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The Oncologist, Vol. 3, No. 6, 424-431, December 1998
© 1998 AlphaMed Press

Original Papers

The Prognostic Value of Thymidylate Synthase and p53 Expression in Patients Treated with Induction Chemotherapy for Squamous Cell Carcinoma of the Head and Neck

Marshall R. Posnera,c, Patrick G. Johnstonf, Roy B. Tishlerc,e, Janet Andersend, Michelangelo Fiorentinoa, Paul M. Bussec,e, Lisa A. Cavacinia, A. Dimitrios Colevasc, John Clarke, Charles M. Norrisb,c

a The Human Monoclonal Antibody Laboratory; b The Division of Otolaryngology, Beth Israel Deaconess Medical Center; c The Head and Neck Oncology Program; d The Division of Biostatistics, Dana-Farber Cancer Institute, Boston, Massachusetts, USA; e The Joint Center for Radiation Therapy, Harvard Medical School, Boston, Massachusetts, USA; f the Department of Oncology, The Queen's University of Belfast, Belfast, United Kingdom

Correspondence: Marshall R. Posner, M.D., Head and Neck Oncology Program, Dana-Farber Cancer Institute, 44 Binney Street, Boston, Massachusetts 02115, USA. Telephone: 617-632-3090; Fax: 617-632-4448; e-mail: marshall_posner{at}dfci.harvard.edu


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
Thymidylate synthase (TS) and p53 are central molecules in the regulation of cell growth. Differences in the intracellular expression of these proteins by tumor cells may have predictive value for response to chemotherapy and early failure in patients with squamous cell cancer of the head and neck (SCCHN). Immunohistochemistry was used to assess the tumor cell expression of TS and p53 in pre-therapy biopsies from patients with advanced SCCHN treated with an induction chemotherapy protocol, PFL. Samples were available from 11 of 16 nonresponders, 13 of 19 early failures with progression within 24 months of treatment, and a random selection of 13 from 45 long-term, disease-free survivors (LTS). High TS expression was seen in the majority of samples from all three groups, 67% versus 78% versus 93%, respectively; however, only one of seven (14%) samples with low TS was from a LTS patient. TS expression did not differ in patients by sex, age, site of primary tumor, differentiation or stage. p53 was expressed in 33% of patient samples and did not predict response or correlate with sex, age, site of primary tumor, differentiation, or stage. Small primary tumors with extensive nodal disease were less likely to express p53 than larger primary tumors with or without nodal involvement. The data suggest that TS and p53 content have a limited prognostic value in patients treated with PFL, although tumors with lower TS expression appeared to be less likely to respond. Differences between this study and other investigations of TS and p53 may be disease site- and regimen-specific. Statistically significant differences between response groups may emerge from larger, site-specific, protocol-driven studies of TS and p53.

Key Words. Cisplatin • 5-Fluorouracil • Immunohistochemistry


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 Conclusion
 References
 
The optimal role of chemotherapy in the treatment of locally advanced squamous cell carcinoma of the head and neck (SCCHN) remains controversial. There is substantial evidence that combination chemotherapy with the agents cisplatinum and 5-fluorouracil (PF) can be an effective part of a curative treatment program. In randomized trials, induction chemotherapy and chemoradiotherapy have been shown to be effective in prolonging disease-free survival (DFS) and overall survival (OS) in patients with unresectable disease [1-3]. Induction chemotherapy has also been shown to be an effective replacement for surgery in patients with resectable disease without compromising survival, creating the opportunity to preserve laryngeal and swallowing function in these patients [4, 5]. Nonetheless, DFS and OS in patients with locally advanced SCCHN remain poor.

