Treatment Of Breast Cancer Research Articles

The Effect and Treatment of PIK3CA Mutations in Breast Cancer: Current Understanding and Future Directions

Gene mutations in PIK3CA, the catalytic subunit of phosphoinositide 3-kinases, are significantly associated with prognosis in breast cancer. This association suggests that breast cancer patients with PIK3CA mutations should receive PIK3CA mutant-specific treatment. This review aimed to investigate novel treatments for PIK3CA-mutant breast cancer. This study investigated the effects of PIK3CA mutations in breast cancer with respect to gene ontology and the PI3K/AKT/mTOR pathway. Subsequently, we comprehensively examined all clinical trials that targeted breast cancer patients with PIK3CA mutations. Finally, this review explored the potential of a new treatment for noncoding RNA.

The Effectiveness of Mind-Body Exercise on Health-Related Quality of Life and Mental Health During and After Breast Cancer Treatment: An Umbrella Review of Meta-Analyses for Randomized Controlled Trials.

Previous studies regarding mind-body exercise among people with breast cancer mostly focused on one type of mind-body exercise and provided conflicting results. This paper aims to systematically synthesize the evidence hierarchy and examine the credibility of previous meta-analyses of different types of mind-body exercises. We searched PubMed, Embase, Cochrane Library, Web of Science, and Epitemonikos from database inception to February 2nd, 2024, for meta-analyses of randomized controlled trials. Included meta-analyses examined the effects of mind-body exercises on at least one outcome of health-related quality of life, cancer-related fatigue, depression, anxiety, and sleep quality in breast cancer patients. The random effects estimates (Hedges'G), 95% prediction interval, small study effect, and excess significance bias were calculated. Furthermore, we categorized meta-analyses based on the evidence credibility criteria and assessed quality using A Measurement Tool to Assess Systematic Reviews 2. The umbrella review included a re-analysis of 16 meta-analyses of 9 articles including 134 randomized controlled trials involving 9469 breast cancer patients and survivors. We identified 3 articles as "low" quality and 6 articles as "critically low" quality. Convincing evidence supported the effectiveness of Yoga intervention in reducing depression symptoms (G = -0.77, 95% Confidence Interval [-0.93, -0.61]). However, 11 meta-analyses were supported by weak evidence (1 for Qigong alleviated depression, 4 for Qigong, Baduanjin, Tai Chi Chuan, and Yoga improved health-related quality of life, 3 for multiple mind-body exercises, Tai Chi Chuan, and Yoga reduced cancer-related fatigue, 2 of Baduanjin and Yoga reduced anxiety, as well as 1 of Yoga improved sleep quality). Mind-body exercises, especially yoga, may be beneficial for improving health-related quality of life and mental health for breast cancer patients. Further high-quality interventions investigating diverse mind-body exercise interventions are warranted to ascertain the effectiveness of health-related quality of life and mental health outcomes.

Exploring the revolutionary potential of MXene nanoparticles in breast Cancer therapy: A review of applications and future prospects.

Exploring the revolutionary potential of MXene nanoparticles in breast Cancer therapy: A review of applications and future prospects.

Molecular Docking and Pharmacological In Silico Evaluation of Camptothecin and Related Ligands as Promising HER2-Targeted Therapies for Breast Cancer

Breast cancer is one of the leading causes of cancer-related mortality in women worldwide, highlighting the importance of effective therapies. This study evaluates the interaction between camptothecin, a potent anticancer agent, and two key receptors implicated in breast cancer progression: HER2 (human epidermal growth factor receptor 2) and EGFR (epidermal growth factor receptor), using molecular docking. The results reveal a stronger binding affinity between camptothecin and HER2 than EGFR, in contrast to neratinib, which demonstrated affinity exclusively for HER2. Camptothecin exhibits significant hydrophobic and pi-alkyl interactions with HER2, whereas its interactions with EGFR are primarily mediated by hydrogen bonds. Molecular dynamics (MD) simulations of the camptothecin-HER2 complex indicate stable binding, with minimal fluctuations observed over 100 nanoseconds, confirming the stability of the ligand–receptor interaction. Pharmacokinetic evaluations, based on Lipinski’s rule of five, demonstrate that camptothecin adheres to essential drug-likeness parameters, suggesting favorable bioavailability. Furthermore, the analysis comparing the pharmacological properties of camptothecin with other well-known anticancer compounds, such as neratinib, shows that camptothecin exhibited superior compliance with drug-likeness rules. Despite its low solubility, the binding stability and pharmacokinetic profile suggest its potential as an effective therapeutic agent for breast cancer, particularly when combined with drug delivery systems that enhance solubility. This work underscores the importance of receptor-specific ligand interactions in drug design and highlights the need for further studies into camptothecin’s clinical applications, especially in HER2-positive breast cancer treatment.

