Tumoral ANXA1 Is a Predictive Marker for Sunitinib Treatment of Renal Cancer Patients

Abstract

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.

Tumor endothelial ELTD1 as a predictive marker for treatment of renal cancer patients with sunitinib

“…The local Research Ethics Committee in Uppsala granted approval for the study (2009/139) and patients still alive gave their written informed consent. The TMA cohort and treatment characteristics have been described previously [11,12,21] (Table 1) [12]. In short, the TMA consists of 139 cases of RCC diagnosed 2006-2010.…”

“…Treatment characteristics for renal cancer patients treated for metastatic disease with sunitinib in the firstand second-line setting [12].…”

“…In another and larger TMA-based study, tumoral expression of programmed death ligand 1 (PD-L1) or PD-L1 plus tumor infiltrating CD8+ T-cells were correlated to significantly shorter PFS and overall survival (OS) in patients treated with sunitinib or pazopanib [10]. We have previously reported TMA-studies indicating that cubilin (CUBN) and annexin A1 (ANXA1) expressed in the tumor cells are predictive markers in mRCC patients treated with sunitinib and sorafenib [11,12].…”

Editorial Comment to Annexin A1 expression is correlated with malignant potential of renal cell carcinoma

“…examined ANXA1 cytoplasmic staining in 77 metastatic RCC cases treated with nephrectomy followed by sunitinib therapy in the first‐ or second‐line setting. Cytoplasmic ANXA1‐negative cases (25/77, 32%) showed better progression‐free survival and overall survival than cytoplasmic ANXA1‐positive cases . Niinivirta et al .…”

“…Cytoplasmic ANXA1-negative cases (25/77, 32%) showed better progression-free survival and overall survival than cytoplasmic ANXA1-positive cases. 3 Niinivirta et al concluded that cytoplasmic expression of ANXA1 was a negative predictive marker for sunitinib treatment in metastatic RCC patients.…”