Two intracellularly expressed proteins, thymidylate synthase (TS) and p53, may have predictive value for response to chemotherapy. TS is a central enzyme in DNA synthesis and one of the principal targets of 5-fluorouracil (5-FU)-based chemotherapy [6]. TS is the major source of thymidylate, an essential molecule for DNA synthesis. Thymidylate is required for the growth of dividing cells and repair of DNA damage. Increased TS expression has been shown to be a predictor of poor response to 5-FU-based chemotherapy in patients with metastatic colorectal and primary gastric carcinoma [7-9]. In adjuvant trials of breast and rectal carcinoma, high TS expression in tumors is associated with a poorer outcome but improved efficacy of 5-FU-containing adjuvant therapy [10, 11]. In a single study of SCCHN, high TS expression in tumor cells was associated with a reduced response rate to induction chemotherapy, which was of borderline statistical significance [12]. The results of these studies are not entirely consistent. Discordant results have also been obtained with studies of p53. p53 is a central mediator of cell growth, cell sensitivity to chemotherapy, radiation-induced DNA damage, and programmed cell death [13-16]. Thus, abnormal expression or function of p53 in primary tumors might be expected to predict responsiveness to chemotherapy and radiation. Aberrant, increased expression of p53 has been associated with both increased and decreased response to platinum-based therapies in several tumor systems [13, 17, 18]. In one study, p53 expression was associated with improved laryngeal preservation after PF chemotherapy without effect on survival or response to chemotherapy [19].

To establish the relative value of tumor cell p53 expression and TS content as predictors of response and locoregional disease control after intensive chemotherapy, we performed a retrospective, hypothesis-generating study of a subset of patients with locally advanced, previously untreated, curable SCCHN treated uniformly on a phase II protocol with induction PFL chemotherapy [20]. Phase II studies of several PFL regimens have demonstrated incremental improvements in complete response (CR) rates and DFS of patients with SCCHN at the cost of considerable toxicity [20-22]. The overall response (OR) rate of 54% obtained in the PFL trial and the long-term DFS of 51% cannot be directly compared with the results obtained in phase III studies; however, in these studies PF has been shown to induce a CR rate in the range of 30%-45% and three- to five-year DFS of only 25%-40% [2, 4, 20, 23]. At the present time, there is no method of predicting which patients might be expected to respond to PF or PFL chemotherapy. We evaluated the TS and p53 expression in tumors from patients treated uniformly on our intensive PFL protocol. We hypothesized that differences in TS and p53 expression would predict chemotherapy response in patients. To enhance our ability to identify predictive differences, we selected for study those patients whose tumors showed primary chemotherapy resistance, by virtue of a failure to respond to chemotherapy or very early relapse, and compared these two groups to a random sample of patients who were long-term disease-free survivors. By selecting resistant patients for study, we hoped to increase the probability of identifying differences that could be definitively evaluated in a prospective study.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 Conclusion
 References
 
Patients and Samples
From 102 patients treated with PFL, we retrospectively identified a subset of patients in whom pretreatment pathological samples could be obtained for additional studies and who fit criteria for study. Study criteria required that patients fit into one of three response categories: nonresponders (NR), early failures (EF), or long-term survivors (LTS). NR must have had a documented failure to respond after two or three cycles of PFL or persistent disease documented immediately after radiotherapy. EF was defined as an initial partial response (PR) or CR to chemotherapy, followed by scheduled planned radiotherapy and surgery resulting in a disease-free state with local progression >=10 months, but within 24 months, of the start of treatment. LTS were defined as patients with a CR or PR to chemotherapy who were rendered disease-free after radiotherapy and planned surgery and in whom there was no evidence of recurrence, metastases, or a second primary and who were alive five or more years after the start of treatment. Patients dying cancer free or from second malignancies in the five-year-period were not included. Since most relapses occur within two years of therapy, this separation captures almost all primary failure and eliminates the majority of early second primary cancers. Of importance in determining the role of tumor-related factors in recurrence and survival, only 6% of patients died in the first five years of this study from non-cancer-related causes [20].

