Topoisomerase I but not thymidylate synthase is associated with improved outcome in patients with resected colorectal cancer treated with irinotecan containing adjuvant chemotherapy

Abstract

BackgroundThymidylate synthase (TS) and Topoisomerase I (Topo I) are significant biomarkers in colorectal cancer (CRC). We aimed to study the expression of TS and Topo I in patients with resected CRC who received adjuvant chemotherapy and correlated it with clinical outcome.MethodsAll patients diagnosed with CRC between 1989 and 2007 and treated with adjuvant chemotherapy within Hellenic Cooperative Oncology Group's (HeCOG) protocols, were identified. Archival paraffin-embedded tumor tissues were used for immunohistochemical detection of TS and Topo I. Immunohistochemistry was performed on tissue microarray slides using monoclonal antibodies against TS and Topo I. The results were correlated with survival (OS) and disease free survival (DFS).ResultsA cohort of 498 patients with a median age of 61 years and Dukes' stage B (49%) and C (51%) fulfilled the criteria of the study. All patients received adjuvant 5-FU-based chemotherapy, 38% irinotecan-containing. Positive TS and Topo I expression was found in 43% and 48% of cases, respectively. Five-year OS was 74% and DFS was 68%. In univariate analysis no association of TS and Topo I expression with OS and DFS was identified. In multivariate analysis however, Topo I expression was associated with a reduced risk of death (HR = 0.61, 95% CI 0.42-0.88, p = 0.009). In the irinotecan-treated subgroup, those patients who expressed Topo I had a better OS (HR = 0.47, 95% CI 0.23-0.94, p = 0.033).ConclusionPatients with resected CRC expressing Topo I seem to benefit from irinotecan-containing adjuvant chemotherapy. However randomised prospective trials are needed to confirm these results.

Topoisomerase‐1 gene copy aberrations are frequent in patients with breast cancer

“…[4][5][6][7][8] These inconsistent results could partly be explained by the fact that immunohistochemistry (IHC) requires suitable and validated antibodies as well as standardized protocols, both of which have been difficult to obtain for Top1 and accordingly Top1 IHC has not yet reached the level for clinical implementation.…”

“…Recently a small study including 28 patients with mBC used a multi-omic molecular profile (MMP) including Topo1 to identify potential therapeutic targets and select individualized treatment. All patients were heavily pretreated with at least three prior treatment regimens (range [3][4][5][6][7][8][9][10][11][12]. Based on the MMP 14 patients were treated with irinotecan or irinotecan plus fluorouracil.…”

“…Two studies found Top1 protein expression predictive of response to irinotecan in both the neo-adjuvant and adjuvant setting of patients with colorectal cancer. 4,5 Also in the metastatic setting, high or moderate expression of Top1 protein correlated with improved survival benefit for patients receiving either irinotecan or oxaliplatin as first line treatment, compared with patients with low Top1 protein expression. 6 However, although using similar technologies, other studies have not found Top1 protein predictive of response in the metastatic setting.…”

Potentially resectable metastatic colorectal cancer: An individualized approach to conversion therapy

“…In particular, ERCC1 polymorphisms, thymidine phosphorylase, or thymidylate synthase expression are associated with the efficacy of oxaliplatin or 5-FU [ [46], [47], [48]]. Efficacy of irinotecan treatment could be associated with topoisomerase I overexpression [ [49], [50]]. As for toxicity, dihydropyrimidine dehydrogenase deficiency and UGT1A1 polymorphism have been correlated with the onset of severe, unexpected toxicity respectively to fluoropyrimidines and irinotecan [[51], [52], [53]].…”

Feasibility of Administering A Modified Outpatient Regimen of Vincristine, Doxorubicin, Cyclophosphamide Alternating with Ifosfamide, and Etoposide (VAC/IE) For High-Risk Desmoplastic Small Round Blue Cell Tumor and the Role of Tumor Profiling in Selecting Treatments

“…Our options for failure in the future are Irinotecan (TEMIRI) [18] however IHC for TOPO1 was negative suggested limited benefit from Irinotecan [19,20] and MGMT IHC was positive (60%) suggest a potential lack of benefit [21,22], therefore Gemcitabine docetaxel was used [23][24][25] given that his tumor was RRM1 negative [26] and TUBB3 negative IHC [27][28][29] suggesting a potential benefit. The restaging scan however showed progression and the patient received Pazopanib as third line treatment progressing after 2 months.…”