Activating ESR1 mutations in hormone-resistant metastatic breast cancer

Robinson, Dan R.; Wu, Yi; Vats, Pankaj; Su, Fengyun; Lonigro, Robert J.; Cao, Xuhong; Kalyana-Sundaram, Shanker; Wang, Rui; Yu, Na; Hodges, Lynda; Gursky, Amy; Siddiqui, Javed; Tomlins, Scott A.; Roychowdhury, Sameek; Pienta, Kenneth J.; Kim, Scott Y. H.; Roberts, Jonathan; Rae, James M.; Poznak, Catherine Van; Hayes, Daniel F.; Chugh, Rashmi; Kunju, Lakshmi P.; Talpaz, Moshe; Schott, Anne F.; Chinnaiyan, Arul M.

doi:10.1038/ng.2823

Cited by 972 publications

(870 citation statements)

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“…This finding is consistent with the known concept of tumor heterogeneity within a primary tumor and metastatic sites (25). These findings are also in accord with recent data demonstrating that acquired ER mutations can be found in liver metastatic lesions, but not pulmonary metastases within the same patient (15), and additional studies revealing that ER mutations are relatively rare in primary breast cancers but are more common after acquired resistance to endocrine therapies (12)(13)(14)16). Gene expression qRT-PCR data from the prior analysis in Fig. 1B correlated with IHC results for the metastatic sites queried in these five patients.…”

Section: Macrod2 Is Amplified In a Subset Of Tamoxifen-resistant Breastsupporting

confidence: 81%

“…In part, this is due to the heterogeneous nature of breast cancers, resulting in multiple mechanisms of resistance. For example, past studies have demonstrated that tamoxifen resistance is mediated by differential expression of nuclear hormone receptor coregulators (2, 3), growth factor signaling crosstalk (4-7), regulation of microRNAs (8), cyclin dependent kinases (CKDs) (9), CDK inhibitors (10,11), and more recently, acquired somatic mutations and alterations in ER (12)(13)(14)(15)(16)(17). Further insight into the molecular mediators of tamoxifen and hormone therapy resistance would have great impact on the ability to target genes and pathways that could overcome drug resistance and lead to improved clinical outcomes.…”

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confidence: 99%

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MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

Mohseni

Cidado

Croessmann

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Tamoxifen is effective for treating estrogen receptor-alpha (ER) positive breast cancers. However, few molecular mediators of tamoxifen resistance have been elucidated. Here we describe a previously unidentified gene, MACROD2 that confers tamoxifen resistance and estrogen independent growth. We found MACROD2 is amplified and overexpressed in metastatic tamoxifen-resistant tumors. Transgene overexpression of MACROD2 in breast cancer cell lines results in tamoxifen resistance, whereas RNAi-mediated gene knock down reverses this phenotype. MACROD2 overexpression also leads to estrogen independent growth in xenograft assays. Mechanistically, MACROD2 increases p300 binding to estrogen response elements in a subset of ER regulated genes. Primary breast cancers and matched metastases demonstrate MACROD2 expression can change with disease evolution, and increased expression and amplification of MACROD2 in primary tumors is associated with worse overall survival. These studies establish MACROD2 as a key mediator of estrogen independent growth and tamoxifen resistance, as well as a potential novel target for diagnostics and therapy.breast cancer | tamoxifen | resistance | MACROD2 | ER positive T he selective estrogen receptor modulator (SERM) tamoxifen is a highly effective drug for the prevention and treatment of estrogen receptor-alpha (ER) positive breast cancers (1). However, resistance to this drug remains a clinically important problem. The molecular mediators of tamoxifen resistance have not been fully elucidated. In part, this is due to the heterogeneous nature of breast cancers, resulting in multiple mechanisms of resistance. For example, past studies have demonstrated that tamoxifen resistance is mediated by differential expression of nuclear hormone receptor coregulators (2, 3), growth factor signaling crosstalk (4-7), regulation of microRNAs (8), cyclin dependent kinases (CKDs) (9), CDK inhibitors (10, 11), and more recently, acquired somatic mutations and alterations in ER (12-17). Further insight into the molecular mediators of tamoxifen and hormone therapy resistance would have great impact on the ability to target genes and pathways that could overcome drug resistance and lead to improved clinical outcomes.In this study we describe a previously unidentified gene, MACROD2, which is amplified and overexpressed in a subset of breast cancers. MACROD2 belongs to a family of genes containing a macro domain, an evolutionarily conserved protein motif (18), whose functional role until recently has been unclear. Studies have demonstrated that MACROD2 deacetylates O-acetyl-ADP ribose, a signaling molecule generated by the deacetylation of acetylated lysine residues in histones and other proteins (19). More recent work demonstrates that MACRO domain containing proteins are involved with mono-ADP ribosylation, and can regulate cell signaling pathways and modify proteins involved with gene transcription (20). Interestingly, MACROD1 (LRP16) has been implicated in modulating ER and androgen receptor (AR) signaling in prio...

