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CES2, ABCG2, TS and Topo-I primary and synchronous metastasis expression and clinical outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI regimen.

Silvestris N, Simone G, Partipilo G, Scarpi E, Lorusso V, Brunetti AE, Maiello E, Paradiso A, Mangia A - Int J Mol Sci (2014)

Bottom Line: Moreover, Cox' multivariate analysis revealed that TS expression was significantly associated with overall survival (p = 0.01).No significant correlation was found between investigated markers expression and clinical response.Topo-I expression resulted in being significantly higher in liver metastases with respect to the corresponding primary tumors (p < 0.0001), emphasizing the role of Topo-I expression in metastatic cancer biology.

View Article: PubMed Central - PubMed

Affiliation: Medical Oncology Unit, National Cancer Research Centre-Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, 70124 Bari, Italy. n.silvestris@oncologico.bari.it.

ABSTRACT
Enzymatic activation of irinotecan (CPT-11) is due to carboxylesterase (CES), and its pharmacological behavior is influenced by drug resistance-related proteins. We previously reported that the clinical response and prognosis of metastatic colorectal cancer (mCRC) patients did not differ in tumors with different thymidylate synthase (TS) or topoisomerase-I (Topo-I) expression. Using immunohistochemistry (IHC), we evaluated the biological role of CES2 and the expression of breast cancer resistance protein (BCRP/ABCG2) in 58 consecutive mCRC patients, who had undergone a first-line CPT-11/5-FU/leucovirin (FOLFIRI) regimen. The expression of these proteins was also examined in a group of synchronous lymph nodes and liver metastases. Furthermore, all samples were revaluated for TS and Topo-I expression. High expression of CES2, ABCG2, TS and Topo-I was observed in 55%, 56%, 38% and 49% of patients, respectively. There was a significant association between high TS and high ABCG2 expression (p = 0.049). Univariate analysis showed that only TS expression significantly impacted on time to progression (p = 0.005). Moreover, Cox' multivariate analysis revealed that TS expression was significantly associated with overall survival (p = 0.01). No significant correlation was found between investigated markers expression and clinical response. Topo-I expression resulted in being significantly higher in liver metastases with respect to the corresponding primary tumors (p < 0.0001), emphasizing the role of Topo-I expression in metastatic cancer biology. In primary tumor tissues, CES2 expression tended to be higher than that observed in liver metastasis tissues (p = 0.05). These preliminary data may suggest CES2 over-expression as a potential marker of malignant phenotype. In light of these findings, we suggest that Topo-I expression together with TS expression could be associated with metastatic progression of CRC. Further studies are warranted with the aim of evaluating the potential predictive and prognostic role of CES2 and ABCG2 in larger series of patients.

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Representative images of immunohistochemical staining for carboxylesterase 2 (CES2), breast cancer resistance protein 2 (ABCG2), thymidylate synthase (TS) and Topo-I in tissues of metastatic colorectal cancer (original magnification 200×). (a) Positive cytoplasmic CES2 expression; (b) Positive membranous and cytoplasmic ABCG2 expression; (c) Positive cytoplasmic TS expression; (d) High nuclear Topo-I expression.
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ijms-15-15767-f001: Representative images of immunohistochemical staining for carboxylesterase 2 (CES2), breast cancer resistance protein 2 (ABCG2), thymidylate synthase (TS) and Topo-I in tissues of metastatic colorectal cancer (original magnification 200×). (a) Positive cytoplasmic CES2 expression; (b) Positive membranous and cytoplasmic ABCG2 expression; (c) Positive cytoplasmic TS expression; (d) High nuclear Topo-I expression.

Mentions: We evaluated 58 patients with mCRC who underwent first-line FOLFIRI chemotherapy. The median age of the patients (33 male and 25 female) was 60 years (range: 37–75 years). The location of cancer was the colon in 24 (41%) and rectum in 34 (59%) patients. The median follow-up from commencement of treatment was 24 months (range: 14–28 months). Time to progression (TTP) and overall survival (OS) were nine months (range: 6–10 months) and 18 months (range: 17–21 months), respectively. One patient (1.8%) showed a complete response (CR); 19 (35%) patients showed partial response (PR); 16 (30%) patients had stable disease (SD); and 18 (33%) patients had progressive disease (PD). Four patients were not evaluable for response. All 58 samples were tested with CES, 57 with Topo-I and ABCG2, and 56 samples were tested for TS. Cytoplasmic CES2 overexpression (Subgroups 2 + 3) was present in 55% of tumor tissues. Regarding ABCG2 expression, most positive tumor samples showed a membranous staining and some diffuse cytoplasmic staining. Fifty six percent of tumor tissues showed a strong positivity (Subgroup 2). Over-expression of cytoplasmic TS immunoreactivity was observed in 38% of the tumor tissues. The percentage of nuclear Topo-I positive tumors was 49% (Figure 1).


CES2, ABCG2, TS and Topo-I primary and synchronous metastasis expression and clinical outcome in metastatic colorectal cancer patients treated with first-line FOLFIRI regimen.

