Chemotherapy In Head And Neck Squamous Cell Carcinoma Research Articles

Role of celecoxib in reducing cognitive impairment in patients receiving definitive chemoradiation for head and neck carcinoma: A phase II randomized placebo controlled trial (CELCI-HN study).

TPS12150 Background: Head and neck squamous cell carcinoma (HNSCC) is common in the Indian subcontinent and majority (65%) patients present in an advanced stage. Chemotherapy related cognitive impairment (CRCI) is a poorly defined and underestimated phenomenon in the HNSCC population. Through this study, we are attempting to establish evidence of activity of agents targeting neuro-inflammation in reducing or halting cognitive decline associated with definitive chemoradiotherapy for head and neck malignancies without adding to treatment-associated toxicity. This study can potentially aid in developing a cost effective approach with a readily available and cheap agent like celecoxib in improving the quality of life in this cohort of patients. Methods: This is a single center, double blinded placebo controlled phase 2 randomized trial. We intend to randomize 92 non metastatic HNSCC patients registered at a large tertiary cancer center of North India {Department of Medical Oncology (Head and Neck Cancer Clinic, All India Institute of Medical Sciences-National Cancer Institute, India)} planned for definitive chemoradiation (CTRT) with or without induction chemotherapy. Patients in the experimental arm will receive celecoxib 100 mg or matched placebo tablet orally twice a day starting with day 1 of initiation of definitive chemoradiotherapy/induction chemotherapy for a duration of 6 months or until unacceptable toxicity. Our primary objective is to determine the activity of celecoxib versus placebo in reducing cognitive decline in patients undergoing definitive CTRT with or without induction chemotherapy in HNSCC through patient reported outcome tools (FACT cog questionnaire). Secondary objectives include assessment of adverse event profile (measured using CTCAE v5.0), objective assessment of neurocognitive decline using neuropsychological battery of tests, to identify predictors of cognitive decline on the basis of site of malignancy, radiation dose to the base of skull and brainstem, age, comorbidities and educational status. Tertiary objective include evaluation of inflammatory biomarkers e.g serum COX-2, serum Interleukin and tumor necrosis factors-alpha levels at the end of therapy and on follow up. Clinical trial information: CTRI/2022/09/045579.

Results from two phase II studies of SI-B001, an EGFR×HER3 bispecific antibody, with/without chemotherapy in patients (pts) with recurrent and metastatic head and neck squamous cell carcinoma (HNSCC).

6037 Background: SI-B001 is an EGFR×HER3 bispecific antibody. We present the efficacy and safety results from two ongoing studies of SI-B001, S209 and S206, in recurrent and metastatic HNSCC. Methods: S209 included pts with recurrent and metastatic HNSCC progressed on prior anti-PD-1/L1 plus platinum-based chemotherapy (PBC). Pts were treated with SI-B001 16mg/kg IV QW. S206 included pts with recurrent and metastatic HNSCC progressed on prior anti-PD-1/L1 with or without PBC and received no more than two lines of treatment. Pts enrolled in S206 were divided into two groups: Group A, pts without prior exposure to paclitaxel were treated with SI-B001 (12mg/kg IV QW) plus paclitaxel (80mg/m2 IV QW); Group B, pts with prior exposure to paclitaxel were treated with SI-B001 (12mg/kg IV QW) plus docetaxel (35mg/m2 IV D1D8D15 Q4W). The study endpoints of the two studies were identical. The primary endpoint was objective response rate (ORR) by investigator per RECIST v1.1. Secondary endpoints were ORR by independent central review, progression-free survival (PFS), disease control rate (DCR), duration of response (DOR), overall Survival (OS), and safety. Results: As of Dec 31, 2022, 11 pts in S209 received SI-B001. Pts had a median of 4 prior lines of therapy. In 9 out of 11 pts who have at least 1 post baseline tumor assessment in S209, ORR (n/N) was 22.2% (2/9), mPFS [95%CI] was 2.7 [1.8-7.9] mo. 29 pts in S206 received SI-B001 plus chemotherapy, including 19 pts in Group A and 10 pts in Group B. In 22 pts who had at least 1 post baseline tumor assessment, ORR was 45.5% (10/22), mPFS was 5.1 [3.7-5.6] mo. 1 nasal sinus cancer pt enrolled had stable disease (SD). 14 out of the 18 pts who have at least 1 post baseline tumor assessment in Group A, ORR was 64.3% (9/14) mPFS was 5.6 [5.1-6.3] mo. 8 out of 10 pts who have at least 1 post baseline tumor assessment in Group B, ORR was 12.5% (1/8), mPFS was 1.9 [1.2-3.7] mo. The most common grade 3 and above treatment-related adverse events (TRAEs) in S209 was Hypomagnesaemia (9%). The most common grade 3+ TRAEs in S206 were rash (16%), anaemia (8%) and white blood cell count decreased (8%). No SI-B001 drug-related deaths occurred in either study. Conclusions: SI-B001 plus paclitaxel demonstrated potential improvements in ORR and DCR compared with SI-B001 monotherapy in recurrent and metastatic HNSCC. The toxicity of SI-B001 plus chemotherapy in HNSCC is manageable and tolerable. Clinical trial information: NCT05044897 ; NCT05054439 . [Table: see text]

