|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Journal of Clinical Oncology, Vol 22, No 24 (December 15), 2004: pp. 4901-4906 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.05.071 Prediction of TP53 Status for Primary Cisplatin, Fluorouracil, and Leucovorin Chemotherapy in Ethmoid Sinus Intestinal-Type AdenocarcinomaFrom the Medical Oncology Department, Head and Neck Unit, Unit of Experimental Molecular Pathology, Pathology Department, Medical Statistics and Biometrics, Department of Pathology, Department of Radiotherapy, Surgical Head and Neck Department, and Department of Experimental Oncology, Istituto Nazionale Tumori Milano; and Istituto Federazione Italiana Ricerca Cancro, Institute of Molecular Oncology, Milano, Italy. Address reprint requests to Lisa Licitra MD, Medical Oncology Department, Head and Neck Unit, Istituto Nazionale Tumori, Via Venezian 1, 20133 Milan-Italy; e-mail: lisa.licitra{at}istitutotumori.mi.it
PURPOSE: To assess the role of TP53 status in predicting pathologic complete remission after primary chemotherapy in patients with ethmoidal intestinal-type adenocarcinoma (ITAC). PATIENTS AND METHODS: Thirty patients with ethmoidal ITAC enrolled onto a phase II study received chemotherapy with cisplatin, fluorouracil, and leucovorin (PFL) followed by surgery and radiation. On surgical specimens, absence of viable tumor cells was defined as pathologic complete remission (pCR). TP53 status/p53 function, analyzed on pretreatment biopsies, were retrospectively correlated with pathologic results and patient outcome.
RESULTS: Twelve patients achieved a pCR; 18 patients did not (overall response rate, 40%). In patients with wild-type (wt) TP53 or functional p53 protein, the pCRs were 83% and 80%, respectively; in patients with mutated TP53 or impaired p53 protein, pCRs were 11% and 0%, respectively (P CONCLUSION: The results indicate the existence of two genetic ITAC subgroups, defined by differences in TP53 mutational status or protein functionality, that strongly influence pathologic response to primary chemotherapy and, ultimately, prognosis. PFL seems to be highly effective in terms of pCR and disease-free survival in the presence of a wt or a still-efficient p53 protein, even when encoded by a mutated TP53 gene (eg, early-stop codon mutation), but ineffective in ITACs carrying a disabled p53 protein. Whether this model is extensible to other head and neck cancers needs appropriate investigation.
Intestinal-type adenocarcinoma (ITAC) is an uncommon tumor of the sinonasal cavity characterized by high local aggressiveness and poor outcome. Several epidemiologic studies point out the association of ITAC with professional exposure to wood, leather, textile, cereal, or cement dust.1 Surgery is considered the standard treatment. The difficulty in obtaining a radical resection with negative margins, along with unsatisfactory outcome results, has increased the use of multimodality therapy, including chemotherapy and radiotherapy.2-6 Primary chemotherapy, although generally associated with good tumor response, is not currently considered a standard approach in head and neck squamous cell carcinoma (HNSCC) because of lack of improvement in survival.7 However, a patient's complete response to primary chemotherapy has been recognized as a strong favorable prognostic factor in HNSCC as well as in ITAC.6,8-10 The availability of biologic markers able to predict the response to primary chemotherapy would be advantageous and enable optimal patient selection, which would maximize treatment benefit and avoid unnecessary toxicity arising from patients being treated with potentially ineffective drugs. Mounting evidence at both the preclinical and clinical levels demonstrates that the so-called resistance to systemic drugs is partly due to the genetic make-up of a given tumor and especially to the functional status of genes involved in cell death pathways, such as TP53 and p16INK4a.11-13 One of the most important functions of p53 is the activation of genes involved in cell cycle arrest and DNA repair after DNA damage and apoptosis. In this context, TP53 mutations, which disable apoptosis, confer insensitivity to chemotherapeutic agents acting through this pathway. Many cytotoxic therapies rely on inducing p53-dependent apoptotic cell death. These drugs include cisplatin and fluorouracil, both belonging to the group of DNA-damaging treatments, which were used preoperatively in our study.6,14-16 Clinical attempts to use chemosensitivity studies in relation to TP53 status for therapy guidance have shown a trend toward a better response for wild-type (wt) TP53–carrying cancers, which was mainly dependent on the tumor type and the drugs used.15,17-23 Conversely, TP53 mutations have been recognized as negative independent predictors of response to platinum and fluorouracil chemotherapy in HNSCC.24-26 Both observations point out the relevance of efficient apoptosis for a tumor response to a DNA-damaging treatment. In a previous investigation carried out on a series of ITACs treated by surgery alone, we demonstrated that the presence of TP53 mutations is one of the main genetic hallmarks of this tumor.27 Considering the close correlation between ITAC and professional exposure, the link between genotoxic exposition and loss of p53 function, and the relationship between TP53 functional status and response to DNA-damaging treatment, we decided to investigate a series of patients with ITAC in which the TP53 gene mutation profile had been retrospectively assessed on pretreatment biopsy and who were treated within a prospective phase II study with cisplatin, fluorouracil, and leucovorin (PFL) followed by surgery and postoperative radiation. The results demonstrate that TP53 is a promising marker for predicting pathologic tumor response to primary chemotherapy.
