146P - ESR1 fusions as potential mechanism of resistance to endocrine therapy in metastatic breast cancer

Background

Gene fusions are integral to pathway discovery of several solid tumors, including advanced lung cancers. However, their clinical significance in breast cancer is not well evaluated.

Methods

We retrospectively reviewed NGS profiling of 503 tissues of breast cancers of all stages including 2 cases of breast adenoid cystic carcinoma. We further evaluated the tissue RNA based comprehensive fusion analysis for 930 fusion partners in 51 genes.

Results

In tissue-based sequencing, TP53 was the most commonly altered gene (52%). PIK3CA and ESR1 mutations were detected in 32% and 7% respectively. AKT1 was mutated in 4% and PTEN in 5%. NF1 was mutated in 3%. ERBB2 amplification was observed in 10% of the cases. In a sub cohort comprising 330 specimens, TMB analysis showed a median TMB of 5 mut/Mb (range 1 - 88 mut/Mb), and 16% specimens with TMB-High (≥10 mut/mb). The fusion analysis revealed 38 fusions in 7 % (35/503) cases. The most commonly observed fusions were in ESR1 contributing to 53% of total fusions followed by WNT pathway associated RSPO2 fusions. The RSPO2-EIF3E fusions were more common in TNBC. MYB-NFIB fusion were observed in both cases of adenoid cystic carcinoma of breast. ESR1 fusions were present in hormone receptor-positive breast cancers and were linked to prior endocrine therapy use. ESR1 fusions were the sole driver of potential endocrine resistance in most of these cases with no simultaneous ESR1 mutations observed. ESR1 fusions are potential recurrent drivers of endocrine therapy resistance and are impervious to ER-targeted therapies. Table: 146P

Types of ESR1 fusion variants

Conclusions

We observed ESR1 fusions in advanced hormone-positive breast cancer cases, and probabe mechanisms of resistance to hormonal therapy. They were observed predominantly as mutually exclusive from ESR1 mutations. Clinical studies need to focus on outcomes of hormone therapies in these ESR1 fusion-positive patients, as there are no clear guidelines available currently for management of this cohort.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

Datar Cancer Genetics.

Funding

Has not received any funding.

Disclosure

S. Limaye, A.K. Vaid, A. Gaya, T. Crook: Non-Financial Interests, Personal, Advisory Board: Datar Cancer Genetics. D.S. Patil: Financial Interests, Personal, Full or part-time Employment: Datar Cancer Genetics.