Table 1.
Biomarkers discovered recently for breast cancer.
| Type | Biomarkers | Clinical Value | Clinical Validation/Research Design | References |
|---|---|---|---|---|
| DNA | Immune response-related genes (BTN3A2, CD2 and TRBC1) | may be used to identify patients with a good prognosis in HR−/HER2+ breast cancer. | Measured the tissues from 819 breast cancer patients. | [30] |
| Immunity genes (APOBEC3G, CCL5, CCR2, CD2, CD27, CD3D, CD52, CORO1A, CXCL9, GZMA, GZMK, HLA-DMA, IL2RG, LCK, PRKCB, PTPRC, and SH2D1A) | immunity gene expression was an important parameter for prognosis. | Tested on 225 breast tumor FFPE tissues. | [31] | |
| T helper type-1 gene signatures (IFNG, STAT1, GRZM, CXCL9) | are correlated with favorable clinical outcome, particularly in ER- tumors. | [32,33,34] | ||
| methylated 14-3-3 σ | as a blood-based biomarker for breast cancer diagnosis. | meta-analysis | [35] | |
| methylated APC and RARβ2 | might be valuable serum-based molecular markers for early detection of early-stage breast cancer, low grade tumors and TNBC. | Tested on serum samples from 121 breast cancer patients, 79 patients with benign breast diseases, and 66 healthy controls. | [36] | |
| S100P and HYAL2 hypomethylation | as breast cancer biomarkers for early stage detection. |
S100P: Validation I: 235 familial breast cancer cases and 206 controls; Validation II: 189 sporadic breast cancer cases and 189 controls; Validation III: 156 sporadic breast cancer cases and 151 controls. HYAL2: first validation round: 338 breast cancer cases and 507 controls; second validation round: 189 breast cancer cases and 189 controls. |
[37,38] | |
| long noncoding RNA 299 gene (LINC00299) methylation | for early detection of TNBC in young women. | Examined blood samples of 154 TNBC cases and 159 breast cancer-free matched controls. | [39] | |
| ESR1 mutations | 1. ESR1 Y537S mutation promotes resistance to fulvestrant. 2. may have clinical utility in directing further endocrine therapy. 3. ESR1 mutations are prevalent in ER-positive aromatase inhibitor-treated metastatic breast cancer predicting its prognosis. |
1. Testing the blood samples of 195 patients from the PALOMA-3 cohort; 2. In the SoFEA trial, plasma samples of 162 patients were tested; in the PALOMA3 trial, plasma samples of 360 patients were tested. 3. In the BOLERO-2 cohort, 541 plasma samples were examined. |
[40,41,42] | |
| TP53 mutation | associated with better prognosis in metaplastic breast cancer with increased RFS and OS. | Examined the clinical outcomes data of 52 archived samples. | [43] | |
| a 14-gene prognostic signature (PFKL, P4HA2, GRHPR, SDC3, PPP1R15A, SIAH2, NDRG1, BTG1, TPD52, MAFF, ISG20, LALBA, ERRFI1, and VHL) | could serve as a potential prognostic biomarker for breast cancer. | Clinical data from 1097 cases were obtained from the TCGA database. 113 adjacent normal samples and 1039 breast cancer patients were followed-up for ≥1 month. |
[44] | |
| 28-CpG based methylation panel | could independently predict the overall survival of breast cancer patients. Patients with high methylation risk were associated with tumor heterogeneity and poor survival. |
The DNA methylation profile of The Cancer Genome Atlas Breast Invasive Carcinoma (TCGA-BRCA) included a total of 890 breast cancer samples. A total of 62, 118, 188, 70, and 58 breast cancer samples were included in GSE37754, GSE72245, GSE75067, GSE78754, and GSE72251. 40 normal breast samples and 80 breast cancer samples in GSE666952. |
[45] | |
| MicroRNAs | miR-21 and/or miR-221 | can be successfully applied as breast cancer biomarkers. | Tested the sera of 50 patients with breast cancer, 25 fibroadenoma, and 25 healthy controls. | [46,47] |
| six miRNA signature, miR-21, miR-221, miR-210, miR-195, miR-145, and let-7a | for early detection of TNBC. | Examined 85 paired tumor tissues and sera with an equal number of adjacent normal tissue margins and normal sera from healthy women and 15 benign fibroadenomas. | [48] | |
