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Molecular Oncology, Markers, Clinical Correlates |
, and Thymidylate Synthase for Neoadjuvant Cisplatin-based Chemotherapy in Head and Neck Cancer1
Lombardi Cancer Center, Georgetown University, Washington, D.C. 20007 [H. S., A. A. R., B. T., M. La., A. B., M. Le., K. J. C.]; Johns Hopkins Oncology Center, Baltimore, Maryland 21205 [E. I. H., A. A. F.]; Queens University, Belfast, United Kingdom BT9 7AB [P. G. J.]; and Department of Otolaryngology, Kanazawa University, Kanazawa, Ishikawa 920, Japan [H. S.]
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ABSTRACT |
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 Top ABSTRACT INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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(GST), thymidylate synthase (TS), c-erbB2, and multidrug resistance-associated protein was examined by immunohistochemistry. Expression of glutathione synthetase mRNA was measured by in situ hybridization. The overall response rate for cisplatin-based neoadjuvant treatment was 79%. The expression of several of the tumor markers was associated with resistance to neoadjuvant treatment, but none reached statistical significance. Overall survival (OS) was strongly correlated with the absence of p53 expression. The OS at 3 years was 81% in the p53-negative group, whereas it was 30% in the p53-positive group for patients treated with neoadjuvant chemotherapy (P < 0.0001). Expression of GST and TS was also significantly correlated with decreased OS after neoadjuvant treatment. At 3 years, the OS rate was 82% in the low GST score group, compared to 46% in the high GST score group (P = 0.0018). In the TS-negative group, the 3-year OS rate was 71% compared with 40% in the TS-positive group (P = 0.0071). We conclude that p53, GST, and TS may be clinically important predictors of survival in patients receiving neoadjuvant chemotherapy for head and neck cancer. |
INTRODUCTION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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30% have been reported when cisplatin is combined with 5-fluorouracil (5-FU) (1)
. These numbers fall dramatically in patients with relapsed tumors after surgery and/or radiotherapy who show only a 30% overall response rate to the same cisplatin-based chemotherapy (2)
. Neoadjuvant chemotherapy has been used increasingly in the last decade for organ preservation and for unresectable disease in head and neck tumors (3, 4, 5, 6, 7) . However, despite the high response rate to neoadjuvant chemotherapy, there is no clear evidence of improved survival for patients treated with cisplatin-based chemotherapy in this setting. Some investigators have concluded that neoadjuvant chemotherapy should not be offered to patients with locally advanced head and neck cancer if improved survival is to be the criteria for selection of treatment (8) .
At the present time, there are no accepted prognostic markers that can guide the selection and treatment of patients with head and neck squamous carcinomas or predict the long-term outcome of such treatment. In theory, such markers would be very useful, especially in the neoadjuvant setting because alternative treatments including surgery could be offered to patients who are likely to fail after neoadjuvant treatment.
In head and neck cancer, a number of cellular factors may be important in clinical resistance to both cisplatin and 5-fluorouracil, which are the most widely used drugs for neoadjuvant treatment. Several cellular products are potentially important in regulating cellular resistance to cisplatin-based chemotherapy in head and neck cancer.
The tumor-suppressor gene product, p53, has been correlated with poor response to cisplatin-based chemotherapy in lung and ovarian cancers (9, 10, 11) . In patients with invasive bladder cancer undergoing neoadjuvant chemotherapy, p53 mutations have been associated with poor response and prognosis (12) . This may result from an impaired ability of mutant p53 to induce apoptosis following DNA damage through transactivation of bax (13) .