PFL treatment has been described previously [20]. In brief, between 1987 and 1991, 102 patients were entered on the PFL protocol. Patients received cisplatinum 25 mg/m2/day for five days (days 1-5) by continuous i.v. infusion with leucovorin 500 mg/m2/day for six days (days 1-6) and 5-FU, 800 mg/m2/day for five days (days 2-6). Treatment was repeated every 28 days for a total of three cycles. Patients were restaged after cycle 2 and cycle 3 and began definitive radiotherapy after cycle 3. Patients generally had a small biopsy taken from the primary site or, occasionally, by fine needle aspiration of nodal disease, thus limiting the amount of tissue available for studies and the number of evaluable patients. Three patients died during chemotherapy and were excluded from analysis. There were 16 NR patients, and samples were available on 11 (69%). Archival samples from the original biopsies were not available in the remaining five patients. Nineteen patients had EF and there were informative samples on 13 (68%). Archival samples from the original biopsies were not available in the remaining six patients. A total of 13 LTS with available samples were randomly selected from the 50 LTS patients. Five patients did not have obtainable material; thus, 13 of 45 (29%) LTS patients were studied. Fourteen patients died of disease or other causes in the period between the cutoffs. A total of 37 patients were studied. While this was only a fraction of patients treated on study, all the NR and EF patients with useful material were represented. This study was powered to see only major differences because of the low number of NR and EF. Although a binomial analysis of outcomes was made, the sizes of the study groups only provide an 80% power to detect a 60% difference, limiting the ability to see subtle influences. This was considered adequate for hypothesis generation.

Immunohistochemistry
Blocks of paraffin-embedded tissues were obtained from the original primary biopsies in all study patients, and slides were generated from tumor-containing materials for immunohistochemistry. The slides were stained for TS expression as previously described, using the TS106 murine monoclonal antibody. A negative control antibody was used for each sample and positive control slides were used to confirm antibody function. TS staining was analyzed and scored by investigators (P.G.J., K.B.) who were blinded to the clinical and pathological data. TS expression was scored as focal or diffuse staining on the basis of a 25% cut-off of the number of cells stained. Intensity of staining was graded on a 0 to 3+ system, as previously described [11]. The relative intensity of staining is based on the assessment of two observers, and this semiquantitative scale has been validated by close agreement (>90%) between blinded investigators [11]. Focal staining and diffuse staining were considered in equal grades for purposes of this analysis and is consistent with past studies [10, 11, 24, 25]. p53 was detected using the DO7 monoclonal antibody [26], as previously described. p53 staining was graded as present or absent in viable tumor cells in the specimens and was considered positive if staining was observed in >10% of the nuclei of viable tumor cells.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 Conclusion
 References
 
Between 1987 and 1991, 102 patients were entered on the PFL protocol [20]. The overall CR rate to induction chemotherapy was 54%, the major (CR and PR) response rate was 81%, and the long-term control rate was 51%. Three patients died of toxicity during therapy, and 16 of the remaining 99 patients were NR to initial chemotherapy. In addition to the 16 NR, an additional 33 patients failed, died, or developed a second primary in the first five years of follow-up. We identified 11 non-responding patients who by definition failed induction chemotherapy and in whom sufficient original pretreatment pathology specimens could be obtained. We identified a second set of 13 patients who failed (EF) within 10-24 months of the start of therapy and in whom sufficient pretreatment material was available from the original biopsy. Later relapses are rare among patients treated for SCCHN on combination therapy protocols, and reappearance of tumor in such patients may be due to second primaries. Finally, we identified 13 LTS from whom pathology was available for study. The tumors from these patients represented tumors sensitive to the combined therapeutic interventions.

Thirty-four patients had samples informative for TS, and 36 had samples informative for p53. The characteristics of these patients are summarized in Table 1. The patients are evenly matched for age, with a slightly higher weighting for females in the LTS. Sites are distributed throughout the head and neck, with the exception of a high number of nasopharyngeal carcinoma (NPC) in the NR cases due to a 29% rate of persistent disease after radiotherapy among NPC patients treated with PFL. Differentiation in the NPC cases was evenly distributed among the three established histologic types (data not shown). Oral cavity and oropharynx were the sites identified in the largest fraction of patients.


