The potential of hypoxia markers as target for breast molecular imaging - a systematic review and meta-analysis of human marker expression

Arthur Adams, Aram S A van Brussel, Jeroen F. Vermeulen, Willem P. Mali, Elsken van der Wall, Paul J. van Diest, Sjoerd G. Elias

Research output: Contribution to journalArticle

Abstract

Background: Molecular imaging of breast cancer is a promising emerging technology, potentially able to improve clinical care. Valid imaging targets for molecular imaging tracer development are membrane-bound hypoxia-related proteins, expressed when tumor growth outpaces neo-angiogenesis. We performed a systematic literature review and meta-analysis of such hypoxia marker expression rates in human breast cancer to evaluate their potential as clinically relevant molecular imaging targets.Methods: We searched MEDLINE and EMBASE for articles describing membrane-bound proteins that are related to hypoxia inducible factor 1α (HIF-1α), the key regulator of the hypoxia response. We extracted expression rates of carbonic anhydrase-IX (CAIX), glucose transporter-1 (GLUT1), C-X-C chemokine receptor type-4 (CXCR4), or insulin-like growth factor-1 receptor (IGF1R) in human breast disease, evaluated by immunohistochemistry. We pooled study results using random-effects models and applied meta-regression to identify associations with clinicopathological variables.Results: Of 1,705 identified articles, 117 matched our selection criteria, totaling 30,216 immunohistochemistry results. We found substantial between-study variability in expression rates. Invasive cancer showed pooled expression rates of 35% for CAIX (95% confidence interval (CI): 26-46%), 51% for GLUT1 (CI: 40-61%), 46% for CXCR4 (CI: 33-59%), and 46% for IGF1R (CI: 35-70%). Expression rates increased with tumor grade for GLUT1, CAIX, and CXCR4 (all p <0.001), but decreased for IGF1R (p <0.001). GLUT1 showed the highest expression rate in grade III cancers with 58% (45-69%). CXCR4 showed the highest expression rate in small T1 tumors with 48% (CI: 28-69%), but associations with size were only significant for CAIX (p <0.001; positive association) and IGF1R (p = 0.047; negative association). Although based on few studies, CAIX, GLUT1, and CXCR4 showed profound lower expression rates in normal breast tissue and benign breast disease (p <0.001), and high rates in carcinoma in situ. Invasive lobular carcinoma consistently showed lower expression rates (p <0.001).Conclusions: Our results support the potential of hypoxia-related markers as breast cancer molecular imaging targets. Although specificity is promising, combining targets would be necessary for optimal sensitivity. These data could help guide the choice of imaging targets for tracer development depending on the envisioned clinical application.

Original languageEnglish (US)
Article number538
JournalBMC Cancer
Volume13
DOIs
StatePublished - Nov 10 2013
Externally publishedYes

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CXC Chemokines
Molecular Imaging
Facilitative Glucose Transport Proteins
Chemokine Receptors
Somatomedin Receptors
Meta-Analysis
Breast
Confidence Intervals
Breast Diseases
Neoplasms
Breast Neoplasms
Immunohistochemistry
Carbonic Anhydrase II
Lobular Carcinoma
Hypoxia-Inducible Factor 1
Carcinoma in Situ
MEDLINE
Patient Selection
Membrane Proteins
Carbonic Anhydrase IX

Keywords

  • Benign breast disease
  • Breast cancer
  • C-X-C chemokine receptor type-4
  • CAIX
  • Carbonic anhydrase-IX
  • Carcinoma in situ
  • CXCR4
  • Expression prevalence
  • Glucose transporter-1
  • GLUT1
  • IGF1R
  • Immunohistochemistry
  • Insulin-like growth factor-1 receptor
  • Meta-analysis
  • Molecular imaging
  • Normal breast tissue
  • Systematic review

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Adams, A., van Brussel, A. S. A., Vermeulen, J. F., Mali, W. P., van der Wall, E., van Diest, P. J., & Elias, S. G. (2013). The potential of hypoxia markers as target for breast molecular imaging - a systematic review and meta-analysis of human marker expression. BMC Cancer, 13, [538]. https://doi.org/10.1186/1471-2407-13-538

The potential of hypoxia markers as target for breast molecular imaging - a systematic review and meta-analysis of human marker expression. / Adams, Arthur; van Brussel, Aram S A; Vermeulen, Jeroen F.; Mali, Willem P.; van der Wall, Elsken; van Diest, Paul J.; Elias, Sjoerd G.

In: BMC Cancer, Vol. 13, 538, 10.11.2013.

