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New Therapeutic Approaches, Biomarkers for Diagnosis, Prognosis and Therapy Prediction in Breast Cancer and Breast Cancer Recurrence

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A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Oncology".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 26847

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Dr. Marco Fiorillo

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Guest Editor

Biomedical Research Centre, University of Salford, Manchester, UK
Interests: cancer stem cells (CSCs); breast cancer metabolism; cancer biomarkers; anticancer therapy; FDA drugs

Special Issue Information

Dear Colleagues,

Over the last two decades, the tumor recurrence has become a worldwide problem of high scientific and clinical interest. The clinical data show that nearly 30% of breast cancer patients undergo recurrence during follow-up.

The latest scientific evidence shows that breast cancer recurrence times vary considerably, influenced by classical prognostic factors and adjuvant treatment strategies. More precisely, the state of the estrogen receptor (ER) provides a clinically useful distinction as recurrences in patients with ER-negative disease occur earlier during follow-up, while in those with ER-positive disease, relapses continue to occur later in follow-up. The late relapses evident in ER-positive disease suggest that the mechanisms related to disease recurrence are different from the disease itself, in which cancer cells can remain dormant for an extended period of time, despite adjuvant therapies.

In fact, the phenomenon of resistance to adjuvant therapies of this small population of cancer cells is the subject of numerous scientific studies, where many scientists are investigating the metabolic and microenvironmental changes in the various models in order to understand the disease recurrence mechanisms, discover new biomarkers for the early detection of breast cancer relapse, and predict treatment efficacy.

However, despite these efforts, the incidence of breast cancer recurrence is currently increasing because of the ability of breast cancer cells to become resistant to the common therapies, resulting in a strong increase in metastatic capacity.

In this Special Issue, we will focus on generating better models of relapse, resulting in a more complete understanding of the metabolic and regulatory mechanisms of drug resistance, the role of the microenvironment in breast cancer, the role of genetic predisposition in the control and prognosis of breast cancer, and other molecular differences that could lead to the development and discovery of new targeted biomarkers and therapeutic approaches that offer a unique opportunity to better define the patterns of late recurrence in breast cancer.

Dr. Marco Fiorillo
Guest Editor

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Keywords

breast cancer
targeted therapy
combination therapy
breast cancer biomarkers
cancer stem cells (CSCs)
metastasis
drug resistance
in silico modeling
3D cell models
in vivo modeling
prognostic analysis

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Published Papers (9 papers)

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Research

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17 pages, 2415 KiB

Open AccessArticle

Plasma Levels and Diagnostic Utility of VEGF in a Three-Year Follow-Up of Patients with Breast Cancer

by Grażyna E. Będkowska, Ewa Gacuta, Monika Zbucka-Krętowska, Paweł Ławicki, Maciej Szmitkowski, Adam Lemancewicz, Joanna Motyka, Agnieszka Kobus, Monika Chorąży, Marlena Paniczko and Sławomir Ławicki

J. Clin. Med. 2021, 10(22), 5452; https://doi.org/10.3390/jcm10225452 - 22 Nov 2021

Cited by 10 | Viewed by 1750

Abstract

Breast cancer is the most common malignancy in women globally. The increasing worldwide incidence of this type of cancer illustrates the challenge it represents for healthcare providers. Therefore, new tumor markers are constantly being sought. The aim of this study was to assess plasma concentrations and the diagnostic power of VEGF in 100 patients with early-stage breast cancer, both before and after surgical treatment and during a three-year follow-up. The control groups included 50 subjects with benign breast tumors (fibroadenoma) and 50 healthy women. The VEGF concentration was determined using enzyme-linked immunosorbent assay (ELISA) and the CA 15-3 concentration was determined by chemiluminescent microparticle immunoassay (CMIA). We observed significantly higher preoperative plasma concentrations of VEGF and CA 15-3 in patients with breast cancer. VEGF, similar to CA 15-3, demonstrated high diagnostic utility in the assessment of the long-term efficacy of surgical removal of the tumor. Determinations of VEGF had the highest diagnostic usefulness in the detection of breast cancer recurrence (SE 40%, SP 92%, PPV 67%, NPV 79%). Additionally, the highest values of SE, NPV and AUC were observed during the combined analysis with CA 15-3 (60%; 84%; 0.7074, respectively). Our study suggests a promising diagnostic utility of VEGF in the early stages of breast cancer and in the evaluation of the efficacy of the surgical treatment of breast cancer as well as the detection of breast cancer recurrence, particularly in a combined analysis with CA 15-3 as a new diagnostic panel. Full article

