ABSTRACT
BACKGROUND: Tumor human papillomavirus (HPV) status is an important prognostic factor in locoregionally advanced squamous cell carcinoma of the head and neck (SCCHN). Prognostic value in recurrent and/or metastatic (R/M) disease remains to be confirmed. This retrospective analysis of the EXTREME trial, comparing chemotherapy plus cetuximab with chemotherapy first line in R/M SCCHN, investigated efficacy and prognosis according to tumor p16 and HPV status. PATIENTS AND METHODS: Paired tissue samples were used: p16INK4A expression was assessed by immunohistochemistry, and HPV status determined in extracted DNA samples using oligonucleotide hybridization assays. RESULTS: Altogether, 416 of 442 patients had tumor samples available for p16 and HPV: 10% of tumors were p16 positive and 5% were HPV positive. Adding cetuximab to chemotherapy improved survival, irrespective of tumor p16 or HPV status. This pattern remained in a combined analysis of p16 and HPV. p16 positivity and HPV positivity were associated with prolonged survival compared with p16 negativity and HPV negativity. Subgroup analysis of patients with oropharyngeal cancer demonstrated a similar pattern to all evaluable patients. CONCLUSION: The results from this analysis suggest that p16 and HPV status have prognostic value in R/M SCCHN and survival benefits of chemotherapy plus cetuximab over chemotherapy alone are independent of tumor p16 and HPV status.
Subject(s)
Antibodies, Monoclonal, Humanized/administration & dosage , Carcinoma, Squamous Cell/drug therapy , Cyclin-Dependent Kinase Inhibitor p16/isolation & purification , Head and Neck Neoplasms/drug therapy , Neoplasm Recurrence, Local/drug therapy , Aged , Carcinoma, Squamous Cell/genetics , Carcinoma, Squamous Cell/pathology , Carcinoma, Squamous Cell/virology , Cetuximab , Cyclin-Dependent Kinase Inhibitor p16/genetics , Disease-Free Survival , Female , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/pathology , Head and Neck Neoplasms/virology , Humans , Male , Middle Aged , Neoplasm Metastasis , Neoplasm Recurrence, Local/genetics , Neoplasm Recurrence, Local/pathology , Neoplasm Recurrence, Local/virology , Papillomaviridae/genetics , Papillomaviridae/isolation & purification , Papillomaviridae/pathogenicity , PrognosisABSTRACT
Two strains of tomato aspermy cucumovirus, 1-TAV and V-TAV, differ in the severity of the symptoms induced in Nicotiana tabacum: 1-TAV induces a severe chlorotic mottle that appears 5 days post inoculation (d.p.i.) in the second systemic leaf, while V-TAV-infected plants show a mild chlorotic mottle, unevenly distributed in the leaf lamina, that appears 7 d.p.i. in the third or fourth systemic leaf. The manipulation of full-length cDNA clones giving infectious transcripts of V-TAV RNAs 1, 2, and 3 and 1-TAV RNA 3 revealed that the slow, mild phenotype of V-TAV maps to the movement protein (MP) gene. By site-directed mutagenesis it was further shown that this phenotype co-segregates with a single nucleotide substitution that introduces an in-frame UAA stop codon at the fourth position of the MP open reading frame of V-TAV. The presence of this stop codon results in a diminished expression of the MP in both tobacco protoplasts and leaves. Analyses of the progress of infection and of the time course of MP and coat protein accumulation show that the low level of MP in V-TAV-infected leaves limits the rate of cell-to-cell movement and leads to the mild phenotype. Data from the infectivity of RNA 3 transcripts with or without this stop codon, plus data from in vitro translation of virion or transcript RNA 3, suggest that the small amount of MP observed in V-TAV-infected leaves is expressed from a minor RNA 3 subpopulation lacking the stop codon.
