Anti-HER2 therapy efficacy in HER2-negative metastatic breast cancer with HER2-amplified circulating tumor cells: results of the CirCe T-DM1 trial

Bidard, F-C; Cottu, Paul; Dubot, Coraline; Vénat-Bouvet, Laurence; Lortholary, Alain; Bourgeois, H.; Bollet, M.; Hanon, V. Servent; Luporsi-Gely, Elisabeth; Espié, Marc; Guiu, Séverine; Dièras, Véronique; Sablin, Marie Paule; Neffati, Souhir; Berger, Frédérique; Pierga, J-Y; Jacot, William

doi:10.1093/annonc/mdx363.033

Cited by 9 publications

(7 citation statements)

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“…The ongoing DETECT III trial aims to demonstrate the benefit from Lapatinib therapy in initially HER-2-negative patients, who are HER-2-positive on CTCs [7]. The CirCe T-DM1 trial showed that HER-2/neu gene amplification in CTCs from 7 HER-2-negative MBC patients occurs in a minor CTC subpopulation [26]. Overall a low response rate was reported (1/7), questioning the clinical utility of anti-HER-2 therapy in patients with HER-2 amplification in a minor subset.…”

Section: Discussionmentioning

confidence: 99%

HER-2 status of circulating tumor cells in a metastatic breast cancer cohort: A comparative study on characterization techniques

et al. 2019

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Background Personalized targeted treatment in metastatic breast cancer relies on accurate assessment of molecular aberrations, e.g. overexpression of Human Epidermal growth factor Receptor 2 (HER-2). Molecular interrogation of circulating tumor cells (CTCs) can provide an attractive alternative for real-time biomarker assessment. However, implementation of CellSearch-based HER-2 analysis has been limited. Immunofluorescent (IF) image interpretation is crucial, as different HER-2 categories have been described. Major questions in CTC research are how these IF categories reflect gene expression and amplification, and if we should consider ‘medium’ HER-2 expressing CTCs for patient selection. Methods Tumor cells from spiked cell lines (n = 8) and CTCs (n = 116 samples) of 85 metastatic breast cancer patients were enriched using CellSearch. Comparative analysis of HER-2 expression by IF imaging (ACCEPT, DEPArray, and visual scoring) with qRT-PCR and HER-2/neu FISH was performed. Results Automated IF HER-2-profiling by DEPArray and ACCEPT delivered comparable results. There was a 98% agreement between 17 trained observers (visual scoring) and ACCEPT considering HER-2 neg and HER-2 high expressing CTCs. However, 89% of HER-2 med expressing CTCs by ACCEPT were scored negative by observers. HER-2 high expressing tumor cells demonstrated HER-2/neu gene amplification, whereas HER-2 neg and HER-2 med expressing tumor cells and CTCs by ACCEPT were copy-number neutral. All patients with HER-2-positive archival tumors had ≥1 HER-2 high expressing CTCs, while 80% of HER-2-negative patients did not. High relative gene expression of HER-2 measured on enriched CTC lysates correlated with having ≥1 HER-2 high expressing CTCs. Conclusion Automated images analysis has enormous potential for clinical implementation. HER-2 characterization and clinical trial design should be focused on HER-2 high expressing CTCs.

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Section: Discussionmentioning

confidence: 99%

HER-2 status of circulating tumor cells in a metastatic breast cancer cohort: A comparative study on characterization techniques

et al. 2019

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“…Several ongoing clinical trials have measured CTCs in order to orient therapeutic decisions (DETECT III (NCT01619111); CirCe T-DM1 (NCT01975142); Treat CTC trial (NCT01548677; [33,34,35]). Many of these trials have not presented the final survival analysis yet but results from published data are still conflicting.…”

Section: Breast Cancer Stem Cells As Markers For Prognosis and Thementioning

confidence: 99%

The Role of Breast Cancer Stem Cells as a Prognostic Marker and a Target to Improve the Efficacy of Breast Cancer Therapy

Scioli

Storti

D’Amico

et al. 2019

Cancers

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Breast cancer is the most common form of tumor in women and the leading cause of cancer-related mortality. Even though the major cellular burden in breast cancer is constituted by the so-called bulk tumor cells, another cell subpopulation named cancer stem cells (CSCs) has been identified. The latter have stem features, a self-renewal capacity, and the ability to regenerate the bulk tumor cells. CSCs have been described in several cancer types but breast cancer stem cells (BCSCs) were among the first to be identified and characterized. Therefore, many efforts have been put into the phenotypic characterization of BCSCs and the study of their potential as prognostic indicators and therapeutic targets. Many dysregulated pathways in BCSCs are involved in the epithelial–mesenchymal transition (EMT) and are found up-regulated in circulating tumor cells (CTCs), another important cancer cell subpopulation, that shed into the vasculature and disseminate along the body to give metastases. Conventional therapies fail at eliminating BCSCs because of their quiescent state that gives them therapy resistance. Based on this evidence, preclinical studies and clinical trials have tried to establish novel therapeutic regimens aiming to eradicate BCSCs. Markers useful for BCSC identification could also be possible therapeutic methods against BCSCs. New approaches in drug delivery combined with gene targeting, immunomodulatory, and cell-based therapies could be promising tools for developing effective CSC-targeted drugs against breast cancer.

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“…For this reason, biopsy and analysis of the primary tumor must still be used in conjunction with CTC molecular characterization for accurate determination of guided therapies. The intrinsic heterogeneity of protein expression across the CTC population and between the primary and circulating tumor populations makes the use of CTCs as a “liquid biopsy” for real-time monitoring of cancer lesions and targeted treatment response challenging [56].…”

Section: Current Use Of Ctcsmentioning

confidence: 99%

Fugitives on the run: circulating tumor cells (CTCs) in metastatic diseases

Mamdouhi

Twomey

McSweeney

et al. 2019

Cancer Metastasis Rev

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The presence of circulating tumor cells (CTCs) in the bloodstream signals the existence of a tumor and denotes risk of metastatic spread. CTCs can be isolated and analyzed to monitor cancer progression and therapeutic response. However, CTC isolation devices have shown considerable variation in detection rates, limiting their use as a routine diagnostic and monitoring tool. In this review, we discuss recent advances in CTC detection methodologies and associated clinical studies. We provide perspective on the future direction of CTC isolation and molecular characterization towards developing reliable biomarkers that monitor disease progression or therapeutic response.

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Anti-HER2 therapy efficacy in HER2-negative metastatic breast cancer with HER2-amplified circulating tumor cells: results of the CirCe T-DM1 trial

Cited by 9 publications

References 0 publications

HER-2 status of circulating tumor cells in a metastatic breast cancer cohort: A comparative study on characterization techniques

HER-2 status of circulating tumor cells in a metastatic breast cancer cohort: A comparative study on characterization techniques

The Role of Breast Cancer Stem Cells as a Prognostic Marker and a Target to Improve the Efficacy of Breast Cancer Therapy

Fugitives on the run: circulating tumor cells (CTCs) in metastatic diseases

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