Glutathione and other components of the glutathione metabolic pathway may also have a critical role in determining the cellular sensitivity to cisplatin-based chemotherapy. Glutathione is a ubiquitous tripeptide, which has been hypothesized to protect against the DNA damaging effects of agents such as cisplatin by conjugating toxic moieties including metal compounds in the cytoplasm and preventing DNA interaction (14
, 15)
. More recent data suggest that the cytoprotective effect of glutathione may in fact be secondary to enhanced DNA repair and increased ability to recover from intracellular toxic events that follow cisplatin-induced DNA damage (16)
. Glutathione may also be important in protecting the cell from other potentially damaging molecules such as oxygen free radicals. Studies from this laboratory and elsewhere have demonstrated that cellular glutathione levels are inversely correlated with cisplatin sensitivity in head and neck cancer cells (17
, 18)
. GSTs have been shown to catalyze conjugation of glutathione to a number of chemotherapy agents including cisplatin (19
, 20)
. The cisplatin/glutathione complex may be ejected from the cell in an ATP-dependent fashion. The cellular protective action of glutathione has been believed to be a result from the conjugation of the peptide to the cytotoxic chemotherapy agents mediated by the catalytic enzymes known collectively as GSTs (15
, 16)
. The predominant GST isoform in head and neck cancer is GST (21)
. Immunohistochemical studies have shown that GST expression may predict response to cisplatin-based chemotherapy in patients with non-small cell lung cancer (22)
.
The MRP is a 190-kDa transmembrane transport protein that is thought to function as an ATP-dependent export pump for conjugates of glutathione and cytotoxic drugs such as cisplatin (23) . Overexpression of MRP might then be expected to increase cellular resistance to some chemotherapy agents.
TS catalyzes the methylation of dUMP to dTMP, an essential step in DNA biosynthesis. TS is a critical target for fluoropyrimidine drugs such as 5-FU (24) . Overexpression of both TS protein and mRNA have been correlated with resistance to 5-FU chemotherapy in patients with rectal, gastric cancers as well as head and neck cancers (25 , 26 ) .
The c-erbB2 oncoprotein is a 185-kDa transmembrane protein transmembrane protein with tyrosine kinase activity (27) . C-erbB2 is expressed in a significant subset of head and neck cancers (28) . Studies in breast and ovarian cancers indicate that activation of c-erbB2 may inhibit cisplatin-induced DNA repair, thereby enhancing cytotoxicity (29 , 30) .
In this study, we retrospectively analyzed these tumor markers in a series of 68 patients from two institutions who received cisplatin-based neoadjuvant chemotherapy (cisplatin/5-FU or cisplatin/paclitaxel) and compared those data with treatment response and survival.
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PATIENTS AND METHODS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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Evaluation of Response and Survival.
Clinical response scoring for this study was determined by retrospective chart review. CR was defined as complete disappearance of tumor by physical examination and for radiographic evaluation. PR was a 50% reduction in tumor mass measured in two dimensions either by physical examination and/or radiographic evaluation of >1-month duration. NR represented no significant change in tumor dimension, whereas PD represented a 25% enlargement in tumor dimension while on therapy. DFS and OS were determined from the date of initial diagnostic biopsy. DFS was measured from initial biopsy until local recurrence or distant metastasis. Death without recurrence was not counted as an event. OS was estimated until death by any cause or the date of last patient contact.
Immunohistochemical Staining.