Patients The case material was made up of 30 consecutive cases enrolled onto a prospective study with available baseline biopsies suitable for molecular analysis of TP53 status. The molecular assessment was performed retrospectively so that results were not available at the time of treatment. From November 1996 to January 2003, 30 patients with an ITAC histology were treated prospectively within a phase II study with primary chemotherapy followed by anterior craniofacial resection and radiotherapy. The study's background, rationale, patient selection criteria, and results evaluation based on the first 23 cases have been given in a previous article reporting the clinical series.6 The treatment plan consisted of primary PFL chemotherapy for five courses followed by anterior craniofacial resection and postoperative external portal beam radiotherapy. The PFL regimen included leucovorin 250 mg/m2/d given for the first 5 days as a 120-hour continuous infusion, fluorouracil 800 mg/m2/d delivered as a 96-hour continuous infusion on day 2 through day 5, and cisplatin 100 mg/m2 administered on day 2. Each cycle was repeated every 21 days for five courses. Response to chemotherapy was assessed clinically and/or radiologically according to the WHO criteria after every other planned course of therapy and with computed tomography or magnetic resonance imaging after the third and fifth course and in all cases before surgery. In case of progressive disease, stable disease, or minimal response, chemotherapy was discontinued and the patient was referred to surgical treatment. After surgery, all gross specimens were carefully evaluated, and surface-labeled sections were taken. The pathologic response to chemotherapy was determined by a thorough examination that included 20 to 25 tumor sections. A complete pathologic remission (pCR) was defined as absence of any viable tumor cells.
Molecular Analysis of TP53 Gene on Pretreated Biopsies TP53 screening and sequencing. The samples were screened by double-gradient denaturating gradient gel electrophoresis analysis, performed as previously described.27 Briefly, after electrophoresis, gels were stained with ethidium bromide. Samples with mutations were identified by the presence of abnormal migration pattern compared with a control carrying a wt TP53 (SiHa cell line) and with samples carrying well-known mutations. The cases showing an abnormal double-gradient denaturating gradient gel electrophoresis were further amplified and then subjected to automated DNA sequencing (ABIprism 377; Applied Biosystems, Mouza-Milan, Italy) as previously described.27 The detected mutations were confirmed at least twice by independent amplifications and sequence reactions.
Statistical Analysis
Among the 30 patients investigated, age varied between 23 and 70 years (median age, 59 years). There were 27 male patients and three female patients. A history of genotoxic exposures related to working activities was recorded in 26 patients (87%). Sixty percent of patients achieved a clinical response (complete response rate, 17%; partial response rate, 43%). Therefore, the overall response rate was 40% (95% exact CI, 23% to 59%). Table 1 details TP53 gene status and p53 protein properties with respect to pathologic response to chemotherapy. Twelve patients achieved a pCR, whereas 18 patients were found to have microscopic residual tumor in the surgical specimen, thus not achieving a pCR.
TP53 mutational analysis was successfully performed in all 30 cases of ITACs. Seventeen (57%) of 30 cases were found to be mutated in the hot-spot exons (5 through 8). Position and incidence of the mutations can be summarized as follows: nine base substitutions were located in exon 5, one was located in exon 6, and three were located in exon 7. Moreover, we identified two silent mutations, which do not result in a change in the amino acid sequence and thus harbor a functional p53 protein,29 and one nonsense mutation leading to a premature stop codon. In addition, we detected 10 missense mutations resulting in an amino acid substitution, one base substitution in intron 6, one insertion in exon 6, and two deletions in exon 5 and in exon 8. All such types of mutations are considered disabling by definition.30 In all responsive and nonresponsive cases showing in TP53 gene a wt configuration from exon 5 to 8, we extended the molecular analysis to exons 4, 9, and 10. Only one case turned out to carry a nonsense mutation in exon 10. Overall, in terms of TP53 status, we identified 12 wt cases and 18 mutated cases. However, a functional p53 protein was present in 15 cases (12 wt, two silent mutations, and one early premature stop codon). Disabling mutations were detected in 15 cases. Table 2 lists T stage, treatments, and response to primary chemotherapy according to TP53 status and p53 properties.