Mechanisms involved in cancer stem cell resistance in head and neck squamous cell carcinoma.

Despite scientific advances in the Oncology field, cancer remains a leading cause of death worldwide. Molecular and cellular heterogeneity of head and neck squamous cell carcinoma (HNSCC) is a significant contributor to the unpredictability of the clinical response and failure in cancer treatment. Cancer stem cells (CSCs) are recognized as a subpopulation of tumor cells that can drive and maintain tumorigenesis and metastasis, leading to poor prognosis in different types of cancer. CSCs exhibit a high level of plasticity, quickly adapting to the tumor microenvironment changes, and are intrinsically resistant to current chemo and radiotherapies. The mechanisms of CSC-mediated therapy resistance are not fully understood. However, they include different strategies used by CSCs to overcome challenges imposed by treatment, such as activation of DNA repair system, anti-apoptotic mechanisms, acquisition of quiescent state and Epithelial-mesenchymal transition, increased drug efflux capacity, hypoxic environment, protection by the CSC niche, overexpression of stemness related genes, and immune surveillance. Complete elimination of CSCs seems to be the main target for achieving tumor control and improving overall survival for cancer patients. This review will focus on the multi-factorial mechanisms by which CSCs are resistant to radiotherapy and chemotherapy in HNSCC, supporting the use of possible strategies to overcome therapy failure.

Targeting the Tumor Microenvironment through mTOR Inhibition and Chemotherapy as Induction Therapy for Locally Advanced Head and Neck Squamous Cell Carcinoma: The CAPRA Study.

Simple SummaryThe PI3K-AKT-mTOR pathway is dysregulated in 70% of head and neck squamous cell carcinoma (HNSCC) and linked to the tumor microenvironment. This weekly induction treatment combined the mTOR inhibitor everolimus with carboplatin-paclitaxel chemotherapy for locally advanced T3-4/N0-3 HNSCC. In 41 patients, safety profile was favorable and overall response rate was 75.6%. Translational data demonstrated specific target engagement with p-S6K decrease in tumor tissue and pro-immunogenic cytokine release in peripheral blood. Induction treatment with chemotherapy and mTOR inhibitors may provide new therapeutic options and rationale for combinations with immune oncology agents for locally advanced HNSCC.Mammalian target of rapamycin (mTOR) regulates cellular functions by integrating intracellular signals and signals from the tumor microenvironment (TME). The PI3K-AKT-mTOR pathway is activated in 70% of head and neck squamous cell carcinoma (HNSCC) and associated with poor prognosis. This phase I-II study investigated the effect of mTOR inhibition using weekly everolimus (30 mg for dose level 1, 50 mg for dose level 2) combined with weekly induction chemotherapy (AUC2 carboplatin and 60 mg/m2 paclitaxel) in treatment-naïve patients with locally advanced T3-4/N0-3 HNSCC. Patients received 9 weekly cycles before chemoradiotherapy. Objectives were safety and antitumor activity along with tissue and blood molecular biomarkers. A total of 50 patients were enrolled. Among 41 evaluable patients treated at the recommended dose of 50 mg everolimus weekly, tolerance was good and overall response rate was 75.6%, including 20 major responses (≥50% reduction in tumor size). A significant decrease in expression of p-S6K (p-value: 0.007) and Ki67 (p-value: 0.01) was observed in post-treatment tumor tissue. Pro-immunogenic cytokine release (Th1 cytokines IFN-γ, IL-2, and TNF-β) was observed in the peripheral blood. The combination of everolimus and chemotherapy in HNSCC was safe and achieved major tumor responses. This strategy favorably impacts the TME and might be combined with immunotherapeutic agents.

