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