Cardiotoxicity of breast cancer drug treatments.

Cardiotoxicity of breast cancer drug treatments.

A Facile Way to Enhance the Therapeutic Efficacy of Hydrophobic Drugs via Amorphous Solid Dispersions.

Approximately 40% of marketed drugs and 75% of invested drugs in the pharmaceutical field are poorly soluble hydrophobic drugs with minimal solubility in water which make them difficult to be absorbed by the body and significantly limiting their applications. Among chemotherapeutic agents, numerous antitumor drugs such as platinum compounds, camptothecin, paclitaxel and others are also restricted in processing and preparation due to solubility issues. Therefore, improving the solubility and enhancing the therapeutic efficacy of drugs have always been significant research topics in current pharmaceutics. Herein, we propose an amorphous solid dispersion system PRTA-DOX, involving the protein drug protamine sulphate and hydrophobic doxorubicin as the model hydrophobic drug. In previous studies, ASD (Amorphous Solid Dispersion) has been demonstrated to enhance the solubility of hydrophobic drugs and result in a storage-stable system. Protamine sulphate as a marketed drug is reliable in safety and conveniently obtained. Doxorubicin, an antitumor drug with a broad antitumor spectrum, is commonly used in the treatment of breast cancer. Typically, doxorubicin is prepared in the form of a hydrochloride salt to increase its solubility. However, the utilization of doxorubicin hydrochloride is reduced due to drug resistance issues in biological cells and it exhibits higher toxicity to the body. In this system, protamine sulphate which is rich in arginine guanidino hydrophobic planes physically mixes with doxorubicin which is a hydrophobic molecule with aromatic rings and they are connected through weak interactions: π-π conjugation. They constitute an amorphous solid dispersion system which increases the solubility of hydrophobic doxorubicin, enhances cellular uptake, mitigate some cellular drug resistance and thereby achieves the purpose of improving therapeutic efficacy.

Lin28/let-7 axis in breast cancer.

Let-7 microRNAs are tumor suppressor microRNAs, and their reduced expression frequently occurs in various types of cancers, including breast cancer. A notable correlation exists between decreased let-7 microRNA levels and the overexpression of Lin28A and Lin28B, particularly in breast cancer cases with poor prognoses. Dysregulation of Wnt signaling significantly contributes to the upregulation of Lin28A and Lin28B in breast cancer. Both Lin28A and Lin28B operate from different cellular compartments to inhibit the biogenesis of let-7 microRNAs, which are essential for the post-transcriptional regulation of genes involved in key cellular functions such as proliferation, differentiation, and apoptosis. Decreased expression of let-7 microRNAs leads to the overexpression of oncogenes such as K-ras, C-myc, and SOX-2 in breast cancer. Overexpression of Lin28A associated with reduced let-7 microRNA levels is observed in estrogen receptor positive, estrogen receptor negative, and human epidermal growth factor receptor 2 positive breast cancers, whereas Lin28B overexpression with reduced let-7 microRNA levels occurs specifically in triple negative breast cancer. This review aims to dissect the molecular interplay between Lin28A, Lin28B, and let-7 microRNAs, elucidating their roles in breast carcinogenesis, metastasis, and the development of resistance to conventional treatments like radiation and chemotherapy. Additionally, the review addresses potential therapeutic avenues offered by let-7 microRNAs or their mimics, as well as Lin28A and Lin28B inhibitors, in the treatment of breast cancer.

