Comment on: EGFR mutational status in Brazilian patients with penile carcinoma

Abstract

The authors describe the results on EGFR molecular alterations of 29 Brazilian patients with penile carcinoma (PC). DNA extracted from frozen tumor tissue of all patients was submitted to direct sequencing of the four exons (18 – 21) responsible for the EGFR tyrosine-kinase activity. Corroborating the data by Di Lorenzo et al. published in Expert Opin Ther Targets, none of the sequenced tumor samples showed relevant alterations in the four studied exons of the EGFR gene.

Keywords::

• EGFR mutations
• molecular diagnostics
• penile carcinoma
• target therapy
• tyrosine-kinase inhibitors

Dear Editor,

Penile carcinoma (PC) is a worrisome issue in developing countries. Thus, the recent publication by Di Lorenzo et al. [1] in this journal, on the mutational status of EGFR in PC, has caught our attention. In Brazil its incidence is higher than in industrialized countries, especially in less wealthy regions [2]. Therapeutic options are limited, with poor prognosis, especially for patients with metastatic disease. Therefore, new therapeutic targets are warranted, like EGFR. Di Lorenzo et al. evaluated the immunohistochemical expression of two markers for EGFR mutations (E746-A750, for deletion in exon 19; and L858R, for a point mutation in exon 21) on formalin-fixed, paraffin-embedded samples of 30 patients with PC. Although all of them were immunoreactive for EGFR, none presented the markers for such genetic alterations. We would like to further support their findings, by describing the results on EGFR molecular alterations of 29 Brazilian patients with PC. This study was undertaken after approval by the Ethics Committee of our institution, and applied on frozen samples. All cases were submitted to direct sequencing of the four exons encoding the EGFR tyrosine-kinase (TK) domain 18 – 21, frequently mutated in non-small cell lung carcinoma (NSCLC) [3]. PCR products were purified with ExoSAP-IT (Affimetryx, Santa Clara, CA, USA). Each exon was amplified individually and sequenced in both directions, using Big Dye v.3.1 (Applied Biosystems, Bedford, MA, USA), and separated on ABI Prism 3130xl (Applied Biosystems). Sequences were analyzed with the CLC Bio software and compared with the EGFR sequence. Corroborating the data by Di Lorenzo et al., none of the sequenced tumor samples showed relevant alterations in the four exons studied. However, 19 out of the 29 cases exhibited an alteration in exon 20 (p.Q787Q), which has been described as a single nucleotide polymorphism in other tumor types, without clinical significance [4]. Patients with NSCLC harboring these activating mutations have demonstrated dramatic response to treatment with TK inhibitors targeting EGFR, like erolitinib and gefitinib. However, in PC, different alterations might play a role in the receptor's expression and activation. Regarding antibody-based therapies (cetuximab, for instance), EGFR protein overexpression could be predictive of drug response. This approach was reported as presenting clinical benefits in a single patient with recurrent PC [5]. As the knowledge on the molecular mechanisms of PC is still limited, because of the relative rarity of this tumor in wealthier regions of the globe, further studies are necessary to support new therapeutic alternatives.

Declaration of interest

This work was supported by the Fundação de Amparo à Pesquisa do Estado de São Paulo (Foundation for Research Support of the State of São Paulo, or FAPESP). The authors declare that there is no conflict of interest associated with this letter.

Bibliography

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Authors' reply

Therapeutic improvements in the management of inoperable penile cancer have been incredibly slow [1]. The use of cisplatin and 5-fluorouracil was based on only a few cases (< 10) reported decades ago until recent results published by our work group [2]. On such basis, we appreciate the efforts by Da Silva et al., who provide useful data about EGFR mutational status in penile cancer. It must be noted that presence of Q787Q silent mutations in exon 20 was not clearly associated to response to gefitinib or erlotinib in lung cancer, as discussed by Jia and Chen [3]. Given the rarity of the disease, the lack of interest of big pharmaceutical companies and the difficulty in enrolling patients in prospective trials, we still believe that experimentation of erlotinib and gefitinib is not presently a priority in penile cancer.