68P - ESR1 gene mutation in hormone receptor (HR)-positive metastatic breast cancers: An NGS-based exploratory study on Indian population

Background

ESR1 gene mutation is an important prognostic and predictive biomarker in endocrine resistant metastatic breast cancers. There is limited knowledge on the incidence and types of ESR1 mutations in Indian breast cancer patients.

Methods

The research was conducted in ambispective manner, on HR-positive and HER2-negative MBCs. Next generation sequencing was done on formalin-fixed paraffin embedded (FFPE) tissues. DNA was extracted by enzymatic method, and library preparation was performed using QIAseq Target DNA Panel kit, for ESR1 and PIK3CA genes. Sequencing was done on Illumina HiSeq X series. The NGS output data was analyzed using in-house developed bioinformatics pipeline.

Results

Approximately 80 cases were subjected for NGS after successful DNA extraction and library preparation. Approximately 18 different ESR1 gene mutations were detected in 27.5% cases. Majority (n = 14) were clustered in ligand binding domain. Maximum mutations occurred at codon L536 (n = 8), L536P being the most common. Pathogenic variants D538Q and S463P were also detected. Patients with mutations were frequently above 50 years, post-menopausal, with IDC-NST morphology, grade 2 tumours, with strong ER, moderate PR and Ki67 >14%. The mutations were significantly associated visceral metastasis (p=0.02). The frequency of ESR1 mutations in metastatic samples was 24%, with higher frequency in bones than viscera. The mutations were detected in ovaries, distant lymph nodes, liver, brain and pleura. About 29.4% of treatment naïve MBCs harbored ESR1 mutation. We also detected mutation in a treatment naïve primary breast tumor, in post-aromatase inhibitors (30%) and post-tamoxifen (27.3%) treated samples. About 50% (11/22 patients) of ESR1 mutated patients also had PIK3CA mutations.

Conclusions

The overall frequency of ESR1 mutation in our study was in concordance with earlier studies. Unlike most of the earlier digital PCR-based studies, NGS helped us to detect new variants, whose pathogenic significance has not still been established. We were also able to detect mutations in rare instances, such as treatment-naïve and tamoxifen-treated cases, which warrant further exploration and validation.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

Kidwai Memorial Institute of Oncology.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.