Integrated bulk and single-cell transcriptomic analysis unveiled a novel cuproptosis-related lipid metabolism gene molecular pattern and a risk index for predicting prognosis and antitumor drug sensitivity in breast cancer

Breast cancer is the second most prevalent malignant tumor worldwide and is highly heterogeneous. Cuproptosis, a newly identified form of cell death, is intimately connected to lipid metabolism. This study investigated breast cancer heterogeneity through the lens of cuproptosis-related lipid metabolism genes (CLMGs), with the goal of predicting patient prognosis, immunotherapy efficacy, and sensitivity to anticancer drugs. By utilizing transcriptomic data from The Cancer Genome Atlas (TCGA) for breast cancer, we identified 682 CLMGs and applied the nonnegative matrix factorization (NMF) method to categorize breast cancer patients into four distinct clusters: cluster 1, ‘‘immune-cold and stroma-poor’’; cluster 2, ‘‘immune-infiltrated’’; cluster 3, ‘‘stroma-rich’’; and cluster 4, ‘‘moderate infiltration’’. We subsequently developed a risk model based on CLMGs that incorporates ACSL1, ATP2B4, ATP7B, ENPP6, HSPH1, PIP4K2C, SRD5A3, and ULBP1. This model demonstrated excellent prognostic predictive performance in both the internal (testing and entire sets) and external (GSE20685 and Kaplan–Meier Plotter sets) validation sets. High-risk patients presented lower expression levels of immune checkpoint-related genes and lower immunophenoscores (IPSs), whereas low-risk patients presented higher CD8+ T-cell infiltration levels and IPSs. Furthermore, the risk index was positively correlated with tumor cell stemness and could predict sensitivity to anticancer drugs. We also confirmed that SRD5A3 was highly expressed in breast cancer and participated in promoting the proliferation and migration of breast cancer cells. In conclusion, the results of this study provide new insights and strategies for assessing prognosis and implementing precision treatment for breast cancer through the lens of CLMGs.

MHC-I upregulation by macbecin II in the solid tumors potentiates the effect of active immunotherapy.

We aimed to restore MHC-I expression on the surface of solid tumors including breast cancer and melanoma cells to regain sensitivity to immunotherapy and suppress metastatic progression. We screened a natural compound library and identified macbecin II as a reagent that upregulates MHC-I expression and induces antigen-dependent cell death in pre-invasive and invasive breast cancer models. Furthermore, we employed active immunotherapy using engineered small extracellular vesicles from dendritic cells (DCs) as a tumor vaccine (IL2-ep13nsEV) in combination with macbecin II for personalized breast cancer treatment. We found that macbecin II induced MHC-I-dependent antigen presentation and that IL2-ep13nsEV synergized with macbecin II inducing cell death, reducing metastasis, and boosting immune cell infiltration. In addition, macbecin II potentiated the effects of anti-PD-1 immunotherapy in suppressing tumor growth and metastasis. Mechanistically, macbecin II upregulated MHC-I expression post-translationally by rescuing it from lysosomal degradation. Our findings revealed a strong efficacy of macbecin II in regulating MHC-I expression and following antigen-dependent cell death. Therefore, combining active immunotherapies and macbecin II represents an effective strategy to prevent growth and progression ofsolid tumors includingbreast cancerand melanoma.

Insight into the inhibitory activity of mangiferin and Silybin against HER2 and EGFR using theoretical and experimental approaches

Despite the advances made in diagnosing and treating breast cancer, it continues to pose a significant threat to women’s health. High-risk mutations can lead to high resistance to current treatments and poor prognosis. Therefore, new treatment strategies are needed. Mangiferin and silybin, two natural substances obtained from plants, have demonstrated encouraging results as anticancer drugs. This study investigated the activity of these compounds against two therapeutic targets, human epidermal growth factor receptor 2 (HER2) and epidermal growth factor receptor (EGFR). We assessed the binding affinity and stability of these compounds with the active sites of wild-type and mutated HER2 and EGFR by using computational screening techniques, namely molecular docking, density functional theory, and molecular dynamics (MD) simulations with the MMGBSA method. We used molecular docking, triplicate MD simulations summing 300 ns each, and density functional theory analysis to estimate the binding mechanism of mangiferin and silybin inside the wild-type and mutated EGFR and HER2 active regions. Moreover, an in vitro experiment showed that mangiferin and silybin inhibited the growth of two HER2-positive breast cancer cell lines, BT-474 and SK-BR-3, at micromolar concentrations. These findings suggest the potential for developing novel anticancer therapies that specifically target EGFR and HER2.

Dosimetric effect of silicone-based gel on skin surface during volumetric modulated arc therapy for breast cancer.