Research output: Contribution to journalArticle

Adams, Arthur ; van Brussel, Aram S A ; Vermeulen, Jeroen F. ; Mali, Willem P. ; van der Wall, Elsken ; van Diest, Paul J. ; Elias, Sjoerd G. / The potential of hypoxia markers as target for breast molecular imaging - a systematic review and meta-analysis of human marker expression. In: BMC Cancer. 2013 ; Vol. 13.
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abstract = "Background: Molecular imaging of breast cancer is a promising emerging technology, potentially able to improve clinical care. Valid imaging targets for molecular imaging tracer development are membrane-bound hypoxia-related proteins, expressed when tumor growth outpaces neo-angiogenesis. We performed a systematic literature review and meta-analysis of such hypoxia marker expression rates in human breast cancer to evaluate their potential as clinically relevant molecular imaging targets.Methods: We searched MEDLINE and EMBASE for articles describing membrane-bound proteins that are related to hypoxia inducible factor 1α (HIF-1α), the key regulator of the hypoxia response. We extracted expression rates of carbonic anhydrase-IX (CAIX), glucose transporter-1 (GLUT1), C-X-C chemokine receptor type-4 (CXCR4), or insulin-like growth factor-1 receptor (IGF1R) in human breast disease, evaluated by immunohistochemistry. We pooled study results using random-effects models and applied meta-regression to identify associations with clinicopathological variables.Results: Of 1,705 identified articles, 117 matched our selection criteria, totaling 30,216 immunohistochemistry results. We found substantial between-study variability in expression rates. Invasive cancer showed pooled expression rates of 35{\%} for CAIX (95{\%} confidence interval (CI): 26-46{\%}), 51{\%} for GLUT1 (CI: 40-61{\%}), 46{\%} for CXCR4 (CI: 33-59{\%}), and 46{\%} for IGF1R (CI: 35-70{\%}). Expression rates increased with tumor grade for GLUT1, CAIX, and CXCR4 (all p <0.001), but decreased for IGF1R (p <0.001). GLUT1 showed the highest expression rate in grade III cancers with 58{\%} (45-69{\%}). CXCR4 showed the highest expression rate in small T1 tumors with 48{\%} (CI: 28-69{\%}), but associations with size were only significant for CAIX (p <0.001; positive association) and IGF1R (p = 0.047; negative association). Although based on few studies, CAIX, GLUT1, and CXCR4 showed profound lower expression rates in normal breast tissue and benign breast disease (p <0.001), and high rates in carcinoma in situ. Invasive lobular carcinoma consistently showed lower expression rates (p <0.001).Conclusions: Our results support the potential of hypoxia-related markers as breast cancer molecular imaging targets. Although specificity is promising, combining targets would be necessary for optimal sensitivity. These data could help guide the choice of imaging targets for tracer development depending on the envisioned clinical application.",
keywords = "Benign breast disease, Breast cancer, C-X-C chemokine receptor type-4, CAIX, Carbonic anhydrase-IX, Carcinoma in situ, CXCR4, Expression prevalence, Glucose transporter-1, GLUT1, IGF1R, Immunohistochemistry, Insulin-like growth factor-1 receptor, Meta-analysis, Molecular imaging, Normal breast tissue, Systematic review",
author = "Arthur Adams and {van Brussel}, {Aram S A} and Vermeulen, {Jeroen F.} and Mali, {Willem P.} and {van der Wall}, Elsken and {van Diest}, {Paul J.} and Elias, {Sjoerd G.}",
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T1 - The potential of hypoxia markers as target for breast molecular imaging - a systematic review and meta-analysis of human marker expression

AU - Adams, Arthur

AU - van Brussel, Aram S A

AU - Vermeulen, Jeroen F.

AU - Mali, Willem P.

AU - van der Wall, Elsken

AU - van Diest, Paul J.

AU - Elias, Sjoerd G.

