Glutathione S-transferase Pi expression predicts response to adjuvant chemotherapy for stage C colon cancer: a matched historical control study

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Abstract

Background

This study examined the association between overall survival and Glutathione S-transferase Pi (GST Pi) expression and genetic polymorphism in stage C colon cancer patients after resection alone versus resection plus 5-fluourouracil-based adjuvant chemotherapy.

Methods

Patients were drawn from a hospital registry of colorectal cancer resections. Those receiving chemotherapy after it was introduced in 1992 were compared with an age and sex matched control group from the preceding period. GST Pi expression was assessed by immunohistochemistry. Overall survival was analysed by the Kaplan-Meier method and Cox regression.

Results

From an initial 104 patients treated with chemotherapy and 104 matched controls, 26 were excluded because of non-informative immunohistochemistry, leaving 95 in the treated group and 87 controls. Survival did not differ significantly among patients with low GST Pi who did or did not receive chemotherapy and those with high GST Pi who received chemotherapy (lowest pair-wise p = 0.11) whereas patients with high GST Pi who did not receive chemotherapy experienced markedly poorer survival than any of the other three groups (all pair-wise p <0.01). This result was unaffected by GST Pi genotype.

Conclusion

Stage C colon cancer patients with low GST Pi did not benefit from 5-fluourouracil-based adjuvant chemotherapy whereas those with high GST Pi did.

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Most cited references 40

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Reactive oxygen species in cancer cells: live by the sword, die by the sword.

Paul T. Schumacker (2006)

Reactive oxygen species and tumor biology are intertwined in a complex web, making it difficult to understand which came first, whether oxidants are required for tumor cell growth, and whether oxidant stress can be exploited therapeutically. Evidence suggests that transformed cells use ROS signals to drive proliferation and other events required for tumor progression. This confers a state of increased basal oxidative stress, making them vulnerable to chemotherapeutic agents that further augment ROS generation or that weaken antioxidant defenses of the cell. In this respect, it appears that tumor cells may die by the same systems they require.

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Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial.

Catherine Daly, M Seymour, Peter Selby … (2008)

Candidate predictive biomarkers for irinotecan and oxaliplatin were assessed in 1,628 patients in Fluorouracil, Oxaliplatin, CPT-11: Use and Sequencing (FOCUS), a large randomized trial of fluorouracil alone compared with fluorouracil and irinotecan and compared with fluorouracil and oxaliplatin in advanced colorectal cancer. The candidate biomarkers were: tumor immunohistochemistry for MLH1/MSH2, p53, topoisomerase-1 (Topo1), excision repair cross-complementing gene 1 (ERCC1), O-6-methylguanine-DNA-methyltranserase (MGMT), and cyclooxygenase 2 (COX2); germline DNA polymorphisms in GSTP1, ABCB1, XRCC1, ERCC2, and UGT1A1. These were screened in more than 750 patients for interaction with benefit from irinotecan or oxaliplatin; two markers (Topo1 and MLH1/MSH2) met criteria to be taken forward for analysis in the full population. Primary end points were progression-free survival (PFS) and overall survival. One thousand three hundred thirteen patients (81%) were assessable for Topo1 immunohistochemistry (low, 50% tumor nuclei). In patients with low Topo1, PFS was not improved by the addition of either irinotecan (hazard ratio [HR], 0.98; 95% CI, 0.78 to 1.22) or oxaliplatin (HR, 0.85; 95% CI, 0.68 to 1.07); conversely, patients with moderate/high Topo1 benefited from the addition of either drug (HR, 0.48 to 0.70 in all categories; interaction P = .005; overall, P = .001 for irinotecan; P = .05 for oxaliplatin). High Topo1 was associated with a major overall survival benefit with first-line combination chemotherapy (HR, 0.60; median benefit, 5.3 months); patients with moderate or low Topo1 did not benefit (HR, 0.92 and 1.09, respectively; interaction P = .005). MLH1/MSH2 did not show significant interaction with treatment, although the low rate of loss (4.4%) limits the power of the study for this biomarker. Topo1 immunohistochemistry identified subpopulations that did or did not benefit from irinotecan, and possibly also from oxaliplatin. If verified independently, this information will contribute to the individualization of treatment for colorectal cancer.

