Candidate prognostic markers in breast cancer: focus on extracellular proteases and their inhibitors

Figures & data

Table 1 Clinically utilized biomarkers in breast cancer

Biomarker	Platform	Outcome measure
ER + PR	Tissue-based assay	Response to hormone therapy
HER2	Tissue-based assay	Response to trastuzumab
uPA + PAI-1	Tissue-based assay	Prognosis in lymph node-negative tumors
21-gene signature	Oncotype DX^®	Distant recurrence after treatment with tamoxifen or AIs
70-gene signature	MammaPrint™	Prognostic for 5-year recurrence
97-gene signature	Genomic grade index	Prognostic for relapse after endocrine treatment in ER+tumors
76-gene signature	Rotterdam signature	Prognostic for development of distant metastasis

Notes: Oncotype DX^® (Genomic Health Inc., Redwood City, CA, USA); MammaPrint™ (Agendia Inc., Irvine, CA, USA).

Abbreviations: AIs, aromatase inhibitors; ER, estrogen receptor; PR, progesterone receptor; HER2, receptor tyrosine-protein kinase erbB-2; PAI-1, plasminogen activator inhibitor-1; uPA, urokinase plasminogen activator.

Table 2 Characteristics of 1,545 breast cancer samples (Curtis dataset)

Characteristics	n
Tumor size (cm)
≤2	505
2–4	815
≥4	216
No information	9
Grade
1	128
2	607
3	770
No information	40
Number of positive lymph nodes
0	779
1–3	508
≥4	254
No information	4
Age (years)
20–29	12
30–39	96
40–49	281
50–59	393
60–69	438
70–79	267
≥80	58
PAM50 subtype
Normal	159
Lum A	532
Lum B	380
HER2	190
Basal	280
No information	4
Treatment
None	189
Chemotherapy	40
Radiotherapy	184
Hormone therapy	309
Chemotherapy + radiotherapy	163
Chemotherapy + hormone therapy	28
Hormone therapy + radiotherapy	481
Chemotherapy + hormone therapy + radiotherapy	151

Abbreviations: HER2, receptor tyrosine-protein kinase erbB-2; Lum, luminal.

Table 3 Relationship between MMP expression and disease-specific survival in 1,545 breast cancer patients

Gene	Log-rank P-value	Wald test P-value	Hazard ratio	95% CI
MMP1	0.0023	0.4161	1.058	0.92–1.21
MMP2	0.7380	0.1427	0.857	0.70–1.05
MMP3	0.3930	0.2413	0.941	0.85–1.04
MMP7	0.1470	0.8498	0.995	0.95–1.04
MMP8	0.9380	0.5478	0.837	0.47–1.49
MMP9	0.0004	0.0002	1.110	1.05–1.17
MMP10	0.6070	0.0922	0.897	0.79–1.02
MMP11	0.0011	0.0002	1.124	1.06–1.19
MMP12	0.0001	0.0186	1.088	1.01–1.17
MMP13	0.7730	0.9051	0.992	0.87–1.13
MMP14	0.2150	0.8873	1.032	0.67–1.60
MMP15	0.0000	0.0000	1.708	1.44–2.03
MMP16	0.2560	0.1007	1.520	0.92–2.50
MMP17	0.0410	0.0513	1.843	1.00–3.41
MMP19	0.0062	0.2969	0.756	0.45–1.28
MMP20	0.7830	0.4546	1.169	0.78–1.76
MMP24	0.0212	0.2754	0.811	0.56–1.18
MMP25	0.2590	0.4204	1.303	0.68–2.48
MMP28	0.3330	0.3034	0.744	0.42–1.31

Note: Bold indicates significance P<0.01.

Abbreviations: CI, confidence interval; MMP, matrix metalloproteinases.

Table 4 Relationship between MMP-9, -11, and -15 expression and tumor characteristics

Characteristics	MMP-9	MMP-11	MMP-15
ER status
Positive	3.343	5.036	0.588
Negative	4.362	4.795	0.851
P-value	<0.0001	0.0322	<0.0001
Tumor size (cm)
≤2	3.613	5.046	0.609
>2	3.654	4.907	0.650
P-value	NS	NS	0.032
Tumor grade
1–2	3.217	4.919	0.571
3	4.081	5.024	0.703
P-value	<0.0001	NS	<0.0001
Nodal status
Negative	3.583	4.898	0.624
Positive	3.682	5.038	0.647
P-value	NS	NS	NS
PAM50 subtype
Basal	4.674	4.375	0.655
Other	3.375	5.066	0.631
P-value	<0.0001	<0.0001	0.044

Note: Bold indicates significance P<0.05.