| miR-21 | promotes the transformation and development of breast cancer. | Examined on blood samples of 30 female patients with breast tumors and 30 with benign breast lesions | [49] | |
| Exosomal miR-1246 and miR-21 | for detection of breast cancer. | Tested the plasma of 16 patients with breast cancer and 16 healthy control subjects. | [50] | |
| five-miRNA signature, miR-1246, miR-1307-3p, miR-4634, miR-6861-5p, and miR-6876-5p | for detection of early stage breast cancer. | Tested 1280 serum samples of breast cancer patients, 2836 serum samples from non-cancer controls, 451 from patients with other types of cancers, and 63 from patients with non-breast benign diseases. | [51] | |
| The eight-marker signature (miR-16, let7d, miR-103, miR-107, miR-148a, let-7i, miR-19b, and miR-22) | for early detection of breast cancer including younger women. | Tested plasma from 127 sporadic breast cancer cases and 80 healthy controls. | [52] | |
| a 9-miRNA profile | for early detection of breast cancer. | Examined 116 blood samples including 36 with breast cancer. | [53] | |
| miR-1204 | could be a novel prognostic/diagnostic biomarker for breast cancer patients. | Tested sera from 144 breast cancer patients and 38 healthy controls. | [54] | |
| combination of miR-181b-5p, miR-200b-3p, miR-200c-3p, and miR-203a-3p | could be potential diagnostic biomarkers for inflammatory breast cancer. | Examined tissue specimens of 18 non- inflammatory breast cancer and 17 inflammatory breast cancer patients. | [55] | |
| miR-140 and miR-196a | both miR-140 and miR-196a are promising biomarkers for the diagnosis of breast cancer. | Tested 110 cases of breast cancer and their adjacent non-tumor tissues. | [56] | |
| miR-26a/26b | may be useful markers of the progression of breast cancer. | Examined 29 pairs of fresh breast cancer and adjacent tissues. |
[57] | |
| miR-26b | inhibited TNBC cell proliferation and tumor growth. | - | [58] | |
| miR-182 | contributed to cell progression. | 45 patients with breast cancer. | [59] | |
| miR-224 | inhibited proliferation and migration of breast cancer cells. | Examined serum samples from 45 patients with breast cancer. | [60] | |
| miR-124-3p | reduced breast cancer cell proliferation and metastasis. | Tested 30 breast cancer and normal breast tissues. | [61] | |
| miRNA-17 and miRNA-20b | resistance to taxol in breast cancer patients increased with the loss of miRNA-17 and miRNA-20b. | 55 pairs of breast cancer tissues and adjacent normal tissues were examined. | [62] | |
| miR-18a | overexpression directly led to Dicer repression and confers paclitaxel resistance in TNBC. | Tested 20 TNBC patient tissues. | [63] | |
| miR-90b, 130a, 200b, and 452 | contribute to chemoresistance. | - | [64] | |
| miRNAs 221 and 222 | chemoresistance to fulvestrant, doxorubicin, or trastuzumab. | - | [64] | |
| miRNA 320a | chemoresistance to paclitaxel. | - | [64] | |
| miRNAs let-7, 181a and 145 | chemoresistance to doxorubicin, tamoxifen, or epirubicin. | - | [64] | |
| miRNA 125b | chemoresistance to tamoxifen, letrozole, anastrazole or fulvestrant. | - | [64] | |
| miR200c and miR489 | downregulation of miR200c and miR489 were correlated with better prognosis. | - | [64] | |
| miR484 and miR4443 | upregulation of miR484 and miR4443 were associated with better prognosis. | - | [64] | |
| miR520h and miR125b | upregulation of miR520h and miR125b were correlated with poor prognosis. | - | [64] | |
| miR125b and miR21 | could be novel, noninvasive predictive markers for neoadjuvant chemotherapy response and prognosis in breast cancer. | Examined 118 stage II/III breast cancer patients and 30 healthy adult women. | [65] | |
