CAPG and GIPC1: Breast Cancer Biomarkers for Bone Metastasis Development and Treatment

Jules A Westbrook; David A Cairns; Jianhe Peng; Valerie Speirs; Andrew M Hanby; Ingunn Holen; Steven L Wood; Penelope D Ottewell; Helen Marshall; Rosamonde E Banks; Peter J Selby; Robert E Coleman; Janet E Brown

doi:10.1093/jnci/djv360

CAPG and GIPC1: Breast Cancer Biomarkers for Bone Metastasis Development and Treatment

Jules A Westbrook, David A Cairns, Jianhe Peng, Valerie Speirs, Andrew M Hanby, Ingunn Holen, Steven L Wood, Penelope D Ottewell, Helen Marshall, Rosamonde E Banks, Peter J Selby, Robert E Coleman, Janet E Brown

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Abstract

BACKGROUND: Bone is the predominant site of metastasis from breast cancer, and recent trials have demonstrated that adjuvant bisphosphonate therapy can reduce bone metastasis development and improve survival. There is an unmet need for prognostic and predictive biomarkers so that therapy can be appropriately targeted.

METHODS: Potential biomarkers for bone metastasis were identified using proteomic comparison of bone-metastatic, lung-metastatic, and nonmetastatic variants of human breast cancer MDA-MB-231 cells. Clinical validation was performed using immunohistochemical staining of tumor tissue microarrays from patients in a large randomized trial of adjuvant zoledronic acid (zoledronate) (AZURE-ISRCTN79831382). We used Cox proportional hazards regression, the Kaplan-Meier estimate of the survival function, and the log-rank test to investigate associations between protein expression, clinical variables, and time to distant recurrence events. All statistical tests were two-sided.

RESULTS: Two novel biomarker candidates, macrophage-capping protein (CAPG) and PDZ domain-containing protein GIPC1 (GIPC1), were identified for clinical validation. Cox regression analysis of AZURE training and validation sets showed that control patients (no zoledronate) were more likely to develop first distant recurrence in bone (hazard ratio [HR] = 4.5, 95% confidence interval [CI] = 2.1 to 9.8, P < .001) and die (HR for overall survival = 1.8, 95% CI = 1.01 to 3.24, P = .045) if both proteins were highly expressed in the primary tumor. In patients with high expression of both proteins, zoledronate had a substantial effect, leading to 10-fold hazard ratio reduction (compared with control) for first distant recurrence in bone (P = .008).

CONCLUSIONS: The composite biomarker, CAPG and GIPC1 in primary breast tumors, predicted disease outcomes and benefit from zoledronate and may facilitate patient selection for adjuvant bisphosphonate treatment.

Original language	English
Journal	Journal of the National Cancer Institute
Volume	108
Issue number	4
Early online date	12 Jan 2016
DOIs	https://doi.org/10.1093/jnci/djv360
Publication status	Published - Apr 2016
Externally published	Yes

Bibliographical note

This work was supported by Cancer Research UK (grant number: C18605/A 10048) through a Clinician Scientist Fellowship (to JEB). DAC was supported by a UK Medical Research Council Career Development Fellowship (G0802416).
The authors are solely responsible for the design of the study; the collection, analysis and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication. All authors read and approved the final article.

The authors are especially grateful to Professor Joan Massagué for kindly providing the bone- and lung-homing variants of MDA-MB-231 cells used in this study. We also particularly thank the AZURE trial patients and investigators, Mr. Mike Shires and the staff of the Sheffield and Leeds Experimental Cancer Medicine Centres for infrastructure support

Keywords

Adaptor Proteins, Signal Transducing
Biomarkers, Tumor
Bone Density Conservation Agents
Bone Neoplasms
Breast Neoplasms
Cell Line, Tumor
Diphosphonates
Disease Progression
Female
Humans
Imidazoles
Immunohistochemistry
Kaplan-Meier Estimate
Lung Neoplasms
Microfilament Proteins
Molecular Targeted Therapy
Nuclear Proteins
Odds Ratio
Predictive Value of Tests
Proportional Hazards Models
Randomized Controlled Trials as Topic
Reproducibility of Results
Editorial
Research Support, Non-U.S. Gov't

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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CAPG and GIPC1
This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
Final published version, 4.83 MBLicence: CC BY

