Correlation Among Six Biologic Factors (p53, p21WAF1, MIB-1, EGFR, HER2, and Bcl-2) and Clinical Outcomes After Curative Chemoradiation Therapy in Squamous Cell Cervical Cancer

Yamashita, Hideomi; Murakami, Naoya; Asari, Takao; Okuma, Kae; Ohtomo, Kuni; Nakagawa, Keiichi

doi:10.1016/j.ijrobp.2008.09.005

Cited by 31 publications

(22 citation statements)

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“…EGFR and some of its downstream targets have been studied previously in cervical cancer, but conflicting results about their prognostic significance have been reported (7)(8)(9)(10)(11)(12). Expression of phosphorylated AKT (pAKT) in cervical cancer seemed to be related to local recurrence as a measure for radiation resistance (13), and Faried et al (14) showed that patients with pAKTnegative tumors had a more favorable prognosis.…”

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confidence: 99%

Expression of Epidermal Growth Factor Receptor (EGFR) and Activated EGFR Predict Poor Response to (Chemo)radiation and Survival in Cervical Cancer

Noordhuis

Eijsink

Hoor

et al. 2009

Clinical Cancer Research

102

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Purpose: Activation of the epidermal growth factor receptor (EGFR) signaling pathway has been reported to induce resistance to (chemo)radiation in cancers, such as head and neck cancer, whereas EGFR-targeted agents in combination with (chemo)radiation seem to improve treatment efficacy. The aim of this study was to determine the relation between proteins involved in the EGFR pathway and response to (chemo)radiation and survival in a large, well-documented series of cervical cancer patients. Experimental Design: Pretreatment tissue samples of 375 consecutive International Federation of Gynecologists and Obstetricians stage Ib to IVa cervical cancer patients treated with (chemo)radiation between January 1980 and December 2006 were collected. Clinicopathologic and follow-up data were prospectively obtained during standard treatment and follow-up. Protein expression of EGFR, phosphorylated EGFR (pEGFR), PTEN, phosphorylated AKT, and phosphorylated extracellular signal-regulated kinase (pERK) was assessed by immunohistochemistry on tissue microarrays. Results: EGFR staining was present in 35.3%, pEGFR in 19.7%, PTEN in 34.1%, phosphorylated AKT in 4.1%, and pERK in 29.2% of tumors. pEGFR staining was related to PTEN (P = 0.001) and pERK staining (P = 0.004). EGFR staining was inversely related to PTEN (P = 0.011). In multivariate analysis, membranous staining of EGFR [hazard ratio (HR), 1.84; 95% confidence interval (95% CI), 1.20-2.82; P = 0.005] and cytoplasmic staining of pEGFR (HR, 1.71; 95% CI, 1.11-2.66; P = 0.016) were independent predictors of poor response to (chemo)radiation. Membranous EGFR staining also was an independent prognostic factor for poor disease-specific survival (HR, 1.54; 95% CI, 1.09-2.17; P = 0.014). Conclusions: EGFR and pEGFR immunostainings are frequently observed and independently associated with poor response to therapy and disease-specific survival in cervical cancer patients primarily treated by (chemo)radiation. Our data present the EGFR pathway as a promising therapeutic target in already ongoing clinical trials. (Clin Cancer Res 2009;15(23):7389-97) Standard treatment of locally advanced cervical cancer has changed from radiotherapy alone to concurrent platinum-based chemoradiation. Despite this change, the 5-year survival in patients with locally advanced cervical cancer is still ∼52% (1). Currently, there are no (biological) markers available that accurately predict response to (chemo)radiation.Epidermal growth factor receptor (EGFR) is involved in the ErbB signaling pathway, which is often dysregulated in cancer. Autophosphorylation of EGFR to phosphorylated EGFR (pEGFR) leads to activation of two downstream pathways: the Ras/Raf/ mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase/ERK pathway and the phosphatidylinositol 3-kinase/ AKT pathway. PTEN (phosphatase and tensin homologue deleted on

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confidence: 99%

Expression of Epidermal Growth Factor Receptor (EGFR) and Activated EGFR Predict Poor Response to (Chemo)radiation and Survival in Cervical Cancer

Noordhuis

Eijsink

Hoor

et al. 2009

Clinical Cancer Research

102

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“…Oka et al [2] and Tsuda et al [3] reported a significant correlation of p53 overexpression and poor outcome of cervical cancer. Conversely, in the studies of Lu et al [4] and Yamashita et al [5] p53 overexpression was not correlated with prognosis.…”

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confidence: 80%

“…Niibe et al [6] suggest the possibility that p21 might be a potential suppressor of radiation-induced apoptosis in cervical cancer during radiotherapy. Other studies [5,7] indicated no significant correlation between p21 status and prognosis in cervical cancer treated by radiotherapy.…”

