue dots represent droplets containing FAM-labeled mutant probes hybridized to mutant DNA. Green dots represent HEX-labeled wild-type (WT) probes hybridized to WT DNA. Black dots represent droplets containing both mutant and WT DNA. Abbreviations: FAM, 5′-fluorescein amidite; HEX, hexachloro-fluorescein.

Figure 2.

Targeting the estrogen receptor pathway. (A): In the presence of wild-type estrogen receptor (ESR1), estrogen binds to ESR1, leading to change to agonist conformation, which binds to the estrogen response element in the DNA strand leading to transcription of multiple genes mediating ERE-induced effects, including cellular proliferation. (B): Estrogen receptor (ER)-mediated effects can potentially be inhibited by targeting the ligand (estrogen) as done by aromatase inhibitors or targeting the receptor as done by selective ER degraders. The presence of the ESR1 mutation in the ligand-binding domain results in a constitutive active form of ER that does not require ligand (or estrogen) for activation. These cells are therefore resistant to aromatase inhibitors but could potentially be targeted by SERDs. Abbreviations: ERE, estrogen response element; SERD, selective ER degrader.