PY - 2013/11/10

Y1 - 2013/11/10

N2 - Background: Molecular imaging of breast cancer is a promising emerging technology, potentially able to improve clinical care. Valid imaging targets for molecular imaging tracer development are membrane-bound hypoxia-related proteins, expressed when tumor growth outpaces neo-angiogenesis. We performed a systematic literature review and meta-analysis of such hypoxia marker expression rates in human breast cancer to evaluate their potential as clinically relevant molecular imaging targets.Methods: We searched MEDLINE and EMBASE for articles describing membrane-bound proteins that are related to hypoxia inducible factor 1α (HIF-1α), the key regulator of the hypoxia response. We extracted expression rates of carbonic anhydrase-IX (CAIX), glucose transporter-1 (GLUT1), C-X-C chemokine receptor type-4 (CXCR4), or insulin-like growth factor-1 receptor (IGF1R) in human breast disease, evaluated by immunohistochemistry. We pooled study results using random-effects models and applied meta-regression to identify associations with clinicopathological variables.Results: Of 1,705 identified articles, 117 matched our selection criteria, totaling 30,216 immunohistochemistry results. We found substantial between-study variability in expression rates. Invasive cancer showed pooled expression rates of 35% for CAIX (95% confidence interval (CI): 26-46%), 51% for GLUT1 (CI: 40-61%), 46% for CXCR4 (CI: 33-59%), and 46% for IGF1R (CI: 35-70%). Expression rates increased with tumor grade for GLUT1, CAIX, and CXCR4 (all p <0.001), but decreased for IGF1R (p <0.001). GLUT1 showed the highest expression rate in grade III cancers with 58% (45-69%). CXCR4 showed the highest expression rate in small T1 tumors with 48% (CI: 28-69%), but associations with size were only significant for CAIX (p <0.001; positive association) and IGF1R (p = 0.047; negative association). Although based on few studies, CAIX, GLUT1, and CXCR4 showed profound lower expression rates in normal breast tissue and benign breast disease (p <0.001), and high rates in carcinoma in situ. Invasive lobular carcinoma consistently showed lower expression rates (p <0.001).Conclusions: Our results support the potential of hypoxia-related markers as breast cancer molecular imaging targets. Although specificity is promising, combining targets would be necessary for optimal sensitivity. These data could help guide the choice of imaging targets for tracer development depending on the envisioned clinical application.

AB - Background: Molecular imaging of breast cancer is a promising emerging technology, potentially able to improve clinical care. Valid imaging targets for molecular imaging tracer development are membrane-bound hypoxia-related proteins, expressed when tumor growth outpaces neo-angiogenesis. We performed a systematic literature review and meta-analysis of such hypoxia marker expression rates in human breast cancer to evaluate their potential as clinically relevant molecular imaging targets.Methods: We searched MEDLINE and EMBASE for articles describing membrane-bound proteins that are related to hypoxia inducible factor 1α (HIF-1α), the key regulator of the hypoxia response. We extracted expression rates of carbonic anhydrase-IX (CAIX), glucose transporter-1 (GLUT1), C-X-C chemokine receptor type-4 (CXCR4), or insulin-like growth factor-1 receptor (IGF1R) in human breast disease, evaluated by immunohistochemistry. We pooled study results using random-effects models and applied meta-regression to identify associations with clinicopathological variables.Results: Of 1,705 identified articles, 117 matched our selection criteria, totaling 30,216 immunohistochemistry results. We found substantial between-study variability in expression rates. Invasive cancer showed pooled expression rates of 35% for CAIX (95% confidence interval (CI): 26-46%), 51% for GLUT1 (CI: 40-61%), 46% for CXCR4 (CI: 33-59%), and 46% for IGF1R (CI: 35-70%). Expression rates increased with tumor grade for GLUT1, CAIX, and CXCR4 (all p <0.001), but decreased for IGF1R (p <0.001). GLUT1 showed the highest expression rate in grade III cancers with 58% (45-69%). CXCR4 showed the highest expression rate in small T1 tumors with 48% (CI: 28-69%), but associations with size were only significant for CAIX (p <0.001; positive association) and IGF1R (p = 0.047; negative association). Although based on few studies, CAIX, GLUT1, and CXCR4 showed profound lower expression rates in normal breast tissue and benign breast disease (p <0.001), and high rates in carcinoma in situ. Invasive lobular carcinoma consistently showed lower expression rates (p <0.001).Conclusions: Our results support the potential of hypoxia-related markers as breast cancer molecular imaging targets. Although specificity is promising, combining targets would be necessary for optimal sensitivity. These data could help guide the choice of imaging targets for tracer development depending on the envisioned clinical application.

KW - Benign breast disease

KW - Breast cancer

KW - C-X-C chemokine receptor type-4

KW - CAIX

KW - Carbonic anhydrase-IX

KW - Carcinoma in situ

KW - CXCR4

KW - Expression prevalence

KW - Glucose transporter-1

KW - GLUT1

KW - IGF1R

KW - Immunohistochemistry

KW - Insulin-like growth factor-1 receptor

KW - Meta-analysis

KW - Molecular imaging

KW - Normal breast tissue

KW - Systematic review

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