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Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy.

Annamaria Ruzzo, R Bisonni, Eliana Rulli … (2007)

The objective is to investigate whether polymorphisms with putative influence on fluorouracil/oxaliplatin activity are associated with clinical outcomes of patients with advanced colorectal cancer treated with first-line oxaliplatin, folinic acid, and fluorouracil palliative chemotherapy. Consecutive patients were prospectively enrolled onto medical oncology units in Central Italy. Patients were required to have cytologically/histologically confirmed metastatic disease with at least one measurable lesion. Peripheral blood samples were used for genotyping 12 polymorphisms in thymidylate synthase, methylenetetrahydrofolate reductase, xeroderma pigmentosum group D (XPD), excision repair cross complementing group 1 (ERCC1), x-ray cross complementing group 1, x-ray cross complementing protein 3, glutathione S-transferases (GSTs) genes. The primary end point of the study was to investigate the association between genotypes and progression-free survival (PFS). In 166 patients, ERCC1-118 T/T, XPD-751 A/C, and XPD-751 C/C genotypes were independently associated with adverse PFS. The presence of two risk genotypes (ERCC1-118 T/T combined with either XPD-751 A/C or XPD-751 C/C) occurred in 50 patients (31%). This profiling showed an independent role for unfavorable PFS with a hazard ratio of 2.84% and 95% CI of 1.47 to 5.45 (P = .002). Neurotoxicity was significantly associated with GSTP1-105 A/G. Carriers of the GSTP1-105 G/G genotype were more prone to suffer from grade 3 neurotoxicity than carriers of GSTP1-105 A/G and GSTP1-105 A/A genotypes. A pharmacogenetic approach may be an innovative strategy for optimizing palliative chemotherapy in patients with advanced colorectal cancer. These findings deserve confirmation in additional prospective studies.

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Author and article information

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central

ISSN (Electronic): 1471-2407

Publication date Collection: 2012

Publication date (Electronic): 28 May 2012

Volume: 12

Page: 196

Affiliations

[1 ]Cancer Pharmacology Unit, ANZAC Research Institute, Concord Hospital, The University of Sydney, Sydney, NSW, 2139, Australia

[2 ]Department of Anatomical Pathology, Concord Hospital and Discipline of Pathology, The University of Sydney, Sydney, NSW, 2139, Australia

[3 ]Department of Anatomical Pathology, Concord Hospital, Sydney, NSW, 2139, Australia

[4 ]Cancer Research Program, Garvan Institute of Medical Research and St Vincent’s Clinical School, University of New South Wales, Sydney, NSW, 2052, Australia

[5 ]Australian Proteome Analysis Facility and Department of Chemistry and Biomolecular Sciences, Macquarie University, Sydney, NSW, 2109, Australia

[6 ]Department of Colorectal Surgery, Concord Hospital and Discipline of Surgery, The University of Sydney, Sydney, NSW, 2139, Australia

[7 ]Department of Medicine, Concord Hospital and Discipline of Medicine, The University of Sydney, Sydney, NSW, 2139, Australia

Article

Publisher ID: 1471-2407-12-196

DOI: 10.1186/1471-2407-12-196

PMC ID: 3420323

PubMed ID: 22639861

SO-VID: f8bbce78-1e5e-41bc-9135-a292c4b02b43

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Glutathione S-transferase Pi expression predicts response to adjuvant chemotherapy for stage C colon cancer: a matched historical control study

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Abstract

Background

Methods

Results

Conclusion

Related collections

Karger: Oncology

Most cited references 40

Reactive oxygen species in cancer cells: live by the sword, die by the sword.

Predictive biomarkers of chemotherapy efficacy in colorectal cancer: results from the UK MRC FOCUS trial.

Pharmacogenetic profiling in patients with advanced colorectal cancer treated with first-line FOLFOX-4 chemotherapy.

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