Valerie Speirs
Person: Academic

Cite this

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title = "CAPG and GIPC1: Breast Cancer Biomarkers for Bone Metastasis Development and Treatment",

abstract = "BACKGROUND: Bone is the predominant site of metastasis from breast cancer, and recent trials have demonstrated that adjuvant bisphosphonate therapy can reduce bone metastasis development and improve survival. There is an unmet need for prognostic and predictive biomarkers so that therapy can be appropriately targeted.METHODS: Potential biomarkers for bone metastasis were identified using proteomic comparison of bone-metastatic, lung-metastatic, and nonmetastatic variants of human breast cancer MDA-MB-231 cells. Clinical validation was performed using immunohistochemical staining of tumor tissue microarrays from patients in a large randomized trial of adjuvant zoledronic acid (zoledronate) (AZURE-ISRCTN79831382). We used Cox proportional hazards regression, the Kaplan-Meier estimate of the survival function, and the log-rank test to investigate associations between protein expression, clinical variables, and time to distant recurrence events. All statistical tests were two-sided.RESULTS: Two novel biomarker candidates, macrophage-capping protein (CAPG) and PDZ domain-containing protein GIPC1 (GIPC1), were identified for clinical validation. Cox regression analysis of AZURE training and validation sets showed that control patients (no zoledronate) were more likely to develop first distant recurrence in bone (hazard ratio [HR] = 4.5, 95% confidence interval [CI] = 2.1 to 9.8, P < .001) and die (HR for overall survival = 1.8, 95% CI = 1.01 to 3.24, P = .045) if both proteins were highly expressed in the primary tumor. In patients with high expression of both proteins, zoledronate had a substantial effect, leading to 10-fold hazard ratio reduction (compared with control) for first distant recurrence in bone (P = .008).CONCLUSIONS: The composite biomarker, CAPG and GIPC1 in primary breast tumors, predicted disease outcomes and benefit from zoledronate and may facilitate patient selection for adjuvant bisphosphonate treatment.",

keywords = "Adaptor Proteins, Signal Transducing, Biomarkers, Tumor, Bone Density Conservation Agents, Bone Neoplasms, Breast Neoplasms, Cell Line, Tumor, Diphosphonates, Disease Progression, Female, Humans, Imidazoles, Immunohistochemistry, Kaplan-Meier Estimate, Lung Neoplasms, Microfilament Proteins, Molecular Targeted Therapy, Nuclear Proteins, Odds Ratio, Predictive Value of Tests, Proportional Hazards Models, Randomized Controlled Trials as Topic, Reproducibility of Results, Editorial, Research Support, Non-U.S. Gov't",

author = "Westbrook, {Jules A} and Cairns, {David A} and Jianhe Peng and Valerie Speirs and Hanby, {Andrew M} and Ingunn Holen and Wood, {Steven L} and Ottewell, {Penelope D} and Helen Marshall and Banks, {Rosamonde E} and Selby, {Peter J} and Coleman, {Robert E} and Brown, {Janet E}",

note = "This work was supported by Cancer Research UK (grant number: C18605/A 10048) through a Clinician Scientist Fellowship (to JEB). DAC was supported by a UK Medical Research Council Career Development Fellowship (G0802416). The authors are solely responsible for the design of the study; the collection, analysis and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication. All authors read and approved the final article. The authors are especially grateful to Professor Joan Massagu{\'e} for kindly providing the bone- and lung-homing variants of MDA-MB-231 cells used in this study. We also particularly thank the AZURE trial patients and investigators, Mr. Mike Shires and the staff of the Sheffield and Leeds Experimental Cancer Medicine Centres for infrastructure support",

year = "2016",

month = apr,

doi = "10.1093/jnci/djv360",

language = "English",

volume = "108",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "4",

}

TY - JOUR

T1 - CAPG and GIPC1

T2 - Breast Cancer Biomarkers for Bone Metastasis Development and Treatment

AU - Westbrook, Jules A

AU - Cairns, David A

AU - Peng, Jianhe

AU - Speirs, Valerie

AU - Hanby, Andrew M

AU - Holen, Ingunn

AU - Wood, Steven L

AU - Ottewell, Penelope D

AU - Marshall, Helen

AU - Banks, Rosamonde E

AU - Selby, Peter J

AU - Coleman, Robert E

AU - Brown, Janet E

N1 - This work was supported by Cancer Research UK (grant number: C18605/A 10048) through a Clinician Scientist Fellowship (to JEB). DAC was supported by a UK Medical Research Council Career Development Fellowship (G0802416). The authors are solely responsible for the design of the study; the collection, analysis and interpretation of the data; the writing of the manuscript; and the decision to submit the manuscript for publication. All authors read and approved the final article. The authors are especially grateful to Professor Joan Massagué for kindly providing the bone- and lung-homing variants of MDA-MB-231 cells used in this study. We also particularly thank the AZURE trial patients and investigators, Mr. Mike Shires and the staff of the Sheffield and Leeds Experimental Cancer Medicine Centres for infrastructure support

