Kinome reprogramming as a therapeutic opportunity in ESR1 fusion driven breast cancer but not in gynecologic cancers.
Authors: Ravi Chakra Turaga, Shivani Jagannathan Murali, Cristina Ivan, Bharath Kumar Karre, Chao Sima, Asfetaw Abera, Milan Radovich, Heather O'Neill
Journal: Journal of Clinical Oncology (2024)

1045 Background: The administration of specific tyrosine-kinase inhibitors in kinase fusion positive cancers has led to significant improvement in clinical outcomes. Gene fusions involving the ESR1 gene, a non-kinase, have been previously reported in breast and gynecologic cancers including ovarian cancer and uterine cancer. However, ERa inhibitors proved to be ineffective in ESR1 fusion positive cases, we have effectively characterized ESR1 fusions and hypothesized a surrogate downstream target as an effective approach to target ESR1 fusion positive breast cancer. Methods: We retrospectively analyzed 216,176 samples submitted for clinical molecular profiling at Caris Life Sciences via Caris MI Tumor Seek (Phoenix, AZ). Gene fusion detection was performed on mRNA isolated from a FFPE tumor sample using the Illumina NovaSeq platform. All ESR1 fusions with ≥ 3 junction reads were identified for manual review and for domain prediction, breakpoints, frame retention and co-occurring alterations by NGS. WES data was also investigated to evaluate co-occurring pathogenic mutations to establish the oncogenicity of gene fusions. Results: ESR1 fusions had the highest frequency in gynecologic and breast cancer. We evaluated ESR1 expression in cases with ESR1 fusions detected and observed higher expression of ESR1 in breast cancer, ovarian cancer (P&lt;0.0001) and uterine cancer (P&lt;0.0001) compared to respective cancer cases as determined by TPM values. The Kaplan-Meier curve also indicated poor prognosis for breast cancer patients with ESR1 fusions (619 days [n=105]) as opposed to patients who did not harbor any ESR1 variants (1396 days [n=755]; P&lt;0.0001). Further, pathway analysis was performed on breast cancer ESR1 fusion positive and negative cases to discern specific downstream markers that might be upregulated. It was observed that RET(p&lt;0.0001), IGF1R(p=0.0001) and FGFR3 (p&lt;0.0001) were upregulated in ESR1 fusion positive breast cancer cases which may be largely determined by the TP53-FOXA1-ER alpha transcriptional axis. However, no significant increase of RET, IGF1R and FGFR3 was observed in gynecologic cancers, owing to high TP53 mutation frequency observed in ovarian cancer (90%) and uterine cancer (82%) compared to breast cancer(19%). Conclusions: We highlight that ESR1 fusions can be reliably detected in patients with breast cancer, ovarian cancer, and endometrial cancers. ESR1 fusions lose the ligand binding domain and cannot be targeted using current estrogen modulators or degraders. We have discovered the upregulation of oncogenic kinase signaling in ESR1 fusion positive breast cancer, but not in gynecologic cancers. Our observations highlight enhanced oncogenic kinase signaling as a surrogate approach with clinically approved kinase inhibitors for targeting ESR1 fusion positive breast cancer cases but not in ovarian and uterine cancers.