Prognostic Cell Biological Markers in Cervical Cancer Patients Primarily Treated With (Chemo)radiation: A Systematic Review

doi:10.1016/j.ijrobp.2010.09.043

International Journal of Radiation OncologyBiologyPhysics

Volume 79, Issue 2, 1 February 2011, Pages 325-334

https://doi.org/10.1016/j.ijrobp.2010.09.043 Get rights and content

The aim of this study was to systematically review the prognostic and predictive significance of cell biological markers in cervical cancer patients primarily treated with (chemo)radiation. A PubMed, Embase, and Cochrane literature search was performed. Studies describing a relation between a cell biological marker and survival in ≥50 cervical cancer patients primarily treated with (chemo)radiation were selected. Study quality was assessed, and studies with a quality score of 4 or lower were excluded. Cell biological markers were clustered on biological function, and the prognostic and predictive significance of these markers was described. In total, 42 studies concerning 82 cell biological markers were included in this systematic review. In addition to cyclooxygenase-2 (COX-2) and serum squamous cell carcinoma antigen (SCC-ag) levels, markers associated with poor prognosis were involved in epidermal growth factor receptor (EGFR) signaling (EGFR and C-erbB-2) and in angiogenesis and hypoxia (carbonic anhydrase 9 and hypoxia-inducible factor-1α). Epidermal growth factor receptor and C-erbB-2 were also associated with poor response to (chemo)radiation. In conclusion, EGFR signaling is associated with poor prognosis and response to therapy in cervical cancer patients primarily treated with (chemo)radiation, whereas markers involved in angiogenesis and hypoxia, COX-2, and serum SCC-ag levels are associated with a poor prognosis. Therefore, targeting these pathways in combination with chemoradiation may improve survival in advanced-stage cervical cancer patients.

Introduction

Cervical cancer is one of the most common malignancies among women worldwide (1). Standard treatment of locally advanced cervical cancer is concurrent platinum-based chemoradiation, resulting in a 5-year survival of only 66% (2). Currently, the most important prognostic factors in advanced-stage cervical cancer primarily treated with (chemo)radiation are clinicopathologic factors, including stage and tumor histology (3). Besides clinicopathologic factors, many cell biological markers have been studied in relation to survival and/or response to (chemo)radiation. Especially markers involved in tumorigenesis and tumor progression, such as genes associated with apoptosis, angiogenesis, and cell growth, have been investigated extensively. At the moment the focus of improving survival rates is mainly on targeted therapies in combination with standard chemoradiation (4). Cell biological markers may be helpful to select patients who may benefit from additional treatment and in identifying new potential targets for therapy. Therefore, the aim of this systematic review was to identify prognostic and predictive cell biological markers in cervical cancer patients primarily treated with (chemo)radiation and to review their potential application in treatment of advanced-stage cervical cancer.

Section snippets

Search strategy

A PubMed, Embase, and Cochrane literature search was performed on March 1, 2010, to identify studies on prognostic cell biological markers in cervical cancer. Medical Subject Heading terms used for the primary search were “uterine cervical neoplasm,” “biological markers,” “genes neoplasm,” “neoplasm proteins,” “prognosis,” and “tumor marker.” References from included reviews were also hand-searched to identify missing relevant publications. The total number of identified publications was 1590

Results

In total, 42 studies concerning 82 cell biological markers were selected for this systematic review. In univariate analysis 34 cell biological markers showed a relation with survival, and 27 were independently associated with survival. In the next subsections the prognostic significance of these cell biological markers will be described. Details of all studies that were included in this systematic review are given in Table E1.

Discussion

This systematic review summarizes the prognostic and predictive value of cell biological markers in cervical cancer patients primarily treated with (chemo)radiation. Clusters with the strongest prognostic factors consist of markers involved in angiogenesis and hypoxia and markers involved in the EGFR pathway. Furthermore, COX-2 immunostaining and serum SCC-ag levels seem to be prognostic markers. Besides the prognostic significance, associations with response to (chemo)radiation were also

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Cited by (74)