Paraffin blocks were obtained from the departments of pathology, Georgetown University and Johns Hopkins University or from the referring institution. Analysis of TS and GSH-S was carried out on only the 50 cases from Georgetown University. Paraffin sections (5 µm) were deparaffinized in xylene, rehydrated through graded alcohols, and washed in PBS. Endogenous peroxidase was blocked using 3% hydrogen peroxide solution. Following incubation in normal goat serum (Biogenex, San Ramon, CA) at room temperature for 20 min., the primary antibodies were diluted in 1% BSA and 1% sodium azide according to the following concentrations: anti-p53 mouse monoclonal antibody (BP53.12, Zymed, South San Francisco, CA), 1:50; anti-TS mouse monoclonal antibody (TS106, gift from Dr. Patrick G. Johnston, The Queen’s University of Belfast, United Kingdom; Ref. 31
), 1:200; anti-GST rabbit polyclonal antibody (Novocastra, Newcastle upon Tyne, United Kingdom), 1:200; anti-c-erbB2 mouse monoclonal antibody (Novocastra, Newcastle upon Tyne, United Kingdom), 1:40; and anti-MRP rabbit polyclonal antibody (gift from Dr. Gary D. Kruh, Fox Chase Cancer Center, Philadelphia, PA; Ref. 32
), 1:300. The diluted antibodies were added, and the slides were incubated at room temperature for 1 h. Slides were washed in Cadenza buffer, and the reaction was visualized with the BioGenex multilink system (BioGenex, San Ramon, CA). The slides were incubated with multilink solution (bio-tinylated goat antimouse and rabbit immunoglobulin) at 37°C for 20 min followed by horseradish peroxidase-conjugated streptavidin (37°C, 20 min) according to the manufacturer’s protocol. The peroxidase reaction was developed using diaminobenzidine solution. The slides were counterstained with hematoxylin, then mounted. A positive control tissue was included with each set of sections stained. For GST, normal human kidney known to be positive was used. The positive control slides for p53 and c-erbB2 were human ovarian cancers known to be positive. For TS, normal human colon tissue was used as a positive control. The positive control for MRP was normal human kidney. In negative controls, the primary antibody solution was replaced by PBS with 1% BSA and 0.1% sodium azide.
In Situ Hybridization.
Because no antibody was available for GSH-S, in situ hybridization was performed. Briefly, paraffin sections (5 µm) were deparaffinized in xylene, rehydrated through graded alcohols, and incubated in proteinase K solution at 37°C for 30 min. The slides were incubated in hybridization buffer with 35S radiolabeled antisense probe at 55°C overnight to allow for cellular localization. The antisense probe was synthesized using a cDNA for human GSH-S (gift from Dr. Philip G. Board, The Australian National University, Canberra, Australia; Ref. 33
). The next day, single-stranded RNA was degraded by the addition of RNase A and was washed off in graded salt solution. The slides were rinsed in graded alcohol, air-dried, dipped in appropriate diluted liquid emulsion (NTB2, Kodak), allowed to air dry, and placed in light-tight boxes for incubation in a -70°C freezer. After a 4-week exposure, slides were developed by hand and counterstained with hematoxylin.
Scoring.
Immunohistochemical staining and in situ hybridization reactivity for GSH-S were assessed independently by each of two investigators who were blind to the patients’ identity and clinical outcome. For p53, specific nuclear staining of >5% of the cancer cells was considered positive (most positive cases showed nuclear staining in the majority of tumor cells). TS expression was scored positive if any specific cytoplasmic staining was detected. GST expression was quantified by use of a visual grading system based on the intensity of cytoplasm staining (0–3) as follows: grade 0, no immunoreactivity; grade 1, weak immunoreactivity slightly stronger than background staining; grade 2, clear immunoreactivity in more than half of the cancer cells; grade 3, strong immunoreactivity as dark as nuclear counter stain in the majority of cancer cells. For statistical analysis, grades 2 and 3 were classified as high GST immunoreactivity, and grades 0 and 1 were classified as low GST immunoreactivity (34)
. For c-erbB2 and MRP, specific membrane staining of >5% of the cancer cells was counted as positive. Cytoplasmic staining was not scored. For GSH-S, slides were counted as positive only if there was a specific signal (accumulation of silver grains) on the tumor epithelial cells.
Statistical Analysis.
Univariate analyses for recurrence-free survival and OS included Kaplan-Meier survival estimation (Prism, GraphPad Software, Inc., San Diego, CA), with statistical significance assessed via the log-rank test and the Gehan-Wilcoxon test. Multivariable statistical models were generated using a proportional hazards regression approach. Stepwise model building was done manually based on the likelihood ratio test and changes to parameter estimates for variables already in the model. Interactions were tested using cross-product terms. Both forward and backward stepwise approaches yielded the same final models.