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  		Table 1. Patient characteristics
 
The results of monoclonal antibody staining in the primary tumor samples from the patients are summarized in Table 2, which shows that p53 was aberrantly expressed in one-third of patient samples. There was no difference between NR samples and LTS samples, with 38% and 40% of patients having p53 expression, respectively. The EF group had the lowest fraction of p53 positive samples, 23%. None of these differences had statistical significance and no apparent biological significance could be predicted with regard to efficacy of chemotherapy. TS expression was high in the majority of patient samples, although the NR expressed less TS than did EF or LTS patients (67% versus 78% versus 93%, respectively). In this study, 6 of 21 (29%) NR and early failures had 0 or 1+ TS expression compared to 1 of 13 (8%) long-term responders. Thus, low TS might predict poor response and poor locoregional control with PFL chemotherapy, as only one of seven (14%) patients with low tumor TS was a LTS.


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  		Table 2. p53 and TS expression
 
An analysis of p53 results based on T stage, N stage and overall stage was performed and is shown in Table 3. The patient population was divided into smaller and larger primary tumors and nodal disease. As can be seen, there was no difference in the extent of nodal disease and p53 expression. Interestingly, fewer smaller primary tumors were associated with expression of p53. Smaller tumors in this study were associated with more extensive nodal disease since only advanced stage patients were entered on the study. This suggests that lack of p53 expression may be associated with earlier nodal metastases and slightly more aggressive tumors.


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  		Table 3. p53 expression and tumor and nodal stage
 
In further analysis, the patients were subdivided into different disease categories based on traditional staging or as small primary disease with large nodal disease. One patient with a T2N1 tumor was eliminated from this analysis because of the intermediate nature of the nodal disease but was included in the traditional staging analysis. As can be seen from these data (presented in Table 4), larger primaries are more frequently associated with aberrant p53 expression. Traditional staging was not informative in this analysis because there were too few patients with Stage III disease. Differences in TS expression were not observed when the data were analyzed by stage or primary tumor size. Additional analysis based on site of disease, age and sex of the patient, and differentiation of tumor were also not evidently different with regard to p53 or TS expression.


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  		Table 4. p53 expression and primary tumor size
 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
Conclusion
 References
 
To establish the potential value of TS and p53 expression as predictors of response and local control from intensive chemotherapy in SCCHN, we have evaluated the expression of these two proteins by immunohistochemistry in the tumor cells from primary tumor biopsies of patients treated with induction PFL chemotherapy for locally advanced, previously untreated tumors. These two proteins are biologically important mediators of growth, viability, and response to therapy in tumor cells. The relationship of their expression to clinical outcomes may provide insights into their biological role in the continued growth and therapeutic responsiveness of these malignancies. In the present study, we retrospectively evaluated tumor samples from patients treated with an aggressive, 5-FU-based regimen with a high clinical response rate and local control rate. We hypothesized that if expression of these proteins were central determinants of the responsiveness of these tumors, then there would be large differences between NR/EF and LTS patients that should be discernible in the restricted number of patients available in each category. A key element in this study was the exclusion of patients dying from other causes or at intermediate time points so that the primary analysis could be focused on tumor responses and control rather than assess the risk of second cancers or be confounded from comorbid illnesses. Our results suggest a limited role for TS and p53 in predicting responsiveness to PFL induction chemotherapy.

TS expression and function have been studied as predictors of response and prognosis in selected malignancies. It has been reported that increased TS biochemical activity or expression in tumor tissue is associated with a reduced responsiveness to 5-FU-based chemotherapy and to a worse prognosis in patients with gastric cancer [7]. In patients with disseminated colorectal carcinoma, high intratumoral TS also predicts lack of response and decreased survival [8, 9]. These studies measured gross tumoral TS levels and employed protracted 5-FU infusions at low dose. In another study of gastric cancer and neoadjuvant therapy with a short infusion of 5-FU, leucovorin, and interferon-{alpha}2a, low TS expression was predictive for favorable responses [27]. For patients with primary rectal carcinoma, high tumoral TS expression is associated with a poorer prognosis than low TS levels, but high TS was also associated with improved DFS in patients treated with 5-FU-based adjuvant therapy over those with low TS levels [10]. In node-positive breast cancer, high TS levels were also associated with a significantly worse overall prognosis. However, there was a relatively greater impact of 5-FU-based adjuvant therapy on improving DFS than in untreated control treated and untreated low-TS patients [11]. Both of these studies evaluated bolus regimens of 5-FU in an adjuvant setting and employed immunohistochemistry methodology to quantify TS.

