Multifactorial Approach to Predicting Resistance to Anthracyclines

Desmedt, Christine; Leo, Angelo Di; Azambuja, Evandro de; Larsimont, Denis; Haibe‐Kains, Benjamin; Selleslags, Jean; Delaloge, Suzette; Duhem, Caroline; Kains, Jean-Pierre; Carly, Birgit; Maerevoet, Marie; Vindevoghel, A.; Rouas, Ghizlane; Lallemand, Françoise; Durbecq, Virginie; Cardoso, Fátima; Salgado, Roberto; Rovere, Rodrigo Kraft; Bontempi, Gianluca; Michiels, Stefan; Buyse, Marc; Nogaret, Jean-Marie; Qi, Yuan; Symmans, Fraser; Pusztai, Lajos; D’Hondt, Véronique; Piccart‐Gebhart, Martine; Sotiriou, Christos

doi:10.1200/jco.2010.31.2231

Cited by 172 publications

(121 citation statements)

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“…pCR was defined as loss of the invasive component of the primary tumor in one study (33) and no residual invasive cancer in the breast and axillary lymph nodes in other seven studies (34)(35)(36)(37)(38).…”

Section: Discussionmentioning

confidence: 99%

“…We further evaluated whether AR mRNA expression were associated with response to neoadjuvant CT (anthracyclines AE taxanes). Out of 1,005 patients from eight datasets (33)(34)(35)(36)(37)(38), 235 (23%) patients achieved pCR, 765 (76%) did not, while five samples were inadequate for the analysis. High AR expression levels showed significant association with lower pCR rate (OR, 0.57; 95% CI, 0.44-0.74, P < 0.001) in the univariate analysis while not significant in a multivariate model (OR, 0.74; 95% CI, 0.54-1.01, P ¼ 0.063; Fig.…”

Section: Prognostic Significance Of Ar Expressionmentioning

confidence: 99%

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The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data

Božović-Spasojević

Zardavas

Brohée

et al. 2017

Clinical Cancer Research

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Purpose: Androgen receptor (AR) expression has been observed in about 70% of patients with breast cancer, but its prognostic role remains uncertain.Experimental Design: To assess the prognostic role of AR expression in early-stage breast cancer, we performed a metaanalysis of studies that evaluated the impact of AR at the protein and gene expression level on disease-free survival (DFS) and/or overall survival (OS). Eligible studies were identified by systematic review of electronic databases using the MeSH-terms "breast neoplasm" and "androgen receptor" and were selected after a qualitative assessment based on the REMARK criteria. A pooled gene expression analysis of 35 publicly available microarray data sets was also performed from patients with early-stage breast cancer with available gene expression and clinical outcome data.Results: Twenty-two of 33 eligible studies for the clinical meta-analysis, including 10,004 patients, were considered as evaluable for the current study after the qualitative assessment. AR positivity defined by IHC was associated with improved DFS in all patients with breast cancer [multivariate (M) analysis, HR 0.46; 95% confidence interval (CI) 0.37-0.58, P < 0.001] and better OS [M-HR 0.53; 95% CI, 0.38-0.73, P < 0.001]. Thirty-five datasets including 7,220 patients were eligible for the pooled gene expression analysis. High AR mRNA levels were found to confer positive prognosis overall in terms of DFS (HR 0.82; 95% CI 0.72-0.92;P ¼ 0.0007) and OS (HR 0.84; 95% CI, 0.75-0.94; P ¼ 0.02) only in univariate analysis.Conclusions: Our analysis, conducted among more than 17,000 women with early-stage breast cancer included in clinical and gene expression analysis, demonstrates that AR positivity is associated with favorable clinical outcome. Clin Cancer Res; 23(11); 2702-12. Ó2016 AACR.

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Section: Discussionmentioning

confidence: 99%

Section: Prognostic Significance Of Ar Expressionmentioning

confidence: 99%

The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data

Božović-Spasojević

Zardavas

Brohée

et al. 2017

Clinical Cancer Research

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“…In order to investigate this, we used a collection of breast cancer studies where patients had received neo-adjuvant cytotoxic chemotherapy [26][27][28][29] and for whom data on pathological complete response (pCR) were available (N = 871). A tumor is said to have undergone pCR if, following surgery, no residual tumor cells remain upon pathological examination.…”

