More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene *ESR1*), the most important factor for directing anti-estrogenic endocrine therapy. Although mutation in *ESR1* is known as an acquired mechanism of resistance to endocrine therapy (ET), found in 12-55% of metastatic breast cancers treated previously with ET, the impact of *ESR1* mutation on therapy response in primary breast cancer is unclear.
**Patients and Methods**
In this study we analyzed 3217 real-world and population-based early-stage primary breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096). Tissues were sampled from initial diagnosis prior to any treatment and analyzed for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by SAGAsafe droplet digital PCR.
**Results**
We identified *ESR1* resistance mutations in 30 cases (0.9%), of which 29 were ER-positive (1.1%). In ER-positive disease, presence of *ESR1* mutation was significantly associated to poor relapse-free survival (RFS) and overall survival (OS) (p=0.011 and p=0.019, respectively), and moreover predicted poor RFS and OS within the patient group that received ET (p=0.007 and p=0.010, respectively).
**Conclusions**
These results indicate that *ESR1* mutations at diagnosis of untreated primary breast cancer are rare, however we confirm for the first time that such early mutations predict eventual resistance to standard hormone therapy in the adjuvant setting. If replicated, tumor *ESR1* screening may be considered in ER-positive primary breast cancer and, in mutated cases, ER-degraders such as fulvestrant or other therapeutic options may be considered as more appropriate. ">
Background
More than three-quarters of primary breast cancers are positive for estrogen receptor alpha (ER; encoded by the gene ESR1), the most important factor for directing anti-estrogenic endocrine therapy. Although mutation in ESR1 is known as an acquired mechanism of resistance to endocrine therapy (ET), found in 12-55% of metastatic breast cancers treated previously with ET, the impact of ESR1 mutation on therapy response in primary breast cancer is unclear.
Patients and Methods
In this study we analyzed 3217 real-world and population-based early-stage primary breast cancers (within the SCAN-B study, ClinicalTrials.gov NCT02306096). Tissues were sampled from initial diagnosis prior to any treatment and analyzed for the presence of ESR1 mutations using RNA sequencing. Mutations were verified by SAGAsafe droplet digital PCR.
Results
We identified ESR1 resistance mutations in 30 cases (0.9%), of which 29 were ER-positive (1.1%). In ER-positive disease, presence of ESR1 mutation was significantly associated to poor relapse-free survival (RFS) and overall survival (OS) (p=0.011 and p=0.019, respectively), and moreover predicted poor RFS and OS within the patient group that received ET (p=0.007 and p=0.010, respectively).
Conclusions
These results indicate that ESR1 mutations at diagnosis of untreated primary breast cancer are rare, however we confirm for the first time that such early mutations predict eventual resistance to standard hormone therapy in the adjuvant setting. If replicated, tumor ESR1 screening may be considered in ER-positive primary breast cancer and, in mutated cases, ER-degraders such as fulvestrant or other therapeutic options may be considered as more appropriate.