N6-methyladenosine-associated prognostic pseudogenes contribute to predicting immunotherapy benefits and therapeutic agents in head and neck squamous cell carcinoma.

Rationale: N6-methyladenosine (m6A) is involved in critical cancerous processes. Pseudogenes play various roles in carcinogenesis and progression. However, the functional roles of m6A-associated pseudogenes in head and neck squamous cell carcinoma (HNSCC) are largely unknown. Methods: We systematically analyzed the mRNA profile of 24 m6A regulators and 13931 pseudogenes from The Cancer Genome Atlas HNSCC dataset and ultimately identified 10 m6A-associated prognostic pseudogenes, which were validated in the Gene Expression Omnibus and our hospital datasets. Based on the risk score of m6A-associated pseudogenes, comprehensive analytical frameworks and experimental validation were implemented among pseudogene-defined low-/high-risk subtypes. Results: Here, we found expression pattern of m6A-associated pseudogenes was significantly associated with infiltrating immune cell compositions, and the expression of antitumor immune response markers, including T cell exhaustion, antigen presentation, interferon, and kinase genes. The m6A-associated pseudogenes, which had dramatic m6A peaks and higher m6A levels, could regulate the expression of targeted immune-involved genes through miRNAs. We experimentally validate the oncogene PDIA3P1, and tumor-suppressor RRN3P3, which promote the RNA and protein expression of their targeted immune-involved genes AKT1 and EZH2 via miR-34a-5p and miR-26b-5p, respectively. Moreover, HNSCC patients in the high-risk subtype could benefit more from immune checkpoint inhibitors therapy. Furthermore, doxorubicin and topotecan were considered to hold the most promising therapeutic potential robustly in silico evidence and in vitro experiments for HNSCC patients in the high-risk subtype. Conclusions: Our discovery revealed that the 10 m6A-associated prognostic pseudogenes significantly contribute to predicting immunotherapy benefits and therapeutic agents, which might bring some potential implications for both immunotherapy and chemotherapy in HNSCC.

P38 Mitogen-activated protein kinase modulates cisplatin resistance in Head and Neck Squamous Cell Carcinoma cells

ObjectiveThis study aims to investigate the role of p38 Mitogen-activated protein kinase (MAPK) in imparting cisplatin resistance in head and neck squamous cell carcinoma (HNSCC) cells. DesignLaboratory generated cisplatin resistant HNSCC cells were treated with p38 inhibitor and were subjected to increasing dosage of cisplatin. Western blot, immunohistochemistry and RT PCR analysis were performed to investigate expression level of p-p38 and Cancer stem cell (CSC) markers in cisplatin resistant HNSCC cells with or without p38 inhibitor. Chemoresistance, wound healing capacity and Spheroids formation capacity were assessed following p38 inhibition in cisplatin resistant HNSCC cell lines. In addition, alkaline comet assay and γ-H2AX immunostaining were performed to evaluate the DNA damage response and repair abilities in cisplatin resistant HNSCC cells after p38 inhibition. ResultsIt was observed that following p38 inhibition, cisplatin resistant HNSCC cells exhibited significant reduction in expression of CSC markers, β-catenin, reduced migration potential and sphere forming ability along with increased apoptotic index demonstrating there was increased sensitivity towards Cisplatin. Molecular docking study identified several interface amino acid residues between p-p38 with CSC markers (Klf4 and CD44). p38 inhibited cisplatin resistant HNSCC cells also exhibited increased DNA damage as measured by Comet assay and γ-H2AX foci formation index. There was significant decrease in DNA repair as confirmed by reduced ERRC1 expression. ConclusionsOur study demonstrated that p38 MAPK inhibition can be a targeted approach to overcome resistance in HNSCC thereby escalating the effectiveness of chemotherapy in HNSCC.

Multi-kinase inhibitors and cisplatin for head and neck cancer treatment in vitro.