PY - 2016/4

Y1 - 2016/4

N2 - BACKGROUND: Bone is the predominant site of metastasis from breast cancer, and recent trials have demonstrated that adjuvant bisphosphonate therapy can reduce bone metastasis development and improve survival. There is an unmet need for prognostic and predictive biomarkers so that therapy can be appropriately targeted.METHODS: Potential biomarkers for bone metastasis were identified using proteomic comparison of bone-metastatic, lung-metastatic, and nonmetastatic variants of human breast cancer MDA-MB-231 cells. Clinical validation was performed using immunohistochemical staining of tumor tissue microarrays from patients in a large randomized trial of adjuvant zoledronic acid (zoledronate) (AZURE-ISRCTN79831382). We used Cox proportional hazards regression, the Kaplan-Meier estimate of the survival function, and the log-rank test to investigate associations between protein expression, clinical variables, and time to distant recurrence events. All statistical tests were two-sided.RESULTS: Two novel biomarker candidates, macrophage-capping protein (CAPG) and PDZ domain-containing protein GIPC1 (GIPC1), were identified for clinical validation. Cox regression analysis of AZURE training and validation sets showed that control patients (no zoledronate) were more likely to develop first distant recurrence in bone (hazard ratio [HR] = 4.5, 95% confidence interval [CI] = 2.1 to 9.8, P < .001) and die (HR for overall survival = 1.8, 95% CI = 1.01 to 3.24, P = .045) if both proteins were highly expressed in the primary tumor. In patients with high expression of both proteins, zoledronate had a substantial effect, leading to 10-fold hazard ratio reduction (compared with control) for first distant recurrence in bone (P = .008).CONCLUSIONS: The composite biomarker, CAPG and GIPC1 in primary breast tumors, predicted disease outcomes and benefit from zoledronate and may facilitate patient selection for adjuvant bisphosphonate treatment.

AB - BACKGROUND: Bone is the predominant site of metastasis from breast cancer, and recent trials have demonstrated that adjuvant bisphosphonate therapy can reduce bone metastasis development and improve survival. There is an unmet need for prognostic and predictive biomarkers so that therapy can be appropriately targeted.METHODS: Potential biomarkers for bone metastasis were identified using proteomic comparison of bone-metastatic, lung-metastatic, and nonmetastatic variants of human breast cancer MDA-MB-231 cells. Clinical validation was performed using immunohistochemical staining of tumor tissue microarrays from patients in a large randomized trial of adjuvant zoledronic acid (zoledronate) (AZURE-ISRCTN79831382). We used Cox proportional hazards regression, the Kaplan-Meier estimate of the survival function, and the log-rank test to investigate associations between protein expression, clinical variables, and time to distant recurrence events. All statistical tests were two-sided.RESULTS: Two novel biomarker candidates, macrophage-capping protein (CAPG) and PDZ domain-containing protein GIPC1 (GIPC1), were identified for clinical validation. Cox regression analysis of AZURE training and validation sets showed that control patients (no zoledronate) were more likely to develop first distant recurrence in bone (hazard ratio [HR] = 4.5, 95% confidence interval [CI] = 2.1 to 9.8, P < .001) and die (HR for overall survival = 1.8, 95% CI = 1.01 to 3.24, P = .045) if both proteins were highly expressed in the primary tumor. In patients with high expression of both proteins, zoledronate had a substantial effect, leading to 10-fold hazard ratio reduction (compared with control) for first distant recurrence in bone (P = .008).CONCLUSIONS: The composite biomarker, CAPG and GIPC1 in primary breast tumors, predicted disease outcomes and benefit from zoledronate and may facilitate patient selection for adjuvant bisphosphonate treatment.

KW - Adaptor Proteins, Signal Transducing

KW - Biomarkers, Tumor

KW - Bone Density Conservation Agents

KW - Bone Neoplasms

KW - Breast Neoplasms

KW - Cell Line, Tumor

KW - Diphosphonates

KW - Disease Progression

KW - Female

KW - Humans

KW - Imidazoles

KW - Immunohistochemistry

KW - Kaplan-Meier Estimate

KW - Lung Neoplasms

KW - Microfilament Proteins

KW - Molecular Targeted Therapy

KW - Nuclear Proteins

KW - Odds Ratio

KW - Predictive Value of Tests

KW - Proportional Hazards Models

KW - Randomized Controlled Trials as Topic

KW - Reproducibility of Results

KW - Editorial

KW - Research Support, Non-U.S. Gov't

U2 - 10.1093/jnci/djv360

DO - 10.1093/jnci/djv360

M3 - Article

C2 - 26757732

SN - 0027-8874

VL - 108

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 4

ER -

CAPG and GIPC1: Breast Cancer Biomarkers for Bone Metastasis Development and Treatment

Abstract

Bibliographical note

Keywords

UN SDGs

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