This study aims to quantify and compare the dosimetric effects of varying thicknesses of StrataXRT, a silicone-based gel, and other topical agents on the skin surface during volumetric modulated arc therapy (VMAT) for breast cancer. A VMAT plan was created for breast cancer treatment using a female RANDO phantom with a prescription dose of 50Gy in 25 fractions. The planning target volume (PTV) encompassed the left breast and the regional lymph nodes. Irradiation was performed using a 6 MV photon beam. Three topical agents (StrataXRT, Hirudoid Soft Ointment, and RINDERON-Vs Ointment) having eight thicknesses (0.0-1.5mm) were evaluated. Dosimetry was conducted using Gafchromic EBT4 films at three anatomical locations-subclavicular, medial, and lateral aspects of the left breast. Mean dose enhancement ratios (DERs) of 102%-116% were observed in VMAT for topical agent thicknesses of 0.1-0.5mm, increasing to 116%-126% at 1.0 and 1.5mm. Among the evaluated agents, StrataXRT consistently exhibited the lowest DER, with a statistically significant difference (p<0.05). This study demonstrated that StrataXRT exhibited the lowest DER among the evaluated topical agents in VMAT for breast cancer. Thicknesses exceeding 0.5mm potentially exceeded the threshold dose for acute skin reactions.

Trends in breast cancer mortality in Peru and its geographical areas from 2013 to 2022 and prediction until 2027

BackgroundIn 2022, breast cancer was one of the most commonly diagnosed neoplasms and the leading cause of cancer death among women worldwide. In Peru, reports on mortality due to this neoplasm are scarce, especially after implementing strategies to reduce its impact. This study aimed to estimate mortality rates for breast cancer in Peru and its geographic regions from 2013 to 2022 and to project its evolution to 2027.MethodsAn observational ecological study of multiple time series was conducted. Data were obtained from the Ministry of Health’s death database via SINADEF. Mortality rates per 100,000 women were calculated using the direct method and Segi’s world standard population. Mortality trends were analyzed using the Annual Percent Change (APC) calculated with Joinpoint regression software. Predictions for 2027 were also made using the Nordpred package in R Studio.ResultsIn 2013, the departments with the highest breast cancer mortality rates in Peru were Ica, Callao, Lambayeque and La Libertad. In 2022, Ancash and Tumbes were added, with Tumbes having the highest rates. For women under 50, Lambayeque and Madre de Dios led in 2013, while for women over 50, Tumbes had the highest mortality rate in 2022. Peru reported a significant increase of 3.97% on an annual basis for the entire period. According to regions, Rainforest region (APC = + 8.37) and the Rainforest region (APC = + 11.55) showed significant increases in mortality rates, while no significant changes were observed in the Coastal region. Moreover, an increase in breast cancer mortality in Peru is projected for the year 2027.ConclusionBreast cancer mortality in Peru has shown a constant increase, with significant regional disparities. The highest rates were recorded in the coastal region, although the Andean and jungle regions experienced the most pronounced increases. These disparities may be attributed to data underreporting during the COVID-19 pandemic and unequal access to diagnostic and treatment services. The findings highlight the urgent need for focused public health interventions to reduce these regional gaps and improve breast cancer management outcomes.

Cell-free supernatant of Clostridium leptum inhibits breast cancer cell proliferation.

Breast cancer has emerged as the leading cause of global cancer incidence, surpassing lung cancer. Accumulating evidence suggests that probiotics exhibit inhibitory effect on breast cancer progression, highlighting the need to identify gut flora-derived probiotics with potential anti-breast cancer properties. Here, we investigated the effect of the cell-free supernatant of C. leptum (ClCFS) on breast cancer cells by MTT assay. Untargeted metabolomics analysis was employed to characterize metabolite alterations in ClCFS. Furthermore, the core targets were predicted by the protein-protein interaction network and the signaling pathways were enriched by the Kyoto Encyclopedia of Genes and Genomes analysis. Our findings demonstrated that ClCFS inhibited the proliferation of breast cancer cells and that the main metabolite of ClCFS might be acetylcarnitine. Utilizing network pharmacological analysis, we identified apoptosis-related signaling pathways as the principal mechanisms underlying ClCFS activity. Furthermore, five core targets of STAT3, IL-1β, BCL2, CASP3, and ESR1 were identified. This study elucidates the main bioactive constituent and the potential targets of ClCFS against breast cancer. It provides a new understanding of the pharmacological activity of ClCFS in breast cancer treatment.

