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      Consistent administration of cetuximab is associated with favorable outcomes in recurrent/metastatic head and neck squamous cell carcinoma in an endemic carcinogen exposure area: a retrospective observational study

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          Abstract

          Background

          This study aimed to analyze the clinical outcomes associated with patients with recurrent/metastatic head and neck squamous cell carcinoma (RM HNSCC) who received cetuximab-based chemotherapy in a real-world clinical setting.

          Methods

          Clinical data were extracted from RM HNSCC patients diagnosed between 2016 and 2019. Kaplan–Meier survival estimates and Cox proportional hazards model were used for survival analyses.

          Results

          Of 106 RM HNSCC patients (mean age = 55.1 years), 38.7% exhibited recurrent disease and 61.3% had metastatic disease. The majority of patients showed a habit of addictive substance use, including alcohol (67.0%), betel nuts (71.7%), or tobacco (74.5%). The primary tumor sites included the oral cavity (64.1%), hypopharynx (19.8%), and oropharynx (16.0%). The median number of cetuximab cycles for the 106 patients was 11 (2–24). The disease control rate (DCR) was 48.1%, and the overall response rate (ORR) was 28.3%. The median progression-free survival (PFS) and overall survival (OS) were 5.0 and 9.23 months, respectively. Patients treated with more than 11 cycles of cetuximab exhibited a longer median PFS and median OS than did patients treated with less than 11 cycles (median PFS: 7.0 vs. 3.0 months, p < 0.001; OS: 12.43 vs. 4.46 months, p = 0.001). Patients without previous concurrent chemoradiotherapy (CRT) had a better median PFS than did those with previous CRT (6.0 vs. 4.0 months, p = 0.046). Multivariable analysis revealed that perineural invasion and fewer cycles of cetuximab (<11 cycles) were independent risk factors associated with disease progression. In addition, the reduction in treatment cycles of cetuximab and advanced lymph node metastasis were independent prognostic factors predicting poorer overall survival.

          Conclusion

          Our study provides important real-world data regarding cetuximab-containing treatment in RM HNSCC. Consistent administration of cetuximab could be associated with more favorable outcomes in RM HNSCC in endemic carcinogen exposure areas.

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          Most cited references 28

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          Evidence for a causal association between human papillomavirus and a subset of head and neck cancers.

          High-risk human papillomaviruses (HPVs) are etiologic agents for anogenital tract cancers and have been detected in head and neck squamous cell carcinomas (HNSCCs). We investigated, retrospectively, an etiologic role for HPVs in a large series of patients with HNSCC. Tumor tissues from 253 patients with newly diagnosed or recurrent HNSCC were tested for the presence of HPV genome by use of polymerase chain reaction (PCR)-based assays, Southern blot hybridization, and in situ hybridization. The viral E6 coding region was sequenced to confirm the presence of tumor-specific viral isolates. Exons 5-9 of the TP53 gene were sequenced from 166 specimens. The hazard of death from HNSCC in patients with and without HPV-positive tumors was determined by proportional hazards regression analysis. HPV was detected in 62 (25%) of 253 cases (95% confidence interval [CI] = 19%-30%). High-risk, tumorigenic type HPV16 was identified in 90% of the HPV-positive tumors. HPV16 was localized specifically by in situ hybridization within the nuclei of cancer cells in preinvasive, invasive, and lymph node disease. Southern blot hybridization patterns were consistent with viral integration. Poor tumor grade (odds ratio [OR] = 2.4; 95% CI = 1.2- 4.9) and oropharyngeal site (OR = 6.2; 95% CI = 3.1-12.1) independently increased the probability of HPV presence. As compared with HPV-negative oropharyngeal cancers, HPV-positive oropharyngeal cancers were less likely to occur among moderate to heavy drinkers (OR = 0.17; 95% CI = 0.05-0.61) and smokers (OR = 0.16; 95% CI = 0.02-1.4), had a characteristic basaloid morphology (OR = 18.7; 95% CI = 2.1-167), were less likely to have TP53 mutations (OR = 0.06; 95% CI = 0.01-0. 36), and had improved disease-specific survival (hazard ratio [HR] = 0.26; 95% CI = 0.07-0.98). After adjustment for the presence of lymph node disease (HR = 2.3; 95% CI = 1.4- 3.8), heavy alcohol consumption (HR = 2.6; 95% CI = 1.4-4.7), and age greater than 60 years old (HR = 1.4; 95% CI = 0.8-2.3), all patients with HPV-positive tumors had a 59% reduction in risk of death from cancer when compared with HPV-negative HNSCC patients (HR = 0.41; 95% CI = 0.20-0.88). These data extend recent molecular and epidemiologic studies and strongly suggest that HPV-positive oropharyngeal cancers comprise a distinct molecular, clinical, and pathologic disease entity that is likely causally associated with HPV infection and that has a markedly improved prognosis.
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            Expression of epidermal growth factor receptor and survival in upper aerodigestive tract cancer.

