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- Title
CAPG and GIPC1: Breast Cancer Biomarkers for Bone Metastasis Development and Treatment.
- Authors
Westbrook, Jules A.; Cairns, David A.; Jianhe Peng; Speirs, Valerie; Hanby, Andrew M.; Holen, Ingunn; Wood, Steven L.; Ottewell, Penelope D.; Marshall, Helen; Banks, Rosamonde E.; Selby, Peter J.; Coleman, Robert E.; Brown, Janet E.; Peng, Jianhe; Banks, Rozalind E
- Abstract
<bold>Background: </bold>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.<bold>Methods: </bold>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.<bold>Results: </bold>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).<bold>Conclusions: </bold>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.
- Subjects
BIOMARKERS; CAPPING proteins; BONE metastasis; BREAST cancer; THERAPEUTICS; DIPHOSPHONATES; IMIDAZOLES; BONE tumors; BREAST tumors; CARRIER proteins; CELL lines; DRUG therapy; IMMUNOHISTOCHEMISTRY; LUNG tumors; MICROFILAMENT proteins; RESEARCH evaluation; RESEARCH funding; PREDICTIVE tests; PROPORTIONAL hazards models; NUCLEAR proteins; DISEASE progression; KAPLAN-Meier estimator; ODDS ratio
- Publication
JNCI: Journal of the National Cancer Institute, 2016, Vol 108, Issue 4, p1
- ISSN
0027-8874
- Publication type
editorial
- DOI
10.1093/jnci/djv360