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[Cancer Research 62, 6414-6417, November 15, 2002]
© 2002 American Association for Cancer Research

Advances in Brief

Cyclin B1 Overexpression and Resistance to Radiotherapy in Head and Neck Squamous Cell Carcinoma1

Khaled A. Hassan, K. Kian Ang2, Adel K. El-Naggar, Michael D. Story, Janet I. Lee, Diane Liu, Waun K. Hong and Li Mao

Departments of Thoracic/Head and Neck Medical Oncology [K. A. H., J. I. L, W. K. H., L. M.], Pathology [A. K. E-N.], Biostatistics [D. L.], and Radiation Oncology [K. K. A., M. D. S.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030


   ABSTRACT
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 ABSTRACT
Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 
Radiotherapy (RT) and surgery are the cornerstones in treating head and neck squamous cellcarcinoma (HNSCC). RT is effective in the initial treatment of early to intermediate stage HNSCC but less effective for locally advanced disease, some cases of which are best managed using the combination of surgery and RT. Although various clinical/pathologic parameters have been used to classify patients according to their likelihood of responding to RT, they have generally low predictive value. We have shown previously that cyclin B1 is associated with a poor clinical outcome in HNSCC patients. In this study, we investigate the potential role of cyclin B1 in assessing RT response in patients with HNSCC. Tumor specimens obtained from 80 patients participated in a prospective Phase III clinical trial addressing the dose and fractionation regimen of postoperative RT were analyzed for cyclin B1 expression by immunohistochemistry. Patients were classified according to currently accepted clinical/pathologic parameters into three risk groups, i.e., low, intermediate, and high risk, and received surgery alone, surgery plus intermediate-dose RT, and surgery plus high-dose RT, respectively. The median follow-up duration was 4.9 years. Cyclin B1 overexpression was noted in 38 of the 80 (47%) HNSCC tumors. Interestingly, 11 of the 38 patients (29%) with cyclin B1-overexpressing tumors experienced local or nodal recurrence compared with only 3 of 42 patients (7%) having carcinomas with no or weak cyclin B1 expression (P = 0.01). When locoregional control was used as the end point for the high-risk group, patients whose tumors showed cyclin B1 overexpression had a statistically significant higher tumor recurrence and metastasis compared with patients whose tumors showed no cyclin B1 overexpression (P = 0.01). Our results indicate that tumors overexpressing cyclin B1 may be resistant to RT, and cyclin B1 may be an indicator of the risk of locoregional recurrence and metastasis in patients having HNSCC receiving RT.


   Introduction
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 ABSTRACT
 Introduction
Materials and Methods
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 Discussion
 REFERENCES
 
RT3 or surgery alone remains the standard treatment modality for patients having early to intermediate HNSCC, whereas RT in combination with surgery or chemotherapy is used for those with locally advanced tumors (1) . RT is generally preferred because of better organ preservation (2) , but the relapse occurs in those with more advanced tumor (3) , which indicates the presence of residual tumor cells after treatment (4) . Thus, identification of patients with tumor cells resistant to RT may provide tools for predicting clinical outcome after RT, and molecules responsible for such resistance may be used as markers for molecular classification and targets for individualized therapy.

Survival in patients having locally advanced HNSCC has not changed significantly over the past 2 decades (5) . The overall rate of recurrence ranges from 30% to 50%, whereas the rate ranges from 20% to 30% if the tumor can be completely resected (with histopathologically negative surgical margins) and treated with adjunctive RT (4 , 6) . Currently, the clinical/pathologic parameters used to predict risk of recurrence are location of the primary tumor (7) , surgical margin status (8) , perineural invasion (9) , number and location of positive neck nodes (10) , and presence of ECE (11) . These parameters may be used to classify patients into various risk groups, and determine the respective treatment modality and, to some extent, therapy outcome (12) . Despite extensive surgical resection and RT, the locoregional recurrence remains high in patients with high-risk tumor features. Several reasons have been implicated for the RT failure, such as presence of hypoxic tumor cells or lack of reoxygenation (13) , presence of inherently radioresistant tumor cells (14) , and redistribution of tumor cells within the cell cycle after irradiation (15) . However, the molecular basis for such resistance to RT remains to be explored.