Multidrug resistance (MDR) remains one of the major causes of suboptimal outcome following therapy in head and neck squamous cell carcinoma (HNSCC). ATP-binding cassette (ABC) transporters are overexpressed in HNSCC, which contributes to the limited effect of chemotherapeutic treatment. In addition to their named function, tyrosine kinase inhibitors (TKIs) have been revealed to impact on ABC transporter activity and expression. Therefore, the present study aimed to investigate the effects of combination therapy using different TKIs combined with cisplatin. Reverse transcription-quantitative PCR was used to characterize ABC transporter and receptor expression in 5 HNSCC cell lines treated with 3 different TKIs (pazopanib, dovitinib, nintedanib) and cisplatin. Treatment efficacy was analyzed using a crystal violet staining assay. Analysis of ABC transporter (ABCB1, ABCC1 and ABCG2) genetic alterations was performed using The Cancer Genome Atlas. Statistical analysis was conducted to evaluate the effects of mono- and combination treatment. With the exception of ABCB1, all of the investigated ABC transporters were expressed in each cell line. The additive effects of TKI + cisplatin combination treatment were observed for pazopanib in three cell lines, nintedanib in four cell lines, and were not observed for dovitinib in any of the cell lines investigated. The combination of multi-kinase inhibitors and conventional chemotherapy in HNSCC may strengthen the use of current therapeutic strategies; nintedanib appears to be the most suitable TKI for combination therapy. Further efforts are required to classify TKI efficacy with regard to cisplatin resistance.

Molecular Markers of Anticancer Drug Resistance in Head and Neck Squamous Cell Carcinoma: A Literature Review.

This manuscript provides an update to the literature on molecules with roles in tumor resistance therapy in head and neck squamous cell carcinoma (HNSCC). Although significant improvements have been made in the treatment for head and neck squamous cell carcinoma, physicians face yet another challenge—that of preserving oral functions, which involves the use of multidisciplinary therapies, such as multiple chemotherapies (CT) and radiotherapy (RT). Designing personalized therapeutic options requires the study of genes involved in drug resistance. This review provides an overview of the molecules that have been linked to resistance to chemotherapy in HNSCC, including the family of ATP-binding cassette transporters (ABCs), nucleotide excision repair/base excision repair (NER/BER) enzymatic complexes (which act on nonspecific DNA lesions generated by gamma and ultraviolet radiation by cross-linking and forming intra/interchain chemical adducts), cisplatin (a chemotherapeutic agent that causes DNA damage and induces apoptosis, which is a paradox because its effectiveness is based on the integrity of the genes involved in apoptotic signaling pathways), and cetuximab, including a discussion of the genes involved in the cell cycle and the proliferation of possible markers that confer resistance to cetuximab.

Lactate Dehydrogenase B Is Associated with the Response to Neoadjuvant Chemotherapy in Oral Squamous Cell Carcinoma

Oral squamous cell carcinoma (OSCC) comprises a subset of head and neck squamous cell carcinoma (HNSCC) with poor therapeutic outcomes and high glycolytic dependency. Neoadjuvant chemotherapy regimens of docetaxel, cisplatin and 5-fluorouracil (TPF) are currently accepted as standard regimens for HNSCC patients with a high risk of distant metastatic spread. However, the antitumor outcomes of TPF neoadjuvant chemotherapy in HNSCC remain controversial. This study investigated the role of lactate dehydrogenase B (LDHB), a key glycolytic enzyme catalyzing the inter-conversion between pyruvate and lactate, in determining chemotherapy response and prognosis in OSCC patients. We discovered that a high protein level of LDHB in OSCC patients was associated with a poor response to TPF regimen chemotherapy as well as poor overall survival and disease-free survival. Our in-depth study revealed that high LDHB expression conferred resistance to taxol but not 5-fluorouracil or cisplatin. LDHB deletion sensitized OSCC cell lines to taxol, whereas the introduction of LDHB decreased sensitivity to taxol treatment. Taxol induced a pronounced impact on LDHB-down-regulated OSCC cells in terms of apoptosis, G2/M phase cell cycle arrest and energy metabolism. In conclusion, our study highlighted the critical role of LDHB in OSCC and proposed that LDHB could be used as a biomarker for the stratification of patients for TPF neoadjuvant chemotherapy and the determination of prognosis in OSCC patients.

YM155 Reverses Cisplatin Resistance in Head and Neck Cancer by Decreasing Cytoplasmic Survivin Levels