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Section: Macrod2 Is Amplified In a Subset Of Tamoxifen-resistant Breastsupporting

confidence: 81%

mentioning

confidence: 99%

MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

Mohseni

Cidado

Croessmann

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…We considered concordant DNA alterations only when the exact same sequencing alteration was present in both biopsies. It is critical to detect specific sequencing variants that may guide resistance patterns to treatment such as endocrine therapy, for example, mutations in ESR1 (28). Collectively, these data indicate that ctDNA may be best utilized as a predictive tool to identify certain important genomic alterations given the high specificity.…”

Section: Discussionmentioning

confidence: 99%

Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Circulating Tumor DNA in Breast Cancer

Chae

Davis

Jain

et al. 2017

Molecular Cancer Therapeutics

119

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While identifying genomic alterations in tumor tissue is the current gold-standard technique for molecular profiling, circulating tumor DNA (ctDNA) represents a noninvasive method of assessing genomic alterations using peripheral blood. The concordance of genomic alterations between two commercially available ctDNA and tissue biopsies was compared in 45 patients with breast cancer using paired next-generation sequencing tissue and ctDNA biopsies. Across all genes, concordance between the two platforms was 91.0% to 94.2%. When only considering genomic alterations in either assay (e.g., excluding wild type/wild type genes), concordance was 10.8% to 15.1% with full plus partial concordance of 13.8% to 19.3%. Concordant mutations were associated with significantly higher variant allele frequency. Over half of mutations detected in either technique were not detected using the other biopsy technique. Including variants of unknown significance, the average number of alterations per patient was significantly higher for tissue (4.56) compared with ctDNA (2.16). When eliminating alterations not detectable in the ctDNA assay, mean number of alterations for tissue and ctDNA was similar (2.67 for tissue, 2.16 for ctDNA). Across five representative genes (TP53, PIK3CA, ERBB2, BRCA1, and BRCA2), sensitivity and specificity were 35.7% and 95.0%, respectively. Concordance when genomic alterations was detected in either tissue or ctDNA was low with each technique detecting a significant amount of nonoverlapping mutations. Potential explanations for the lack of concordance include tumor heterogeneity, different sequencing techniques, spatial and temporal factors, and potential germline DNA contamination. The study indicates that both tissue and blood-based NGS may be necessary to describe the complex biology of breast cancer.

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“…Previous studies have reported that TP53 mutations are found in more than 80% of ctDNA samples. Mutations in the ESR1 gene are acquired in approximately 20% of breast cancers patients treated with endocrine agents and constitute a mechanism of resistance to aromatase inhibitors [38][39][40].…”

Section: Discussionmentioning

confidence: 99%

WITHDRAWN: Prognostic value of circulating tumor DNA in breast cancers

Gui¹,

Chen²,

Xu³

et al. 2018

Oncotarget

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Circulating tumor DNA (ctDNA) comprises single-or double-stranded DNA that likely originates from cancer cells. The prognostic value of ctDNA detection in breast cancer patients is currently under debate. Here, we conducted the first comprehensive meta-analysis of the published literature on the prognostic relevance of ctDNA, in patients with early-and advanced-stage disease.The PubMed and Embase databases were searched for studies on ctDNA in breast cancer patients.The main outcomes analyzed were overall survival (OS) and disease-free survival (DFS) in early-stage breast cancer patients as well as progression-free survival (PFS) and OS in metastatic breast cancer patients. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using random and fixed-effects models. A total of 16 studies involving 2070 participants were identified as eligible for inclusion in our meta-analysis, and the results of the pooled analysis showed that the presence of ctDNA was significantly associated with poor OS (HR = 1.98; 95% CI: 1.38-2.83, P = 0.0002) and DFS/PFS (HR = 1.87; 95% CI: 1.35-2.60, P = 0.0002) in the total breast cancer population. Furthermore, subgroup analysis revealed that associations between the presence of ctDNA and the outcome endpoints (OS and PFS) were significant within the metastatic breast cancer patient group and in patients with TP53 or ESR1 mutations in ctDNA.The TP53 and ESR1 mutations in ctDNA are potential prognostic biomarkers and promising therapeutic targets for advanced breast cancer.www.impactjournals.com/oncotarget/

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Activating ESR1 mutations in hormone-resistant metastatic breast cancer

Cited by 972 publications

References 41 publications

MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

MACROD2 overexpression mediates estrogen independent growth and tamoxifen resistance in breast cancers

Concordance of Genomic Alterations by Next-Generation Sequencing in Tumor Tissue versus Circulating Tumor DNA in Breast Cancer

WITHDRAWN: Prognostic value of circulating tumor DNA in breast cancers

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