Because cellular radiation sensitivity varies among the phases of the cell cycle, with cells at G2 or M phase being more sensitive than those in other phases, it is logical to assess the impact of expression of molecules regulating G2/M phase, such as cyclin B1, cdc2, and cdc25, on radiation response. In particular, cyclin B1 and cdc2 are the components of the maturation/mitosis-promoting factor and key players in G2-M transition (16) . Cyclin B1 binds to cdc2, which becomes dephosphorylated and relocated to the nucleus. Whereas the level of cdc2 expression is typically constant throughout the cell cycle, cyclin B1 expression is cyclic and peaks at the G2-M transition (16, 17, 18) . We and others have shown that cyclin B1 is overexpressed frequently in HNSCC and associated with a poor clinical outcome (19 , 20) . Therefore, we analyzed the cyclin B1 expression in tumors of 80 patients, enrolled in a multicenter Phase III clinical trial, who underwent treatment at the University of Texas M. D. Anderson Cancer Center to determine its potential role in predicting the response of HNSCC to RT. Our data indicate that cyclin B1 is overexpressed frequently in HNSCC and that this overexpression is associated with radioresistance, resulting in a poor locoregional control.


   Materials and Methods
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results
 Discussion
 REFERENCES
 
Study Population.
The study population consisted of 59 men and 21 women, with ages ranging from 32 to 83 and a mean of 56.4 years (SD ±10.8). All 80 of the patients underwent treatment at M. D. Anderson Cancer Center from August 1991 to March 1995 as part of a multicenter prospective randomized trial. All of the patients had histologically proven advanced squamous cell carcinoma of the oral cavity, oropharynx, larynx, or hypopharynx, and deemed likely to require treatment using a combination of surgery and postoperative radiation. Patients with Zubrod performance status of 0–2 were registered, and underwent surgical resection of their primary tumor and neck dissection. They were assigned to three risk categories based on surgical-pathologic findings, i.e., primary disease site, surgical margin status, perineural invasion, number and location of positive lymph nodes, and presence of ECE of nodal disease. Patients having no adverse pathologic factors or one factor other than ECE were considered to have low or intermediate risk of recurrence, respectively, and, hence, had no postoperative RT or received conventionally fractionated RT to a dose of 57.6 Gy in 32 fractions over 6.5 weeks, respectively. Patients with ECE or >=2 other features were considered to have a high risk of recurrence and were randomized to receive RT to a dose of 63 Gy in 35 fractions over 7 weeks (conventional fractionation) or over 5 weeks (accelerated fractionation; Ref. 21 ). The follow-up schedule was every 2–3 months over the first year, every 3–4 months over the second year, and semiannually thereafter. The median follow-up duration was 4.9 years (range of 22–83 months).

Immunohistochemistry for Cyclin B1 Protein Expression.
Paraffin-embedded, 4-µm-thick tissue sections obtained from all 80 of the primary tumors were stained for cyclin B1 protein expression using a monoclonal antibody (NCL-Cyclin B1; Novocastra, Newcastle, United Kingdom). Slides containing the sections were baked at 60°C for 1 h and then deparaffinized in a series of xylene baths. The slides were then rehydrated in graded alcohol. To retrieve antigenicity, the tissue sections were heated using a microwave in 10 mM citrate buffer (pH 6.0) three times for 3 min each. The sections were then immersed in methanol containing 0.3% hydrogen peroxide for 20 min to block endogenous peroxidase activity and were incubated in 2.5% blocking serum to reduce the staining background. Sections were incubated overnight at 4°C using the anticyclin B1 antibody at a dilution of 1:15. The sections were processed using the standard avidin-biotin system for staining according to the manufacturer’s protocols (Vector Laboratories, Burlingame, CA). Diaminobenzidine was used as a chromogen, and hematoxylin was used for counterstaining. Tissue sections of normal lymph nodes were used as positive staining controls and were also stained after omitting the primary antibody to confirm the staining specificity.