In SCCHN, the expression of TS is not as predictive of response or locoregional control. In the single trial reported by Johnston et al., TS expression was examined in patients treated on four separate studies using PFL, PFL with interferon-{alpha}2b (PFL-IFN), or PFL with methotrexate [12]. Although an inverse association between TS staining and response was observed, this was of borderline significance. In a subset analysis of patients treated with three cycles of PFL-IFN, higher TS levels were associated with diminished CR rates. Survival was not associated with TS levels despite a diminished CR rate in patients expressing high TS staining. In the present study, low TS expression was associated with progressive disease or early failure after chemotherapy, but this difference was not statistically significant due to small numbers. These results contrast with the results of the prior study in SCCHN. A number of factors may contribute to this difference. The patient populations are not directly comparable, different treatment regimens were used, and interferon-{alpha}2b might alter the activity or expression of TS.

The specific treatment regimen used in this study, PFL, may play an important role in the results. In PFL, the dose intensity of 5-FU and leucovorin is high, and the inhibition of TS may be more complete than in PF regimens. This notion is supported by other studies that have reported that the AUC of 5-FU infusion correlates with the response rate and toxicity in patients with SCCHN and that tumor levels of reduced folates are significantly reduced [28, 29]. The complete response rate from PFL is also higher than that observed with PF regimens [20]. In the present study, low TS expression was observed in nonresponding tumors and EF. Because low TS may be associated with a lower growth fraction in the tumor or less rapidly dividing cells, aggressive chemotherapy may be less effective. There has not been a thorough evaluation of response and growth fraction in PFL-treated patients. The determination of growth fraction in head and neck cancers is complex because of the rapid potential doubling time of the tumors and the frequent distribution of cells to nondividing or differentiating compartments [30]. The data also suggest that high TS staining is of less importance in assessing the potential of a specific tumor for response to PFL chemotherapy. We suggest that the value of TS staining for prognosis may also be regimen-specific and thus, less intensive 5-FU-based therapy such as PF might yield different results. Similarly, in studies with regimens based on protracted low-dose infusion of 5-FU or short boluses of 5-FU with or without leucovorin, the relative amount of intratumoral TS may be an important predictor of response, particularly in tumor systems where the rate of response is relatively low compared with SCCHN. Finally, the agents delivered with 5-FU may have an impact on the expression of TS and the ability of new TS protein to be produced in the tumor cells in response to 5-FU based inhibition [31].

p53 alterations are the most frequent genetic changes in human tumors [13]. Modifications of p53 function can occur as a result of mutation in p53 or the presence of a modifying protein such as MDM2 or human papilloma virus E6 [13, 32, 33]. These abnormalities can only partially be assessed by immunohistochemistry measurement of p53 expression or by identification of mutations via molecular techniques. Aberrant expression can result from an inactivating mutation in p53 or by other mechanisms of p53 functional inhibition such as MDM2 protein-mediated segregation of the protein [33]. The prognostic value of p53 expression in SCCHN is controversial. p53 expression in tumor cells has been associated with worse survival, early failure, and increased risk of second primary tumors in one study of patients treated with standard radiotherapy and/or surgery with heterogeneous tumors [34]. In a second study, p53 mutations were associated with an increased risk of failure after treatment with standard radiotherapy and surgery in a heterogeneous tumor group [35]. In contrast with the results found in these studies, another study of a heterogeneous group of tumors treated with primary radiotherapy demonstrated no prognostic value to p53 expression for survival or DFS. Only patients' smoking history correlated with expression of p53 [36]. In a study of laryngeal tumors treated with radiotherapy and/or surgery, expression of p53 was associated with improved DFS and OS; however, in two additional studies of laryngeal tumors, p53 expression was not predictive for prognosis [37-39].