| miR-106b | is a putative plasma marker for risk assessment in patients with breast cancer. | Examined the tissue and plasma samples from 173 patients with primary breast cancer and 50 women with fibroadenoma. | [66] | |
| pre-miR-488 | could be a novel prognostic biomarker for predicting recurrence in breast cancer patients. | Tested the blood from 356 female patients with breast cancer without distant metastases, preoperative therapy or previous treatment for various cancers, 330 invasive ductal carcinomas (IDC), 26 were ductal carcinomas in situ (DCIS), and 11 healthy volunteers. |
[67] | |
| miR-130b | contributes to MDR through PI3K/Akt signaling pathway. | Tested 29 pairs of breast cancer tissues and their adjacent noncancerous tissues. | [68] | |
| miR-9 | inhibit metastasis. | - | [69] | |
| miR-205 | inhibit metastasis. | Tested on 40 pairs of TNBC and their adjacent normal breast tissues. | [70,71] | |
| miR-628 | inhibit metastasis. | - | [72] | |
| cicRNAs | hsa_circ_0001785 | the potential diagnostic biomarker for breast cancer. | Examined the plasma of 57 breast cancer patients and 17 age-matched healthy individuals. | [73] |
| Combination of hsa_circ_006054, hsa_circ_100219, and hsa_circ_406697 | may be diagnostic biomarker for breast cancer. | Tested 51 breast cancer and adjacent normal tissues. | [74] | |
| hsa_circ_0001982 | hsa_circ_0001982 knockdown suppressed breast cancer cell proliferation and invasion and induced apoptosis by targeting miR-143. | Examined 29 breast cancer tissues and adjacent normal tissues. | [75] | |
| circRNA-000911 | enhanced expression of circRNA-000911 suppressed cell proliferation, migration and invasion, and promoted the apoptosis of breast cancer cells. | Human circRNA microarray analysis. | [76] | |
| circ-ABCB10 | circ-ABCB10 knockdown suppressed the proliferation and increased apoptosis of breast cancer cells. | Tested 36 cancer and adjacent noncancerous tissues. | [77] | |
| circGFRA1 | Knockdown of circGFRA1 inhibited proliferation and promoted apoptosis in TNBC. | Examined 51 TNBC tissues and their paired adjacent normal tissues. | [78] | |
| circ_0006528 | may play a role in breast cancer chemoresistance. | - | [79] | |
| Protein | 4-test combination of TAP + CEA + CA125 + CA15-3 | higher sensitivity than the traditional test, i.e., CEA, CA125, or CA15-3 and may be auxiliary used in early screening. | Tested on blood of 261 women with operable benign breast disease and 348 with breast cancer. | [80] |
| TFF1, TFF2 and TFF3 | for breast cancer screening. | Examined sera in 94 breast cancer patients and 84 health check females, and breast cancer tissues. | [81] | |
| Pleiotrophin (PTN) | PTN could be a potential biomarker for the presence of breast cancer. | Tested sera in 105 breast cancer patients and 40 healthy volunteers using ELISA. In addition, PTN expression was examined in 80 BC tissues in a nested case-control study by immunohistochemistry. | [82] | |
| Combination of miR-127-3p and HE4 | Greatly improved the sensitivity of breast cancer diagnosis and may be a candidate biomarker for early detection and diagnosis of breast cancer. | Examined plasma in 102 patients with breast cancer, and 87 patients with benign breast tumors and 90 healthy volunteers as control. | [83] | |
| Combination of VEGF and CA 15-3 | showed the highest usefulness in the diagnosis of early breast cancer. | Tested plasma in 100 breast cancer patients, and 50 patients with benign breast tumors, and 50 healthy women as control. | [84] | |
| Combination of AGR3 and AGR2 | showed the potential usability of AGR3 and AGR2 as biomarkers for blood-based early detection of human breast cancer. | Examined 190 breast carcinomas and 39 normal breast tissues; 40 breast cancer and 40 healthy serum samples. |
[85] | |