Tumor stage reflects the accrual criteria of the protocol in which patients were enrolled. The majority of patients received postoperative radiation. Typically, no patients had a nodal extension of disease. T stage and the frequency and dose range of radiotherapy were not significantly associated with TP53 status or p53 properties. However, T stage tended to be higher in the presence of mutated TP53 or impaired p53 protein (P = .0869 in the latter case). Treatment consisted of primary chemotherapy followed by surgery and postoperative radiation. According to the protocol design, clinically responding patients received three or more cycles, whereas nonresponding patients received two or fewer cycles.
The pathologic response rate was strongly associated with TP53 status/p53 function. A high response rate was obtained in patients with wt TP53 (83%; 95% CI, 52% to 98%) or functional p53 protein (80%; 95% CI, 52% to 96%), as compared with a significantly lower response rate (P With a median follow-up time of 55 months, not one of the 12 patients achieving a pCR after chemotherapy had a relapse. By contrast, 10 of the 18 cases with residual tumor after primary chemotherapy showed a recurrence at a median time of 49 months (P = .0061, log-rank test).
To verify whether the TP53 deregulation profile of ITAC influences treatment activity, we assessed the TP53 gene mutation profile of pretreatment biopsies in a series of 30 ITAC patients enrolled in a prospective study who were treated with chemotherapy with PFL followed by surgery and postoperative radiation therapy. Twelve patients achieved a surgically assessed pCR after primary chemotherapy, and 18 patients did not. Considering that similar regimens under the same conditions provide in HNSCC less impressive pCR rates, our results suggest a good activity of this regimen in ITAC and possibly in other adenocarcinomas of the head and neck. In particular, a significantly higher pCR rate (83%) was observed in patients carrying tumors with wt TP53. By contrast, 89% of patients bearing mutated TP53 tumors did not achieve a pCR. These observations are not in contrast to those reported in HNSCC patients similarly treated. This is true in particular when, like in our study, the reference biomarker was studied by gene sequencing instead of its protein expression. Moreover, a similar correlation between gene status and response was found when it was looked at in cases achieving a pathologically negative biopsy after induction chemotherapy.24-26 Considering the functional properties of p53 mutations, predictivity decreased from 83% to 80% for responders, whereas predictivity was 100% in nonresponders. In detail, all cases achieving a pCR carried a functional p53 (wt type in 10 cases; functionally silent mutation in one case; an early premature stop codon mutation in another), whereas all cases carrying a disabling p53 mutation, corresponding to 15 cases with missense, frame-shift, or late-stop codon mutations, were resistant. Case numbers 11 and 20 are particularly worth mentioning. Both cases harbor nonsense mutations that are currently thought to be disabling mutations. However, the premature Gln136Stop/CAA>TAA mutation leads to a very short protein, which is promptly degraded through ubiquitin-proteasome pathway. By contrast, the Glu339Stop/GAG>TAG mutation retains all aminoacidic sequences but the oligomerization site. Consistently, the former has been recently reported to be responsive to DNA-damaging treatment in breast cancer,31 whereas the second one has been reported to lack DNA-binding and transactivation capacities and thus to code a disabling protein.32 In three cases in which pCR was not achieved, two carrying wt p53 and one a silent mutation, one can speculate that other genetic events might be involved or that, according to pharmacogenetic findings, different patients may have different drug metabolization ability. These results fit with our current understanding of the molecular basis of drug action and the interplay of the tumor genetic background with chemotherapy and offer an explanation for the pCR rate after PFL treatment in ITACs, as well as after other DNA-damaging–based compounds in other tumors, such as HNSCC and carcinoma of the colon and ovary. The PFL regimen, like most compounds exerting their cytotoxic effects through DNA damage, requires a functional apoptotic machinery. On the other hand, the presence of a wt gene may favor tumor control through the maintenance of a functioning cell cycle