(This article belongs to the Special Issue New Therapeutic Approaches, Biomarkers for Diagnosis, Prognosis and Therapy Prediction in Breast Cancer and Breast Cancer Recurrence)

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13 pages, 1467 KiB

Open AccessArticle

Immunohistochemistry for Thymidine Kinase-1 (TK1): A Potential Tool for the Prognostic Stratification of Breast Cancer Patients

by Giuseppe Nicolò Fanelli, Rosa Scarpitta, Paola Cinacchi, Beatrice Fuochi, Anna Szumera-Ciećkiewicz, Katia De Ieso, Paola Ferrari, Andrea Fontana, Mario Miccoli, Antonio Giuseppe Naccarato and Cristian Scatena

J. Clin. Med. 2021, 10(22), 5416; https://doi.org/10.3390/jcm10225416 - 19 Nov 2021

Cited by 13 | Viewed by 2400

Abstract

Breast cancer (BC) is the most frequent non-cutaneous malignancy in women. Histological grade, expression of estrogen and progesterone receptors (ER and PgR), overexpression/amplification of the human epidermal growth factor receptor 2 (HER2) oncogene, and proliferative activity measured with ki-67 provide important information on the biological features of BC and guide treatment choices. However, a biomarker that allows a more accurate prognostic stratification is still lacking. Thymidine kinase-1 (TK1), a ubiquitous enzyme involved in the pyrimidine nucleotide recovery pathway, is a cell-proliferation marker with potential prognostic and predictive impacts in BC. Eighty (80) cases of invasive BC with a long-term follow-up were retrospectively selected, and clinicopathological data were collected for each patient. TK1 tissue expression was evaluated immunohistochemically. Data suggested that TK1 expression levels are positively correlated with ER and PgR expression, and negatively correlated with HER2 status and the impact on patients’ distant recurrence-free survival (DRFS): in detail, among patients undergoing adjuvant chemotherapy, lower TK1 levels are correlated with better DRFS. Therefore, these results contribute to furthering the knowledge of TK1, suggesting a possible and important role of this enzyme as a biomarker in the stratification of BC patients. Full article

(This article belongs to the Special Issue New Therapeutic Approaches, Biomarkers for Diagnosis, Prognosis and Therapy Prediction in Breast Cancer and Breast Cancer Recurrence)

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15 pages, 2231 KiB

Open AccessArticle

Diagnostic and Prognostic Potential of MiR-379/656 MicroRNA Cluster in Molecular Subtypes of Breast Cancer

