Which threshold for ER positivity? a retrospective study based on 9639 patients

Yi, Mi Suk; Huo, Lei; Koenig, Kimberly; Mittendorf, Elizabeth A.; Meric‐Bernstam, Funda; Kuerer, Henry Mark; Bedrosian, Isabelle; Buzdar, Aman U.; Symmans, W. Fraser; Crow, J.; Bender, Matthew T.; Shah, R. R.; Hortobágyi, Gabriel N.; Hunt, Kelly K.

doi:10.1093/annonc/mdu053

Cited by 189 publications

(170 citation statements)

References 24 publications

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“…Given the results presented here demonstrating minimal efficacy with ER-targeting agents in PDX models with low/no ER/PR expression, this concept warrants further investigation. Indeed, a recent retrospective study comparing patients with tumors that were 1%-9% ER-positive versus greater than 10% ER positive suggested that the patients with lower ER positivity did not benefit from endocrine therapy (39). In fact, the lack of response to endocrine therapies in these patients was similar to patients with basal (ER-negative) disease; however, it would be important to confirm this with a randomized clinical study.…”

Section: Discussionmentioning

confidence: 99%

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models

Bihani

Patel

Arlt

et al. 2017

Clinical Cancer Research

116

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Purpose: Estrogen receptor-positive (ER þ ) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER þ breast cancer. Experimental Design: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER þ breast cancer models, including several patientderived xenograft models.

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Section: Discussionmentioning

confidence: 99%

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models

Bihani

Patel

Arlt

et al. 2017

Clinical Cancer Research

116

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“…Note that ER, PR, and HER2 were stained on tissue microarray slides in all cohorts, as these biomarkers are relative to Ki67 homogenously distributed in breast cancer tissue [26][27][28] and thereby well accepted for analysis in biopsies and tumor cores. 29,30 Gene Expression Assays For our first cohort, RNA was extracted from frozen tumor tissue using AllPrep DNA/RNA/Protein mini kit (Qiagen, Hilden, Germany) and assessed to ensure high quality (RIN 48). Next, 1 μg of RNA was used for rRNA depletion using the Ribo-Zero removal kit (Illumina, San Diego, CA, USA).…”

Section: Immunohistochemistrymentioning

confidence: 99%

Digital image analysis outperforms manual biomarker assessment in breast cancer

Stålhammar

Martínez

Lippert³

et al. 2016

Modern Pathology

145

116

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In the spectrum of breast cancers, categorization according to the four gene expression-based subtypes 'Luminal A,' 'Luminal B,' 'HER2-enriched,' and 'Basal-like' is the method of choice for prognostic and predictive value. As gene expression assays are not yet universally available, routine immunohistochemical stains act as surrogate markers for these subtypes. Thus, congruence of surrogate markers and gene expression tests is of utmost importance. In this study, 3 cohorts of primary breast cancer specimens (total n = 436) with up to 28 years of survival data were scored for Ki67, ER, PR, and HER2 status manually and by digital image analysis (DIA). The results were then compared for sensitivity and specificity for the Luminal B subtype, concordance to PAM50 assays in subtype classification and prognostic power. The DIA system used was the Visiopharm Integrator System. DIA outperformed manual scoring in terms of sensitivity and specificity for the Luminal B subtype, widely considered the most challenging distinction in surrogate subclassification, and produced slightly better concordance and Cohen's κ agreement with PAM50 gene expression assays. Manual biomarker scores and DIA essentially matched each other for Cox regression hazard ratios for all-cause mortality. When the Nottingham combined histologic grade (Elston-Ellis) was used as a prognostic surrogate, stronger Spearman's rank-order correlations were produced by DIA. Prognostic value of Ki67 scores in terms of likelihood ratio χ 2 (LR χ 2 ) was higher for DIA that also added significantly more prognostic information to the manual scores (LR− Δχ 2 ). In conclusion, the system for DIA evaluated here was in most aspects a superior alternative to manual biomarker scoring. It also has the potential to reduce time consumption for pathologists, as many of the steps in the workflow are either automatic or feasible to manage without pathological expertise.

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“…However prospective data addressing the optimal cutoff level correlated with the efficacy of endocrine treatment are lacking. In retrospective studies survival rates of patients with tumours expressing ER in 1e9% did not significantly differ from patients with ER <1% tumours [8]. In molecular subtyping studies most tumours expressing ER 1e9% show ERÀ, basal-like molecular characteristics [9].…”

Section: Introductionmentioning

confidence: 85%