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Table 1 Cumulative list of circulating biomarkers in liquid biopsies of early and metastatic stage breast cancer patients

From: The double agents in liquid biopsy: promoter and informant biomarkers of early metastases in breast cancer

No.

Clinical Study

Endpoints

Source

Samples

Method of detection

Biomarkers

Ref

1.

CTC-specific miRNAs

Enhance the prognostic accuracy of CTCs in MBC

LB – CTCs (peripheral blood)

MBC with CTC ≥5/7.5 mL (n = 16); patients with CTC = 0/7.5 mL (n = 16) and healthy donors (n = 8)

CellSearch system for CTC detection

⬆ CTC-specific miR-106b;

⬆ E-cadherin;

⬆ vimentin

[65]

2.

Clinical Trials NCT00433511

CTCs to predict late clinical recurrence in HER2- BC

LB – CTCs (peripheral blood)

547 Lymph Node Positive and High Risk Lymph Node Negative BC

CellSearch system for CTC detection

higher recurrence risk is associated with higher CTC burden.

[75]

3.

The LiqBreasTrack cohort study (Nov 2016-Feb 21)

Progression-free survival (PFS) between the first T-DM1 administration and progressive disease or last follow-up.

LB – ctDNA (plasma)

28 BC tissues (n = 14); 337 plasma (n = 20)

Targeted NGS and dPCR

⬆ MYC/FGFR1/ESR1 amplifications;

⬇ HER2 amplifications;

⬇ PIK3CA mutations

[79]

4.

Long non-coding RNAs

Diagnosis of early stage BC and patients with larger tumors (> 2 cm)

LB – lincRNA:miRNA (blood)

25 controls and 70 BC patients

q-PCR

⬆ LINC00511 and onco-miR-301a-3p;

⬇ miR-185-3p

[92]

5.

Circulating microRNAs

Predict the CTC status of patients with MBC

LB –Ct miRNAs (plasma)

269 samples (61 CTC-positive, 72 CTC-negative, 60 CTC-low MBC cases, and 76 controls)

TaqMan Human MicroRNA array

⬆ miR-141, miR-200a, miR-200b, miR-200c, miR-203, miR-210, miR-375, and miR-801 upregulated in CTC+ MBC;

⬇ miR-768-3p in MBC;

[99]

6.

SUCCESS A trial – MicroRNAs as prognostic markers in post-operative EBC patients

Associate whole blood miRNA profiles, presence of circulating tumor cells (CTCs) and clinical outcome in post-op EBC patients

LB – whole blood (pre-adjuvant therapy, post-adjuvant therapy, 2 years follow up)

48 post-operative patients; 17 female healthy donors as negative controls

miRNA quantitative PCR

⬆ miR-19a, miR-22 and miR-127 in EBCs;

⬆ miR-127 correlated with the presence of CTCs

[101]

7.

Precursor miRNAs of oncomiRs (miR526b and miR655)

Differentiate malignant tumors from benign lesions

LB – pri-miRNA (plasma)

90 malignant tumors; 20 benign lesions (control)

q-PCR

⬆ pri-miR526b and pri-miR655 in Stage I plasma and malignancy

[102, 103]

8.

4-circulatory miRNA signature in plasma of EBC

Early detection of (ER/PR+) IDC-BC from healthy controls

LB – miRNAs (plasma)

41 early invasive ductal carcinoma (IDC) Lebanese BC patients; 32 healthy controls

miRNA quantitative PCR

⬆ miR-145, miR-139-5p, miR-425-5p, and miR-130a upregulated in EBC plasma

[106]

9.

5-miRNA signature

Discern high- and low-risk of relapse (early recurrence and those with no recurrence) in post-operative BC patients

MiRNAs - Tumor (tissue sample)

71 primary BC (group A – disease-free); (group B - early relapse); (group C - late relapse)

Microarray and RT-qPCR validation

⬇ miR-149, miR-10a, miR-20b, miR-30a-3p and miR-342-5p in high-risk, early recurrence group

[108]

10.

Exosomal miRNAs

Diagnostic markers for BC

LB – miRs (plasma)

16 healthy plasma and 16 BC plasma

NGS, q-PCR

⬆ miR-1246 and miR-21

[117]

11.