The cyclin B1 labeling index was defined as the percentage of tumor cells displaying cytoplasmic or nuclear immunoreactivity. Labeling index was derived by calculating the number of cyclin B1-stained tumor cells among at least 1000 tumor cells from representative areas of each tissue section. On the basis of our previous study, a cutoff point of 15% was used, i.e., staining of >15% of the cells was considered positive, denoting overexpression. Cells were counted in at least four fields (at x400) in these areas. Two investigators (K. A. H. and A. K. E-N.) scored all of the slides without knowing the clinical features and treatment outcome.

Statistical Analysis.
Survival curves were estimated using the Kaplan-Meier method and compared using the log-rank test. Fisher exact test and the {chi}2 test were used to analyze the association between two categorical variables. P <= 0.05 was considered statistically significant. Event-free survival accounted for locoregional recurrence, metastasis, and death as events.


   Results
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 Introduction
 Materials and Methods
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Discussion
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Cyclin B1 expression was detected mainly in the cytoplasm, although nuclear staining was also observed. In histologically normal squamous epithelium, cyclin B1 expression was minimal and presents as rare, faintly positive stained cells in the basal epithelial cells. The overall frequency was always <1%. In tumor tissues, the patterns of staining were generally heterogeneous with some tumors rarely expressing positively stained cells, whereas others showed positive staining in the majority of the cells (Fig. 1)Citation .



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  		Fig. 1. Immunohistochemical staining pattern of cyclin B1 in HNSCC. a, normal stratified squamous epithelium with cyclin B1 staining in the basal and parabasal layers (x200). b, predominantly negative staining in carcinoma cells with few positive cells (x100). c, uniform staining in most of the tumor cells (x100).

 
We used the 15% labeling index as the cutoff point for definition of cyclin B1 overexpression as it provided the best fit in our previous study (19) . On the basis of this criterion, 38 of the 80 (47%) HNSCC specimens were judged to have cyclin B1 overexpression. Negative or low-level expression of cyclin B1 was recorded in the remaining 42 (53%) tumor specimens. Table 1Citation summarizes the distribution of the cyclin B1 expression status and clinical-pathologic parameters. No significant association between cyclin B1 expression and clinical stage, tumor grade, age, and gender was observed.


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  		Table 1 CyclinB1 status in HNSCC tumors according to clinical/pathological features of patients

 
Correlating the cyclin B1 status with the treatment outcome in the entire patient population (Fig. 2a)Citation revealed that cyclin B1 overexpression was associated with a high rate of locoregional recurrence or metastasis (P = 0.01). Eleven of the 38 patients (29%) with cyclin B1-overexpressing tumors had recurrence above the clavicle or metastasis, whereas only 3 of the 42 patients (7%) not having tumor cyclin B1 overexpression experienced locoregional relapse or metastasis during a similar follow-up duration (55.2 and 57.4 months, respectively). In the high-risk group (Fig. 2b)Citation , patients having cyclin B1 overexpressing tumors had a significantly higher locoregional recurrence and metastasis rate than did patients whose tumors showed no cyclin B1 overexpression (P = 0.01; log-rank test).



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  		Fig. 2. Freedom from locoregional recurrence or distant metastasis as a function of cyclin B1 expression in the entire study population (a) or high-risk group (b).

 
Fig. 3Citation presents the correlation between cyclin B1 expression and event-free survival. Of the 27 high-risk patients having cyclin B1 overexpressing tumors, 6 (22%) were alive without tumor recurrence compared with 13 of the 29 patients (45%) not having cyclin B1-overexpressing tumors (P = 0.05). The sample size in the low and intermediate-risk groups was too small to perform separate analyses. These results suggested that cyclin B1 is a significant marker in determining the risk of locoregional recurrence or metastasis in patients receiving postoperative RT and is superior to currently used surgical/pathological risk factors.



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  		Fig. 3. Event-free survival as a function of cyclin B1 expression in the entire study population (a) or high-risk group (b).

