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Old 08-18-2021, 09:20 AM   #1
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Join Date: Nov 2005
Posts: 530
ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-posi

ESR1 mutation as an emerging clinical biomarker in metastatic hormone receptor-positive breast cancer


Abstract In metastatic hormone receptor-positive breast cancer, ESR1 mutations are a common cause of acquired resistance to
the backbone of therapy, estrogen deprivation by aromatase inhibition. How these mutations affect tumor sensitivity
to established and novel therapies are active areas of research. These therapies include estrogen receptor-targeting
agents, such as selective estrogen receptor modulators, covalent antagonists, and degraders (including tamoxifen,
fulvestrant, and novel agents), and combination therapies, such as endocrine therapy plus CDK4/6, PI3K, or mTORC1
inhibition. In this review, we summarize existing knowledge surrounding the mechanisms of action of ESR1 muta-
tions and roles in resistance to aromatase inhibition. We then analyze the recent literature on how ESR1 mutations
affect outcomes in estrogen receptor-targeting and combination therapies. For estrogen receptor-targeting therapies
such as tamoxifen and fulvestrant, ESR1 mutations cause relative resistance in vitro but do not clearly lead to resist-
ance in patients, making novel agents in this category promising. Regarding combination therapies, ESR1 mutations
nullify any aromatase inhibitor component of the combination. Thus, combinations using endocrine alternatives to
aromatase inhibition, or combinations where the non-endocrine component is efficacious as monotherapy, are still
effective against ESR1 mutations. These results emphasize the importance of investigating combinatorial resistance,
challenging as these efforts are. We also discuss future directions and open questions, such as studying the differ-
ences among distinct ESR1 mutations, asking how to adjust clinical decisions based on molecular surveillance testing,
and developing novel therapies that are effective against ESR1 mutation.
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