Higher Anti-Tumor Efficacy of the Dual HER3-EGFR Antibody MEHD7945a Combined with Ionizing Irradiation in Cervical Cancer Cells
2020, International Journal of Radiation Oncology Biology Physics
The outcome of locally advanced cervical cancer (LACC) is dismal. Biomarkers are needed to individualize treatments and to improve patient outcomes. Here, we investigated whether coexpression of epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3) could be an outcome prognostic biomarker, and whether targeting both EGFR and HER3 with a dual antibody (MEHD7945A) enhanced ionizing radiation (IR) efficacy.
Expression of EGFR and HER3 was evaluated by immunohistochemistry in cancer biopsies (n = 72 patients with LACC). The antitumor effects of the MEHD7945A and IR combotherapy were assessed in 2 EGFR- and HER3-positive cervical cancer cell lines (A431 and CaSki) and in A431 cell xenografts. The mechanisms involved in tumor cell radiosensitization were also studied. The interaction of MEHD7945A, IR, and cisplatin was evaluated using dose–response matrix data.
EGFR and HER3 were coexpressed in only in 7 of the 22 biopsies of FIGO IVB cervix cancer. The median overall survival was 14.6 months and 23.1 months in patients with FIGO IVB tumors that coexpressed or did not coexpress EGFR and HER3, respectively. In mice xenografted with A431 (squamous cell carcinoma) cells, MEHD7945A significantly increased IR response by reducing tumor growth and increasing cleaved caspase-3 expression. In A431 and CaSki cells, the combotherapy increased DNA damage and cell death, particularly immunogenic cell death, and decreased survival by inhibiting the MAPK and AKT pathways. An additive effect was observed when IR, MEHD7945A, and cisplatin were combined.
Targeting EGFR and HER3 with a specific dual antibody enhanced IR efficacy. These preliminary results and the prognostic value of EGFR and HER3 coexpression should be confirmed in a larger sample.
Change in Patterns of Failure After Image-Guided Brachytherapy for Cervical Cancer: Analysis From the RetroEMBRACE Study
2019, International Journal of Radiation Oncology Biology Physics
Citation Excerpt :
Reliance on conventional prognostic factors such as FIGO stage and pelvic nodal status to select patients for prophylactic PAN RT or adjuvant systemic treatment may therefore be insufficient. In recent years, there have been reports of promising imaging, immunohistochemical, and serum biomarkers for early prediction of treatment response for cervical cancer.14,15 For example, positron emission tomography–CT,16 dynamic contrast-enhanced MRI,17 and diffusion-weighted MRI18 before or during chemo-RT have all been reported to correlate with local control and survival.
Image guided adaptive brachytherapy (IGABT) for cervical cancer improves pelvic control and survival across all stages. Improvement in pelvic control is larger in advanced stages, but improvement in survival is similar across stages. This paper analyzes the patterns of failure in the RetroEMBRACE cohort to investigate this discrepancy.
731 patients from 12 institutions treated with chemoradiation therapy and magnetic resonance imaging or computed tomography–based IGABT were evaluated. The pattern of failure at time of first relapse was analyzed.
Three hundred twenty-five failures (single and synchronous) occurred in 222 of 731 patients (30%). Among the 325 failures, 9% were local and 6% regional. Pelvic (local or regional) failures made up 13%, paraaortic node (PAN) 9%, systemic 21%, and distant (systemic + PAN) 24%. Of the 222 patients with treatment failure, 21% had pelvic failure alone, 57% had distant failure alone, and 23% had both pelvic and distant failure. Of all failures that occurred, 40% to 50% occurred in the first year, with a further 20% to 30% occurring in the second year. Although local, regional, and PAN failure tended to plateau after year 3, systemic failure continued to occur up to year 10.
Implementation of IGABT has changed the patterns of relapse after chemoradiation therapy for cervical cancer. The predominant failure after IGABT is systemic, whereas the predominant failure with conventional brachytherapy is pelvic. Effective treatments to eradicate micrometastases in PAN and distant organs are needed in addition to IGABT and chemoradiation therapy to maximize local, regional, PAN, and systemic control and improve survival.
The association between serum squamous cell carcinoma antigen and recurrence and survival of patients with cervical squamous cell carcinoma: A systematic review and meta-analysis
2018, Gynecologic Oncology
The aim of this systematic review and meta-analysis was to pool association effects of serum squamous cell carcinoma antigen (SCC-Ag) on recurrence and mortality in mainly squamous cell cervical cancer patients.
MEDLINE and Scopus databases were searched up to June 29, 2016. Studies assessing effects of SCC-Ag on recurrence and death in cervical cancer patients were included. Data extraction was independently performed by two reviewers. A meta-analysis was applied for pooling the effects (i.e., risk ratio (RR), hazard ratio (HR), and unstandardized mean difference (USMD)) of SCC-Ag measured before and after treatment on recurrence and death.
A total of 61 studies were included. For pretreatment SCC-Ag and recurrence, the pooled RR, HR, and USMD for high versus low serum SCC-Ag were 2.44(95% CI: 1.91, 3.13), 2.23(95% CI: 2.03, 2.45), −7.7(95% CI: -31.7, 16.4), respectively. The corresponding effects for the posttreatment period were 3.91(95% CI: 2.96, 5.16), 3.14(95% CI: 1.29, 7.65), and 3.2(95% CI: -10.6, 17.0), respectively. In addition, patients with high level of pretreatment serum SCC-Ag were also at a higher risk for death than patients with low serum SCC-Ag with a pooled RR of 3.66(95% CI: 2.24, 5.98), pooled HR of 2.50(95% CI: 1.85, 3.37), and pooled USMD of 7.10(95% CI: 4.26, 9.94). The posttreatment serum SCC-Ag effects also reflected a similar trend.
The serum SCC-Ag was consistently associated with recurrence and mortality of newly diagnosed cervical cancer. This marker may be useful in monitoring disease progression in cervical cancer patients.
Prospero registration number is: CRD42016044024.
Glut-1 expression in small cervical biopsies is prognostic in cervical cancers treated with chemoradiation
2017, Clinical and Translational Radiation Oncology
Citation Excerpt :
However, post-therapy FDG-PET is unable to inform the design of investigations or therapeutic interventions before or during treatment. There have been numerous putative pathobiological prognostic factors studied, including factors involving the angiogenesis, hypoxia, epidermal growth factor receptor and COX-2 pathways [8]. We set out to assess the prognostic significance of biomarkers for metabolism (glucose transporter-1 [Glut-1]), proliferation (Ki-67) and hypoxia (hypoxia-inducible factor-1α [Hif-1α] and carbonic anhydrase IX [CA-9]) in cervical cancer patients treated with chemoradiation.
Chemoradiation (CRT) is standard therapy for locally advanced cervical cancer (LACC). However, there is a lack of biomarkers to identify patients at high relapse-risk. We examine metabolic (glucose transporter-1 [Glut-1]), hypoxic (hypoxia inducible factor [HIF-1α]; carbonic anhydrase [CA-9]) and proliferative (Ki-67) markers for prognostic utility in LACC.
60 LACC patients treated with CRT had pre-treatment biopsies. Immunohistochemistry was performed for Glut-1, HIF-1a and CA-9, to generate a histoscore from intensity and percentage staining; and Ki-67 scored by percentage of positive cells. For each biomarker, treatment response and survival was compared between low and high-staining groups by logrank testing and multivariate analyses.
High Glut-1 expression was associated with inferior progression-free survival (PFS), (hazard ratio [HR] 2.8, p = 0.049) and overall survival (OS), (HR 5.0, p = 0.011) on multifactor analysis adjusting for stage, node positivity, tumour volume and uterine corpus invasion. High Glut-1 correlated with increased risk of distant failure (HR 14.6, p = 0.001) but not local failure. Low Glut-1 was associated with higher complete metabolic response rate on post-therapy positron emission tomography scan (odds ratio 3.4, p = 0.048). Ki-67 was significantly associated with PFS only (HR 1.19 per 10 units increase, p = 0.033). Biomarkers for hypoxia were not associated with outcome.
High Glut-1 in LACC is associated with poor outcome post CRT. If prospectively validated, Glut-1 may help select patients for more intensive treatment regimens.
Cyclooxygenase-2 – characteristics, functions and possible use as a biomarker in human and animal oncology – a review
2024, Journal of Elementology
Identification of Potential Diagnostic and Prognostic Biomarkers for Cervical Cancer
2023, Research Square

