Elsevier

Gynecologic Oncology

Volume 104, Issue 2, February 2007, Pages 326-330
Gynecologic Oncology

Expression of class III β tubulin in cervical cancer patients administered preoperative radiochemotherapy: Correlation with response to treatment and clinical outcome

https://doi.org/10.1016/j.ygyno.2006.08.046Get rights and content

Abstract

Objectives.

Alterations of the β subunit of tubulin have been reported to be predictive of resistance to radiation and antitubulin agents in several solid tumors. The aim of the study was to investigate the clinical role of β III tubulin expression as prognostic factor for survival and as a predictive parameter of response to preoperative radiochemotherapy in a single institutional series of locally advanced cervical cancer (LACC) patients.

Methods.

The study included 98 LACC patients admitted to the Gynecologic Oncology Unit, Catholic University of Rome and Campobasso between January 1998 and January 2005. Immunohistochemistry was performed by using the polyclonal rabbit anti-β III tubulin antibody (Covance, Princeton, NJ, USA). The value of 10% immunostained tumor cells was arbitrarily chosen as cut-off value to distinguish cases with high versus low β III tubulin content.

Results.

In the whole series, β III tubulin immunoreaction was detectable in 66/98 cases (67.3%), and the percentage of positively stained cells ranged from 0 to 100% (median = 10%). The percentages of cases with high β III tubulin expression were shown not to be differently distributed according to clinico-pathological characteristics. There was no statistically significant difference in the distribution of cases with high β III tubulin expression according to clinical and pathological response to treatment. During the follow-up period, recurrence and death of disease occurred in 15 and 13 cases, respectively. There was no difference in disease-free and overall survival in cases with high versus low β III tubulin expression.

Conclusions.

The assessment of class III β tubulin status seems of little usefulness in order to identify LACC patients with poor chance of response to concomitant radiochemotherapy and unfavorable prognosis.

Introduction

In the last few years, the vast majority of clinical trials have demonstrated an advantage in terms of overall survival for locally advanced cervical cancer (LACC) patients treated with concomitant radiation and cisplatin-based chemotherapy [1], [2], [3], [4], [5], [6], which currently represents the gold standard in the treatment of these patients.

In addition, the use of a three-modality approach including radiochemotherapy followed by surgery [7], [8], [9] has been investigated on the basis of the potential advantages related to surgical removal of radio- and chemoresistant tumor foci, the possibility to obtain the pathological assessment of response and the potential favorable psychological impact of “feeling free of disease”. Indeed, we and other authors have recently reported that radiochemotherapy followed by radical surgery yields a very high rate of pathological complete response to treatment and favorable clinical outcome in LACC patients [9], [10].

Besides clinico-pathological parameters, such as stage and tumor volume, very few data about the involvement of biological factors in predicting radiochemotherapy response in cervical cancer have been reported until now [11], [12].

Among the biomolecules determining resistance to radiochemotherapy, such as apoptosis related factors, and peptidic growth factors [13], [14], [15], much attention has been also focused on the role of organelles or molecules involved in mitosis control and cell cycle checkpoints [16], [17]: more recently, alterations of the β subunit of tubulin, which dimerizes with α-tubulin in the microtubule assembly, have been reported to be predictive of radioresistance in rectal tumors [18]. In addition, point mutations of tubulin genes as well as overexpression of selective β tubulin isotypes have been associated with resistance to antitubulin agents, such as taxanes and vinorelbine, and poor overall survival in ovarian as well as other solid tumors [19], [21], [22], [23].

The biochemical basis linking β III tubulin overexpression to a more aggressive clinical behavior is still far from being clarified: an appealing working hypothesis comes from the observations that the promoter of β tubulin gene contains transcription factors involved in the hypoxic response [24], [25]. It is conceivable that, in case of tumor hypoxia, often related to anemia, overexpression of β III tubulin may occur, thus representing a marker of the so called “hypoxia lethal phenotype” characterized by the transcription of genes relevant for tumor cell survival, and neoangiogenesis [26], as well as resistance to chemo- and radiotherapy and poor clinical outcome [27], [28]. In this context, it is worth noting that anemia has been recently shown to be strongly associated with poor response to treatment and unfavorable survival in LACC patients administered preoperative chemoradiation [29].

To our knowledge, no data have been reported until now on the clinical role of the expression of class III β tubulin in predicting clinical outcome in cervical carcinoma.

The aim of the study was to investigate the clinical role of β III tubulin as predictor of survival and response to preoperative radiochemotherapy in a single institutional series of locally advanced cervical cancer patients.

Section snippets

Patients

The study included 98 cervical cancer patients admitted to the Gynecologic Oncology Unit, Catholic University of Rome and Campobasso between January 1998 and January 2005. Staging was performed according to FIGO classification. Pretreatment evaluation consisted of a history and physical examination, biopsy and gynecologic examination under general anesthesia, abdominal pelvic MRI, pelvic ultrasonography and chest X-ray. Cystoscopy and sigmoidoscopy were performed when indicated. The medical

Results

The study included 98 stage IB2–IVA cervical cancer patients: median age was 52.5 years (range: 25–80). Six patients were stage IB2, 71 patients were stage IIB, while advanced stage of disease was observed in 21 patients. Most tumors were squamous cell carcinoma (n = 94), 2 were adenocarcinoma and 2 were adenosquamous. The other clinico-pathological characteristics are summarized in Table 1.

In the whole series, β III tubulin immunoreaction was detectable in 66/98 cases (67.3%), and the percentage

Discussion

This is the first study analyzing the association between the expression of β III tubulin protein and clinical outcome in LACC patients submitted to preoperative radiochemotherapy.

The association between β III tubulin overexpression and poor prognosis has been reported in several human tumors including lung, breast and ovarian cancer [20], [21], [22], [23] and often related to poor chance of response to antitubulin agents [22], [23].

Moreover, the biological rationale linking β III tubulin

Acknowledgments

This work was financially supported by grants from Associazione Italiana per la Ricerca sul Cancro (A.I.R.C), and Ministero dell'Istruzione, Universita', e Ricerca (M.I.U.R. Project 4210011).

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