The original author list of this Preview included a formatting error that has been corrected in the list above and with the Preview online.924 Cell 162, 924, August 13, 2015 ª2015 Elsevier Inc.
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.
Two recent observations have connected the innate immune DNA cytosine deaminase APOBEC3B to the genetic evolution of breast cancer. First, APOBEC3B was shown to be up-regulated in the majority of breast cancers, and, in breast cancer cell lines, its activity was causally linked to a doubling of the number of C-to-T transitions over time and to a delay in cell cycle progression (1). Second, sequencing of the complete genome of 21 breast cancers independently suggested that APOBEC deaminase activity could be responsible for 2 of 5 mutational imprints identified, which involved clustered (also called kataegis) and dispersed C-to-T transition mutations in the context of 5’TC dinucleotide motifs (2). In the current study, we addressed a possible association of APOBEC3B expression with outcome in clinical breast cancer. For this we measured using real-time RT-PCR APOBEC3B mRNA levels in 1,491 primary invasive breast cancers and correlated these levels with disease-free survival (DFS), metastasis-free survival (MFS) and overall survival (OS) using univariate and multivariable Cox regression analysis. In addition, we independently validated our findings in available gene expression datasets with appropriate follow-up. In univariate analyses including all patients, increasing levels of APOBEC3B mRNA analyzed as a continuous variable were significantly associated with shorter DFS, MFS and OS (Hazard Ratio [HR] = 1.29, 1.31 and 1.36, respectively, all P<0.001). To determine the relation of APOBEC3B mRNA expression with the natural course of the disease without the potential confounding effects of systemic adjuvant therapy, we restricted our next analyses to MFS in 829 patients with lymph node-negative disease who had not received any (neo)adjuvant systemic therapy. This analysis showed that APOBEC3B mRNA expression was, in univariate, and in multivariable analysis, including the traditional prognostic factors (age, menopausal status, tumor size, grade and steroid hormone receptors), a marker of pure prognosis specifically in patients with estrogen receptor-positive (ER+) disease (univariate HR = 1.30; P = 0.003; multivariate HR = 1.22, P = 0.042). To substantiate and validate our findings, we analysed 4 independent available datasets containing in total 5,760 breast cancer cases in which APOBEC3B mRNA expression was measured by probes on microarrays and found that higher APOBEC3B mRNA expression (dichotomised by mean) was significantly associated with poor outcome in all 4 cohorts ([Metabric, 1,491 ER+ cases, HR = 1.82; P<0.001], [Affymetrix compiled dataset-1, 2,407 cases, HR = 2.22; P = 0.001], and [BIG 1-98; 1,207 cases, HR = 2.13; P<0.001 of late recurrence>5 years], and [Affymetrix dataset-2, 643 ER+ cases, HR = 2.04; P = 0.001]). Altogether, our analyses show that APOBEC3B mRNA - and as a result likely DNA deamination – is a validated predictor of poor outcome in breast cancer, supporting the notion that APOBEC3B is a potentially interesting clinical target for therapeutic intervention to prevent breast cancer progression and metastasis, particularly in ER+ disease. 1. Burns, M.B. et al. Nature 494, 366-70 (2013); 2. Nik-Zainal, S. et al. Cell 149, 979-93 (2012). Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S6-05.
Background: We showed that decreased expression levels of EZH2 are associated with a favorable outcome to tamoxifen in advanced breast cancer. Furthermore, EZH2 knockdown in MCF7 cells resulted in estrogen receptor (ER) upregulation and increased sensitivity to anti-estrogens. Recently, EZH2 has been identified as a target of miRNA26A1 and miRNA101. Objective: To associate miRNA26A1 and miRNA101 expression levels with: A) EZH2 and B) molecular pathways and C) outcome to first-line tamoxifen monotherapy for advanced disease. Materials & Methods: Expression levels of miRNA26A1, miRNA101, EZH2 and references (miRNA-132 and miRNA-374) were measured using quantitative Real-Time Polymerase Chain Reaction (qRT-PCR) in 235 ER-positive primary breast cancer specimens from patients with advanced disease. The levels of expression were related to clinicopathologic factors and disease outcome. Pathway analysis was performed in a subset of 65 ER-positive tumors with available gene expression microarray data available. Computations were performed with STATA and P-values <0.05 were considered statistically significant. Results: The miRNA26A1 levels were significantly associated with levels of ER, progesterone (PgR), HER2 and EGFR, whereas miRNA101 levels showed significant relations with PgR expression and menopausal status. The miRNA26A1 and miRNA101 levels showed an inverse relation with EZH2 mRNA levels (Spearman Rank Correlation of -0.21 and -0.15, respectively, P<0.05). As continuous variable in univariate analysis, miRNA26A1 (Hazard Ratio (HR) =0.13, 95 % CI: 0.06-0.28) correlated with Time to Progression (TTP), while miRNA101 did not (HR=0.87, 95% CI: 0.70-1.07). In multivariate analysis including traditional predictive factors, the third with highest miRNA26A1 levels (HR=0.49, 95% CI: 0.34-0.72) alone, or combined with the third with lowest EZH2 levels (HR=0.56, 95% CI: 0.35-0.88) were associated with a favorable TTP independently of traditional factors. Pathway analyses identified 2 overlapping, cell cycle, related pathways with two genes (CCNE1and CDC2) differentially expressed (P<0.05) between tumors with high and low levels of miRNA26A1 and EZH2, respectively. Levels of CCNE1 and CDC2 were tested in the 235 tumors and showed as continuous variables also a significant association with TTP (HR=1.27, 95% CI: 1.12-1.45 and HR=1.53, 95% CI: 0.129-1.81). Conclusions: The miRNA26A1 and miRNA101 levels have an inverse relation with levels of EZH2, however, only miRNA26A1 has predictive value in advanced breast cancer. Pathways comparison between miRNA26A1 and EZH2 identified 2 overlapping cell cycle related pathways and the genes CCNE1 and CDC2. Low levels of EZH2, CCNE1 and CDC2 and high levels of miRNA26A1 are associated with a favorable outcome to tamoxifen therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-16.
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