Abbreviations: NS, not significant; MMP, matrix metalloproteinases; ER, estrogen receptor.

Table 5 Relationship between ADAMs expression and disease-specific survival in 1,545 breast cancer patients

Gene	Log-rank P-value	Wald test P-value	Hazard ratio	95% CI
ADAM2	0.9050	0.2979	1.179	0.86–1.61
ADAM7	0.5940	0.3963	0.785	0.45–1.37
ADAM8	0.0000	0.0000	1.515	1.30–1.76
ADAM9	0.1120	0.0990	1.134	0.98–1.31
ADAM10	0.8210	0.6193	0.878	0.52–1.47
ADAM11	0.0870	0.0160	1.651	1.10–2.48
ADAM12	0.0140	0.0280	0.607	0.39–0.95
ADAM15	0.0470	0.0112	1.180	1.04–1.34
ADAM17	0.0000	0.0000	1.569	1.35–1.82
ADAM18	0.5490	0.9882	1.005	0.55–1.85
ADAM19	0.2750	0.5536	1.212	0.64–2.29
ADAM22	0.5200	0.7431	0.888	0.44–1.81
ADAM23	0.8010	0.9831	0.995	0.60–1.64
ADAM28	0.9540	0.4527	0.879	0.63–1.23
ADAM33	0.4050	0.3003	0.730	0.40–1.32

Note: Bold indicates significance P<0.01.

Abbreviation: CI, confidence interval.

Table 6 Relationship between ADAM-8 and -17 expression and tumor characteristics

Characteristics	ADAM-8	ADAM-17
ER status
Positive	0.942	1.815
Negative	1.225	2.165
P-value	<0.0001	<0.0001
Tumor size (cm)
≤2	0.999	1.860
>2	1.060	1.921
P-value	0.045	NS
Tumor grade
1–2	0.906	1.818
3	1.147	2.007
P-value	<0.0001	<0.0001
Nodal status
Negative	1.011	1.856
Positive	1.051	1.936
P-value	NS	0.019
PAM50 subtype
Basal	1.304	2.205
Other	0.952	1.825
P-value	<0.0001	<0.0001

Note: Bold indicates significance P<0.05.

Abbreviations: NS, not significant; ER, estrogen receptor.

Table 7 Relationship between TIMP expression and disease-specific survival in 1,545 breast cancer patients

Gene	Log-rank P-value	Wald test P-value	Hazard ratio	95% CI
TIMP1	0.4920	0.6019	1.042	0.89–1.22
TIMP2	0.3580	0.3157	0.948	0.85–1.05
TIMP3	0.0740	0.0319	0.911	0.84–0.99
TIMP4	0.0000	0.0000	0.687	0.59–0.80

Note: Bold indicates significance P<0.01.

Abbreviation: CI, confidence interval.

Table 8 Select candidate inhibitors of extracellular proteases in cancer

Drug	Specificity	Highest phase completed	Reference
Rebimastat	MMP-2, -9	Phase III	^Citation97
SB-3CT	MMP-2, -9	Preclinical	^Citation98
CGS27023A	MMP-1, -2, -3	Phase I	^Citation99
Minocycline	MMP-1, -2, -3	Preclinical	^Citation100
Tanomastat	MMP-2, -3, -9	Phase III	^Citation101
Batimastat	MMP-1, -2, -3, -7, -9	Phase II	^Citation102
Neovastat	MMP-1, -2, -7, -9, -13	Phase III	^Citation103
Metastat (COL-3)	MMP-1, -2, -8, -9, -13	Phase II	^Citation104
Prinomastat	MMP-2, -3, -7, -9, -13	Phase III	^Citation105
Genistein	MMP-2, -9, MT1-, MT2-, MT3-MMP	Phase II	^Citation106
Marimastat	MMP broad spectrum	Approved	^Citation107
GI254023X	ADAM-10	Preclinical	^Citation108
PF-5480090	ADAM-17	Preclinical	^Citation109
KB-R7785	ADAM-10, -12	Preclinical	^Citation110
GW280264X	ADAM-10, -17	Preclinical	^Citation108
INCB3619	ADAM-10, -17	Preclinical	^Citation111
INCB7839	ADAM-10, -17	Terminated	^Citation112
Upamostat (WX-671)	uPA	Phase II	^Citation113
Aprotinin	uPA	Terminated	^Citation114

Abbreviations: MMP, matrix metalloproteinases; uPA, urokinase plasminogen activator; MT, membrane type.