Exosomal miRNAs

Diagnostic markers for BC subtypes

LB – miRs (serum)

Control (n-16); LA (n-16); TNBC (n-16)

RNA-seq; q-PCR

⬆ miR-142-5p, miR-320a and miR-4433b-5p

[118]

12.

Exosomal miRNAs

The diagnostic role of miR-106a-363 cluster in BC

LB - miRs (plasma, serum)

(400 plasma) - 200 BC patients and 200 healthy controls (HCs); (406 serum) - 204 BC patients and 202 HCs

q-PCR

⬆ plasma miRNAs (miR-106a-3p, miR-106a-5p, miR-20b-5p, miR-92a-2-5p);

⬆ serum miRNAs (miR-106a-5p, miR-19b-3p, miR-20b-5p, and miR-92a-3p)

[119]

13.

Circulating miRNAs

Diagnosis of early BC

LB - miRs (plasma)

65 BC patients and 34 HCs

real-time PCR (RQPCR)

⬆ miR-99a, miR-130a,

miR-484 and miR-1260a

[121]

14.

Circulating miRNAs

Early detection markers for breast cancer

LB – miRs (plasma)

127 sporadic breast cancer cases and 80 healthy controls

TaqMan low-density arrays (TLDA) and qPCR)

⬆ miR-148b, miR-409-3p and miR-801

[122]

15.

Circulating miRNAs

Detect malignant from benign pre-treatment plasma of BC

LB – miRs (plasma)

Benign - 40; Non-metastatic BC – 54; Metastatic BC - 14

Microarray

⬆ hsa-miR-652-5p

[123]

16.

Circulating miRNAs

Early stage BC

LB – miRs (blood)

83 BC patients; 63 Healthy controls

real-time PCR (RQPCR)

⬆ miR-195

[124]

17.

Circulating miRNAs

Early stage BC

LB – miRs (serum)

210 BC patients; 102 Healthy controls

real-time PCR (RQPCR)

⬆ miR-195

[125]

18.

Circulating Biomarkers (miRNA+ protein)

ER+ BC to Bone metastasis

LB – exosomal miRs (blood)

23 ER+ BC patients; 22 healthy donors

Microarray; Western blot

⬆ exosomal miR-19a and Integrin-Binding Sialoprotein (IBSP)

[130]

19.

The NeoALTTO Study cohort

Pathological complete response (pCR) to single agent trastuzumab-based neoadjuvant therapy (NAC).

LB – miRs (plasma)

52 BC patients; 752 microRNAs

PCR assay

⬆ ct-miR-148a-3p,

⬆ ct-miR-374a-5p;

⬆ ct-miR-140-5p

[131]

20.

TNBC Exosomal miRs

Identify refractory and poor NAC responders

LB – miRs (Blood)

200 BC patients

droplet digital PCR (ddPCR)

⬇ miR-185, miR-4283, miR-5008, miR-3613;

⬆ miR-1302, miR-4715, miR-3144

[132]

21.

Circulatory miRNAs

Detect early stage BC

LB – miRs (serum)

1280 BC serum; 2836 non-cancer control; 63 non-breast benign samples

Microarray

⬆ miR-1246, miR-1307-3p, miR-4634, miR-6861-5p and miR-6875-5p)

[133]

22.

SUCCESS trial

Association of plasma miRs and BC invasiveness

LB – miRs (plasma)

111 BC patients (pre & post chemo); 46 Healthy controls

q-PCR

⬆ miR-16, miR-27a and miR-132 (pre-chemo);

⬇ miR-27a and miR-132 (post-chemo);

⬆ miR-107 (ER- tumors)

[134]

23.

Circulating biomarker (miRNAs + proteins)

Prognostic biomarkers of BC

LB – miRs; proteins (plasma)

30 BC patients; 10 HCs; 253 BC plasma samples

droplet digital PCR (ddPCR)

⬆ miR-923 and CA 15–3

[135]

24.

Circulating tumor cells (CTCs) and serum exosomal miRNAs

Diagnostic and predictive biomarkers of relapse post-NAC

LB – CTCs; miRs (serum)

53 post-NAC BC patients; 8 HCs; 6 metastatic patients from the NAC cohort

qPCR

⬆ miRNA-21, miRNA-222 and miRNA-155 correlate with CTCs in Metastatic patients

[136]