The epidermal growth factor receptors as biological targets in penile cancer

Lorenzo, Giuseppe Di; Buonerba, Carlo; Ferro, Matteo; Calderoni, Giuseppe; Bozza, G.; Federico, Piera; Tedesco, Beatrice; Ruggieri, Vitalba; Aieta, Michele

doi:10.1517/14712598.2015.993377

Cited by 23 publications

(18 citation statements)

References 14 publications

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“…[45] showed that hsa-miR-145 overexpression altered MMP1 and MMP9 mRNA and protein levels, with subsequent inhibition of invasion, metastasis and angiogenesis in gastric cancer cells. Although some prognostic molecular makers have been reported in PeCa, the stratification of the patients is currently based on clinical and histopathological features [11, 31, 39, 46, 47]. In the present study, MMP1 showed superior performance in discriminate lymph node metastasis in PeCa compared with established clinical-pathological parameters.…”

Section: Discussionmentioning

confidence: 55%

“…Recently, EGFR gene mutation, amplification and overexpression have been described in PeCa, suggesting the potential of using therapeutic strategies targeting EGFR in a selected group of patients [34, 35]. Currently, EGFR-targeted therapies are found to be clinically useful in PeCa patients (approximately 30 cases) [34–39]. Although the EGFR expression levels were not identified in this study, four ligands of EGFR ( AREG , EREG, TGFA and EPGN ) were overexpressed, as well as the downstream effector NRAS .…”

Section: Discussionmentioning

confidence: 99%

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Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

et al. 2017

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Penile carcinoma (PeCa) is an important public health issue in poor and developing countries, and has only recently been explored in terms of genetic and epigenetic studies. Integrative data analysis is a powerful method for the identification of molecular drivers involved in cancer development and progression. miRNA and mRNA expression profiles followed by integrative analysis were investigated in 23 PeCa and 12 non-neoplastic penile tissues (NPT). Expression levels of eight miRNAs and 10 mRNAs were evaluated in the same set of samples used for microarray and in a validation set of cases (PeCa = 36; NPT = 27). Eighty-one miRNAs and 2,697 mRNAs were identified as differentially expressed in PeCa. Integrative data analysis revealed 255 mRNAs potentially regulated by 68 miRNAs. Using RT-qPCR, eight miRNAs and nine transcripts were confirmed as altered in PeCa. We identified that MMP1, MMP12 and PPARG and hsa-miR-31-5p, hsa-miR-224-5p, and hsa-miR-223-3p were able to distinguish tumors from NPT with high sensitivity and specificity. Higher MMP1 expression was detected as a better predictor of lymph node metastasis than the clinical-pathological data. In addition, PPARG and EGFR were highlighted as potential pathways for targeted therapy in PeCa. The analysis based on HPV positivity (7 of 23 cases) revealed five miRNA and 13 mRNA differentially expressed. Although in a limited number of cases, HPV positive PeCa presented less aggressive phenotype in comparison with negative cases. Overall, an integrative analysis using mRNA and miRNA profiles revealed markers related with tumor development and progression. Furthermore, MMP1 expression level was a predictive marker for lymph node metastasis in patients with PeCa.

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Section: Discussionmentioning

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Integrative miRNA and mRNA analysis in penile carcinomas reveals markers and pathways with potential clinical impact

et al. 2017

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“…Evidence of activity of anti-EGFR agents in advanced penile cancer was originally reported when administered as single agent (Necchi et al, 2016b) or in combination with chemotherapy (Rescigno et al, 2012). In a literature review of individual data of 28 patients with advanced penile cancer receiving anti-EGFR monoclonal antibodies (cetuximab, panitumumab, and nimotuzumab), a 50% radiological response rate was achieved, but a median PFS of only approximately 3 months (interquartile range, 1.5–5.78, Di Lorenzo et al, 2015). From a biological perspective, EGFR appears a promising target in penile cancer, as it is universally expressed and frequently phosphorylated (Di Lorenzo et al, 2013a), but infrequently amplified (Di Lorenzo et al, 2013a), or mutated (Di Lorenzo et al, 2013b), while mutations of downstream signaling proteins (such as KRAS/BRAF) are rare (Gou et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Prognostic and Predictive Factors in Patients with Advanced Penile Cancer Receiving Salvage (2nd or Later Line) Systemic Treatment: A Retrospective, Multi-Center Study