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RESULTS |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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). GST was observed mainly in the cytoplasm of cancer cells with 53% high scores (36 of 68; Fig. 1B
). TS expression was observed in the cytoplasm of the cancer cells in 29 of 50 cases (58%; Fig. 1C
). Positive membrane staining for c-erbB2 was detectable in 21 of 68 cases (31%), and positive membrane staining for MRP was found in 29/68 cases (43%). GSH-S was detected in cancer cells in 13/50 cases (26%).
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scores or TS-positive tumors had well-differentiated tumors (GST, P < 0.001; TS, P = 0.023).
Association of Tumor Marker Expression with Chemotherapy Response.
The overall chemotherapy response rate for neoadjuvant treatment was 79% (54 of 68 cases). Table 2
shows the relationship between tumor markers and clinical response to neoadjuvant chemotherapy. Although there was a trend between expression of several tumor markers and clinical resistance to chemotherapy, none of the tumor markers measured were significantly correlated with response. Other parameters, such as age, gender, clinical stage, T stage, N stage, and tumor differentiation were not significantly correlated with clinical response to chemotherapy.
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shows the association of chemotherapy response and tumor markers with DFS in the 68 patients analyzed. DFS (or PFS in patients who had less than a PR to induction chemotherapy and were never free of disease) was significantly correlated with clinical response to neoadjuvant chemotherapy for all patients (P < 0.0001; Hazard ratio, 4.67; Fig. 2A
). Poor response to treatment (NR, PR) was associated with shorter PFS. At 24 months after diagnosis, the PFS rate was 60% in responders, whereas it was zero in nonresponders.
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). Expression of GST was associated with decreased DFS in neoadjuvant treatment cases. DFS was 55% at 3 years after diagnosis in patients with low GST scores, although it was 39% in patients with high GST scores (P = 0.119; Hazard ratio, 1.7). Expression of c-erbB2, TS, MRP, or GSH-S were not significantly correlated with DFS in patients treated with neoadjuvant chemotherapy. Clinical parameters including age, gender, clinical stage, T stage, site of primary tumor, and tumor differentiation were not correlated with DFS in neoadjuvant cases. As expected, patients with no neck disease had a better prognosis than patients with clinically positive necks.
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shows the association of chemotherapy response and tumor markers with OS. OS was significantly correlated with clinical response to neoadjuvant chemotherapy (P < 0.0001; Hazard ratio, 4.51; Fig. 2B
). Poor response (PD, NR) was associated with shorter OS. For neoadjuvant treatment, expression of p53 was very significantly correlated with OS (P < 0.0001; Hazard ratio, 5.37; Fig. 3B
). OS was 81% at 3 years after diagnosis in patients with p53-negative tumors, compared to 30% in patients with p53-positive tumors. A significant association was also observed between high GST scores and shorter OS for neoadjuvant treatment (P = 0.0018; Hazard ratio, 3.78; Fig. 4A
). Those patients with significant TS expression had an overall poorer survival compared with patient whose tumors did not express TS (P = 0.0071; Hazard ratio, 2.93; Fig. 4B
).
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Multivariate Analysis.
No variables demonstrated statistically significant associations with DFS. Four variables were significant predictors of OS: lymph node metastases, p53 overexpression, high GST expression, and TS expression. There was a statistically significant interaction between p53 and GST. The final multivariable model is shown in Table 5
. (Because of the interaction, the effect of p53 mutation versus wild-type is shown separately for each GST level.)
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DISCUSSION |
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TopABSTRACTINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONREFERENCES |
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, and TS are associated with poor prognosis in head and neck tumor patients treated with neoadjuvant cisplatin/5-FU or cisplatin/paclitaxel. Loss of wild-type p53 function has been associated with chemotherapy resistance in vitro (13) and in vivo (10 , 11) . p53 may participate in cellular pathways leading to apoptosis following treatment with DNA-damaging agents such as cisplatin (35, 36, 37) . Our data indicate that overexpression of p53 protein as determined by immunohistochemistry is a strong indicator of poor prognosis. Similar data have been demonstrated in bladder cancer where p53 overexpression has also been associated with decreased survival (12) . Analysis of the data from the Veterans Affairs larynx preservation trial similarly indicated that p53 was not associated with chemotherapy response but was correlated with decreased patient survival (38) .
