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Tumoral ANXA1 Is a Predictive Marker for Sunitinib Treatment of Renal Cancer Patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University Hospital, Department of Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University Hospital, Department of Oncology.ORCID iD: 0000-0002-0594-724x
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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2017 (English)In: Journal of Cancer, ISSN 1837-9664, E-ISSN 1837-9664, Vol. 8, no 19, p. 3975-3983Article in journal (Refereed) Published
Abstract [en]

Background and aims: There is no established predictive marker for the treatment of renal cancer. Metastatic renal cell carcinoma (mRCC) patients are often treated with sunitinib, a tyrosine kinase inhibitor. Sunitinibs anti-cancer effect is at least partly mediated through interfering with angiogenesis. Our aim with the current study was to assess annexin A1 (ANXA1), which stimulates angiogenesis, as a predictive marker for sunitinib therapy in mRCC patients. Since previous studies have indicated a predictive potential for cubilin, we also investigated the predictivity of ANXA1 combined with cubilin.

Methods: ANXA1 expression was analysed in tumor tissue from a cohort of patients with advanced RCC (n= 139) using immunohistochemistry. Ninety-nine of the patients were treated with sunitinib in the first or second-line setting. Twenty-two of these were censored because of toxicity leading to the termination of treatment and the remaining (n= 77) were selected for the present study.

Results: Twenty-five (32%) out of seventy-seven of the tumors lacked ANXA1 in the cytoplasm. On statistical analyses using Kaplan-Meier method, aNXA1 negative tumors were significantly associated with a longer treatment benefit in terms of progression free survival (PFS). Overall survival was also significantly better for patients with ANXA1 negative tumors. The combined ANXA1 positive and cubilin negative expression could more accurately than ANXA1 alone define the group not benefitting from treatment.

Conclusions: Our results indicate that cytoplasmic expression of ANXA1 is a negative predictive marker for sunitinib therapy in mRCC patients. A possible explanation for this finding is that sunitinibs anti-angiogenic effect cannot overcome the pro-angiogenic drive from many ANXA1 proteins.

Place, publisher, year, edition, pages
2017. Vol. 8, no 19, p. 3975-3983
Keywords [en]
Renal cancer, sunitinib, tissue microarray, predictive marker, ANXA1
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-339521DOI: 10.7150/jca.20889ISI: 000418498600007PubMedID: 29187872OAI: oai:DiVA.org:uu-339521DiVA, id: diva2:1176296
Available from: 2018-01-22 Created: 2018-01-22 Last updated: 2018-10-09Bibliographically approved
In thesis
1. Intratumoral Predictive Markers in Metastatic Renal Cancer Patients
Open this publication in new window or tab >>Intratumoral Predictive Markers in Metastatic Renal Cancer Patients
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

There is no established predictive marker for the treatment of metastatic renal cell cancer (mRCC) patients. With a predictive marker, patients unlikely to respond could be selected upfront and offered other therapy options. Thereby, unnecessary toxicity could be avoided and costs would be reduced. Tyrosine kinase inhibitors (TKI) are the cornerstone in the treatment of mRCC. The aim of the thesis was to evaluate and hopefully define tumoral predictive markers for treatment with the common TKIs sunitinib and sorafenib.

The studies are based on immunohistochemical analyses of renal cancer tissues from 139 primary tumors sampled in a tissue microarray. Three proteins with a specific and differential expression in RCC were chosen in co-operation with the Human Protein Atlas project. Since TKIs block vascular endothelial growth factor receptors (VEGFR) on tumor vessels, angiogenesis associated proteins were also analysed as putative predictive biomarkers.

In two studies, the renal proteins cubilin (CUBN) and pyruvate kinase L/R (PKLR) were investigated. Our results indicate that these membranous proteins are positive predictive factors for sunitinib and sorafenib therapies. Patients with high membranous expressions of CUBN and PKLR respectively experienced significantly longer progression free survivals (PFS) and overall survivals (OS) compared to the other patients. Combining CUBN and PKLR negative tumors, a patient group with a particularly short PFS could be defined, possibly consisting of patients not benefitting at all from treatment with sunitinib or sorafenib.

Studies of tumoral annexin A1 (ANXA1) and epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1 (ELTD1) demonstrated predictive potential for sunitinib but not for sorafenib treatment. A low cytoplasmic expression of ANXA1 was significantly associated with longer PFS and OS in patients treated with sunitinib. A combined analysis with CUBN and ANXA1 expression indicated a higher predictive value than the expressions of either marker alone. We further observed that a high vascular endothelial expression of ELTD1 is predictive for a longer PFS and OS in sunitinib treated patients. The expressions of CD34 which is a marker of the number of vessels and the sunitinib target VEGFR2 failed to demonstrate significant associations with PFS.

To conclude, our real world studies indicate that CUBN, PKLR, ANXA1 and ELTD1 are potential tumoral biomarkers, to predict benefit from treatment with sunitinib (all four proteins) and sorafenib (CUBN and PKLR) in patients suffering from mRCC.

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 55
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1504
Keywords
Renal cell cancer, predictive marker, tyrosine kinase inhibitor, tissue microarray, cubilin, annexin A1, PKLR, ELTD1
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-360251 (URN)978-91-513-0467-0 (ISBN)
Public defence
2018-12-01, Enghoffsalen, Akademiska Sjukhuset, ingång 50, Uppsala, 09:15 (Swedish)
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Available from: 2018-11-07 Created: 2018-10-09 Last updated: 2018-11-19

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