arrest mechanism. This explains why complete responses may be restricted to functional p53–bearing ITACs. The finding that the same type of response may be observed in other types of tumors is not surprising, because tumors sharing similar functional profiles are expected to show similar treatment responses, irrespective of the histotype and tumor site. Outside head and neck tumors, similar results were seen in colon adenocarcinoma treated with fluorouracil33-35 and ovarian cancer treated with platinum-based regimens.15 In other instances, this correlation was not found. This could be due either to the use of drugs that depend on a functional p53 for their action given irrespectively to tumor p53 status segregation36 or to the different methodologies used in assessing the TP53/p53 status as immunocytochemistry versus gene mutation detection, as already mentioned.37-39 In the present series, wt TP53 represents a robust predictive factor for pCR, and pCR in turn represents a strong prognostic factor. Both such factors predict an effective response to chemotherapy. The optimal outcome of patients achieving a pCR, where 100% were without evidence of relapse, as compared with those who did not, where 44% had already had a relapse, gives support to this assumption. Furthermore, because the efficiency of the apoptosis machinery relies on tumor make-up, it is not unexpected that in our series, TP53 status correlates with pCR better than with T extension. From our results, it also seems that the presence of a disabling p53 is a stronger predictor for PFL failure in ITACs. TP53 mutations, which disable apoptosis, may confer insensitivity to DNA-damaging chemotherapeutic agents. On the basis of the lack of evidence supporting any benefit of induction chemotherapy in ITAC, as well as for other head and neck cancers, the rational approach would be to not administer induction PFL to patients with mutated p53, reserving it only for patients with functioning p53 in order to maximize the probability of pCR, possibly allowing organ-preserving approaches. On the other hand, future research on induction chemotherapy should focus on new drug combinations that can be effective in mutated p53-carrying ITACs. We are well aware that a randomized trial on this rare tumor type is practically unfeasible. However, as an explorative future study, we are planning to evaluate the pCR rate of mutated cases treated with p53-independent drugs, such as taxanes. In conclusion, although the predictive value of TP53 needs to be confirmed in larger series of patients with ITAC, our preliminary results support the notion that p53 status represents a promising biomarker to predict response to chemotherapy. The presence of a wt or still-efficient p53 protein encoded by a mutated TP53 gene (eg, early-stop codon mutation), as well as the presence of a disabling p53 protein, may affect the pCR. These findings also suggest that it might be useful to assess the value of primary treatments tailored to different genotypes across different histotypes. This molecular partitioning of histotypes might allow a survival improvement with currently available treatments. Whether this model can be applied to other head and neck cancers should be evaluated in appropriate studies.
The authors indicated no potential conflicts of interest.
We thank the following pathologists who kindly contributed case material: G. Giacomini, Casa di cura "S. Camillo", Forte dei Marmi (Lucca); A. Tomezzoli, Ospedale Maggiore, Verona; A. Coci, Ospedale, Vigevano; C. Paties, Ospedale San Raffaele, Milano; U. Magrini, Università, Pavia; D. Messina, Azienda ospedaliera "S. Antonio Abate", Trapani; C. Capella, Ospedale di Circolo/Fondazione E. Macchi, Varese; A. Colavecchio, Ospedale Maggiore, Crema; F. Tanda, Università, Sassari; M. Biancalani, Ospedale "S. Giuseppe", Firenze; C. Gentili, Presidio ospedaliero, Camaiore (Lucca); G. Salomoni, Ospedale generale di zona "S. Giuseppe", Milano; E. Tafani, Azienda ospedaliera "G. Salvini", Garbagnate Milanese (Milan); D. Tricoli, Ospedale Gravina, Caltagirone (Catania); G. Angeli, Presidio ospedaliero "S. Andrea", Vercelli; G. Marchetti, Azienda ospedaliera pisana, Pisa; G. Sangalli, Azienda ospedaliera "Ospedale di Circolo", Busto Arsizio (Varese); R. Barbozza, Ospedale, Feltre (Belluno); M. Cardarelli, Azienda ospedaliera, Macerata; G.A. Arrigoni, Azienda ospedaliera, Treviso; M. Giansanti, Università degli Studi, Perugia; and C. Schena, Ospedale "Guglielmo da Saliceto", Piacenza, Italy.