| COL11A1, COMP, and COL10A1 | may be useful in diagnostic assessment for breast cancers | Discovery dataset: 50 healthy donors, 42 patients with benign breast disease, and 52 patients with invasive breast cancer; validation cohort: 52 healthy donors, 49 benign breast disease, and 66 invasive breast cancer. |
[86] | |
| CA15-3 included in the diagnostic panel constituted of 4 protein peaks [m/z 3972, 6850, 8115 (Bc2), and 8949 (Bc3)] | distinguished invasive ductal carcinoma from healthy controls and benign breast diseases. | Tested the sera from 62 patients with invasive ductal carcinoma, and 47 non-cancerous individuals (16 healthy controls and 31 patients with benign breast diseases). |
[87] | |
| Serum autoantigens (LGALS3, PHB2, MUC1 and GK2) in combination with CA 15-3 | had better diagnostic values compared with anti-CA 15-3 alone for early-stage breast cancer. | Examined the sera from 100 breast cancer patients and 50 healthy subjects. | [88] | |
| A combination of six antigens, RAD50, PARD3, SPP1, NY-BR-62, and NY-CO-58 | could discriminate breast cancer patients from healthy controls. | Tested the sera of 112 patients with breast cancer and 35 patients with no neoplasm (control group); Cancer and non-cancerous breast tissue samples were obtained from 17 female patients with primary breast carcinomas and 7 patients with fibrocystic disease. |
[89] | |
| A combination of serum protein biomarkers and tumor associated autoantibodies | the benefit of the integration of SPB and TAAb for detecting breast cancer. | Using a retrospective cohort of sera from 18 participants with no breast diseases, 92 participants with benign breast diseases, and 100 participants with breast cancers. | [90] | |
| Sex hormones: estradiol, testosterone, and SHBG | Integration of hormone measurements in clinical risk prediction models may represent a strategy to improve breast cancer risk stratification. | Tested blood of 1217 breast cancer cases (430 pre- and 787 postmenopausal) and 1976 matched Controls. |
[91] | |
| CCL25/CCR9 chemokine signaling | promotes migration and invasion in different cell lines by selective regulating several EMT markers. | - | [92] | |
| CCL18-PITPNM3 chemokine signaling | promotes the invasion and metastasis of breast cancer through the PI3K/Akt/GSK3β/Snail pathway. | - | [93,94] | |
| TNBC-specific RBP, NONO | NONO is highly expressed in TNBC and is associated with poor patient outcomes, a potential therapeutic target in TNBC. | Tested on tissue microarray. | [95] | |
| Peptides KNG1K438-R457 and C3fS1304-R1320 | differentiate BRCA1 mutant breast cancer from sporadic B breast cancer and cancer-free BRCA1 mutant carriers. | Examined on serum samples from 55 carriers of hereditary BRCA1 mutations, of whom 28 were diagnosed with breast cancer, and 27 remained cancer-free, 39 were diagnosed with sporadic breast cancer, and 38 were healthy controls. | [96] | |
| Lipid | 27-hydroxycholesterol | may offer a novel breast cancer risk strategy. | Tested on sera of 530 incident invasive breast cancer cases and 1036 control participants from Heidelberg cohort of EPIC. | [97,98] |
| Exosome | fibronectin | This liquid biopsy to detect fibronectin on circulating extracellular vesicles could be a promising method to detect early breast cancer. | Tested on plasma samples from 70 disease-free individuals, 240 breast cancer patients, 40 breast cancer patients after surgical resection, 55 patients with benign breast tumor, and 80 patients with non-cancerous diseases (thyroiditis, gastritis, hepatitis B, and rheumatoid arthritis. | [99] |
| Del-1 | is a promising marker for identification of patients with early-stage breast cancer and distinguish breast cancer from benign breast tumors and noncancerous diseases. | Measured in plasma samples from 81 healthy controls, 269 patients with breast cancer, 50 breast cancer patients after surgical resection, 64 patients with benign breast tumors, and 98 patients with noncancerous diseases. | [100] |