Serum SDF-1 levels are a reliable diagnostic marker of feline mammary carcinoma, discriminating HER2-overexpressing tumors from other subtypes

Abstract

The feline mammary carcinoma (FMC) is the third most common tumor in cat, sharing many clinicopathological features with human breast cancer and thus, considered a suitable model for comparative oncology. Due to its poor prognosis, further studies are required to improve the diagnostic accuracy and treatment of cats with spontaneous mammary carcinoma. Recently, it was reported that the overexpression of stromal cell-derived factor-1 (SDF-1) has great value in human breast cancer diagnosis, suggesting that diagnostic tools and therapies targeting the SDF-1 ligand can improve the clinical outcome. In this study, we aimed to evaluate if serum SDF-1 levels can also be used as a biomarker of mammary carcinoma in cats and to analyze if serum SDF-1 levels are associated with clinicopathological features, linked to a specific FMC subtype or correlated with the tumor expression of SDF-1 receptor, the chemokine C-X-C motif receptor 4 (CXCR4). Results showed that cats with mammary carcinoma had significantly higher serum SDF-1 levels than healthy controls (p=0.035) and ROC analysis revealed that the best cut-off value to differentiate sick from healthy animals was 2 ng/ml (specificity: 80%; sensitivity: 57%; AUC=0.715). Significant associations were also found between cats with elevated serum SDF-1 concentrations (≥ 2 ng/ml) and HER2-overexpressing mammary carcinomas (Luminal B-like and HER2-positive subtypes, p<0.0001), CXCR4-negative mammary carcinomas (p=0.027), mammary carcinomas with small size (<3 cm, p=0.027) and tumors with low Ki-67 expression (p=0.012). No statistical associations were found between serum SDF-1 levels and overall or disease-free survival. In summary, our results show that serum SDF-1 levels can be used as a biomarker of feline mammary carcinoma, especially in cats with HER2-overexpressing mammary tumors. Data suggest that targeted therapies against the SDF-1 ligand and/or its CXC4 receptor may be effective for the treatment of FMC, as described for human breast cancer, strengthening the concept that spontaneous feline mammary carcinoma is a suitable model for comparative oncology.

Intratumoral collagen signatures predict clinical outcomes in feline mammary carcinoma

“…Staining primary tumors for Bcl-2, an anti-apoptotic protein, revealed that increased Bcl-2 positivity was associated with longer survival, disease-free survival and cancer-specific survival [49]; however only a small proportion of FMT were positive for Bcl-2 in this study, and thus this marker may only be used to prognosticate a subpopulation of feline patients. Consistent with the ability of SDF-1 to predict outcome in human patients, SDF-1 was also found to be higher in cats with FMT compared to healthy individuals, although it was unable to predict outcome [50]. Finally, sphingosine kinase-1 (SPHK1) was found to be increased in FMT vs normal mammary tissue, and levels within primary tumors correlated with grade, lymphovascular invasion, and ER negativity.…”

Emerging Biomarkers and Targeted Therapies in Feline Mammary Carcinoma

“…Furthermore, overexpression of several molecular biomarkers is also associated with poor prognosis, e.g., macrophage-stimulating protein receptor (RON), related to tumor invasion, cyclo-oxygenase (COX)-2, expressed in malignant FMCs, and topoisomerase IIβ binding protein 1 (TopBP1), which is similar to BRAC2 in HBC [ 31 , 58 ]. Interestingly, the CXCR4/CXCL12 axis, which controls cell survival, migration and proliferation, is also a key factor in feline breast cancer progression and metastasis, as reported for HBC [ 59 , 60 ], and it’s disruption is associated with lower OS time [ 60 , 61 , 62 ]. Additionally, CXCL12 has been reported as a blood serum marker in the cat, particularly for HER2-positive tumors [ 62 ].…”

“…Interestingly, the CXCR4/CXCL12 axis, which controls cell survival, migration and proliferation, is also a key factor in feline breast cancer progression and metastasis, as reported for HBC [ 59 , 60 ], and it’s disruption is associated with lower OS time [ 60 , 61 , 62 ]. Additionally, CXCL12 has been reported as a blood serum marker in the cat, particularly for HER2-positive tumors [ 62 ]. Finally, analysis of the vascular endothelial growth factor (VEGF) status, shows that this molecule is overexpressed in more aggressive carcinomas [ 50 , 63 ], playing an important role in tumor-associated angiogenesis.…”

Neutrophil‐to‐lymphocyte ratio is an independent prognostic marker for feline mammary carcinomas

“…The prognosis is poor to guarded for most cats with mammary carcinomas, 11 but strongly dependent on several clinical and histological factors, such as tumour size, nodal metastasis, World Health Organization (WHO) clinical stage, histological type, lymphovascular invasion, mitotic index and histological grade 1,12‐18 . Several molecular and serum markers have also been associated with prognosis, namely: the level of expression of the cyclooxygenase‐2 enzyme, human epidermal growth factor receptor‐2 (HER2), oestrogen and progesterone receptors, Ki‐67, AgNORs count, stromal cell‐derived factor‐1, programmed death ligand‐1 and cytotoxic T‐lymphocyte‐associated antigen 4 18‐26 . The clinical application of some of these markers is limited and others are only available after histological evaluation of both tumour and lymph nodes.…”