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Circulating microRNAs as Liquid Biopsy: Comparison
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Please note this is a comparison between Version 2 by Conner Chen and Version 1 by Han Kiat Ong.

Circulating microRNAs (miRNAs) as liquid biopsy proposes a prospect of noninvasive sampling of breast cancer (BC) patient that allows for more personalized management of cancer with the possibility of complementing and supporting clinical assessment in early detection, classification of molecular subtypes and monitoring of recurrence and metastatic spread.

  • liquid biopsy
  • circulating miRNA
  • breast cancer

1. Introduction

Globally, breast cancer (BC) remains the most common cancer and the leading cause of cancer death for women [1]. Despite the advancement in BC screening, diagnostics and therapy, the overall rates of BC incidence and mortality around the world have been on an increasing trend. Although BC mortality rates have declined over time in most high-income countries (HICs) [2], they remain high and are increasing in many low-middle-income and low-income countries [3[3][4],4], partly due to poor awareness and perception of early BC detection, leading to delays in diagnosis and treatment [1]. Recent studies show that the mortality rate is also compounded by disparities in BC screening between rural and urban rural/urban areas [5] as well as among those from different socio-economic and ethnic backgrounds of HICs [2]. Nevertheless, there has been a more established understanding of the heterogenous nature of BC and its application in the development of personalized medicine and targeted therapy [6]. However, the complex interaction within the tumor microenvironment (TME) and the influence of cancer stem cells (CSCs) from cancer recurrence to drug resistance [7] as well as population-based variation in terms of immunological response [8] continue to pose challenges in deciphering feasible approaches in managing BC diagnosis, monitoring and administrating effective treatment options. In the past decade, the evolution of BC diagnosis and classification has resulted in greater supporting tools, ranging from classical mammography and histopathology [9] to molecular-based markers and multigene prognosticators [10], which ultimately guided the overall management of BC (Table 1) [11,12,13,14][11][12][13][14]. Still, many if not all of these existing tools are heavily reliant on invasive tissue biopsies as the starting point for screening and monitoring BC progression, evaluating cancer prognosis and deciding on the best therapeutic options. Moreover, studies have shown that the BC signatures are often not clearly manifested and well represented in the current screening methods, namely mammography [15] and tissue biopsies [16]—more so in the diagnosis of metastatic cancers [17]. Liquid biopsy (LB), on the other hand, has emerged as a potential feasible approach in overcoming these shortfalls, from obtaining samples in a noninvasive manner to early detection of cancer and more comprehensive monitoring [18[18][19],19], thereby offering patients less stressful experiences and a better sense of worthiness in managing cancer treatments. Among the commonly known cancer biomarkers in LB [19], circulating microRNAs (miRNAs) stand out as a feasible and practical option [20].
Cancer Type Benign Pre-Malignant/

In-Situ

(20–25%) [13]		 Malignant/Invasive [IDC (80%), ILC (20%)] [13]
Categories Fibroadenoma

Intraductal papilloma

Lipoma		 Early Breast Cancer

Detection		 Molecular Subtypes (St Gallen) Recurrence/

Metastatic
Lubular Carcinoma In-situ (LCIS) Ductal Carcinoma In-situ (DCIS) Luminal A Luminal B

(HER2-)		 Luminal B (HER2+) HER2+ Enriched TNBC
Cancer/Bio markers

[11,12][11][12]		   ER, PR, HER2 & Ki67 (low < 10%);

Germline test

BRCA1 & 2 (High risk group)		 ER+; PR+; HER2−; Ki67 low (<10–14%);

Germline test

BRCA1 & 2 (High Risk Group)		 ER+; PR−; HER2−; Ki67 high (>14–30%); Germline test

BRCA1 & 2 (High Risk Group)		 ER+; PR+/−; HER2+; Ki67 high/low;

Germline test

BRCA1 & 2 (High Risk Group)		 ER−; PR−; HER2+; Ki67 high;

