ESR1 Gene Mutations and Liquid Biopsy in ER-Positive Breast Cancers: A Small Step Forward, a Giant Leap for Personalization of Endocrine Therapy?

SIMPLE SUMMARY: Endocrine therapy (ET) remains the mainstay of treatment for Hormone Receptor-positive breast cancer, both in the early and advanced settings. The acquisition of mutations in the ESR1 gene encoding the estrogen receptor represents one of the main resistance mechanisms to ET. A conventional tumor tissue biopsy can be used to detect ESR1 mutations; however, these mutations are less likely to present on initial tissue biopsy, and such an invasive approach is hardly repeatable over time for longitudinal disease monitoring. The research of ESR1 mutations in liquid biopsies based on the analysis of circulating cell-free DNA in plasma is of increasing interest and has been recently recommended to guide therapy in patients with estrogen receptor-positive breast cancers at progression under ET. This comprehensive review reports the most recent advances and recommendations in this field and compares the different techniques available for the analysis of the ESR1 gene in liquid biopsy. ABSTRACT: The predominant forms of breast cancer (BC) are hormone receptor-positive (HR+) tumors characterized by the expression of estrogen receptors (ERs) and/or progesterone receptors (PRs). Patients with HR+ tumors can benefit from endocrine therapy (ET). Three types of ET are approved for the treatment of HR+ BCs and include selective ER modulators, aromatase inhibitors, and selective ER downregulators. ET is the mainstay of adjuvant treatment in the early setting and the backbone of the first-line treatment in an advanced setting; however, the emergence of acquired resistance can lead to cancer recurrence or progression. The mechanisms of ET resistance are often related to the occurrence of mutations in the ESR1 gene, which encodes the ER-alpha protein. As ESR1 mutations are hardly detectable at diagnosis but are present in 30% to 40% of advanced BC (ABC) after treatment, the timeline of testing is crucial. To manage this resistance, ESR1 testing has recently been recommended; in ER+ HER2− ABC and circulating cell-free DNA, so-called liquid biopsy appears to be the most convenient way to detect the emergence of ESR1 mutations. Technically, several options exist, including Next Generation Sequencing and ultra-sensitive PCR-based techniques. In this context, personalization of ET through the surveillance of ESR1 mutations in the plasma of HR+ BC patients throughout the disease course represents an innovative way to improve the standard of care.