Supported in part by Associazione Italiana per la Ricerca sul Cancro, Milan, Italy. S.P. and M.A.P. contributed equally to this work. Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Barnes L: Intestinal-type adenocarcinoma of the nasal cavity and paranasal sinuses. Am J Surg Pathol 10:192-202, 1986[CrossRef][Medline] 2. Wax MK, Yun KJ, Wetmore SJ, et al: Adenocarcinoma of the ethmoid sinus. Head Neck 17:303-311, 1995[Medline]
3. Brasnu D, Laccourreye O, Bassot V, et al: Cisplatin-based neoadjuvant chemotherapy and combined resection for ethmoid sinus adenocarcinoma reaching and/or invading the skull base. Arch Otolaryngol Head Neck Surg 122:765-768, 1996 4. Jiang GL, Morrison WH, Garden AS, et al: Ethmoid sinus carcinomas: Natural history and treatment results. Radiother Oncol 49:21-27, 1998[CrossRef][Medline] 5. Lee MM, Vokes EE, Rosen A, et al: Multimodality therapy in advanced paranasal sinus carcinoma: Superior long-term results. Cancer J Sci Am 5:219-223, 1999[Medline]
6. Licitra L, Locati LD, Cavina R, et al: Primary chemotherapy followed by anterior craniofacial resection and radiotherapy for paranasal cancer. Ann Oncol 14:367-372, 2003 7. Pignon JP, Bourhis J, Domenge C, et al: Chemotherapy added to locoregional treatment for head and neck squamous-cell carcinoma: Three meta-analyses of updated individual data—MACH-NC Collaborative Group, Meta-Analysis of Chemotherapy on Head and Neck Cancer. Lancet 355:949-955, 2000[Medline] 8. Dreyfuss AI, Clark JR: Analysis of prognostic factors in squamous cell carcinomas of the head and neck. Hematol Oncol Clin North Am 5:701-712, 1991[Medline] 9. Cognetti F, Pinnaro P, Ruggeri EM, et al: Prognostic factors for chemotherapy response and survival using combination chemotherapy as initial treatment of advanced head and neck squamous cell cancer. J Clin Oncol 7:829-837, 1989[Abstract] 10. Jacobs C, Goffinet DR, Goffinet L, et al: Chemotherapy as a substitute for surgery in the treatment of advanced resectable head and neck cancer: A report from the Northern California Oncology Group. Cancer 60:1178-1183, 1987[CrossRef][Medline]
11. Lowe SW, Bodis S, McClatchey A, et al: p53 status and the efficacy of cancer therapy in vivo. Science 266:807-810, 1994 12. Johnstone RW, Ruefli AA, Lowe SW: Apoptosis: A link between cancer genetics and chemotherapy. Cell 108:153-164, 2002[CrossRef][Medline] 13. Schmitt CA, Fridman JS, Yang M, et al: A senescence program controlled by p53 and p16 ink4a contributes to the outcome of cancer therapy. Cell 109:335-346, 2002[CrossRef][Medline]
14. Righetti SC, Della Torre G, Pilotti S, et al: A comparative study of p53 gene mutations, protein accumulation and response to cisplatin-based chemotherapy in advanced ovarian cancer. Cancer Res 56:689-693, 1996
15. Lavarino C, Pilotti S, Oggionni M, et al: p53 gene status and response to platinum/paclitaxel-based chemotherapy in advanced ovarian carcinoma. J Clin Oncol 18:3936-3945, 2000 16. Bunz F, Hwang PM, Torrance C, et al: Disruption of p53 in human cancer cells alters the responses to therapeutic agents. J Clin Invest 104:263-269, 1999[Medline]
17. Reles A, Wen WH, Schmider A, et al: Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer. Clin Cancer Res 7:2984-2997, 2001 18. Aas T, Borresen AL, Geisler S, et al: Specific P53 mutations are associated with de novo resistance to doxorubicin in breast cancer patients. Nat Med 2:811-814, 1996[CrossRef][Medline]
19. Kandioler-Eckersberger D, Ludwig C, Rudas M, et al: TP53 mutation and p53 overexpression for prediction of response to neoadjuvant treatment in breast cancer patients. Clin Cancer Res 6:50-56, 2000 20. Bertheau P, Plassa F, Espie M, et al: Effect of mutated TP53 on response of advanced breast cancers to high-dose chemotherapy. Lancet 360:852-854, 2002[CrossRef][Medline]