Germline test

BRCA1 & 2 (High Risk Group)		 ER−; PR−; HER2−; Ki67 high; (CK 5/6+; EGFR+); Germline test

BRCA1 & BRCA2 (High Risk Group)		 Metastatic Site: Bone, liver, lungs, brain

ESCAT score:

I = Good prognosis

II = Poor Prognosis
Frequency of cases [14]   20–25% 40–50% 20–30% 20–30% 15–20% 10–20% 4%
Histological grade (Majority)     Well

differentiated

(G1)		 Moderately

differentiated

(G2)		 Moderately

differentiated

(G2)		 Poorly

differentiated

(G3)		 Poorly

differentiated

(G3)		 Poorly

differentiated

(G4)
TNM Stage   NR I-III I-III I-III I-III I-III IV
Prognosis   NR Good Intermediate Intermediate Poor Poor Poor
Response to therapies [11,12,14][11][12][14]   Surgery

Breast-conserving surgery (BCS)

Radiotherapy Lumpectomy

Mastectomy		 Endocrine Endocrine

Chemotherapy		 Endocrine

Chemotherapy

Targeted Therapy		 Chemotherapy

Targeted Therapy		 Chemotherapy

PARP inhibitors		 Chemotherapy

CKD4/6 Inhibitor Fulvestrant
Abbreviations: BRCA 1 & 2: Breast Cancer gene 1 and 2; TNM: tumor, node, and metastasis; DCIS: Ductal Carcinoma In-situ; ESCAT: ESMO Scale for Clinical Actionability of molecular Targets; ER: Estrogen receptor; HER2: Human epidermal growth factor receptor; IDC: Invasive Ductal Carcinoma; ILC: Invasive Lobular Carcinoma; LCIS: Lubular Carcinoma In-situ; PALB2: Partner and localizer of BRCA2; PDL1: Program death-ligand 1; PR: Progesterone receptor, 2; MSI: Microsatellite instability.

2. Current Trends and Research Outcomes of Circulating miRNA as Liquid Biopsy

Circulating miRNAs are extracellular miRNAs that are present in body fluids, such as blood, serum, plasma, milk, saliva and urine, either in the form of free-circulating miRNAs or encapsulated within extracellular vesicles (EVs), such as exosomes [24,25,26][21][22][23]. The advancement in molecular biology techniques has allowed scientists to employ different methods, such as real-time polymerase chain reaction (qPCR) [27][24], miRNA-sequencing (miRNA-seq) [28][25] and microarray [29][26], to detect the levels of circulating miRNAs among BC patients. These techniques have been reported to play essential roles in the diagnosis, classification and prognosis of BC [30,31][27][28].

