Towards personalized treatment for early stage HER2-positive breast cancer

Goutsouliak, Kristina; Veeraraghavan, Jamunarani; Sethunath, Vidyalakshmi; Angelis, Carmine De; Osborne, C. Kent; Rimawi, Mothaffar F.; Schiff, Rachel

doi:10.1038/s41571-019-0299-9

Cited by 204 publications

(177 citation statements)

References 175 publications

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“…Human epidermal growth factor receptor 2 (Her2)-positive breast cancer is a highly dangerous breast cancer subtype, accounting for about 15-20% of breast cancer patients [14,15]. Although anti-Her2 targeting drugs such as trastuzumab, pertuzumab and ado-trastuzumab emtansine significantly improved the prognosis of patients with Her2-positive early breast cancer, these drugs not only improved the therapeutic effect, but also increased the treatment cost and adverse reactions [16][17][18].…”

Section: Discussionmentioning

confidence: 99%

Development of a risk scoring system for evaluating the prognosis of patients with Her2-positive breast cancer

Gao

Zhuang

et al. 2020

Cancer Cell Int

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Background: As one of the many breast cancer subtypes, human epidermal growth factor receptor 2 (Her2)-positive breast cancer has higher invasiveness and poor prognosis, although the advent of anti-Her2 drugs has brought good news to patients. However, the emergence of drug resistance still limits its clinical efficacy, so there is an urgent need to explore new targets and develop a risk scoring system to improve treatments and evaluate patient prognosis.Methods: Differentially expressed mRNAs associated with Her2-positive breast cancer were screened from a TCGA cohort. The prognostic risk scoring system was constructed according to univariate and Lasso Cox regression model analyses and combined with clinical factors (such as age and TNM) for univariate and multivariate analyses to verify the specificity and sensitivity of the risk scoring system. Finally, based on correlation and CNV mutation analyses, we explored the research value of the mRNAs involved in the system as key genes of the model. Results:In this study, six mRNAs were screened and identified to construct a prognostic risk scoring system, including four up-regulated mRNA (RDH16, SPC25, SPC24, and SCUBE3) and two down-regulated mRNA (DGAT2 and CCDC69). The risk scoring system can divide Her2-positive breast cancer samples into high-risk and low-risk groups to evaluate patient prognosis. In addition, whether through the time-dependent receiver operating characteristics curve or compared with clinical factors, the risk scoring system showed high predictive sensitivity and specificity. Moreover, some CNV mutations in mRNA increase patient risk by influencing expression levels.Conclusion: The risk scoring system constructed in this study is helpful to improve the screening of high-risk patients with Her2-positive breast cancer and is beneficial for implementing early diagnosis and personalized treatment. It is suggested that these mRNAs may play an important role in the progression of Her2-positive breast cancer.

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Section: Discussionmentioning

confidence: 99%

Development of a risk scoring system for evaluating the prognosis of patients with Her2-positive breast cancer

Gao

Zhuang

et al. 2020

Cancer Cell Int

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“…And patient responsiveness is often difficult to predict. For example, despite the effectiveness of trastuzumab in HER2 positive patients, some might suffer relapse with unknown reasons (3).…”

Section: Introductionmentioning

confidence: 99%

ORN: Extracting Latent Pathway Activities in Cancer with OR-gate Network

Liang

Zhu²,

2020

Preprint

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Pathway level understanding of cancer plays a key role in precision oncology. In this study, we developed a novel data-driven model, called the OR-gate Network (ORN), to simultaneously infer functional relationships among mutations, patient-specific pathway activities, and gene co-expression. In principle, logical OR gates agree with mutual exclusivity patterns in somatic mutations and bicluster patterns in transcriptomic profiles. In a trained ORN, the differential expression profiles of tumours can be explained by somatic mutations perturbing signalling pathways. We applied ORN to lower grade glioma (LLG) samples in TCGA and breast cancer samples from METABRIC. Both datasets have shown pathway patterns related to immune response and cell cycles. In LLG samples, ORN identified multiple metabolic pathways closely related to glioma development and revealed two pathways closely related to patient survival. Additional results from the METABRIC datasets showed that ORN could characterize key mechanisms of cancer and connect them to less studied somatic mutations (e.g., BAP1, MIR604, MICAL3, and telomere activities), which may generate novel hypothesis for targeted therapy.

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“…Breast cancer (BC) has the highest incidence of any cancer not only in China (38.9% of total cases) but also worldwide (30% of total cases) and is also second most common female malignancy worldwide [1,2]. Based on the expression of different molecular biomarkers, breast cancer patients are grouped into four molecular subtypes: luminal A, luminal B, HER-2 enriched, and triple-negative BC(TNBC) [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Upregulated CDKN2A expression may be an independent protective factor in Luminal-like breast cancer

Qiu¹,

Lu²,

Wu³

2020

Preprint

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Background: Previous studies revealed that CDKN2A (cyclin-dependent kinase inhibitor 2A) functioned as a tumour suppressor in various types of malignant tumours. The aim of the study was to clarify the value of CDKN2A expression in the prognosis of breast cancer.Method: Using the Cancer Genome Atlas (TCGA) database, we compared CDKN2A mRNA levels between breast cancer tissues and normal tissues and analyzed the relationship between clinical features and CDKN2A expression with the Wilcox test and the Kruskal-Wallis test. Kaplan-Meier and Cox analyses were performed to determine the correlation between CDKN2A expression and breast cancer prognosis. Gene set enrichment analysis (GSEA) was performed using the TCGA data set.Results: We first found that CDKN2A expression was markedly higher in breast cancer tissues than in normal tissues using the TCGA database (P=0.000). In addition, CDKN2A mRNA expression in breast cancer was positively correlated with age (P=0.018), histological types (P=0.028), ER status (P=0.000), PR status (P=0.000) and molecular subtypes (P=0.000). Kaplan-Meier analysis showed that increased CDKN2A expression was associated with increased survival time in breast cancer patients (P=0.000), especially in Luminal-like subtype. Univariate and multivariate Cox analyses indicated that CDKN2A expression was an independent prognostic biomarker for breast cancer (P=0.037). GSEA suggested that pathways involving cell adhesion molecules (CAMs), cytokine-receptor interactions, cytosolic DNA sensing, the cell cycle, and killer cell-mediated cytotoxicity were differentially enriched in the CDKN2A-high expression group.Conclusion: Our research demonstrated that high CDKN2A mRNA expression was an independent protective factor for improved prognosis in Luminal-like breast cancer. Additionally, the signaling pathways related to CAMs, cytokine-receptor interactions, cytosolic DNA sensing, the cell cycle, and killer cell-mediated cytotoxicity regulated by CDKN2A mRNA expression should be further studied.

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Towards personalized treatment for early stage HER2-positive breast cancer

Cited by 204 publications

References 175 publications

Development of a risk scoring system for evaluating the prognosis of patients with Her2-positive breast cancer

Development of a risk scoring system for evaluating the prognosis of patients with Her2-positive breast cancer

ORN: Extracting Latent Pathway Activities in Cancer with OR-gate Network

Upregulated CDKN2A expression may be an independent protective factor in Luminal-like breast cancer

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