Dataset Information

Automated Quantification of Extranuclear ER? using Phosphor-integrated Dots for Predicting Endocrine Therapy Resistance in HR⁺/HER2^- Breast Cancer.

ABSTRACT: In addition to genomic signaling, Estrogen receptor alpha (ER?) is associated with cell proliferation and survival through extranuclear signaling contributing to endocrine therapy (ET) resistance. However, the relationship between extranuclear ER? and ET resistance has not been extensively studied. We sought to measure extranuclear ER? expression by immunohistochemistry using phosphor-integrated dots (IHC-PIDs) and to assess its predictive value for ET resistance. After quantitative detection of ER? by IHC-PIDs in vitro, we developed "the nearest-neighbor method" to calculate the extranuclear ER?. Furthermore, tissue sections from 65 patients with HR+/HER2- BC were examined by IHC-PIDs, and the total ER?, nuclear ER?, extranuclear ER? PIDs score, and ratio of extranuclear-to-nuclear ER? (ENR) were measured using the novel method. We demonstrate that quantification of ER? using IHC-PIDs exhibited strong correlations to real-time qRT-PCR (r² = 0.94) and flow cytometry (r² = 0.98). High ER? ENR was significantly associated with poor overall survival (p = 0.048) and disease-free survival (DFS) (p = 0.007). Multivariate analysis revealed that the ER? ENR was an independent prognostic factor for DFS [hazard ratio, 3.8; 95% CI, 1.4-11.8; p = 0.006]. Our automated measurement has high accuracy to localize and assess extranuclear ER?. A high ER? ENR in HR⁺/HER2^- BC indicates decreased likelihood of benefiting from ET.

SUBMITTER: Guo Z

PROVIDER: S-EPMC6520781 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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Automated Quantification of Extranuclear ERα using Phosphor-integrated Dots for Predicting Endocrine Therapy Resistance in HR<sup>+</sup>/HER2<sup>-</sup> Breast Cancer.

Guo Zhaorong Z Tada Hiroshi H Kitamura Narufumi N Hamada Yoh Y Miyashita Minoru M Harada-Shoji Narumi N Sato Akiko A Hamanaka Yohei Y Tsuboi Kouki K Harada Nobuhisa N Takano-Kasuya Mayumi M Okada Hisatake H Nakano Yasushi Y Ohuchi Noriaki N Hayashi Shin-Ichi SI Ishida Takanori T Gonda Kohsuke K

Cancers 20190412 4

In addition to genomic signaling, Estrogen receptor alpha (ERα) is associated with cell proliferation and survival through extranuclear signaling contributing to endocrine therapy (ET) resistance. However, the relationship between extranuclear ERα and ET resistance has not been extensively studied. We sought to measure extranuclear ERα expression by immunohistochemistry using phosphor-integrated dots (IHC-PIDs) and to assess its predictive value for ET resistance. After quantitative detection of ...[more]

PMID: 31013810

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Project description:Breast cancer (BC) is the most common malignancy in women worldwide, with approximately two-thirds having hormone receptor-positive (HR+) tumors. New endocrine therapy (ET) strategies include combining ET agents as well as adding inhibitors targeting growth factors, angiogenesis, the mechanistic target of rapamycin, phosphoinositide 3-kinase (PI3K), or cyclin-dependent kinase 4/6 to ET. Level 1 evidence supports use of fulvestrant plus anastrozole or palbociclib plus letrozole as first-line therapy for HR+/HER- advanced BC with special consideration for the former in ET-naïve patients, as well as everolimus plus exemestane or palbociclib plus fulvestrant as second-line therapy with special consideration in select first-line patients. Although the safety profiles of these combinations are generally predictable and manageable, both everolimus and palbociclib are associated with an increased risk of potentially serious or early-onset toxicities requiring individualized a priori adverse event risk stratification, earlier and more rigorous agent-specific monitoring, and patient education. Although each of these combinations improves progression-free survival, none with the exception of anastrazole plus fulvestrant have demonstrated improved overall survival. PI3K catalytic-? mutations assessed from circulating tumor DNA represent the first potentially viable serum biomarker for the selection of ET combinations, and new data demonstrate the feasibility of this minimally invasive technique as an alternative to traditional tissue analysis. Therapeutic ratios of select ET combinations support their use in first- and second-line settings, but optimal sequencing has yet to be determined.2017;22:12-24 IMPLICATIONS FOR PRACTICE: Emerging data show that new endocrine therapy (ET) combinations can improve progression-free and overall survival outcomes in patients with hormone receptor-positive, HER2-negative (HR+/HER-) advanced breast cancer. Level 1 evidence supports consideration of dual ET regimens, particularly in ET-naïve patients, or palbociclib plus letrozole as first-line therapy, as well as the addition of mTOR or CDK4/6 inhibitors to established ET in the second-line setting and in select first-line patients. Some combinations are associated with increased risk of class-specific toxicities that will require individualized risk stratification, earlier and more rigorous agent-specific monitoring, and patient education. Recent data on a noninvasive biomarker assay that predicts response to a phosphoinositide 3-kinase inhibitor demonstrates the feasibility of this minimally invasive technique as an alternative to traditional tissue analysis.