Section: Intclust Subtypes Show Large Differences In Chemosensitivitymentioning

confidence: 99%

Genome-driven integrated classification of breast cancer validated in over 7,500 samples

et al. 2014

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Background: IntClust is a classification of breast cancer comprising 10 subtypes based on molecular drivers identified through the integration of genomic and transcriptomic data from 1,000 breast tumors and validated in a further 1,000. We present a reliable method for subtyping breast tumors into the IntClust subtypes based on gene expression and demonstrate the clinical and biological validity of the IntClust classification. Results: We developed a gene expression-based approach for classifying breast tumors into the ten IntClust subtypes by using the ensemble profile of the index discovery dataset. We evaluate this approach in 983 independent samples for which the combined copy-number and gene expression IntClust classification was available. Only 24 samples are discordantly classified. Next, we compile a consolidated external dataset composed of a further 7,544 breast tumors. We use our approach to classify all samples into the IntClust subtypes. All ten subtypes are observable in most studies at comparable frequencies. The IntClust subtypes are significantly associated with relapse-free survival and recapitulate patterns of survival observed previously. In studies of neo-adjuvant chemotherapy, IntClust reveals distinct patterns of chemosensitivity. Finally, patterns of expression of genomic drivers reported by TCGA (The Cancer Genome Atlas) are better explained by IntClust as compared to the PAM50 classifier.

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“…The genes were chosen from literature review on the basis of their being identified as (i) possible prognostic factors in residual disease at protein (4,(6)(7)(8)(9)(10) or mRNA level (11), (ii) as significantly up-or downregulated, but of unknown prognostic value in residual disease (12)(13)(14)(15)(16)(17)(18)(19)(20), (iii) as predictive of chemotherapy resistance (6,11,16,19,(21)(22)(23)(24)(25)(26)(27)(28)(29), and/or (iv) identified as possible prognostic factors over several previous datasets (26,(30)(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41). In addition to the previously established prognostic factors ESR1 and ERBB2, the genes were also chosen to represent different pathways and biological processes of known implication in tumor progression or response to therapy, such as stemcellness (ALDH1A1, CD44, and STAT3), proliferation (TOP2A, MKI67, and AURKA), apoptosis (BCL2, BCL2L1, and PAWR), immunologic response (CD3D, CXCL13, and STAT1), epithelial-to-mesenchymal transition (EMT; SNAI1, SNAI2, SOX9, and TWIST), stromal activation (DECORIN, ...…”

Section: Introductionmentioning

confidence: 99%

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

Klintman

Buus

Cheang

et al. 2016

Clinical Cancer Research

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Purpose: The primary aim was to derive evidence for or against the clinical importance of several biologic processes in patients treated with neoadjuvant chemotherapy (NAC) by assessing expression of selected genes with prior implications in prognosis or treatment resistance. The secondary aim was to determine the prognostic impact in residual disease of the genes' expression. Experimental Design: Expression levels of 24 genes were quantified by NanoString nCounter on formalin-fixed paraffin-embedded residual tumors from 126 patients treated with NAC and 56 paired presurgical biopsies. The paired t test was used for testing changes in gene expression, and Cox regression and penalized elastic-net Cox Regression for estimating HRs. Results: After NAC, 12 genes were significantly up- and 8 downregulated. Fourteen genes were significantly associated with time to recurrence in univariable analysis in residual disease. In a multivariable model, ACACB, CD3D, MKI67, and TOP2A added prognostic value independent of clinical ER−, PgR−, and HER2− status. In ER+/HER2− patients, ACACB, PAWR, and ERBB2 predicted outcome, whereas CD3D and PAWR were prognostic in ER−/HER2− patients. By use of elastic-net analysis, a 6-gene signature (ACACB, CD3D, DECORIN, ESR1, MKI67, PLAU) was identified adding prognostic value independent of ER, PgR, and HER2. Conclusions: Most of the tested genes were significantly enriched or depleted in response to NAC. Expression levels of genes representing proliferation, stromal activation, metabolism, apoptosis, stemcellness, immunologic response, and Ras–ERK activation predicted outcome in residual disease. The multivariable gene models identified could, if validated, be used to identify patients needing additional post-neoadjuvant treatment to improve prognosis. Clin Cancer Res; 22(10); 2405–16. ©2016 AACR.

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Multifactorial Approach to Predicting Resistance to Anthracyclines

Abstract: Given its high NPV, the A-Score could become, if further validated, a useful clinical tool to identify those patients who do not benefit from anthracyclines and could therefore be spared the non-negligible adverse effects.

Cited by 172 publications

References 28 publications

The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data

The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data

Genome-driven integrated classification of breast cancer validated in over 7,500 samples

Changes in Expression of Genes Representing Key Biologic Processes after Neoadjuvant Chemotherapy in Breast Cancer, and Prognostic Implications in Residual Disease

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