The number of studies of p53 expression in chemotherapy-treated, curable patients with SCCHN is limited. In patients with laryngeal carcinoma treated with induction PF chemotherapy for organ preservation or standard surgery and radiotherapy, the expression of p53 was associated with improved organ preservation, although survival was not affected in either arm [19]. Approximately 60% of tumors expressed p53 in the chemotherapy and standard therapy arms. In a follow-up study, limited sequencing of p53 in exons 5 and 8 demonstrated mutations in 17 of 44 (39%) laryngeal tumors and expression in 26 (59%). Only 10 tumors that expressed p53 had a mutation, as did seven of 18 tumors that did not express [40]. Thus, expression of p53 and mutations in p53 did not overlap in 23 of 44 (52%) patients. The relative value of p53 mutation and expression in predicting prognosis and responsiveness to therapy is largely unexplored in large, protocol-driven trials. In addition, the role of p53 in mediating tumor cell responses to DNA damaging agents such as radiotherapy, cisplatinum, and 5-FU is not well understood and may be dependent on the functional status of p53, the specific mode of p53 inactivation, and the status of functionally related molecules.

In the present study, p53 expression did not predict response to chemotherapy or early failure. A relatively lower fraction of small tumors with advanced nodal presentations expressed p53. This result is similar to a recently published analysis in which a trend can be seen in the data toward less frequent mutation of p53 among patients with small primary lesions and larger nodal disease [35]. The data in the present study do not support a role for p53 expression as a prognostic indicator in PFL-based trials, although data in laryngeal carcinoma suggest a predictive role for p53 expression in patients treated with PF for organ preservation. An analysis of patients treated on large, protocol-driven trials might yield important biologic data on the value of p53 expression as a prognostic indicator for early and advanced disease in specific anatomical sites.


   Conclusion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
References
 
We conclude from the data presented in this exploratory study that immunohistochemistry assessment of TS and p53 expression have a limited impact on the prediction of response and DFS in patients treated with PFL induction chemotherapy. However, tumors with lower TS expression appeared to be less likely to respond to PFL. Statistically significant differences between response groups may emerge from larger studies. Differences may also be specific to disease site and 5-FU-based regimens. It is possible that with less intensive regimens than PFL, TS might be predictive of response and may be helpful in selecting dose intensity for individual patients. Of interest, p53 expression in patients with small tumors and larger nodal disease was less frequent than in those with larger primaries with or without nodal disease. This observation suggests that p53 expression in tumor cells may have biological value in predicting metastatic behavior. There are a number of different methods for assessing p53 functionality. Aberrant p53 expression is only part of a complex picture of p53 function. p53 may be functionally impaired by deletion, mutation, suppression, or increased degradation [15, 32, 33]. Until a functional assay for p53 is available, it may be difficult to sort out the impact of p53 on tumor prognosis and response to therapy. In the absence of such an assay, multiple techniques may be necessary to assess p53 function. Further studies of TS expression and p53 in large protocol-driven trials appear to be indicated given the discordant results in this and other studies in SCCHN.


   Acknowledgments
 
We would like to thank Dr. Massimo Loda from the Department of Pathology, Beth Israel Deaconess Medical Center, for his advice and Ms. Maura Galvin from the Human Monoclonal Antibody Laboratory, and Raj Mishra from the Department of Pathology, Beth Israel Deaconess Medical Center for their technical support. We would also like to thank Lee Thornhill and Andrea Schneider from the Head and Neck Oncology Program at the Dana-Farber Cancer Institute for their help in data and sample acquisition on the patient population.

This study was supported in part by research donations to the Dana-Farber Cancer Institute from patients treated in the Head and Neck Oncology Program and from a Grant-in-Aid from Rhône-Poulenc Rorer Pharmaceutical, Inc.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 Conclusion
 References
 

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accepted for publication October 2, 1998.





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