Cisplatin is one of the commonly used chemotherapeutic drugs for the treatment of head and neck squamous cell carcinoma (HNSCC). However, acquisition of cisplatin resistance is common in patients with HNSCC, and it often leads to local and distant failure. In this study, we showed that survivin expression is significantly upregulated in HNSCC primary tumors and cell lines. In addition, survivin levels were significantly higher in human papilloma virus-negative patients that normally respond poorly to cisplatin treatment. Survivin expression was further increased in cisplatin-resistant cells (CAL27-CisR) as compared with its parent cells (CAL27). Therefore, we hypothesized that targeting of survivin in HNSCC could reverse the resistant phenotype in tumor cells, thereby enhancing the therapeutic efficacy of cisplatin. We used both in vitro and in vivo models to test the efficacy of YM155, a small molecule survivin inhibitor, either as a single agent or in combination with cisplatin. YM155 significantly decreased survivin levels and cell proliferation in a dose-dependent manner. In addition, YM155 pretreatment significantly reversed cisplatin resistance in cancer cells. Interestingly, YM155 treatment altered the dynamic localization of survivin in cells by inducing a rapid reduction in cytoplasmic survivin, which plays a critical role in its antiapoptotic function. In a severe combined immunodeficient mouse xenograft model, YM155 significantly enhanced the antitumor and antiangiogenic effects of cisplatin, with no added systemic toxicity. Taken together, our results suggest a potentially novel strategy to use YM155 to overcome the resistance in tumor cells, thereby enhancing the effectiveness of the chemotherapy in HNSCC.

A pilot study of raltegravir and cisplatin in head and neck squamous cell carcinoma (HNSCC).

TPS5602 Background: Metnase is a recently characterized DNA repair component present in anthropoid primates. Metnase, the fusion of a SET histone methylase domain and a Transposase nuclease (Tn) domain, enhances DNA double-stranded break (DSB) repair. The Tn domain trims free DNA ends for optimal end-joining, and is required to re-start stalled replication forks. The SET domain di-methylates H3K36 at the DSB, recruiting non-homologous end-joining repair components. Cisplatin (CDDP), the central chemotherapy in HNSCC, covalently binds DNA leading to intra- and interstrand crosslinks (ICL). In addition to blocking strand transcription and segregation, the ICL stalls DNA replication fork progression leading to collapse and DSB. The role of Metnase in DNA repair, including overcoming the stalled replication fork, makes it a potential therapeutic target. We hypothesize that Metnase inhibition may be a useful adjunct to CDDP. 3D modeling of the Metnase Tn domain identified significant homology with human immunodeficiency virus 1 (HIV-1) integrase. A virtual screen of the Chem Div library identified the HIV-1 integrase inhibitor, raltegravir, as a lead compound for inhibiting the Metnase Tn domain. We designed a pilot study in HNSCC to evaluate potentiation of CDDP DNA damage by raltegravir. Methods: The primary objective of this window-of-opportunity study is to analyze biomarkers of DNA damage, fork arrest, and apoptosis in serial tumor biopsies from patients (pts) with HNSCC undergoing CDDP, with and without raltegravir. Eligible pts: 1) have HNSCC with tumor site amenable to repeat, awake biopsy; 2) are appropriate candidates for CDDP. Pts are treated with 2 doses of CDDP 30 mg/m2. One CDDP dose is administered with raltegravir 400 mg bid for 5 days, starting the day before CDDP. Pts undergo 3 research biopsies, at baseline and 48-72 hours after each CDDP. Serial biopsies will be evaluated for expression changes in γH2AX, Annexin V, pChk1, pChk2, and p53BP1 by immunohistochemistry. Numerical increase in biomarker expression in tumors exposed to CDDP-raltegravir vs. CDDP will justify development of a phase I/II study. Four of 12 pts have enrolled and completed all biopsies. Supported by a grant from the American Cancer Society.

Abstract 3744: Acetylated tubulin (AT) levels predicts response to TPF chemotherapy in locally advanced head and neck squamous cell carcinoma (HNSCC)