21. Kandioler-Eckersberger D, Kappel S, Mittlbock M, et al: The TP53 genotype but not immunohistochemical result is predictive of response to cisplatin-based neoadjuvant therapy in stage III non-small cell lung cancer. J Thorac Cardiovasc Surg 117:744-750, 1999 22. Vogt U, Zaczek A, Klinke F, et al: p53 Gene status in relation to ex vivo chemosensitivity of non-small cell lung cancer. J Cancer Res Clin Oncol 128:141-147, 2002[CrossRef][Medline]
23. Wattel E, Preudhomme C, Hecquet B, et al: p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 84:3148-3157, 1994 24. Fouret P, Temam S, Charlotte F, et al: Tumour stage, node stage, p53 gene status, and bcl-2 protein expression as predictors of tumour response to platin-fluorouracil chemotherapy in patients with squamous-cell carcinoma of the head and neck. Br J Cancer 87:1390-1395, 2002[CrossRef][Medline]
25. Temam S, Flahault A, Perie S, et al: p53 gene status as a predictor of tumor response to induction chemotherapy of patients with locoregionally advanced squamous cell carcinomas of the head and neck. J Clin Oncol 18:385-394, 2000
26. Cabelguenne A, Blons H, de Waziers I, et al: p53 alterations predict tumor response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma: A prospective series. J Clin Oncol 18:1465-1473, 2000 27. Perrone F, Oggionni M, Birindelli S, et al: TP53, p14ARF, p16INK4a and H-ras gene molecular analysis in intestinal type adenocarcinoma of the nasal cavity and paranasal sinuses. Int J Cancer 105:196-203, 2003[CrossRef][Medline] 28. Birindelli S, Perrone F, Oggionni M, et al: Rb and TP53 pathway alterations in sporadic and NF1-related malignant peripheral nerve sheath tumors. Lab Invest 81:833-844, 2001[Medline]
29. Strauss BS: Silent and multiple mutations in p53 and the question of the hypermutability of tumors. Carcinogenesis 18:1445-1452, 1997
30. Harris CC: Structure and function of the p53 suppressor gene: Clues for rational cancer therapeutic strategies. J Natl Cancer Inst 88:1442-1455, 1996
31. Geisler S, Loning PE, Aas T, et al: Influence of TP53 gene alterations and c-erbB-2 expression on the response to treatment with doxorubicin in locally advanced breast. Cancer Res 61:2505-2512, 2001 32. Rollenhagen C, Chene P: Characterization of p53 mutants identified in human tumors missense mutation in the tetramerization domain. Int J Cancer 78:372-376, 1998[CrossRef][Medline]
33. Ahnen DJ, Feigl P, Quan G, et al: Ki-ras mutation and p53 overexpression predict the clinical behavior of colorectal cancer: A Southwest Oncology Group study. Cancer Res 58:1149-1158, 1998
34. Elsaleh H, Powell B, McCaul K, et al: P53 alteration and microsatellite instability have predictive value for survival benefit from chemotherapy in stage III colorectal carcinoma. Clin Cancer Res 7:1343-1349, 2001 35. Liang JT, Huang KC, Cheng YM, et al: P53 overexpression predicts poor chemosensitivity to high-dose 5-fluorouracil plus leucovorin chemotherapy for stage IV colorectal cancers after palliative bowel resection. Int J Cancer 97:451-457, 2002[CrossRef][Medline]
36. Kinzler KW, Vogelstein B: Cancer therapy meets p53. N Engl J Med 331:49-50, 1994 37. Taylor D, Koch WM, Zahurak M, et al: Immunohistochemical detection of p53 protein accumulation in head and neck cancer: Correlation with p53 gene alterations. Hum Pathol 30:1221-1225, 1999[CrossRef][Medline] 38. Ma L, Ronai A, Riede UN, et al: Clinical implication of screening p53 gene mutations in head and neck squamous cell carcinomas. J Cancer Res Clin Oncol 124:389-396, 1998[CrossRef][Medline] 39. Casey G, Lopez ME, Ramos JC, et al: DNA sequence analysis of exons 2 through 11 and immunohistochemical staining are required to detect all known p53 alterations in human malignancies. Oncogene 13:1971-1981, 1996[Medline] Submitted May 12, 2004; accepted September 22, 2004.
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
TOP
ABSTRACT
INTRODUCTION
.0001). At a median 55-month follow-up, all pCR patients were disease-free; 44% of nonresponding patients experienced relapse (P = .0061). 