Project description:BackgroundEstrogen receptor (ER) positive breast cancer is often effectively treated with drugs that inhibit ER signaling, i.e., tamoxifen (TAM) and aromatase inhibitors (AIs). However, 30% of ER+ breast cancer patients develop resistance to therapy leading to tumour recurrence. Changes in the methylation profile have been implicated as one of the mechanisms through which therapy resistance develops. Therefore, we aimed to identify methylation loci associated with endocrine therapy resistance.MethodsWe used genome-wide DNA methylation profiles of primary ER+/HER2- tumours from The Cancer Genome Atlas in combination with curated data on survival and treatment to predict development of endocrine resistance. Association of individual DNA methylation markers with survival was assessed using Cox proportional hazards models in a cohort of ER+/HER2- tumours (N =?552) and two sub-cohorts corresponding to the endocrine treatment (AI or TAM) that patients received (N =?210 and N =?172, respectively). We also identified multivariable methylation signatures associated with survival using Cox proportional hazards models with elastic net regularization. Individual markers and multivariable signatures were compared with DNA methylation profiles generated in a time course experiment using the T47D ER+ breast cancer cell line treated with tamoxifen or deprived from estrogen.ResultsWe identified 134, 5 and 1 CpGs for which DNA methylation is significantly associated with survival in the ER+/HER2-, TAM and AI cohorts respectively. Multi-locus signatures consisted of 203, 36 and 178 CpGs and showed a large overlap with the corresponding single-locus signatures. The methylation signatures were associated with survival independently of tumour stage, age, AI treatment, and luminal status. The single-locus signature for the TAM cohort was conserved among the loci that were differentially methylated in endocrine-resistant T47D cells. Similarly, multi-locus signatures for the ER+/HER2- and AI cohorts were conserved in endocrine-resistant T47D cells. Also at the gene set level, several sets related to endocrine therapy and resistance were enriched in both survival and T47D signatures.ConclusionsWe identified individual and multivariable DNA methylation markers associated with therapy resistance independently of luminal status. Our results suggest that these markers identified from primary tumours prior to endocrine treatment are associated with development of endocrine resistance.

Dataset Information

Automated Quantification of Extranuclear ER? using Phosphor-integrated Dots for Predicting Endocrine Therapy Resistance in HR⁺/HER2^- Breast Cancer.

Publications

Automated Quantification of Extranuclear ERα using Phosphor-integrated Dots for Predicting Endocrine Therapy Resistance in HR<sup>+</sup>/HER2<sup>-</sup> Breast Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

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Dataset Information

Automated Quantification of Extranuclear ER? using Phosphor-integrated Dots for Predicting Endocrine Therapy Resistance in HR+/HER2- Breast Cancer.

Publications

Automated Quantification of Extranuclear ERα using Phosphor-integrated Dots for Predicting Endocrine Therapy Resistance in HR<sup>+</sup>/HER2<sup>-</sup> Breast Cancer.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Automated Quantification of Extranuclear ER? using Phosphor-integrated Dots for Predicting Endocrine Therapy Resistance in HR⁺/HER2^- Breast Cancer.