by Megha Lal, Asgar Hussain Ansari, Anurag Agrawal and Arijit Mukhopadhyay

J. Clin. Med. 2021, 10(18), 4071; https://doi.org/10.3390/jcm10184071 - 9 Sep 2021

Cited by 4 | Viewed by 3200

Abstract

Introduction: Breast cancer is the most frequently diagnosed cancer globally and is one of the most important contributors to cancer-related deaths. Earlier diagnosis is known to reduce mortality, and better biomarkers are needed. MiRNA clusters often co-express and target mRNAs in a coordinated fashion, perturbing entire pathways; they thus merit further exploration for diagnostic or prognostic use. MiR-379/656, at chromosome 14q32, is the second largest miRNA cluster in the human genome and implicated in various malignancies including glioblastoma, melanoma, gastrointestinal tumors and ovarian cancer highlighting its potential importance. In this study, we focus on the diagnostic and prognostic potentials of MiR-379/656 in breast cancer and its molecular subtypes. Materials and Methods: We analyzed miRNA and mRNA next generation sequencing data from 903 primary tumors and 90 normal controls (source: The Cancer Genome Atlas). The differential expression profile between tumor and normal was analyzed using DeSEQ2. Penalized logistic regression modelling (lasso regression) was used to assess the predictive potential of MiR-379/656 expression for tumor and normal samples. The association between MiR-379/656 expression and overall patient survival was studied using Cox Proportional-Hazard Model. The target mRNAs (validated) of MiR-379/656 were annotated via pathway enrichment analysis to understand the biological significance of the cluster in breast cancer. Results: The differential expression analysis for 1390 miRNAs (miRnome) revealed 310 upregulated (22.3%) and 176 downregulated (12.66%) miRNAs in breast cancer patients compared with controls. For MiR-379/656, 32 miRNAs (32/42; 76%) were downregulated. The MiR-379/656 cluster was found to be the most differentially expressed cluster in the human genome (p < 10⁻³⁰). The Basal and Luminal B subtypes showed at least 83% (35/42) of the miRNAs to be downregulated. The binomial model prioritized 15 miRNAs, which distinguished breast cancer patients from controls with 99.15 ± 0.58% sensitivity and 77.78 ± 5.24% specificity. Overall, the Basal and Luminal B showed the most effective predictive power with respect to the 15 prioritized miRNAs at MiR-379/656 cluster. The decreased expression of MiR-379/656 was found to be associated with poorer clinical outcome in Basal and Luminal B subtypes, increasing tumor stage and tumor size/extent, and overall patient survival. Pathway enrichment for the validated targets of MiR-379/656 was significant for cancer-related pathways, especially DNA repair, transcriptional regulation by p53 and cell cycle checkpoints (adjusted p-value < 0.05). Conclusions: Genome informatics analysis of high throughput data for MiR-379/656 cluster has shown that a subset of 15 miRNAs from MiR-379/656 cluster can be used for the diagnostic and prognostic purpose of breast cancer and its subtypes—especially in Basal and Luminal B. Full article

(This article belongs to the Special Issue New Therapeutic Approaches, Biomarkers for Diagnosis, Prognosis and Therapy Prediction in Breast Cancer and Breast Cancer Recurrence)

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14 pages, 3619 KiB

Open AccessArticle

Plasma Concentrations of Matrilysins MMP-7 and MMP-26 as Diagnostic Biomarkers in Breast Cancer

by Barbara Maria Piskór, Andrzej Przylipiak, Emilia Dąbrowska, Iwona Sidorkiewicz, Marek Niczyporuk, Maciej Szmitkowski and Sławomir Ławicki