LeighlNBPaz-AresLDouillardJYRandomized phase III study of matrix metalloproteinase inhibitor BMS-275291 in combination with paclitaxel and carboplatin in advanced non-small-cell lung cancer: National Cancer Institute of Canada-Clinical Trials Group Study BR.18J Clin Oncol200523122831283915837997

 PubMed Web of Science ®Google Scholar

BernardoMMBrownSLiZHFridmanRMobasherySDesign, synthesis, and characterization of potent, slow-binding inhibitors that are selective for gelatinasesJ Biol Chem200227713112011120711790786

 PubMed Web of Science ®Google Scholar

LevittNCEskensFAO’ByrneKJPhase I and pharmacological study of the oral matrix metalloproteinase inhibitor, MMI270 (CGS27023A), in patients with advanced solid cancerClin Cancer Res2001771912192211448904

 PubMed Web of Science ®Google Scholar

GriffinMOFricovskyECeballosGVillarrealFTetracyclines: a pleitropic family of compounds with promising therapeutic properties. Review of the literatureAm J Physiol Cell Physiol20102993C539C54820592239

 PubMed Web of Science ®Google Scholar

HirteHVergoteIBJeffreyJRA phase III randomized trial of BAY 12-9566 (tanomastat) as maintenance therapy in patients with advanced ovarian cancer responsive to primary surgery and paclitaxel/platinum containing chemotherapy: a National Cancer Institute of Canada Clinical Trials Group StudyGynecol Oncol2006102230030816442153

 PubMed Web of Science ®Google Scholar

MacaulayVMO’ByrneKJSaundersMPPhase I study of intrapleural batimastat (BB-94), a matrix metalloproteinase inhibitor, in the treatment of malignant pleural effusionsClin Cancer Res19995351352010100701

 PubMed Web of Science ®Google Scholar

LuCLeeJJKomakiRChemoradiotherapy with or without AE-941 in stage III non-small cell lung cancer: a randomized phase III trialJ Natl Cancer Inst20101021285986520505152

 PubMed Web of Science ®Google Scholar

ChuQSForouzeshBSyedSA phase II and pharmacological study of the matrix metalloproteinase inhibitor (MMPI) COL-3 in patients with advanced soft tissue sarcomasInvest New Drugs200725435936717237909

 PubMedGoogle Scholar

BissettDO’ByrneKJvon PawelJPhase III study of matrix metalloproteinase inhibitor prinomastat in non-small-cell lung cancerJ Clin Oncol200523484284915681529

 PubMed Web of Science ®Google Scholar

KhanSAChattertonRTMichelNSoy isoflavone supplementation for breast cancer risk reduction: a randomized phase II trialCancer Prev Res (Phila)20125230931922307566

 PubMed Web of Science ®Google Scholar

MillerKDGradisharWSchuchterLA randomized phase II pilot trial of adjuvant marimastat in patients with early-stage breast cancerAnn Oncol20021381220122412181245

 PubMed Web of Science ®Google Scholar

HundhausenCMisztelaDBerkhoutTAThe disintegrin-like metalloproteinase ADAM10 is involved in constitutive cleavage of CX3CL1 (fractalkine) and regulates CX3CL1-mediated cell-cell adhesionBlood200310241186119512714508

 PubMed Web of Science ®Google Scholar

McGowanPMMulloolyMCaiazzaFADAM-17: a novel therapeutic target for triple negative breast cancerAnn Oncol201324236236922967992

 PubMed Web of Science ®Google Scholar

JohTKataokaHTanidaSHelicobacter pylori-stimulated interleukin-8 (IL-8) promotes cell proliferation through transactivation of epidermal growth factor receptor (EGFR) by disintegrin and metalloproteinase (ADAM) activationDig Dis Sci200550112081208916240219

 PubMed Web of Science ®Google Scholar

ZhouBBPeytonMHeBTargeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancerCancer Cell2006101395016843264

 PubMed Web of Science ®Google Scholar

WittersLScherlePFriedmanSSynergistic inhibition with a dual epidermal growth factor receptor/HER-2/neu tyrosine kinase inhibitor and a disintegrin and metalloprotease inhibitorCancer Res200868177083708918757423

 PubMed Web of Science ®Google Scholar

HeinemannVEbertMPLaubenderRPBevanPMalaCBoeckSPhase II randomised proof-of-concept study of the urokinase inhibitor upamostat (WX-671) in combination with gemcitabine compared with gemcitabine alone in patients with non-resectable, locally advanced pancreatic cancerBr J Cancer2013108476677023412098

 PubMed Web of Science ®Google Scholar

StillfriedGESaundersDNRansonMPlasminogen binding and activation at the breast cancer cell surface: the integral role of urokinase activityBreast Cancer Res200791R1417257442

 PubMed Web of Science ®Google Scholar