2.1. Diagnostic Significance of Circulating miRNAs in Human Breast Cancer

To date, more than 50 original research articles have reported the roles of circulating miRNAs as a minimally invasive tool in diagnosing BC, either as free-circulating miRNA BC in plasma or serum [32,33][29][30] or transported in EVs and exosomes [34,35][31][32]. Many circulating miRNAs were shown to be elevated in BC patients as compared to healthy controls and these include miR-21 [36][33], miR-24 [32][29], miR-34 [37][34], miR-155 [38][35], miR-140-5p [39][36] and many other miRNAs [40][37]. Similarly, the downregulation of specific circulating miRNAs, such as miR-363-5p [25][22] and miR-4488 [41][38], was demonstrated to be useful to distinguish between BC patients and healthy controls. In addition, the elevation of serum exosomal miR-21-5p and miR-23a-3p levels [33][30] and plasma miR-133a, miR-148b and miR-200 levels [42,43][39][40] was found to be sensitive to distinguish early and advanced BC and this is particularly useful to detect early BC. Other miRNAs that had been reported to be useful in detecting early BC include miR-23b, miR-26b-5p, miR-106b-5p, miR-127-3p, miR-142-3p, miR-142-5p, miR-148b, miR-185-5p, miR-362-5p, miR-409-3p, miR-652 and miR-801 [44,45,46][41][42][43]. On the contrary, the level of circulating miRNAs is helpful to classify BC based on the clinical and histopathological grading [47,48][44][45]. For instance, the increased levels of exosomal miR-363-5p [25][22] and circulating miR-106a levels [49][46] were useful to differentiate BC with and without lymph node involvement. A clinical study reported that the elevation of four serum miRNAs, including miR-16-5p, miR-17-3p, miR-451a and miR-940, was observed in metastatic BC as compared to local, non-metastatic BC [50][47] and downregulation of plasma miR-195 level was also observed in metastatic BC [51][48]. The combined findings from these studies [50,51][47][48] highlighted the significance of circulating miRNA levels in BC staging. In addition, upregulation of plasma exosomal miR-181-5p and miR-222-3p is reported to link to advanced inflammatory BC as compared to non-inflammatory BC [35][32]. In terms of molecular grading, circulating miR-182 and miR-200c were shown to be downregulated and upregulated, respectively, in estrogen receptor (ER)- and progesterone receptor (PR)-positive patients. Upregulation of miR-10b and miR-21 was reported in ER-negative BC according to an Irish study [52][49], whereas suppression of miR-17 was shown to be observed in ER-positive BC [24][21]. For human epidermal growth factor receptor 2 (HER2)-positive patients, circulating miR-373 was reported to be upregulated [24][21] and, in another Chinese study [53][50], it was shown that the circulating level of miR-106a-5p and miR-20b-5p was increased in HER2-negative BC patients. In triple-negative BC (TNBC), serum miR-335 was reported to be downregulated [54][51], whereas serum miR-200c was upregulated [55][52]. Other circulating miRNAs that were upregulated in TNBC include miR-188-5p, miR-642b-3p, miR-1202, miR-1207-5p, miR-1225-5p, miR-1290, miR-3141, miR-4270 and miR-4281 [56][53].