            To determine the expression of epidermal growth factor receptor (EGFR) in head and neck squamous cell carcinoma and to evaluate its prognostic value. EGFR was determined in tumor biopsies obtained from 109 consecutive patients with head and neck cancer (100 men, nine women). Control biopsies were obtained from 94 patients in a symetric nontumoral area of the same anatomic site. EGFR was measured by a binding assay using human recombinant iodine 125-EGF. The presence of detectable EGFR levels was found in all explored tumors with highly marked differences between patients (median, 71 fmol/mg protein; range, 2 to 2,302). In 93 of 94 cases, EGFR levels were higher in tumor samples as compared with healthy control zones. There was no significant difference in EGFR expression according to the various anatomic sites explored or tumoral differentiation status. There was a significant difference of distribution for EGFR levels between stages I and II tumors and stages III and IV tumors. The tumor EGFR levels were not linked to the response to first-line chemotherapy by cisplatin (CDDP) and fluorouracil (5FU). Survival was assessable for 103 patients for overall survival and for 81 patients for recurrence. EGFR overexpression was associated with shorter relapse-free (P = .0125) and overall survival (P = .028) rates. By multivariate analysis, the only significant variable was EGFR for relapse-free survival and tumor staging for overall survival. The association of EGFR to tumor staging markedly improves the significance for overall survival predictability (P = .002). EGFR determination deserves particular attention in head and neck cancer, since it independently carries a strong prognostic value.
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              Functional genomic analysis identified epidermal growth factor receptor activation as the most common genetic event in oral squamous cell carcinoma.

              A 250K single-nucleotide polymorphism array was used to study subchromosomal alterations in oral squamous cell carcinoma (OSCC). The most frequent amplification was found at 7p11.2 in 9 of 29 (31%) oral cancer patients. Minimal genomic mapping verified a unique amplicon spanning from 54.6 to 55.3 Mb on chromosome 7, which contains SEC61G and epidermal growth factor receptor (EGFR). Results from fluorescence in situ hybridization, transcriptome, and immunohistochemistry analyses indicated that the expression level of EGFR, but not of SEC61G, was up-regulated and tightly correlated with DNA copy number in 7p11.2 amplified tumors. Among the members of the erbB family, EGFR (HER1) was found to be the most frequently amplified and highly expressed gene in both human and mouse oral tumors (P < 0.01). Genes for downstream effectors of EGFR, including KRAS, mitogen-activated protein kinase 1, and CCND1, were also found amplified or mutated, which resulted in activation of EGFR signaling in 55% of OSCC patients. Head and neck squamous cancer cells with different EGFR expression levels showed differential sensitivity to antitumor effects of AG1478, a potent EGFR inhibitor. AG1478-induced EGFR inactivation significantly suppressed tumor development and progression in a mouse oral cancer model. Our data suggest that EGFR signaling is important in oral cancer development and that anti-EGFR therapy would benefit patients who carry the 7p11.2 amplicon in their tumors.
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                Author and article information

                Contributors
                Journal
                PeerJ
                PeerJ
                peerj
                peerj
                PeerJ
                PeerJ Inc. (San Diego, USA )
                2167-8359
                10 September 2020
                2020
                : 8
                Affiliations
                [1 ]Graduate Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University , Kaohsiung, Taiwan
                [2 ]Division of Hematology and Oncology, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University , Kaohsiung, Taiwan
                [3 ]Faculty of Internal Medicine, Specialist Nursing office, Kaohsiung Medical University Hospital, Kaohsiung Medical University , Kaohsiung, Taiwan
                [4 ]Department of Nursing, Kaohsiung Medical University Hospital, Kaohsiung Medical University , Kaohsiung, Taiwan
                [5 ]Department of Otolaryngology-Head and Neck Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University , Kaohsiung, Taiwan
                [6 ]Faculty of Medicine, College of Medicine, Kaohsiung Medical University , Kaohsiung, Taiwan
                Article
                9862
                10.7717/peerj.9862
                7487150
                ©2020 Wang et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. For attribution, the original author(s), title, publication source (PeerJ) and either DOI or URL of the article must be cited.

                Funding
                Funded by: Kaohsiung Medical University Hospital
                Award ID: KMUH107-7M12
                Award ID: KMUH108-8R23
                Award ID: KMUH108-8M12
                Award ID: KMHK-DK109004
                This work was supported by the following grants: KMUH107-7M12, KMUH108-8R23, KMUH108-8M12, and KMHK-DK109004 from the Kaohsiung Medical University Hospital. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Drugs and Devices
                Oncology
                Otorhinolaryngology

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