J. Clin. Med. 2021, 10(7), 1436; https://doi.org/10.3390/jcm10071436 - 1 Apr 2021

Cited by 19 | Viewed by 2593

Abstract

Metalloproteinases (MMPs) are a group of proteolytic enzymes involved in the maintenance of a proper structure of extracellular matrix (ECM). Matrilysins (MMP-7 and MMP-26) are members of the MMPs group that show promise as potential breast cancer (BC) markers. The aim of the study was to evaluate plasma levels of MMP-7, MMP-26 and CA 15-3 individually and in combination and assess the diagnostic utility of studied matrilysins in patients with BC. The study group consisted of 120 patients with BC, and the control group consisted of 40 subjects with benign breast cancer and 40 healthy women. Concentrations of MMP-7 and MMP-26 were determined by enzyme-linked immunosorbent assay, and CA 15-3 by chemiluminescent microparticle immunoassay. Plasma levels of MMP-7 were significantly higher in the BC group than in the control group. Concentrations of MMP-26 and CA 15-3 were highest in stages II and IV of the disease. The highest diagnostic sensitivity was observed in stages III and IV BC for the combination of all tested markers (92.5%). The highest diagnostic specificity was noted for all tested parameters combined in the BC group (95.0%). The area under the receiver operating characteristic (ROC) curve (AUC) for the combination of markers (MMP-7+MMP-26+CA 15-3) was the largest (0.9138) in stages III and IV. Individual marker analysis showed that MMP-7 had the highest AUC (0.8894) in advanced stages of the disease. Study results indicate that MMP-7 could be used as an additional marker that would improve the diagnostic utility of CA 15-3 in early stages of BC. Therefore, the combined assessment of MMP-7 and MMP-26 with CA 15-3 might be useful in determining disease progression. Further studies are needed to evaluate whether matrilysins show promise as potential markers for improving the diagnosis of BC. Full article

(This article belongs to the Special Issue New Therapeutic Approaches, Biomarkers for Diagnosis, Prognosis and Therapy Prediction in Breast Cancer and Breast Cancer Recurrence)

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14 pages, 2223 KiB

Open AccessArticle

Quality of Life in Women Subjected to Surgical Treatment of Breast Cancer Depending on the Procedure Performed within the Breast and Axillary Fossa—A Single-Center, One Year Prospective Analysis

by Magdalena Tarkowska, Iwona Głowacka-Mrotek, Tomasz Nowikiewicz, Aleksander Goch and Wojciech Zegarski

J. Clin. Med. 2021, 10(7), 1339; https://doi.org/10.3390/jcm10071339 - 24 Mar 2021

Cited by 6 | Viewed by 2178

Abstract

The aim of this study was to evaluate the quality of life of patients undergoing surgical treatment of breast cancer depending on the type of procedure involving the breast (mastectomy vs. breast conserving treatment) and axillary fossa (sentinel lymph node biopsy vs. axillary lymph node dissection). The prospective study was carried out in a group of 338 females undergoing breast cancer treatment. Study variables were assessed by means of a diagnostic survey using standardized QLQ C30 and BR23 questionnaires as well as the Acceptance of Illness Scale and Mini-MAC scales. The quality of life was assessed at threetime points: on the day before the surgical procedure (I assessment) as well as three and 12 months after surgery (II and III assessment). Statistically significant differences between study groups were observed in the overall quality of life subscale (I, II, III—p < 0.0001), physical functioning (I—p < 0.0001; II—p = 0.0413; III—p < 0.0001), role functioning (I—p = 0.0002; III—p < 0.0001), emotional functioning (III—p = 0.0082), cognitive functioning (I—p = 0.0112; III—p < 0.0001), social functioning (III—p < 0.0001), body image (I, II, III—p < 0.0001), and sexual functioning (I—p = 0.0233; III—p = 0.0011). In most symptomatic scales, significant (p < 0.05) differences were also noted. Mastectomy and limfadenectomy patients were significantly (p < 0.0001) more prone to present with destructive coping strategies one year after surgery. Breast conserving therapy is associated with better quality of life outcomes as compared to mastectomy. Sentinel lymph node biopsy is associated with a lower intensity of adverse changes in multiple dimensions of patients’ functioning. Full article

(This article belongs to the Special Issue New Therapeutic Approaches, Biomarkers for Diagnosis, Prognosis and Therapy Prediction in Breast Cancer and Breast Cancer Recurrence)

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11 pages, 260 KiB

Open AccessArticle

Associations of MDM2 and MDM4 Polymorphisms with Early-Stage Breast Cancer

by Agnė Bartnykaitė, Aistė Savukaitytė, Rasa Ugenskienė, Monika Daukšaitė, Erika Korobeinikova, Jurgita Gudaitienė and Elona Juozaitytė

