title: Epidermal growth factor receptor as an adverse survival predictor in squamous cell carcinoma of the penis.
abstract: Penile carcinoma (PC) is more frequent in underdeveloped countries, generally is diagnosed at an advanced stage when therapeutic options are restricted, and thus is associated with high morbidity/mortality rates. Recent studies have demonstrated clinical benefits with epidermal growth factor receptor (EGFR)-targeted therapy in patients with PC, although there is no test that provides accurate patient selection. The aim of the present study was to evaluate the prognostic value of EGFR gene and protein status in tumor samples from patients with primary penile squamous cell carcinoma. We assessed the expression of wild-type and 2 mutant EGFR isoforms (delA746-E750 and mL858R) by immunohistochemistry in 139 samples, of which 49 were also evaluated for EGFR copy number by fluorescence in situ hybridization (FISH). Positive immunohistochemical staining of wild-type and mutant EGFR was evidenced by complete and strong membranous staining. For FISH analysis, cases were considered unaltered, polysomic, or amplified, as determined by signals of the EGFR gene and chromosome 7. An independent cohort of 107 PC samples was evaluated for mutations in EGFR, KRAS, and BRAF. Protein overexpression was noted in nearly half of the cases and was associated with cancer recurrence (P=.004) and perineural invasion (P=.005). Expression of the 2 mutated EGFR isoforms was not observed. The FISH status was not associated with protein expression. Altered FISH (polysomy and gene amplification) was an independent risk factor for dying of cancer. Only 1 patient of 107 presented KRAS mutations, and no mutations of EGFR or BRAF were observed.
authors.affiliation: Department of Anatomic Pathology, A.C. Camargo Cancer Center, 01508-010, São Paulo, SP, Brazil.
authors.forename: Alice Muglia Thomaz da
authors.initials: AM
authors.lastname: Silva Amancio
authors.affiliation: Department of Anatomic Pathology, A.C. Camargo Cancer Center, 01508-010, São Paulo, SP, Brazil.
authors.forename: Isabela Werneck da
authors.initials: IW
authors.lastname: Cunha
authors.affiliation: Department of Anatomic Pathology, A.C. Camargo Cancer Center, 01508-010, São Paulo, SP, Brazil.
authors.forename: José Ivanildo
authors.initials: JI
authors.lastname: Neves
authors.affiliation: Department of Pathology, Cancer Institute of Ceara, 60351-010, Fortaleza, CE, Brazil.
authors.forename: Josiane da Silva
authors.initials: JD
authors.lastname: Quetz
authors.affiliation: Department of Anatomic Pathology, A.C. Camargo Cancer Center, 01508-010, São Paulo, SP, Brazil.
authors.forename: Dirce Maria
authors.initials: DM
authors.lastname: Carraro
authors.affiliation: Department of Anatomic Pathology, A.C. Camargo Cancer Center, 01508-010, São Paulo, SP, Brazil.
authors.forename: Rafael Malagoli
authors.initials: RM
authors.lastname: Rocha
authors.affiliation: Urology Division, Department of Pelvic Surgical Oncology, A.C. Camargo Cancer Center, 01508-010, São Paulo, SP, Brazil.
authors.forename: Stenio Cássio
authors.initials: SC
authors.lastname: Zequi
authors.affiliation: Instituto de Patologia e Investigacion, Universidad Nacional de Asuncion, 1617, Asuncion, Paraguay.
authors.forename: Antonio Leopoldo
authors.initials: AL
authors.lastname: Cubilla
authors.affiliation: Urology Division, Department of Pelvic Surgical Oncology, A.C. Camargo Cancer Center, 01508-010, São Paulo, SP, Brazil.
authors.forename: Francisco Paulo
authors.initials: FP
authors.lastname: da Fonseca
authors.affiliation: Urology Division, Department of Pelvic Surgical Oncology, A.C. Camargo Cancer Center, 01508-010, São Paulo, SP, Brazil.
authors.forename: Ademar
authors.initials: A
authors.lastname: Lopes
authors.affiliation: Department of Pathology, Cancer Institute of Ceara, 60351-010, Fortaleza, CE, Brazil.
authors.forename: Maria do Perpétuo Socorro Saldanha da
authors.initials: MD
authors.lastname: Cunha
authors.affiliation: Department of Urology, Cancer Institute of Ceara, 60351-010, Fortaleza, CE, Brazil.
authors.forename: Marcos Venício Alves
authors.initials: MV
authors.lastname: Lima
authors.affiliation: Department of Anatomic Pathology, A.C. Camargo Cancer Center, 01508-010, São Paulo, SP, Brazil; Laboratory of Molecular and Investigative Pathology, Faculty of Medical Sciences, State University of Campinas Medical School, 13083-970, Campinas, SP, Brazil.
authors.forename: José
authors.initials: J
authors.lastname: Vassallo
authors.affiliation: Urology Division, Department of Pelvic Surgical Oncology, A.C. Camargo Cancer Center, 01508-010, São Paulo, SP, Brazil.
authors.forename: Gustavo Cardoso
authors.initials: GC
authors.lastname: Guimarães
authors.affiliation: Department of Anatomic Pathology, A.C. Camargo Cancer Center, 01508-010, São Paulo, SP, Brazil; General Pathology, Faculty of Dentistry, University of São Paulo, 05508-000, São Paulo, SP, Brazil. Electronic address: fasoares@cipe.accamargo.org.br.
authors.forename: Fernando Augusto
authors.initials: FA
authors.lastname: Soares
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001706:Biopsy; D002294:Carcinoma, Squamous Cell / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D002897:Chromosomes, Human, Pair 7; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D066246:ErbB Receptors / Q000032:analysis* / Q000235:genetics; D005784:Gene Amplification; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D017404:In Situ Hybridization, Fluorescence; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009364:Neoplasm Recurrence, Local; D010412:Penile Neoplasms / Q000737:chemistry* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D010641:Phenotype; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D012307:Risk Factors; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; C512478:EGFR protein, human; D066246:ErbB Receptors
keywords: EGFR; FISH; Immunohistochemistry; Penile cancer; Prognosis