 

   Discussion
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 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
REFERENCES
 
Locoregional tumor relapse remains a major challenge in the management of advanced HNSCC. In patients who undergo combined surgery and RT, the combination of surgical and pathologic features can to some extent predict the risk of recurrence (12 , 21) . However, ~40% of patients having high-risk features experienced locoregional tumor progression within 5 years after therapy. Consequently, new biomarkers that may allow for better stratification of these patients are clearly needed. Recent advances in the understanding of the molecular biology of HNSCC have opened many new research directions. Currently, increasing effort has been directed at developing molecular-targeted therapies and searching for molecular markers that are useful in either predicting treatment outcome or selecting patients for specific molecular-targeted therapies based on specific tumor characteristics. Three recently published review articles by Smith and Haffty (22) in 1999, Salesiotis and Cullen (23) in 2000, and Quon et al. (24) in 2001 summarized the current status of the search for prognostic/predictive biomarkers. Although none of these studies identified convincing data to warrant routine clinical application of any markers, encouraging leads have been generated for a number of molecules, including p53, epidermal growth factor receptor and one of its ligands, transforming growth factor {alpha}, and cyclin D1 (24) .

In the present study we identified a new marker, cyclin B1, that can additionally identify a subset of HNSCC patients within the high-risk group having a higher probability of tumor relapse. The expression of cyclin B1 in tumor nests was localized mainly in cytoplasm; however, nuclear staining was also observed. It has been reported that cyclin B1/cdc2 complex is active in the cytoplasm and is involved in establishing the mitotic spindle preceding the mitotic nuclear events (25) . Also, cytoplasmic cyclin B1 colocalizes with microtubules during progression through the G2 phase (18) . Another study reported that cytoplasmic cyclin B1 induced mitosis although to a lower extent than nuclear cyclin B1 (26) . On the other hand, it is possible that the overexpressed cytoplasmic cyclin B1 interacts with other cytoplasmic proteins that promote malignant transformation or it accumulates to a level saturating its carrier and remains in the nucleus to induce mitosis (19) . Thus, cyclin B1, through its trafficking between the cytoplasm and the nucleus, seems to play a role in the mitotic process events in both compartments. However, bound by the limits of the aim of the study and the technique used, a detailed explanation for the cytoplasmic localization of cyclin B1 cannot be provided. Unraveling the mechanism by which cyclin B1 overexpression affects tumor response to RT is beyond the scope of this study. However, several possible explanations may be proposed. For example, tumor cells are most sensitive to radiation at both the G2 and M phases of the cell cycle. Overexpression of cyclin B1 may expedite cellular transition through the G2 and M phases thereby reducing the probability of being hit by radiation in these sensitive phases. In addition, because radiation causes mitotic delay in surviving cells, cyclin B1 overexpression may override such arrest resulting in faster cellular repopulation during a course of fractionated RT and thereby reducing tumor control probability. Furthermore, studies have shown that p53 controls a G2 checkpoint and that cyclin B1 overexpression can override the G2/M phase arrest (27 , 28) . This adds to the ability of cyclin B1 to drive cells toward proliferation and prevent p53-controlled apoptosis induced by radiation.

In conclusion, the current correlative study identified cyclin B1 overexpression as a prognostic marker for patients having advanced HNSCC treated with combination of surgery and RT. Overexpression of cyclin B1 may be used to better stratify patients according to their risk level and tumor sensitivity to radiation. However, a prospective study should be performed to verify the potential of using cyclin B1 as a marker for tumor sensitivity.


   FOOTNOTES
 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

1 Supported by National Cancer Institute P01 CA 06294 and R01 CA 84415 (to K. K. A.), National Cancer Institute P01 CA 52051 (to W. K. H.), Cancer Center Grant P30 CA16620, U01 CA 86390, and Tobacco Research Fund from the State of Texas (to M. D. Anderson Cancer Center). W. K. H. is an American Cancer Society Clinical Research Professor. Back

2 To whom requests for reprints should be addressed, at Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: (713) 792-3400; Fax: (713) 794-5573; E-mail: kianang{at}mdanderson.org Back

3 The abbreviations used are: RT, radiotherapy; HNSCC, head and neck squamous cell carcinoma; ECE, extracapsular nodal extension. Back

Received 7/25/02. Accepted 10/ 2/02.


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results
 Discussion
 REFERENCES
 

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