Response to mitoxantrone in advanced breast cancer: correlation with expression of c-erbB-2 protein and glutathione S-transferases

Wright, Christopher; Cairns, John; Cantwell, BrianM.J.; Cattan, A; Hall, Amy B.; Harris, Adrian L.; Horne, C. H. W.

doi:10.1038/bjc.1992.54

Cited by 60 publications

(22 citation statements)

References 30 publications

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“…[32][33][34][35] Results from a study by Muss et al 32 suggest that patients with node positive early breast cancer who overexpress HER-2 may benefit from higher doses of adjuvant chemotherapy particularly when using doxorubicin. Results of this retrospective study indicate that increased dosages of the drugs used in HDCT do not significantly improve response and survival in patients with MBC who overexpress HER-2.…”

Section: Discussionmentioning

confidence: 99%

Expression of C-erbB-2/HER-2 in patients with metastatic breast cancer undergoing high-dose chemotherapy and autologous blood stem cell support

Bewick

Chadderton

Conlon

et al. 1999

Bone Marrow Transplant

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Summary:C-erbB-2/HER-2 (designated HER-2) is overexpressed in both primary and metastatic breast cancer and predicts poor prognosis. We investigated the expression of HER-2 in patients with metastatic breast cancer undergoing high-dose chemotherapy (HDCT) with autologous blood stem cell (ABSC) support and correlated the presence (positive) or absence (negative) of HER-2 overexpression in these patients with response to treatment, progression-free survival (PFS) and overall survival (OS). The level of HER-2 expression was analyzed in 57 patients with metastatic breast cancer undergoing HDCT with ABSC support. Plasma from peripheral blood was taken at three different time points during the course of treatment and was analyzed using an enzyme immunoassay (EIA) to detect circulating levels of the extracellular portion of HER-2. HER-2 levels were elevated (Ͼ0.2 U/mg protein) in 27/57 (47.4%) patients at one or more time points during treatment. The level of HER-2 varied during the course of treatment. Following induction chemotherapy (ICT), five patients who were negative initially, showed overexpression of HER-2. Three patients overexpressed HER-2 only after HDCT/ABSC. Response to treatment was similar in patients independent of plasma HER-2 levels. Overexpression of HER-2 was associated with a significantly shorter PFS (P = 0.004, log rank) and OS (P = 0.003, log rank) after HDCT/ABSC. HER-2 overexpression, patient age, estrogen receptor status, progesterone receptor status, and previous hormone treatment were assessed by univariate and multivariate analysis. Univariate analysis determined that only HER-2 overexpression correlated significantly with decreases in progression free survival (P = 0.005, Cox regression). Decreased overall survival correlated significantly with HER-2 overexpression (P = 0.004) and decreased expression of both estrogen receptor (P = 0.032) and progesterone receptor (P = 0.039). In multivariate analysis of these variables, only HER-2 expression levels proved to be of independent statistical significance in predicting outcome for both PFS (P = 0.007) and OS Correspondence: Dr S Glück, Depts Oncology, Medicine, and Pharmacology and Therapeutics, Faculty of Medicine, University of Calgary, Tom Baker Cancer Centre, 1331, 29th Street NW, Calgary, Alberta, Canada Received 18 August 1998; accepted 5 May 1999 (P = 0.002). These results suggest that overexpression of HER-2, measured by EIA in plasma may predict a shorter PFS and OS in patients with metastatic breast cancer treated with HDCT and ABSC support.

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Section: Discussionmentioning

confidence: 99%

Expression of C-erbB-2/HER-2 in patients with metastatic breast cancer undergoing high-dose chemotherapy and autologous blood stem cell support

Bewick

Chadderton

Conlon

et al. 1999

Bone Marrow Transplant

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“…Results from the Intergroup Study 0011 (Allred et al, 1992) and the International (Ludwig) Breast Cancer Study Group (Gusterson et al, 1992) led investigators to conclude that node-negative breast cancer patients whose tumors contain HER-2/neu overexpression have a less favorable prognosis due to a lack of response to adjuvant cyclophosphamide (CPA), methotrexate (MTX), and 5-¯uorouracil (5-FU)-based chemotherapy (CMF). In addition, in a study of 68 patients with advanced breast cancer, Wright and colleagues reported a shortened survival for patients with HER-2/neu overexpression who were treated with mitoxantrone despite the fact that response rates between HER-2/neu-overexpressing and non-overexpressing tumors were similar, 50% vs 58%, respectively (Wright et al, 1992). A study of HER-2/neu overexpression in epithelial ovarian cancer demonstrated that patients whose tumors had the alteration were more likely to fail chemotherapy with CPA and carboplatin (CBDCA) (Felip et al, 1995).…”

