ESR1 mutations in breast cancer

the area of personalized medicine, the main challenge of treating metastatic breast cancer (BC) remains to improve overall survival without deteriorating quality of life. Around 70% of breast tumors express estrogen receptors (ER+), which makes them usually sensitive to a hormonal blockage. Hormonal therapy is commonly the recommended first-line treatment for ER+ metastatic BC since it can provide a tumor growth arrest with few side-effects [1]. Aromatase inhibitors (AIs) is the actual backbone of hormonal treatment in the metastatic setting for many patients. The rationale of AIs is the inhibition of estrogene synthesis in peripheral tissues leading to complete lack of activation of the ER. If numerous mechanisms of AI resistance may occur, the key role of the estrogen receptor gene (ESR1) mutations was recently investigated. Several hot-spot mutations have been reported, usually modifying the ligand biding domain of the ER, leading to a ligand-independent receptor activity. Collectively, the 5 main mutations (D538G, E380Q and D537S/N/C) represent more than 80% of the ESR1 mutations. These mutations are an acquired molecular event since they are almost absent in primary BC tumour (<2%) but occur in metastatic tissues in around 25-30% of cases secondary to AI exposure [2]. At a glance, the emergence of ESR1 mutations is a marker of AI resistance. Instead repeated biopsies of metastases, it has been demonstrated that the detection of ESR1 mutations in circulating tumor DNA (ctDNA) by digital droplet PCR (ddPCR) is sensitive and highly correlates to the ESR1 mutational status in tumor tissue [3]. Thus, plasma samples from ER+ metastatic BC patients can be regarded as liquid biopsies and might help choosing the right treatment to the right patient at the right time in the near future. Indeed, a growing amount of evidence has supported the potential clinical utility of ESR1 mutational status assessment. We have recently shown that ESR1 mutation can raise during first-line AI treatment in the metastatic setting, with 75% of the ESR1 mutated patients having a detectable circulating mutation at least 3 months before clinical progression [4]. Several studies have reported that the detection of circulating ESR1 mutations was an independent factor of poor prognosis both in progression-free survival [5,6] and in overall survival [4,6]. In terms of treatment, if Editorial the use of CDK or mTOR inhibitors in association with hormonal therapy provides a significant improvement for ER+ metastatic BC, their benefit in case of ESR1 mutation is not yet …