Targeting cell cycle arrest in breast cancer by phytochemicals from Caryto urens L. fruit Ethyl acetate fraction: In Silico and In Vitro validation

Targeting cell cycle arrest in breast cancer by phytochemicals from Caryto urens L. fruit Ethyl acetate fraction: In Silico and In Vitro validation

BreastCancerNet: Flask-Enabled Attention-Driven Hybrid Dual DNN Framework for Real-Time Breast Cancer Prediction.

Breast cancer is the most prevalent cancer among women and poses a significant global health challenge due to its association with uncontrolled cell proliferation. Artificial intelligence (AI) integration into medical practice has shown promise in boosting diagnosis accuracy and treatment protocol optimisation, thus contributing to improved survival rates globally. This paper presents a comprehensive analysis utilizing the Wisconsin Breast Cancer dataset, comprising data from 569 patients and 30 attributes. We propose BreastCancerNet, a hybrid AI architecture that leverages dual deep neural networks (DNNs) coupled with an attention mechanism to enhance breast cancer diagnosis. The proposed framework integrates two distinct DNNs (DNN-I and DNN-II) to extract diverse feature representations from the dataset, which are then concatenated for comprehensive analysis. An attention mechanism is employed to prioritize critical features, thereby improving the model's focus on essential characteristics of the input data. The final classification is performed using a support vector machine (SVM), achieving an impressive accuracy rate of 99.42% in differentiating between malignant and benign cases. Furthermore, we introduce a user-centric web application that facilitates real-time breast cancer detection by allowing users to input new attributes. This intuitive web interface fosters interactive engagement with the predictive algorithm, potentially enhancing breast cancer screening and treatment outcomes.

Breast cancer characteristics in low- and middle-income countries: An umbrella review.

Breast cancer characteristics in low- and middle-income countries: An umbrella review.

Identification of functional biomarkers for personalized nanomedicine in advanced breast cancer in vitro models.

Identification of functional biomarkers for personalized nanomedicine in advanced breast cancer in vitro models.

Introducing carbon quantum dot-Capivasertib drug carrier complex for enhanced treatment of breast cancer.

Capivasertib (AZD5363) is a 2023 FDA-approved pyrrolopyrimidine-derived compound that treats hormone receptor positive, HER2 negative metastatic breast cancer in adult patients. It is a novel pan-AKT kinase catalytic inhibitor in ER + breast cancer cell lines, including MCF7. The dominant influence of carbon quantum dots (CQDs) in combination with multiple chemotherapy drugs is also demonstrated as a drug delivery system that significantly enhances the effectiveness of cancerous tumour treatments by providing reduced side-effects, through targeted delivery of the drug, controlled release, enhanced solubility, permeability and retention. In this study, the impact of the conjugation of AZD5363 drug to N-doped, S-doped, and N/S-doped CQDs was investigated on inducing apoptosis by inhibiting the AKT signalling pathway in the MCF7 cell line. Initially, hydrothermal and pyrolysis methods were used to construct CQDs. Then, the synthesized quantum dots were conjugated with AZD5363 at three different concentrations, i.e., 0.03, 0.3, and 3nM. The MTT test results, on MCF7 cells, showed that although all the studied CQDs were biocompatible, the complex of N/S-doped CQD-AZD5363 at a concentration of 0.03nM was the most effective. After obtaining immunocytochemistry results, flow cytometry and cell invasion tests were employed to demonstrate the high potential of the introduced drug carrier complex in reducing AKT protein expression, induction of apoptosis and prevention of cell metastasis and invasion. According to these results, the binding of N/S-doped CQD to AZD5363 increases the effectiveness of this drug, with reducing the IC50 concentration, and more specificity to cancerous cells, introducing it as a suitable candidate for the treatment of breast cancer.