J. Clin. Med. 2021, 10(4), 866; https://doi.org/10.3390/jcm10040866 - 19 Feb 2021

Cited by 8 | Viewed by 3391

Abstract

Breast cancer is one of the most common cancers worldwide. Single nucleotide polymorphisms (SNPs) in MDM2 and MDM4 have been associated with various cancers. However, the influence on clinical characteristics of breast cancer has not been sufficiently investigated yet. Thus, this study aimed to investigate the relationship between SNPs in MDM2 (rs2279744, rs937283, rs937282) and MDM4 (rs1380576, rs4245739) and I–II stage breast cancer. For analysis, the genomic DNA was extracted from 100 unrelated women peripheral blood. Polymorphisms were analyzed with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) assay. The study showed that MDM2 rs937283 and rs937282 were significantly associated with estrogen receptor status and human epidermal growth factor receptor 2 (HER2) status. SNPs rs1380576 and rs4245739, located in MDM4, were significantly associated with status of estrogen and progesterone receptors. Our findings suggest that rs937283 AG, rs937282 CG, rs1380576 CC, and rs4245739 AA genotypes were linked to hormonal receptor positive breast cancer and may be useful genetic markers for disease assessment. Full article

(This article belongs to the Special Issue New Therapeutic Approaches, Biomarkers for Diagnosis, Prognosis and Therapy Prediction in Breast Cancer and Breast Cancer Recurrence)

11 pages, 1962 KiB

Open AccessArticle

Elucidation of Novel Therapeutic Targets for Breast Cancer with ESR1-CCDC170 Fusion

by Jae Heon Jeong, Jae Won Yun, Ha Young Kim, Chan Yeong Heo and Sejoon Lee

J. Clin. Med. 2021, 10(4), 582; https://doi.org/10.3390/jcm10040582 - 4 Feb 2021

Cited by 8 | Viewed by 3784

Abstract

Among the various types of breast cancer, the luminal B subtype is the most common in young women, and ESR1-CCDC170 (E:C) fusion is the most frequent oncogenic fusion driver of the luminal B subtype. Nevertheless, treatments targeting E:C fusion has not been well established yet. Hence, the aim of this study is to investigate potential therapies targeting E:C fusion based on systematic bioinformatical analysis of the Cancer Genome Atlas (TCGA) data. One thousand related genes were extracted using transcriptome analysis, and major signaling pathways associated with breast cancer were identified with over-representation analysis. Then, we conducted drug-target network analysis based on the OncoKB and CIViC databases, and finally selected potentially applicable drug candidates. Six major cancer-related signaling pathways (p53, ATR/ATM, FOXM1, hedgehog, cell cycle, and Aurora B) were significantly altered in E:C fusion-positive cases of breast cancer. Further investigation revealed that nine genes (AURKB, HDAC2, PLK1, CENPA, CHEK1, CHEK2, RB1, CCNA2, and MDM2) in coordination with E:C fusion were found to be common denominators in three or more of these pathways, thereby making them promising gene biomarkers for target therapy. Among the 21 putative actionable drugs inferred by drug-target network analysis, palbociclib, alpelisib, ribociclib, dexamethasone, checkpoint kinase inhibitor AXD 7762, irinotecan, milademetan tosylate, R05045337, cisplatin, prexasertib, and olaparib were considered promising drug candidates targeting genes involved in at least two E:C fusion-related pathways. Full article

(This article belongs to the Special Issue New Therapeutic Approaches, Biomarkers for Diagnosis, Prognosis and Therapy Prediction in Breast Cancer and Breast Cancer Recurrence)