2.2. Prognostic Significance of Circulating miRNAs in Human Breast Cancer

Apart from being employed as minimally invasive biomarkers in diagnosing and classifying different stages or types of BC [57][54], circulating miRNAs are also important in predicting the prognosis and treatment responses of BC patients [38,58][35][55]. For instance, the expression of miR-155 and miR-1246 was elevated in the plasma exosomes isolated from BC patients, and the upregulation of both miRNA levels was linked to poor survival, recurrence and trastuzumab resistance among BC patients [38][35]. In another study [39][36], downregulation of plasma miR-140-5p was correlated to increased chemoresistance, reduced event-free survival (EFS) and increased recurrence among BC patients. On the other hand, upregulation of exosomal miR-21 [58][55], exosomal miR-34a, miR-182 and miR-183 levels [59][56] was shown to contribute to poor chemotherapy response among BC patients, while the elevation of blood exosomal miR-2392, miR-4448 and miR-4800-3p was demonstrated to correlate to good response after neoadjuvant chemotherapy [60][57]. In terms of response towards targeted therapy, such as trastuzumab, decreased serum levels of miR-16-5p, miR-17-3p, miR-451a and miR-940 were observed in trastuzumab-resistant BC and the increased expression of these miRNAs was shown to promote treatment response to trastuzumab and improve survival among BC patients [50][47]. In another Arabic study [30][27], dysregulations of seven circulating miRNAs that include miR-19a, miR-19b-3p, miR-22-3p, miR-25-3p, miR-93-5p, miR-199a-3p and miR-210-3p were shown to be related to resistance to both chemotherapy and targeted therapy. On the contrary, the upregulation of circulating miR-21 correlated tightly to radio resistance among BC patients [36][33]. Notably, all the circulating miRNAs that were reported to modulate treatment responses in BC patients appeared to share a common function in promoting uncontrolled proliferation and apoptosis evasion among the BC cells [61,62][58][59]. For example, miR-373 was reported to upregulate the expression of vascular endothelial growth factor (VEGF) in BC cells, which would lead to enhanced proliferation and angiogenesis [62][59]. By studying the relationships between circulating miRNA levels, clinical conditions and treatment responses, clinicians could predict the survival and likelihood of disease recurrence among BC patients [63][60]. Elevation of several circulating exosomal miRNAs was shown to be associated with good survival and it was suggested that the upregulation of these miRNAs may improve patient survival by enhancing patient response to chemotherapy [60][57]. On the other hand, the upregulation of exosomal miR-200c [64][61] and miR-24-3p [47][44] was shown to correlate to poor overall survival (OS) among BC patients, as the increased expressions of these miRNAs were hypothesized to directly correlate to advanced disease staging [47,64][44][61]. Similarly, the downregulation of several circulating miRNAs, such as miR-34a [37][34] and miR-335 [54][51], was shown to reduce BC patient survival and this would contribute to an increased likelihood of relapse and recurrence. Metastasis is one of the important factors causing BC recurrence and the dysregulations. Eight miRNAs, including miR-296-3p, miR-575, miR-3610-5p, miR-4483, miR-4710, miR-4755-3p, miR-5698 and miR-8089, were demonstrated to be able to predict the likelihood of recurrence secondary to BC metastasis [31][28]. Other circulating miRNAs that are reported to play vital roles in influencing patient survival include miR-17, miR-18b, miR-103, miR-107, miR-652, miR-26b-5p, miR-106b-5p, miR-142-3p, miR-142-5p, miR-185-5p and miR-362-5p [45,65,66][42][62][63]. Patients with dysregulated circulating levels of these miRNAs were found to have more advanced disease staging and were more prone to face disease relapse and recurrence with reduced survival rate [45,65,66][42][62][63]. In two other studies [29[26][28],31], at least 20 circulating or exosomal miRNAs were reported to be sensitive and useful in distinguishing between recurrent and non-recurrent BC cases and this is helpful to predict patient prognosis and survival.

2.3. Multifunctional Roles of Circulating miRNAs as Potential Biomarker for Human Breast Cancer

Evidently, circulating miRNAs have great potential to be employed as minimally invasive biomarkers in diagnosing BC at an early stage and complementary to the distinguishment of BC based on its clinical and histopathological grading [62,67][59][64]. In addition, circulating miRNAs are also helpful to predict the likelihood of relapse, recurrence and treatment responses among BC patients and this is particularly useful in guiding clinicians in planning a personalized treatment approach for different BC patients [30,68][27][65]. 

2.4. Sensitivity and Specificity Levels of miRNA Detection in BC Patients

Several potential miRNA biomarkers have been identified in BC patients’ serum or plasma. With a receiver operating characteristic (ROC) curve analysis, miR-21-5p was shown to have greater potential in discriminating between BC patients and the control group than that of miR-221-3p [69][66]. Additionally, a recent meta-analysis on miR-21-5p and BC that comprises six publications, consisting of Asian and Caucasian study cohorts, further confirmed the potential early diagnostic role of miR-21-5p in BC patients due to its high pooled AUC and diagnostic odds ratio [70][67]. Further, another recent meta-analysis conducted with the aim of determining the overall diagnostic performance of 56 eligible studies involving circulating miRNAs via qPCR revealed a pooled sensitivity and specificity of 0.85 and 0.83, respectively [71][68]. Moreover, multiple miRNA panels with sensitivity and specificity scores of 0.90 and 0.86, respectively, were significantly higher compared to that of the single miRNA panels with corresponding sensitivity and specificity scores of 0.82 and 0.83, respectively. With regard to specimen type, pool sensitivity and specificity of plasma were 0.83 and 0.85, respectively, and the pool sensitivity and specificity of serum were 0.87 and 0.83, respectively, indicating little difference in the diagnostic performance between serum and plasma samples. These studies revealed that cell-free circuiting miRNA could function as a promising early diagnostic biomarker for the detection of BC [71][68].

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