Section: Introductionmentioning

confidence: 99%

The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells

et al. 1997

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Recent studies indicate that oncogenes may be involved in determining the sensitivity of human cancers to chemotherapeutic agents. To de®ne the eect of HER-2/neu oncogene overexpression on sensitivity to chemotherapeutic drugs, a full-length, human HER-2/neu cDNA was introduced into human breast and ovarian cancer cells. In vitro dose-response curves following exposure to 7 dierent classes of chemotherapeutic agents were compared for HER-2-and control-transfected cells. Chemosensitivity was also tested in vivo for HER-2-and control-transfected human breast and ovarian cancer xenografts in athymic mice. These studies indicate that HER-2/neu overexpression was not sucient to induce intrinsic, pleomorphic drug resistance. Furthermore, changes in chemosensitivity pro®les resulting from HER-2/neu transfection observed in vitro were cell line speci®c. In vivo, HER-2/neu-overexpressing breast and ovarian cancer xenografts were responsive to dierent classes of chemotherapeutic drugs compared to control-treated xenografts with no statistically signi®cant dierences between HER-2/neu-overexpressing and nonoverexpressing xenografts. We found no instance in which HER-2/neu-overexpressing xenografts were rendered more sensitive to chemotherapeutic drugs in vivo. HER-2/neu-overexpressing xenografts consistently exhibited more rapid regrowth than control xenografts following initial response to chemotherapy suggesting that a high rate of tumor cell proliferation rather than intrinsic drug resistance may be responsible for the adverse prognosis associated with HER-2/neu overexpression in human cancers.

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“…8 No relationship was found for GST pi, alpha and mu expression with response to mitoxantrone chemotherapy in advanced breast cancer. 9 Cytochrome P450 (CYPs) enzymes are a multigene family of phase I detoxification enzymes. They are involved in the metabolism of several promutagens and procarcinogens including polycyclic aromatic hydrocarbons and aryl amines to mutagenic or carcinogenic metabolites.…”

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confidence: 99%

Expression of xenobiotic and steroid hormone metabolizing enzymes in human breast carcinomas

Haas

Pierl

Harth

et al. 2006

Intl Journal of Cancer

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The potential to metabolize endogenous and exogenous substances may influence breast cancer development and tumor growth. Therefore, the authors investigated the protein expression of Glutathione S-transferase (GST) isoforms and cytochrome P450 (CYP) known to be involved in the metabolism of steroid hormones and endogenous as well as exogenous carcinogens in breast cancer tissue to obtain new information on their possible role in tumor progression. Expression of GST pi, mu, alpha and CYP1A1/2, 1A2, 3A4/5, 1B1, 2E1 was assessed by immunohistochemistry for primary breast carcinomas of 393 patients from the German GENICA breast cancer collection. The percentages of positive tumors were 50.1 and 44.5% for GST mu and CYP2E1, and ranged from 13 to 24.7% for CYP1A2, GST pi, CYP1A1/2, CYP3A4/5, CYP1B1. GST alpha was expressed in 1.8% of tumors. The authors observed the following associations between strong protein expression and histopathological characteristics: GST expression was associated with a better tumor differentiation (GST mu, p 5 0.018) and with reduced lymph node metastasis (GST pi, p 5 0.02). In addition, GST mu expression was associated with a positive estrogen receptor and progesterone receptor status (p < 0.001). CYP3A4/5 expression was associated with a positive nodal status (p 5 0.018). Expression of CYP1B1 was associated with poor tumor differentiation (p 5 0.049). Our results demonstrate that the majority of breast carcinomas expressed xenobiotic and drug metabolizing enzymes. They particularly suggest that GST mu and pi expression may indicate a better prognosis and that strong CYP3A4/5 and CYP1B1 expression may be key features of nonfavourable prognosis. ' 2006 Wiley-Liss, Inc.Key words: breast carcinoma; GST; CYP; immunohistochemistry; estrogen receptor; progesterone receptor The influence of exogenous and endogenous factors on tumor growth partly depends on the individual potential to metabolize these substances. Phase I and phase II enzymes are key players in the metabolism of a huge number of exogenous and endogenous compounds including steroid hormones. Usually, phase I and phase II are detoxification processes, but this metabolism can also lead to highly reactive electrophiles that can bind to macromolecules, e.g., proteins and DNA. Moreover, these enzymes are highly polymorphic, giving rise to variations in enzymatic activity.1 This may influence predisposition to cancer as well as tumor development and progression.2 Therefore, these enzymes are candidates for the investigation of a potential role in breast cancer.Glutathione S-transferases (GSTs) are phase II metabolizing isoenzymes. They facilitate clearance of endogenous hydrophobic compounds such as hormones, steroids, haem, bilirubin and bile acids. Furthermore, they are essential for metabolism of environmental carcinogens, drugs and pesticides by catalyzing the conjunction of reactive chemical intermediates to soluble glutathione conjugates.3 Seven classes of cytosolic GSTs are recognized in mammalian tissues (alpha, mu, pi, sigma, om...

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Response to mitoxantrone in advanced breast cancer: correlation with expression of c-erbB-2 protein and glutathione S-transferases

Cited by 60 publications

References 30 publications

Expression of C-erbB-2/HER-2 in patients with metastatic breast cancer undergoing high-dose chemotherapy and autologous blood stem cell support

Expression of C-erbB-2/HER-2 in patients with metastatic breast cancer undergoing high-dose chemotherapy and autologous blood stem cell support

The effect of HER-2/neu overexpression on chemotherapeutic drug sensitivity in human breast and ovarian cancer cells

Expression of xenobiotic and steroid hormone metabolizing enzymes in human breast carcinomas

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