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confidence: 90%

“…Also the studies of Pillai et al [20] and Rajkumar et al [21] found poorer survival in patients with Bcl-2 expression. Other studies have not found the prognostic significance of Bcl-2 expression in cervical carcinoma [5,22,23]. Harima et al [24] have not found a correlation between Bcl-2 expression prior radiotherapy and survival, but Bcl-2 expression after administration of 10.8 Gy was the most important predictor of the treatment outcome.…”

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confidence: 95%

“…Kihana et al [16] found that increased expression of HER-2 correlates with a poorer prognosis in patients with cervical adenocarcinoma. The study of Yamashita et al [5] reported a correlation of borderline significance between HER-2 overexpression and unfavorable outcome in patients with cervical squamous cell carcinoma treated with radiotherapy.…”

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confidence: 99%

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Molecular predictive factors of outcome of radiotherapy in cervical cancer

Petera

Sirák²,

Beránek³

et al. 2011

neo

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Radical radiotherapy with concurrent cisplatin-based chemotherapy is an established treatment for cervical cancer patients with stage FIGO IIB and higher. The tumor control can be achieved in 40-80% of patients, the treatment is associated with the risk of late postiradiation complications in 10 -15% of cases. Detection of the factors predictive for tumor control and late morbidity is a possible direction how to individualize radiotherapy dose and technique. The aim of our review is to summarize results of studies inquiring various molecular markers predicting tumor response to radiotherapy and a risk of late complications.A lot of candidate molecules were evaluated in histochemical studies: membrane receptors (EGFR, HER-2), cell cycle regulators (p53, p21), proliferative markers (Ki-67), hypoxia and angiogenetic factors (HIF, VEGF), HPV status, and others (COX-2), with promising results in some of them (HPV, HIF-1α, Ku80, ATM polymorphism).Microarray studies identified decades of genes with different expression in radiosensitive/radioresistant cervical tumors and sets of genes are able to comletely separate responding and nonresponding tumors, but these sets differ across studies. Further well designed studies will be necessary to achieve results matured for use in clinical practice.

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Change in fibroblast growth factor 2 expression as an early phase radiotherapy‐responsive marker in sequential biopsy samples from patients with cervical cancer during fractionated radiotherapy

Nakawatari¹,

Iwakawa

Ohno³

et al. 2010

Cancer

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BACKGROUND:The authors previously demonstrated that fibroblast growth factor 2 (FGF2) expression levels in tumor cells (FGF2-T) may be an indicator of the efficacy of radiotherapy in patients with cervical cancer (CC). In the current study, this finding was extended in newly enrolled patients and was investigated further in stromal FGF2 (FGF2-S) expression. METHODS: Sixty-nine patients with CC were recruited as a validation set for the immunohistochemical detection of FGF2-T from biopsy samples that were taken before (pretreatment) or 1 week after the initiation of radiotherapy (midtreatment). The authors also investigated the expression of FGF2 in tumor FGF2-S and investigated vascular endothelial growth factor (VEGF), and cluster of differentiation 31 (CD31) (also called platelet endothelial cell adhesion molecule) in these patients and in an additional 35 patients from a previous study. RESULTS: FGF2 expression was detected in tumor cells from all patients and in stromal cells from 87% of patients. FGF2-T was significantly higher in midtreatment samples (P = .0002), and a high ratio of midtreatment/pretreatment FGF2-T was related significantly to a better prognosis (P = .025). Increased VEGF expression after the initiation of radiotherapy was related significantly to positive FGF2-S in pretreatment samples (P = .035); however, it was not related to prognosis or microvessel density detected by CD31 expression. CONCLUSIONS: Radiation causes a response in tumor cells and adjacent normal cells and changes the extracellular matrix environment. In this study, the authors confirmed their previous findings and demonstrated that changes in FGF2-T expression may be used as a marker to monitor the effectiveness of radiotherapy in patients with CC. These findings should improve patient selection for molecular targeted therapies, such as cytokine inhibitors, after standard-of-care treatment. Cancer 2010;116:5082-92.

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Correlation Among Six Biologic Factors (p53, p21WAF1, MIB-1, EGFR, HER2, and Bcl-2) and Clinical Outcomes After Curative Chemoradiation Therapy in Squamous Cell Cervical Cancer

Cited by 31 publications

References 40 publications

Expression of Epidermal Growth Factor Receptor (EGFR) and Activated EGFR Predict Poor Response to (Chemo)radiation and Survival in Cervical Cancer

Expression of Epidermal Growth Factor Receptor (EGFR) and Activated EGFR Predict Poor Response to (Chemo)radiation and Survival in Cervical Cancer

Molecular predictive factors of outcome of radiotherapy in cervical cancer

Change in fibroblast growth factor 2 expression as an early phase radiotherapy‐responsive marker in sequential biopsy samples from patients with cervical cancer during fractionated radiotherapy

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