et al. 2016

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Introduction and objectives: Metastatic penile squamous cell carcinoma (PSCC) is associated with dismal outcomes with median overall survival (OS) of 6–12 months in the first-line and <6 months in the salvage setting. Given the rarity of this disease, randomized trials are difficult. Prognostic risk models may assist in rational drug development by comparing observed outcomes in nonrandomized phase II studies and retrospective data vs. predicted outcomes based on baseline prognostic factors in the context of historically used agents. In this retrospective study, we constructed a prognostic model in the salvage setting of PSCC patients receiving second or later line systemic treatment, and also explored differences in outcomes based on type of treatment.Materials and methods: We performed a chart review to identify patients with locally advanced unresectable or metastatic PSCC who received second or later line systemic treatment in centers from North America and Europe. The primary outcome was OS from initiation of treatment, with secondary outcomes being progression-free survival (PFS) and response rate (RR). OS was estimated using the Kaplan-Meier method. Cox proportional hazards regression was used to identify prognostic factors for outcomes using univariable and multivariable models.Results: Sixty-five patients were eligible. Seventeen of 63 evaluable patients had a response (27.0%, 95% confidence interval [CI] = 16.6–39.7%) and median OS and PFS were 20 (95% CI = 20–21) and 12 (95% CI = 12, 16) weeks, respectively. Visceral metastasis (VM) and hemoglobin (Hb) ≤ 10 gm/dl were consistently significant poor prognostic factors for both OS and PFS, and Hb was also prognostic for response. The 28 patients with neither risk factor had a median OS (95% CI) of 24 (20–40) weeks and 1-year (95% CI) OS of 13.7% (4.4–42.7%), while the 37 patients with 1 or 2 risk factors had median OS (95% CI) of 20 (16–20) weeks and 1-year (95% CI) OS of 6.7% (1.8–24.9%). Cetuximab-including regimens were associated with a trend for improved RR compared to other agents (Odds ratio = 5.05, 95% CI = 0.84–30.37, p = 0.077). Taxanes vs. non-taxane, and combination vs. single agent therapy was not associated with improved outcomes. The study is limited by its modest sample size.Conclusion: This is the first prognostic classification proposed for patients receiving salvage systemic therapy for advanced PSCC. The presence of VM and Hb ≤ 10 gm/dl was associated with poor OS and PFS. Cetuximab appeared to be associated with better RR. This prognostic model may assist in salvage therapy drug development for this orphan disease by improving interpretation of outcomes seen in nonrandomized data.

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“…In the ongoing study by Boyle et al ., penile cancer patients are randomized to receive cisplatin–paclitaxel–ifosfamide with or without the addition of the anti-EGFR monoclonal antibody cetuximab. Both EGFR and Ras play an important role in penile cancer, as shown by EGFR overexpression and lack of tumor-suppressor RAS-association domain family 1A protein (RASSF1A) expression in the majority of patients [8]. Although complete responses have been reported with cetuximab, an analysis of 28 patients receiving cetuximab in retrospective series showed a modest PFS of 3 months, and the synergistic effect of cetuximab plus chemotherapy remains to be defined [8].…”

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confidence: 99%

“…Both EGFR and Ras play an important role in penile cancer, as shown by EGFR overexpression and lack of tumor-suppressor RAS-association domain family 1A protein (RASSF1A) expression in the majority of patients [8]. Although complete responses have been reported with cetuximab, an analysis of 28 patients receiving cetuximab in retrospective series showed a modest PFS of 3 months, and the synergistic effect of cetuximab plus chemotherapy remains to be defined [8]. Of note, other members of the EGFR family may be a suitable biological target in penile cancer, such as HER3 and HER4 [9].…”

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confidence: 99%