View all citing articles on Scopus

: Conflict of interest: none.

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Critical ReviewPrognostic Cell Biological Markers in Cervical Cancer Patients Primarily Treated With (Chemo)radiation: A Systematic Review

Introduction

Section snippets

Search strategy

Results

Discussion

Gynecol Oncol

Semin Radiat Oncol

Crit Rev Oncol Hematol

Int J Radiat Oncol Biol Phys

Atheroscler Suppl

Int J Radiat Oncol Biol Phys

Radiother Oncol

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Gynecol Oncol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Crit Rev Oncol Hematol

Int J Radiat Oncol Biol Phys

Int J Radiat Oncol Biol Phys

Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: Individual patient data meta-analysis

Cochrane Database Syst Rev

Expression of epidermal growth factor receptor (EGFR) and activated EGFR predict poor response to (chemo)radiation and survival in cervical cancer

Clin Cancer Res

REporting recommendations for tumour MARKer prognostic studies (REMARK)

Br J Cancer

Tumor marker utility grading system: A framework to evaluate clinical utility of tumor markers

J Natl Cancer Inst

Hypoxia: A key regulator of angiogenesis in cancer

Cancer Metastasis Rev

Hypoxia, angiogenesis and cancer therapy: To breathe or not to breathe?

Cell Cycle

Overexpression of hypoxia-inducible factor 1alpha indicates diminished response to radiotherapy and unfavorable prognosis in patients receiving radical radiotherapy for cervical cancer

Clin Cancer Res

Hypoxia-inducible factor 1alpha expression as an intrinsic marker of hypoxia: Correlation with tumor oxygen, pimonidazole measurements, and outcome in locally advanced carcinoma of the cervix

Clin Cancer Res

Prognostic significance of HIF-2alpha expression on tumor infiltrating macrophages in patients with uterine cervical cancer undergoing radiotherapy

J Med Invest

Tumor-associated carbonic anhydrases are linked to metastases in primary cervical cancer

J Cancer Res Clin Oncol

Critical Review
Prognostic Cell Biological Markers in Cervical Cancer Patients Primarily Treated With (Chemo)radiation: A Systematic Review