Table 1.

Prognostic and predictive value of biological markers in invasive breast carcinoma—primary tumour vs. CTCs. IBC, invasive breast carcinoma; CTCs, circulating tumour cells; PFS, progression-free survival; OS, overall survival.

Analyte	Marker	Prognostic/Predictive Value in IBC-Primary Tumour	Successfully Applied in CTCs	Prognostic or Predictive Value when Examined in CTCs	Reference
DNA	HER2 amplification	Strong predictive value.	Yes, can be robustly assessed.	No confirmed prognostic/predictive value in metastatic breast cancer patients treated with ado-trastuzumab emtansine [111].	[112,113,114,115,116]
	PIK3CA gain-of-function mutation	Prognostic factor linked to good prognosis; not applied in routine clinical practice.	Yes, can be robustly assessed.	Not assessed.	[112,117,118]
	TP53 loss-of-function mutation	Prognostic factor linked to poor prognosis; no predictive value in routine clinical practice.	Yes, can be robustly assessed.	Not assessed.	[117,119]
	RB1	Prognostic factor linked to poor prognosis. Predictive value—low RB1 expression in triple negative/ER-negative breast cancers related to good prognosis in patients treated with chemotherapy.	Yes, can be assessed.	Not assessed.	[118]
	ESR1 mutations	Prognostic factor linked to poor prognosis, potentially to be applied in clinics as a negative predictive factor (hormone resistance).	Yes, can be robustly assessed.	Not assessed.	[119]
	Ion AmpliSeq™ Cancer Hotspot Panel v2	Not assessed.	Yes, can be robustly assessed.	Not assessed.	[10,120]
RNA	ESR1/PGR	Both receptors routinely examined at protein level. Discrepancies between mRNA and protein expression frequently observed, but mRNA evaluation also shown of prognostic/ predictive value.	Yes, can be robustly assessed.	Prognostic value like in primary tumour, discrepant results of predictive value.	[93,105,107].
	HER2	Discrepancies between mRNA and protein levels seen in nearly 25% of patients. Protein examination routinely applied in clinics. mRNA also of both prognostic and predictive value.	Yes, can be robustly assessed.	HER2-positive CTCs are linked to poor prognosis in terms of both OS and PFS.	[108,109,121,122,123]
	EMT pathway molecules	Association between high levels of mesenchymal markers frequently reported. No predictive value or validated clinical application.	Yes, but efficiency of protocol/s still to be improved.	High frequency of mesenchymal CTCs linked to poor prognosis. No data on predictive value.	[62,97,99,124,125]
	PAM50	Prognostic and predictive value comparable to standard predictive factors, useful in clinical practice.	No report on coverage of all genes; single reports on partial assessment of the signature	Not assessed.	[91,126,127,128]
	Prosigna	Routinely applied predictive panel in clinics.	No, cannot be robustly applied.	Not assessed.	[126,127]
	Other panels, including EndoPredict, Mammaprint, OncotypeDx, Breast Cancer Index	Each panel designed to predict outcome; prognostic and predictive values of various panels similarly high across several comparing studies; routinely applied in clinics.	No reports so far.	Not assessed.	[60,126,129,130]
	microRNAs	Some panels of prognostic value when measured in primary tumour, but the known panels mostly applied for free-circulating microRNAs.	On-going research to resolve technical issues.	Not assessed.	[128,131,132,133]
Protein	ER, PR	The most significant prognostic and predictive factors applied in clinics.	Yes, can be robustly assessed.	Prognostic value.	[11,101,103,105,106,107,108]
	HER2	One of the key prognostic and predictive factors applied in clinics.	Yes, can be robustly assessed.	Poor prognostic value in terms of PFS in patients with HER2-positive CTCs in comparison to patients with HER2-negative CTCs, no strong prognostic value regarding OS.	[101,105,106,109]
	Ki67	One of the key prognostic and predictive factors applied in clinics.	Yes, but some technical difficulties still to be overcome.	Not assessed.	[134,135]
	EMT pathway molecules	Prognostic role of E-cadherin, vimentin and keratins.	Yes, can be robustly assessed	EMT activation related with reduced PFS and OS in metastatic patients.	[16,136,137,138]
	Proteomic panels	Prognostic significance of breast cancer subtypes identified by a multi-protein marker set.	Yes, can be assessed.	Not assessed. Used in basic science research.	[139,140]