Silvestris N, Simone G, Partipilo G, Scarpi E, Lorusso V, Brunetti AE, Maiello E, Paradiso A, Mangia A - Int J Mol Sci (2014)

Representative images of immunohistochemical staining for carboxylesterase 2 (CES2), breast cancer resistance protein 2 (ABCG2), thymidylate synthase (TS) and Topo-I in tissues of metastatic colorectal cancer (original magnification 200×). (a) Positive cytoplasmic CES2 expression; (b) Positive membranous and cytoplasmic ABCG2 expression; (c) Positive cytoplasmic TS expression; (d) High nuclear Topo-I expression.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4200864&req=5

ijms-15-15767-f001: Representative images of immunohistochemical staining for carboxylesterase 2 (CES2), breast cancer resistance protein 2 (ABCG2), thymidylate synthase (TS) and Topo-I in tissues of metastatic colorectal cancer (original magnification 200×). (a) Positive cytoplasmic CES2 expression; (b) Positive membranous and cytoplasmic ABCG2 expression; (c) Positive cytoplasmic TS expression; (d) High nuclear Topo-I expression.
Mentions: We evaluated 58 patients with mCRC who underwent first-line FOLFIRI chemotherapy. The median age of the patients (33 male and 25 female) was 60 years (range: 37–75 years). The location of cancer was the colon in 24 (41%) and rectum in 34 (59%) patients. The median follow-up from commencement of treatment was 24 months (range: 14–28 months). Time to progression (TTP) and overall survival (OS) were nine months (range: 6–10 months) and 18 months (range: 17–21 months), respectively. One patient (1.8%) showed a complete response (CR); 19 (35%) patients showed partial response (PR); 16 (30%) patients had stable disease (SD); and 18 (33%) patients had progressive disease (PD). Four patients were not evaluable for response. All 58 samples were tested with CES, 57 with Topo-I and ABCG2, and 56 samples were tested for TS. Cytoplasmic CES2 overexpression (Subgroups 2 + 3) was present in 55% of tumor tissues. Regarding ABCG2 expression, most positive tumor samples showed a membranous staining and some diffuse cytoplasmic staining. Fifty six percent of tumor tissues showed a strong positivity (Subgroup 2). Over-expression of cytoplasmic TS immunoreactivity was observed in 38% of the tumor tissues. The percentage of nuclear Topo-I positive tumors was 49% (Figure 1).

Bottom Line: Moreover, Cox' multivariate analysis revealed that TS expression was significantly associated with overall survival (p = 0.01).No significant correlation was found between investigated markers expression and clinical response.Topo-I expression resulted in being significantly higher in liver metastases with respect to the corresponding primary tumors (p < 0.0001), emphasizing the role of Topo-I expression in metastatic cancer biology.

View Article: PubMed Central - PubMed

Affiliation: Medical Oncology Unit, National Cancer Research Centre-Istituto Tumori "Giovanni Paolo II", Viale Orazio Flacco 65, 70124 Bari, Italy. n.silvestris@oncologico.bari.it.

ABSTRACT
Enzymatic activation of irinotecan (CPT-11) is due to carboxylesterase (CES), and its pharmacological behavior is influenced by drug resistance-related proteins. We previously reported that the clinical response and prognosis of metastatic colorectal cancer (mCRC) patients did not differ in tumors with different thymidylate synthase (TS) or topoisomerase-I (Topo-I) expression. Using immunohistochemistry (IHC), we evaluated the biological role of CES2 and the expression of breast cancer resistance protein (BCRP/ABCG2) in 58 consecutive mCRC patients, who had undergone a first-line CPT-11/5-FU/leucovirin (FOLFIRI) regimen. The expression of these proteins was also examined in a group of synchronous lymph nodes and liver metastases. Furthermore, all samples were revaluated for TS and Topo-I expression. High expression of CES2, ABCG2, TS and Topo-I was observed in 55%, 56%, 38% and 49% of patients, respectively. There was a significant association between high TS and high ABCG2 expression (p = 0.049). Univariate analysis showed that only TS expression significantly impacted on time to progression (p = 0.005). Moreover, Cox' multivariate analysis revealed that TS expression was significantly associated with overall survival (p = 0.01). No significant correlation was found between investigated markers expression and clinical response. Topo-I expression resulted in being significantly higher in liver metastases with respect to the corresponding primary tumors (p < 0.0001), emphasizing the role of Topo-I expression in metastatic cancer biology. In primary tumor tissues, CES2 expression tended to be higher than that observed in liver metastasis tissues (p = 0.05). These preliminary data may suggest CES2 over-expression as a potential marker of malignant phenotype. In light of these findings, we suggest that Topo-I expression together with TS expression could be associated with metastatic progression of CRC. Further studies are warranted with the aim of evaluating the potential predictive and prognostic role of CES2 and ABCG2 in larger series of patients.

Show MeSH
Related in: MedlinePlus