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:BackgroundAdvanced breast cancer (ABC) is characterized by multidimensional clinical complexity that is usually not considered in randomized clinical trials. In the present real-life study, we investigated the link between clinical complexity and quality of life of patients with HR+/HER2- ABC treated with CDK4/6 inhibitors.MethodsWe evaluated multimorbidity burden assessed with the Cumulative Illness Rating Scale (CIRS), polypharmacy and patient-reported outcomes (PROs). PROs were assessed at baseline (T0), after 3 months of therapy (T1), and at disease progression (T2) using EORTC QLC-C30 and QLQ-BR23 questionnaires. Baseline PROs and changes between T0 and T1 were evaluated amongst patients with different multimorbidity burden (CIRS <5 and ≥5) and polypharmacy (<2 or ≥2 drugs).ResultsFrom January 2018 to January 2022, we enrolled 54 patients (median age 66 years, IQR 59-74). The median CIRS score was 5 (IQR 2-7), whilst the median number of drugs taken by patients was 2 (IQR 0-4). No changes in QLQ-C30 final scoring between T0 and T1 were observed in the overall cohort (p=0.8944). At T2, QLQ-C30 global score deteriorated with respect to baseline (p=0.0089). At baseline, patients with CIRS ≥5 had worse constipation than patients without comorbidities (p<0.05) and a lower trend in the median QLQ-C30 global score. Patients on ≥2 drugs had lower QLQ-C30 final scores and worse insomnia and constipation (p<0.05). No change in QLQ-C30 final score from T0 to T1 was observed (p>0.05).ConclusionMultimorbidity and polypharmacy increase the clinical complexity of patients with ABC and may affect baseline PROs. The safety profile of CDK4/6 inhibitors seems to be maintained in this population. Further studies are needed to assess clinical complexity in patients with ABC.This article is part of the Tackling clinical complexity in breast cancer Special Issue: https://www.drugsincontext.com/special_issues/tackling-clinical-complexity-in-breast-cancer/.

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.

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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.