GST expression was also associated with decreased survival in the patients evaluated in this study. GST has been widely studied as a factor contributing to cisplatin resistance in a spectrum of neoplasms (21
, 22)
. We previously demonstrated that expression of GST is associated with poor response to treatment in neoadjuvant and relapsed patients. In that study, GST was a significantly better predictor of response to treatment in relapsed patients than in patients receiving neoadjuvant chemotherapy (36)
. Similarly, in our present study, GST was a weak predictor of response to treatment, although it did have a stronger correlation with OS. Expression of GST has been shown to correlate with decreased survival in several malignancies (39
, 40)
, but a recent study in head and neck tumors demonstrated no clear correlation between GST expression and local control in patients receiving radiation treatment (41)
. Additionally, the association between GST expression and prognosis in other tumors is controversial (42
, 43)
.
Our analysis of TS expression supports previous studies that suggest that this enzyme may be associated with decreased treatment response and survival in patients with advanced head and neck cancer treated with 5-FU-based chemotherapy (26)
. In that study, TS expression was more common in moderately or well-differentiated tumors. We observed the same association between TS expression and tumor differentiation. Similar findings have been demonstrated in other malignancies, suggesting that TS expression may in part determine response to 5-FU-based chemotherapy and influence survival in a broad spectrum of tumors (25)
. The lack of association between TS expression and treatment response in our series may reflect the relatively small number of cases studied and the high overall response rate to neoadjuvant therapy. The observation that expression of p53, GST, and TS were more predictive of poor OS than DFS may indicate that these markers reflect the aggressiveness of disease in these patients. Patients with relapsed tumors that are negative for these factors may have a more indolent course and be more likely to respond to second-line chemotherapy than patients who have relapsed tumors that are positive for p53, GST, and TS. In support of this concept, we previously demonstrated that among relapsed patients, the response to cisplatin-based chemotherapy was 70% for patients whose tumors were GST-negative, but only 8% for patients who had GST-positive tumors (34)
.
Our data indicate that easily measured cellular factors may be important predictors of outcome in patients undergoing neoadjuvant treatment for head and neck malignancies. The magnitude of survival differences seen with p53 and the other markers indicate that these may ultimately be clinically useful in making treatment decisions for patients being considered for neoadjuvant treatment. For example, an attempt at organ preservation may be less attractive for a patient whose tumor profile predicts that he or she will be unlikely to respond or survive with that treatment strategy. If these data can be confirmed, it may be possible to guide the selection of chemotherapy agents based on the individual profile of gene expression in a given tumor. Patients with high TS expression but low c-erbB2 expression may be better candidates for a taxane-based regimen rather than a 5-FU-containing regimen. Additionally, poor prognosis patients may be identified as candidates for clinical trials involving new agents or dose-intensification schemes.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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1 Supported by National Cancer Institute Grant R21CA73866. 
2 To whom requests for reprints should be addressed, at Division of Hematology/Oncology, Georgetown University Medical Center, 3800 Reservoir Road NW, Washington, DC 20007. Phone: (202) 687-2198; Fax: (202) 687-6402; E-mail: cullenk{at}gunet.georgetown.edu
3 The abbreviations used are: CR, complete response; GST, glutathione S-transferase; MRP, multidrug-associated resistance protein; PR, partial response, NR, no response; PD, progressive disease; TS, thymidylate synthase; GSH-S, glutathione synthetase; DFS, disease-free survival; PFS, progression-free survival; OS, overeall survival.
Received 7/27/99; revised 9/ 8/99; accepted 9/ 9/99.
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