Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: First results of the randomised MATADOR trial (BOOG 2004-04)

Rossum, Annelot G.J. van; Kok, Marleen; Werkhoven, Erik van; Opdam, Mark; Mandjes, Ingrid A.M.; Leeuwen-Stok, A. Elise van; Imholz, Alexander L.T.; Portielje, Johanneke E.A.; Bos, Monique M.E.M.; Bochove, Aart van; Wesseling, Jelle; Rutgers, Emiel J.; Linn, Sabine C.; Oosterkamp, Hendrika M.; Trialists', Matador

doi:10.1016/j.ejca.2018.07.013

Cited by 14 publications

(7 citation statements)

References 26 publications

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“…4D and E ). Our findings that some immune cells are enriched in the tumors of the low-risk group is in line with previous findings that high immune infiltrate is correlated with better clinical outcomes ( 23, 35, 36 ), again showing that our method robustly identifies relevant microenvironments. Moreover, in line with the preclinical findings that macrophages can have both tumor-supporting and tumor-suppressing phenotypes, we find macrophages TCD to be present both in a high- and low-risk group.…”

Section: Resultssupporting

confidence: 91%

Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

Kester

Seinstra

Rossum

et al. 2021

Clinical Cancer Research

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Precision medicine for cancer, a strategy to fine-tune treatments based on the properties of a patient tumor, is rapidly improving the clinical management of cancer patients. Here, we introduce Tumor Cell Deconvolution (TCD), a deconvolution algorithm that allows us to precisely map the cellular composition of patient tumors based on bulk RNA sequencing of patients' biopsy. We demonstrate that TCD can be used to identify cell populations that are predictive to response to treatment. With the rapid development of sequencing tools and the lowering of costs that accompany this technique, TCD can be employed in the clinic to characterize the cellular compositions of a tumor, in order to guide treatment decisions and to maximize patient's response to therapies.Research.

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Section: Resultssupporting

confidence: 91%

Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

Kester

Seinstra

Rossum

et al. 2021

Clinical Cancer Research

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“…Strikingly, we observed a specific distribution of PAM50 molecular subtypes (Parker et al , 2009) of breast cancer in relation to activity of GR (Fig 2C): Samples exhibiting high levels of GRa were mostly luminal A, while most samples with low levels of GRa belonged to the luminal B group (Fig 2C). Higher levels of GR activity in Luminal A samples were also observed in the patients of the METABRIC cohort (Curtis et al , 2012) ( n = 1,134 luminal samples; Fig EV3A), as well as in the NKI in‐house MATADOR trial (Van Rossum et al , 2018) ( n = 415 luminal samples; Fig EV3B), validating our findings across multiple patient series. Considering that GR is ubiquitously expressed among different cell types that jointly contribute to the bulk RNA‐sequencing data, we sought to explore GRa using single‐cell (sc) RNA expression data of human breast cancer.…”

Section: Resultssupporting

confidence: 83%

Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity

Prekovic,

Chalkiadakis,

Roest

et al. 2023

EMBO Mol Med

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Glucocorticoid receptor (GR) is a transcription factor that plays a crucial role in cancer biology. In this study, we utilized an in silico‐designed GR activity signature to demonstrate that GR relates to the proliferative capacity of numerous primary cancer types. In breast cancer, the GR activity status determines luminal subtype identity and has implications for patient outcomes. We reveal that GR engages with estrogen receptor (ER), leading to redistribution of ER on the chromatin. Notably, GR activation leads to upregulation of the ZBTB16 gene, encoding for a transcriptional repressor, which controls growth in ER‐positive breast cancer and associates with prognosis in luminal A patients. In relation to ZBTB16's repressive nature, GR activation leads to epigenetic remodeling and loss of histone acetylation at sites proximal to cancer‐driving genes. Based on these findings, epigenetic inhibitors reduce viability of ER‐positive breast cancer cells that display absence of GR activity. Our findings provide insights into how GR controls ER‐positive breast cancer growth and may have implications for patients' prognostication and provide novel therapeutic candidates for breast cancer treatment.

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“…The clinical characteristics of 8 female patients with breast cancer [mean age (range): 51.1 (37-79)] and the regimens of taxane-based chemotherapy over 12 weeks are summarized in Supplementary Tables S2 and S3, respectively. Because the drugs used concomitantly with taxane-based chemotherapy (i.e., bevacizumab, trastuzumab, pertuzumab, cyclophosphamide, and doxorubicin) are not considered risk factors for CIPN (20)(21)(22)(23), we considered it unlikely that they contributed to changes in plasma galectin-3 levels (Supplementary Table S3).…”

Section: Resultsmentioning

confidence: 99%

Pronociceptive Roles of Schwann Cell–Derived Galectin-3 in Taxane-Induced Peripheral Neuropathy

et al. 2021

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Chemotherapy-induced peripheral neuropathy (CIPN) is a severe dose-limiting side effect of taxanes such as paclitaxel and docetaxel. Despite the high medical needs, insufficient understanding of the complex mechanism underlying CIPN pathogenesis precludes any endorsed causal therapy to prevent or relieve CIPN. In this study, we report that elevation of plasma galectin-3 level is a pathologic change common to both patients with taxane-treated breast cancer with CIPN and a mouse model of taxane-related CIPN. Following multiple intraperitoneal injections of paclitaxel in mice, galectin-3 levels were elevated in Schwann cells within the sciatic nerve but not in other peripheral organs or cells expressing galectin-3. Consistent with this, paclitaxel treatment of primary cultures of rat Schwann cells induced upregulation and secretion of galectin-3. In vitro migration assays revealed that recombinant galectin-3 induced a chemotactic response of the murine macrophage cell line RAW 264.7. In addition, perineural administration of galectin-3 to the sciatic nerve of naive mice mimicked paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. By contrast, chemical depletion of macrophages by clodronate liposomes suppressed paclitaxel-induced mechanical hypersensitivity despite the higher level of plasma galectin-3. Deficiency (Galectin-3−/− mice) or pharmacologic inhibition of galectin-3 inhibited paclitaxel-induced macrophage infiltration and mechanical hypersensitivity. In conclusion, we propose that Schwann cell–derived galectin-3 plays a pronociceptive role via macrophage infiltration in the pathogenesis of taxane-induced peripheral neuropathy. Therapies targeting this phenomenon, which is common to patients with CIPN and mouse models, represent a novel approach to suppress taxane-related CIPN. Significance: These findings demonstrate that the elevation of plasma galectin-3 is a CIPN-related pathologic change common to humans and mice, and that targeting galectin-3 is a therapeutic option to delay CIPN progression.

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Adjuvant dose-dense doxorubicin-cyclophosphamide versus docetaxel-doxorubicin-cyclophosphamide for high-risk breast cancer: First results of the randomised MATADOR trial (BOOG 2004-04)

Abstract: ISRCTN61893718 and BOOG 2004-04.

Cited by 14 publications

References 26 publications

Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

Differential Survival and Therapy Benefit of Patients with Breast Cancer Are Characterized by Distinct Epithelial and Immune Cell Microenvironments

Luminal breast cancer identity is determined by loss of glucocorticoid receptor activity

Pronociceptive Roles of Schwann Cell–Derived Galectin-3 in Taxane-Induced Peripheral Neuropathy

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