CAIX is a predictor of pathological complete response and is associated with higher survival in locally advanced breast cancer submitted to neoadjuvant chemotherapy

Abstract

BackgroundLocally advanced breast cancer often undergoes neoadjuvant chemotherapy (NAC), which allows in vivo evaluation of the therapeutic response. The determination of the pathological complete response (pCR) is one way to evaluate the response to neoadjuvant chemotherapy. However, the rate of pCR differs significantly between molecular subtypes and the cause is not yet determined. Recently, the metabolic reprogramming of cancer cells and its implications for tumor growth and dissemination has gained increasing prominence and could contribute to a better understanding of NAC. Thus, this study proposed to evaluate the expression of metabolism-related proteins and its association with pCR and survival rates.MethodsThe expression of monocarboxylate transporters 1 and 4 (MCT1 and MCT4, respectively), cluster of differentiation 147 (CD147), glucose transporter-1 (GLUT1) and carbonic anhydrase IX (CAIX) was analyzed in 196 locally advanced breast cancer samples prior to NAC. The results were associated with clinical-pathological characteristics, occurrence of pCR, disease-free survival (DFS), disease-specific survival (DSS) and overall survival (OS).ResultsThe occurrence of pCR was higher in the group of patients whith tumors expressing GLUT1 and CAIX than in the group without expression (27.8% versus 13.1%, p = 0.030 and 46.2% versus 13.5%, p = 0.007, respectively). Together with regional lymph nodes staging and mitotic staging, CAIX expression was considered an independent predictor of pCR. In addition, CAIX expression was associated with DFS and DSS (p = 0.005 and p = 0.012, respectively).ConclusionsCAIX expression was a predictor of pCR and was associated with higher DFS and DSS in locally advanced breast cancer patients subjected to NAC.

Expression of Glycolysis-Related Proteins in Cancer of Unknown Primary Origin

“…Furthermore, the authors demonstrated that stromal CAIX expression improved the survival rates of colorectal cancer patients, suggesting that tumor hypoxia may influence tumor-associated stromal cells that ultimately contributes to patient prognosis. Although the samples used in the present study were cancer treatment naïve, some studies demonstrated that systemic therapy alters the metabolic phenotype of cancer cells and affects the patient outcomes ( 25 , 56 , 57 ). Goos and co-workers ( 56 ) showed that high GLUT1 expression levels in colorectal cancer liver metastasis were associated with improved survival of patients previously treated with systemic therapy.…”

“…Goos and co-workers ( 56 ) showed that high GLUT1 expression levels in colorectal cancer liver metastasis were associated with improved survival of patients previously treated with systemic therapy. Additionally, a study performed by our group with locally advanced breast tumor patients submitted to neoadjuvant chemotherapy showed that CAIX-positive expression was associated with higher disease-free survival and disease-specific survival, and a pathological complete response after treatment ( 25 ), suggesting that neoadjuvant therapy affects the metabolic phenotype of aggressive glycolytic tumors, favoring the clinical outcomes of breast cancer patients. Regarding the association of MCT1/CD147, GLUT1/MCT4 and CAIX/MCT4 co-expression with higher overall survival of CUP patients, to our best knowledge, this is the first report of MCT association with a good clinical outcome; however, it follows the rationale behind GLUT1 and CAIX findings, with glycolytic CUPs showing a better prognosis.…”

“…Immunohistochemistry for MCT1 and CD147 was performed using a polymer system (Ultra Vision ONE Detection System: HRP Polymer, Lab Vision Corporation, Fremont, CA) as previously described ( 25 ). MCT4 reactions were performed using a streptavidin–biotin–peroxidase complex (Ultravision Detection System: Large Volume Anti-Polyvalent, HRP, Lab Vision Corporation, Fremont, CA), as previously described ( 26 ); finally, MCT2, GLUT1 and CAIX reactions were performed using a biotin-free principle (ADVANCE HRP; Dako, Carpinteria, CA) according to the manufacturer’s instructions and as previously described ( 25 ). For visualization, the slides were incubated with 3,3’-diaminobenzidine (Liquid DAB+ Substrate Chromogen System; Dako, Carpinteria, CA) according to the manufacturer’s instructions, counterstained with hematoxylin and permanently mounted.…”

Betulin Sulfonamides as Carbonic Anhydrase Inhibitors and Anticancer Agents in Breast Cancer Cells

“…Consistent with the results of Chen et al [31], we detected elevated CA IX levels in basal TNBC cell lines (HS578T, MDA-MB-231, BT-20) and high expression of CA XII in luminal hormone receptor-positive (MCF-7, T47D) or HER2-positive (SKBR3) breast cancer cell lines. Some studies have assumed crosstalk between carbonic anhydrases [32][33][34]. In detail, in the colon carcinoma cell line LS174Tr, knockdown of CA 9 revealed up-regulation of CA 12, and increased CA XII expression was observed from the immunohistochemical results of tumor sections of mice injected with CA 9-diminished cells in vivo.…”

Molecular Biomarkers Predict Pathological Complete Response of Neoadjuvant Chemotherapy in Breast Cancer Patients: Review

“…Another protein that is related to pCR is carbonic anhydrase IX (CAIX), which is a transmembrane protein and one of the only two isoenzymes of carbonic anhydrase associated with tumors that may be involved in cell proliferation and transformation [66]. Alves et al first described CAIX expression as a predictor of pCR and its association with DFS and OS in patients with locally advanced BC treated with NAC using doxorubicin, cyclophosphamide, and paclitaxel [66].…”