Abstract Docetaxel acts by binding to β-tubulin, stabilizing microtubules, and causing cell cycle arrest in the G2/M phase of mitosis. Previous reports by our group suggest the absence of acetylated tubulin in tumor samples is a predictor for disease control in patients treated on a phase I trial with Docetaxel and Lonafarnib[1]. In this study, we hypothesize that patients with HNSCC with low levels of microtubule acetylation (i.e. highly dynamic microtubules) as measured by immunohistochemistry (IHC) would respond better to induction therapy with TPF (Docetaxel, Cisplatin and 5FU), and hence the level of acetylated tubulin (AT) would be a predictor of response to TPF. Method: Between July 5th 2006 and September 29th2009, 14 patients with HNSCC were enrolled in a Phase II clinical trial of induction chemotherapy with 3 cycles of TPF followed by local therapy. Patients underwent a biopsy of their primary tumor site prior to initiation of induction TPF. The IHC staining for AT expression was performed on formalin fixed paraffin embedded tissue. The scoring was based on intensity only since tumor cells displayed a homogeneous staining pattern. An AT score of 4 was considered to be high, whereas a stain of 0, 1, 2 or 3 was considered low. Primary tumor sites included oral cavity (OC; n=6), oropharynx (OP; n=5), larynx (L; n=1), sinus (S; n=1), and unknown primary (UP; n=1). All patients had stage IVa or IVb at presentation and had a performance status of 0-2 (Eastern Cooperative Oncology Group ECOG scale). All had at least one uni- or bi-dimensional measurable lesion on imaging. The study closed prematurely due to slow accrual and increased observed complications. A total of 9 patients were evaluated: OC/4, OP/5. Results: After 3 cycles of TPF induction chemotherapy, complete remission (CR) was achieved in 4/9(44.5%), partial remission (PR) in 4/9(44.5%), and progressive disease (PD) in 1/9(11%) of patients. There was a significant correlation between AT staining intensity and response to TPF (p=0.0476). Patients with complete response (CR) or good partial response (GPR) (>60% reduction in tumor measurement) had a significantly lower staining intensity. No correlation was observed between staining intensity and progression free survival (PFS) or overall survival (OS) perhaps due to the small sample size. Conclusion: AT expression seems to correlate with response to TPF chemotherapy in HNSCC. Predicting response to TPF may prove to be useful in customizing care for patients with HNSCC. We are planning a larger scale retrospective analysis of the value of AT expression in predicting outcome for patients with HNSCC. 1. Kauh J, et al., Defining the Interaction of Docetaxel and Lonafarnib in Patients with Advanced Malignancies. AACR meeting, 2008, LB-67, 2008. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3744.

Alterations in the p53 pathway and their association with radio- and chemosensitivity in head and neck squamous cell carcinoma

Chemotherapy and/or radiotherapy are established measures in treatment protocols of head and neck squamous cell carcinoma (HNSCC). However, we still lack reliable predictive markers for the response to radio- and chemotherapy. The p53 pathway is involved in stress response and thus might influence chemo-/radiosensitivity. Using 29 HNSCC cell lines previously characterized for p53 mutations, we simultaneously analyzed several key players in the p53 pathway by RT-PCR, transcript sequencing and immunohistochemistry, and investigated their association with chemosensitivity and radiosensitivity. Cell lines with p53 mutations were slightly more sensitive to cisplatin than those with wild-type p53. The type of mutation did not influence radio- or chemosensitivity. p14(ARF), an activator of p53, was lost or mutated in all cell lines. Three cell lines showed overexpression of HDM-2, a major negative regulator of p53; however, HDM-2 levels did not correlate with radio- or chemosensitivity. HPV-16 oncoproteins were detected in one highly chemoresistant cell line. Our findings suggest that molecular events resulting in the inactivation of the p53 pathway occur in all HNSCC cell lines. However, single alterations in the p53 pathway are not reliable predictors for the response to radio- or chemotherapy in HNSCC.

P53 alterations predict tumor response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma: a prospective series.

The tumor suppressor gene p53 plays a crucial role in cell cycle control and apoptosis in response to DNA damages. p53 gene mutations and allelic losses at 17p are one of the most common genetic alterations in primary head and neck squamous cell carcinoma (HNSCC). Alterations of the p53 gene have been shown to contribute to carcinogenesis and drug resistance. In this prospective series, patients with HNSCC were treated with cisplatin-fluorouracil neoadjuvant chemotherapy. p53 status was characterized in 106 patients with HNSCC (p53 mutations, allelic losses at p53 locus, and plasma anti-p53 antibodies) to determine the existence of a relationship between p53 gene status and response to neoadjuvant chemotherapy. Exons 4 to 9 of the p53 gene were analyzed, and mutations were found in 72 of 106 patients with HNSCC. p53 mutations were associated with loss of heterozygosity at chromosome 17p (P <.001). The prevalence of p53-mutated tumors was higher in the group of patients with nonresponse to neoadjuvant chemotherapy than in the group of responders (81% v 61%, respectively; P <.04). When compiling p53 mutations and anti-p53 antibodies in plasma, the correlation between p53 status and response to chemotherapy was significant (87% v 57%, respectively; P =.003). A multivariate analysis showed that p53 status is an independent predictive factor of response to chemotherapy. This prospective study suggests that p53 status may be a useful indicator of response to neoadjuvant chemotherapy in HNSCC.