Abstract P5-11-02: Recurrent ESR1 fusions in primary tumors; a promising predictive factor for outcome to first-line endocrine therapy?

Abstract

Introduction: While fusion genes have been identified and are being utilized as prognostic and predictive markers in various types of cancer, their relevance still needs to be established and verified for breast cancer. Recently, recurrent estrogen receptor alpha (ESR1) fusion genes have been identified as putative endocrine resistance markers, but their predictive value for response to endocrine therapy has not yet been independently validated. Here we studied the presence of fusions of ESR1 exon 2 with exons 1 to 11 of CCDC170, resulting in constitutively activated CCDC170, of ESR1 exon 4 with AKAP12, a putative tumor-suppressor gene, and ESR1 exon 1 with C6orf211/ARMT1, a methyltransferase and their association with outcome in a large cohort of ESR1-positive metastatic breast cancer patients. Methods: Fusion gene mRNA levels were measured in 307 ESR1-positive primary tumors by quantitative reverse transcriptase PCR (RT-qPCR). If the RT-qPCR generated a positive Cq value, the expected fusion gene product sizes were validated by MultiNA. All patients in this study were hormone-naïve and all experienced a recurrence and subsequently received 1st line endocrine therapy. The association of the presence of ESR1 fusion genes in the primary tumor with disease-free interval (DFI) before, and progression-free survival (PFS) up to 36 months after start with 1st line tamoxifen (n=219) or aromatase inhibitors (n=88), were evaluated. Results: 74 patients (24.1%) experienced a disease recurrence within one year after removal of the primary tumor (mean DFI; 34.8 months) and 257 patients (83.7%) progressed on 1st-line endocrine therapy within 3 years (mean PFS; 12.5 months). For the tamoxifen cohort, ESR1-CCDC170 fusion transcripts were found in 84 patients, of which fusions restricted to exon 1, 4, 6, 10 and 11 of CCDC170 were present in 18 patients who all but one progressed within 3 years (mean PFS 9.1 months). Of note, overall, these 18 patients also had a reduced DFI. Similarly for the 7 patients with ESR1-AKAP12 fusions and the one patient with an ESR1- ARMT fusion; all these patients progressed within 3 years. But in contrast to the ESR1-CCDC170 fusion positive patients, these patients had a prolonged DFI {see Table). Similar observations were made for the smaller AI cohort, though with the - with respect to their predictive value - most relevant ESR1-CCDC170 fusions restricted to exon 4, 5, 6 and 10 of CCDC170 and here we now also observed a decreased DFI for the 7 patients with ESR1-AKAP12 and the 3 patients with ESR1- ARMT1 fusions (see Table). 1st line tamoxifen (n=219)1st line AI (n=88)Fusion% positiveDFI (months) pos/allPFS (months) pos/allFusion% positiveDFI (months) pos/allPFS (months) pos/allE2-CCDC170 Exon 2 to 1/4/6/10/118.2%19.8/27.99.1/12.0E2-CCDC170 Exon 2 to 4/5/6/1012.5%32.4/51.910.5/13.8E2-AKAP123.2%33.1/27.711.9/12.0E2-AKAP128.0%23.6/54.710.3/12.0E2-ARMT10.5%(n=1)(n=1)E2-ARMT13.4%30.3/52.79.3/12.0 Conclusion: Measuring recurrent ESR1 fusions in primary breast cancer might become a promising tool to identify patients with intrinsic resistance to endocrine therapy or aggressive disease biology. Importantly however, which fusions are relevant appears to depend on the type of endocrine therapy given. Citation Format: Sieuwerts AM, Vitale SR, Bos M, Sleijfer S, Martens JW. Recurrent ESR1 fusions in primary tumors; a promising predictive factor for outcome to first-line endocrine therapy? [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-11-02.

Fusion‐associated carcinomas of the breast: Diagnostic, prognostic, and therapeutic significance

“…The average progression-free survival for ESR1::CCDC170 positive and negative patients were 9.1 versus 12.0 months following tamoxifen treatment and 10.5 versus 13.8 months following aromatase inhibitor (AI) treatment, respectively. 50 These differences, however, did not reach statistical significance due to overall poor response of metastatic tumors to endocrine therapy (83.7% patients progressed within 3 years). This study emphasizes the need for future investigation of fusions in primary breast cancer patients treated with adjuvant endocrine therapy and the necessity for long-term follow-up of these patients to verify the correlation of ESR1::CCDC170 with endocrine response.…”

“…This suggests that fusion variants V2 and V4 are associated with lack of response to neoadjuvant letrozole treatment and that truncation of CCDC170 that removes CC1 and CC2 domains is sufficient to confer reduced endocrine sensitivity in patients. Furthermore, another clinical study detected ESR1::CCDC170 in the primary tumors of luminal breast cancer patients that experienced metastatic relapse 50 . The most relevant fusion variants involved ESR1 E2 and CCDC170 E4‐10 (V2‐5) which were detected in 28 of the 307 patients (9.1%) and resulted in a significantly worse disease‐free survival following initial surgery.…”

“…Unfortunately, no comprehensive study has detected ESR1 (exon 6) fusion proteins. In a cohort of advanced breast cancer patients, a 4.5% rate of ESR1::AKAP12 fusions was reported utilizing Reverse transcription‐polymerase chain reaction (RT‐PCR), 50 whereas in an evaluation of ER positive breast cancer patients with targeted sequencing, a 1.6% rate was determined for ESR1 fusions with breakpoints at ESR1 intron 6 52 . Although prevalence is likely underestimated due to limitations in detecting ESR1 (exon 6) fusions resulting from diverse 3′ binding partners, new targeted sequencing techniques are being explored taking advantage of the consistent presence of ESR1 exon and intron 6 in these fusions 30 .…”

“…As all patients included in the study were endocrine naïve, first‐line endocrine therapies were administered upon distant relapse. The average progression‐free survival for ESR1::CCDC170 positive and negative patients were 9.1 versus 12.0 months following tamoxifen treatment and 10.5 versus 13.8 months following aromatase inhibitor (AI) treatment, respectively 50 . These differences, however, did not reach statistical significance due to overall poor response of metastatic tumors to endocrine therapy (83.7% patients progressed within 3 years).…”

“…26,[45][46][47][48] In addition to breast cancer, a recent publication reported ESR1::CCDC170 as a recurrent event in ovarian cancer associated with exceptional short-term patients that experienced metastatic relapse. 50 The most relevant fusion variants involved ESR1 E2 and CCDC170 E4-10 (V2-5) which were detected in 28 of the 307 patients (9.1%) and resulted in a significantly worse disease-free survival following initial surgery. As all patients included in the study were endocrine naïve, first-line endocrine therapies were administered upon distant relapse.…”