The Therapeutic Potential of Baicalin and Baicalein in Breast Cancer: A Systematic Review of Mechanisms and Efficacy

Cancer remains a leading cause of death globally, with breast cancer being the most commonly diagnosed cancer in women. This systematic review focuses on the therapeutic potential of baicalin and baicalein, two bioactive flavonoids derived from Scutellaria baicalensis, in breast cancer treatment. These compounds exhibit anticancer properties through mechanisms such as apoptosis induction, cell cycle arrest, and inhibition of metastasis. Baicalin and baicalein modulate key signaling pathways, including NF-κB, PI3K/AKT/mTOR, and Wnt/β-catenin, and have shown efficacy in both in vitro and in vivo models. Their synergy with chemotherapy agents and incorporation into nanotechnology-based delivery systems highlight opportunities to enhance therapeutic outcomes. However, current evidence is predominantly preclinical, with limited clinical trials to validate their safety and efficacy in humans. Challenges such as poor bioavailability and rapid metabolism also underscore the need for advanced formulation strategies. This review synthesizes current evidence on the molecular mechanisms, therapeutic efficacy, and potential applications of baicalin and baicalein in breast cancer research.

Mobile Electronic Patient-Reported Outcomes and Interactive Support During Breast and Prostate Cancer Treatment: Health Economic Evaluation From Two Randomized Controlled Trials.

Digital interventions for supportive care during cancer treatment incorporating electronic patient-reported outcomes (ePROs) can enhance early detection of symptoms and facilitate timely symptom management. However, economic evaluations are needed. This study aims to conduct a cost-utility analysis of an app for ePRO and interactive support from the perspective of the payer (Region Stockholm Health Care Organization) and to explore its impact on patient health care utilization and costs. Two open-label randomized controlled trials (RCTs) were conducted, including patients undergoing neoadjuvant chemotherapy for breast cancer (B-RCT; N=149) and radiotherapy for prostate cancer (P-RCT; N=150), recruited from oncology clinics at 2 university hospitals in Stockholm, Sweden. EORTC QLQ-C30 scores were mapped to EQ-5D-3L to calculate quality-adjusted life years (QALYs). Intervention and implementation costs and health care costs, obtained from an administrative database, were used to calculate incremental cost-effectiveness ratios (ICERs) in 3 ways: including all health care costs (ICERa), excluding nonacute health care costs (ICERb), and excluding health care costs altogether (ICERc). Nonparametric bootstrapping was used to explore ICER uncertainty. Health care costs were analyzed by classifying them as disease-related or acute. In both RCT intervention groups, fewer QALYs were lost compared with the control group (P<.001). In the B-RCT, the mean intervention cost was €92 (SD €2; €1=US $1.03). The mean cost for the intervention and all health care was €36,882 (SD €1032) in the intervention group and €35,427 (SD €959) in the control group (P<.001), with an ICERa of €202,368 (95% CI €152,008-€252,728). The mean cost for the intervention and acute health care was €3585 (SD €480) in the intervention group and €3235 (SD €494) in the control group (P<.001). ICERb was €49,903 (95% CI €37,049-€62,758) and ICERc was €13,213 (95% CI €11,145-€15,281); 22 out of 74 (30%) intervention group patients and 24 out of 75 (32%) of the control group patients required acute inpatient care for fever. In the P-RCT, the mean intervention cost was €43 (SD €0.2). The mean cost for the intervention and all health care was €3419 (SD €739) in the intervention group and €3537 (SD €689) in the control group (P<.001), with an ICERa of -€1,092,136 (95% CI -€3,274,774 to €1,090,502). The mean cost for the intervention and acute health care was €1219 (SD €593) in the intervention group and €802 (SD €281) in the control group (P<.001). ICERb was €745,987 (95% CI -€247,317 to €1,739,292) and ICERc was €13,118 (95% CI -68,468 to €94,704). As many as 10 out of the 75 (13%) intervention group patients had acute inpatient care, with the most common symptom being dyspnea, while 9 out of the 75 (12%) control group patients had acute inpatient care, with the most common symptom being urinary tract infection. ePRO and interactive support via an app generated a small improvement in QALYs at a low intervention cost and may be cost-effective, depending on the costs considered. Considerable variability in patient health care costs introduced uncertainty around the estimates, preventing a robust determination of cost-effectiveness. Larger studies examining cost-effectiveness from a societal perspective are needed. The study provides valuable insights into acute health care utilization during cancer treatment. ClinicalTrials.gov NCT02479607; https://clinicaltrials.gov/ct2/show/NCT02479607, ClinicalTrials.gov NCT02477137; https://clinicaltrials.gov/ct2/show/NCT02477137. RR2-10.1186/s12885-017-3450-y.