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21 pages, 3718 KiB

Open AccessArticle

8p11.23 Amplification in Breast Cancer: Molecular Characteristics, Prognosis and Targeted Therapy

by Ioannis A. Voutsadakis

J. Clin. Med. 2020, 9(10), 3079; https://doi.org/10.3390/jcm9103079 - 24 Sep 2020

Cited by 17 | Viewed by 3170

Abstract

Background: Amplification of the locus 8p11.23 has been observed in cancer and genes of this locus, including ZNF703 (Zinc finger protein 703), NSD3 (Nuclear receptor binding SET domain protein 3) and FGFR1 (Fibroblast growth factor receptor 1), have been put forward as dominant oncogenes conferring pathophysiologic benefit in cancers with amplifications. However, there is no consensus on the importance of each of them or any other genes of the amplicon or even a consensus on which genes are part of the amplicon. Methods: Publicly available data were used to characterize the locus amplified at 8p11.23 and derive information on each of the genes and roles as oncogenes. The frequency of the amplifications in the locus was examined in the cBioportal platform, and expression levels of the amplicon genes in amplified cases were derived from genomic studies reported in the platform. Examination of the influence of mRNA expressions of each gene of the locus for Recurrence-free survival in breast cancer was performed using K-M plotter. Results: The 8p11.23 amplicon is present in higher frequency in squamous cell lung carcinomas, breast cancers and bladder carcinomas and is only rarely observed in other cancers. The most frequently amplified genes within the amplicon vary between different types of cancers. In breast cancer, amplified cases are most commonly of the luminal B type. Amplified genes are not always over-expressed and there is a low correlation of amplification with over-expression in amplicon genes with variation between genes. The presence of the amplicon does not influence the aneuploidy score or the tumor mutation burden of breast cancers. Regarding prognosis, the two genes of the amplicon whose mRNA hyper-expression portends adverse relapse-free survival in breast cancer are EIF4EBP1 (Eukaryotic transcription initiation factor 4E binding protein 1) and LSM1 (LSM1 homolog, mRNA degradation associated). Conclusion: Besides the previously proposed genes to play a role as dominant oncogenes in the 8p11.23 cancer amplified locus, other genes may also be important in breast cancer based on the high correlation of their amplification and mRNA expression and adverse prognosis conferred by over-expression, consistent with an oncogenic role. Full article

(This article belongs to the Special Issue New Therapeutic Approaches, Biomarkers for Diagnosis, Prognosis and Therapy Prediction in Breast Cancer and Breast Cancer Recurrence)

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Review

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14 pages, 1080 KiB

Open AccessReview

The Role of Circulating Tumor Cells in Chemoresistant Metastatic Breast Cancer

by Lorena Alexandra Lisencu, Eduard-Alexandru Bonci, Alexandru Irimie, Ovidiu Balacescu and Cosmin Lisencu

J. Clin. Med. 2021, 10(4), 684; https://doi.org/10.3390/jcm10040684 - 10 Feb 2021

Cited by 4 | Viewed by 3247

Abstract

Breast cancer is the most frequent form of cancer among women and is one of the leading causes of death. Two routes of the metastatic process have been described: linear and parallel progression. A key factor is represented by circulating tumor cells (CTCs). CTCs detach from the primary tumor or develop from cancer stem cells (CSCs) that undergo epithelial-to-mesenchymal transition (EMT). CTCs migrate to the distant site where the reverse process occurs and a new tumor arises. One of the key problems of metastatic disease is chemoresistance, which leads to treatment failure and, eventually, death. The aim of this review is to present up-to-date data regarding the role of CTCs in chemoresistance in metastatic breast cancer (MBC) patients. A search in Cochrane Library and MEDLINE databases was performed. A total of 125 articles were identified. The results of the final 12 eligible studies revealed that CTCs having stem cell features and those with mesenchymal features are aggressive subtypes of cells that survive chemotherapy, being responsible for chemoresistance and thus for disease progression in MBC patients. The hemodynamic shear stress, alongside dynamic changes among CTCs during the disease, is also an important disease progression factor. Full article

(This article belongs to the Special Issue New Therapeutic Approaches, Biomarkers for Diagnosis, Prognosis and Therapy Prediction in Breast Cancer and Breast Cancer Recurrence)

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