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Intratumoral Predictive Markers in Metastatic Renal Cancer Patients
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
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 [en]
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: urn:nbn:se:uu:diva-360251ISBN: 978-91-513-0467-0 (print)OAI: oai:DiVA.org:uu-360251DiVA, id: diva2:1254681
Public defence
2018-12-01, Enghoffsalen, Akademiska Sjukhuset, ingång 50, Uppsala, 09:15 (Swedish)
Opponent
Supervisors
Available from: 2018-11-07 Created: 2018-10-09 Last updated: 2018-11-19
List of papers
1. Tumoral cubilin is a predictive marker for treatment of renal cancer patients with sunitinib and sorafenib
Open this publication in new window or tab >>Tumoral cubilin is a predictive marker for treatment of renal cancer patients with sunitinib and sorafenib
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2017 (English)In: Journal of Cancer Research and Clinical Oncology, ISSN 0171-5216, E-ISSN 1432-1335, Vol. 143, no 6, p. 961-970Article in journal (Refereed) Published
Abstract [en]

Purpose Tyrosine kinase inhibitors like sunitinib and sorafenib are commonly used to treat metastatic renal cell cancer patients. Cubilin is a membrane protein expressed in the proximal renal tubule. Cubilin and megalin function together as endocytic receptors mediating uptake of many proteins. There is no established predictive marker for metastatic renal cell cancer patients and the purpose of the present study was to assess if cubilin can predict response to treatment with tyrosine kinase inhibitors.

Methods Cubilin protein expression was analyzsed in tumor tissue from a cohort of patients with metastatic renal cell cancer (n = 139) using immunohistochemistry. One hundred and thirty six of the patients were treated with sunitinib or sorafenib in the first- or second-line setting. Thirty of these were censored because of toxicity leading to the termination of treatment and the remaining (n = 106) were selected for the current study.

Results Fifty-three (50%) of the tumors expressed cubilin in the membrane. The median progression-free survival was 8 months in patients with cubilin expressing tumors and 4 months in the cubilin negative group. In addition, the overall survival was better for patients with cubilin positive tumors. We also found that the fraction of cubilin negative patients was significantly higher in the non-responding group (PFS ≤3 months) compared to responding patients (PFS >3 months).

Conclusions We show for the first time that tumoral expression of cubilin is a positive predictive marker for treatment of metastatic renal cell cancer patients with sunitinib and sorafenib.

Keywords
Cubilin, Predictive marker, Renal cancer, Tissue microarray, Tyrosine kinase inhibitor
National Category
Clinical Medicine Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-318129 (URN)10.1007/s00432-017-2365-y (DOI)000401411200005 ()28260162 (PubMedID)
Funder
Knut and Alice Wallenberg Foundation
Available from: 2017-03-23 Created: 2017-03-23 Last updated: 2019-04-02Bibliographically approved
2. Tumoral ANXA1 Is a Predictive Marker for Sunitinib Treatment of Renal Cancer Patients
Open this publication in new window or tab >>Tumoral ANXA1 Is a Predictive Marker for Sunitinib Treatment of Renal Cancer Patients
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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.

Keywords
Renal cancer, sunitinib, tissue microarray, predictive marker, ANXA1
National Category
Cancer and Oncology Clinical Laboratory Medicine
Research subject
Pathology
Identifiers
urn:nbn:se:uu:diva-339521 (URN)10.7150/jca.20889 (DOI)000418498600007 ()29187872 (PubMedID)
Available from: 2018-01-22 Created: 2018-01-22 Last updated: 2019-04-02Bibliographically approved
3. Tumoral pyruvate kinase L/R as a predictive marker for the treatment of renal cancer patients with sunitinib and sorafenib
Open this publication in new window or tab >>Tumoral pyruvate kinase L/R as a predictive marker for the treatment of renal cancer patients with sunitinib and sorafenib
Show others...
2019 (English)In: Journal of Cancer, ISSN 1837-9664, Vol. 10, no 14, p. 3224-3231Article in journal (Other academic) Published
Abstract [en]

Background and aims: Treatment with tyrosine kinase inhibitors (TKI) like sunitinib and sorafenib has improved the prognosis of patients with metastatic renal cell cancer (mRCC). No predictive marker is available to select patients who will gain from these treatments. Tumoral pyruvate kinase L/R (PKLR) is a membrane protein with highly specific expression in the renal tubule. We have previously shown that the tumoral expression of cubilin (CUBN) is associated with progression free survival (PFS) in mRCC patients treated with sunitinib and sorafenib. The aim of the present study was to investigate if PKLR can predict response in these patients, alone and/or in combination with CUBN.

Methods: A tissue microarray (TMA) was constructed of tumor samples from 139 mRCC patients. One hundred and thirty-six of these patients had been treated with sunitinib or sorafenib in the first or second-line setting. Thirty patients suffered from early severe toxicity leading to the termination of treatment. The remaining patients (n=106) were selected for the current study.

Results: Fifty-five (52%) of the tumors expressed membranous PKLR. Patients with PKLR tumor expression experienced a significantly longer PFS compared to patients with no expression (eight versus five months, p = 0.019). Overall survival (OS) was also significantly better for patients with PKLR expression. In addition, the combined expression of PKLR and CUBN resulted in a higher predictive value than either marker alone.

Conclusions: In this real world study we show that tumoral PKLR membrane expression is a positive predictive biomarker for sunitinib and sorafenib treatment in patients suffering from mRCC. Our results also indicate that the combined expression with cubilin more accurately than PKLR alone can select patients with no benefit from treatment.

National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-360611 (URN)10.7150/jca.30130 (DOI)000470088200017 ()
Funder
Knut and Alice Wallenberg Foundation
Available from: 2018-09-16 Created: 2018-09-16 Last updated: 2019-06-26Bibliographically approved
4. Tumor endothelial ELTD1 as a predictive marker for treatment of renal cancer patients with sunitinib
Open this publication in new window or tab >>Tumor endothelial ELTD1 as a predictive marker for treatment of renal cancer patients with sunitinib
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Cancer and Oncology
Research subject
Oncology
Identifiers
urn:nbn:se:uu:diva-360266 (URN)
Available from: 2018-09-11 Created: 2018-09-11 Last updated: 2018-10-09

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