Epidermal Growth Factor Receptor (EGFR)-RAS Signaling Pathway in Penile Squamous Cell Carcinoma

Gou, Hong Feng; Li, Xiang; Qiu, Meng; Cheng, Ke; Li, Long Hao; Hang, Dong; Chen, Ye; Tang, Yuan; Gao, Feng; Zhao, Feng; Men, Hai Tao; Ge, Jun; Su, Jing; Xu, Feng; Bi, Feng; Gao, Jian; Liu, Ji Yan

doi:10.1371/journal.pone.0062175

Cited by 42 publications

(30 citation statements)

References 32 publications

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“…In this series, KRAS mutations were found in high grade, advanced tumors, whilst PIK3CA mutations were found in all histological grades. By contrast, in a series of 95 penile cancers testing BRAF and KRAS mutational status, only a single case was found to harbor a KRAS mutation (Gou et al, ). In our study, somatic mutations were identified in 3/10 in situ SCC and in 19/65 (29%) of invasive SCC, while normal tissues were all wt.…”

Section: Discussionmentioning

confidence: 95%

Identification of somatic gene mutations in penile squamous cell carcinoma

Ferrándiz-Pulido

Hernández‐Losa

Masferrer

et al. 2015

Genes Chromosomes & Cancer

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There is a lack of studies on somatic gene mutations and cell signaling driving penile carcinogenesis. Our objective was to analyze somatic mutations in genes downstream of EGFR in penile squamous cell carcinomas, especially the mTOR and RAS/MAPK pathways. We retrospectively analyzed somatic mutations in 10 in situ and 65 invasive penile squamous cell carcinomas by using Sequenom's Mass Spectrometry iPlex Technology and Oncocarta v1.0 Panel. The DNA was extracted from FFPE blocks and we identified somatic missense mutations in three in situ tumors and in 19 invasive tumors, mostly in PIK3CA, KRAS, HRAS, NRAS, and PDGFA genes. Somatic mutations in the PIK3CA gene or RAS family genes were neither associated with tumor grade, stage or outcome, and were equally often identified in hrHPV positive and in hrHPV negative tumors that showed no p53 expression. Mutations in PIK3CA, KRAS, and HRAS are frequent in penile squamous cell carcinoma and likely play a role in the development of p53-negative tumors. Although the presence of these mutations does not seem to correlate with tumoral behavior or outcome, they could be biomarkers of treatment failure with anti-EGFR mAb in patients with penile squamous cell carcinoma.

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Section: Discussionmentioning

confidence: 95%

Identification of somatic gene mutations in penile squamous cell carcinoma

Ferrándiz-Pulido

Hernández‐Losa

Masferrer

et al. 2015

Genes Chromosomes & Cancer

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“…Furthermore, single biomarker predictor models often have limited power to predict cancer patient survival [26]–[28]. Therefore, the three-gene signature discovered in the present study, which is comprised of molecules within the EGFR/ERK/Fascin signaling pathway, may represent a useful preclinical model for improving ESCC treatment and clinical outcome.…”

Section: Discussionmentioning

confidence: 97%

A Molecular Prognostic Model Predicts Esophageal Squamous Cell Carcinoma Prognosis

et al. 2014

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BackgroundEsophageal squamous cell carcinoma (ESCC) has the highest mortality rates in China. The 5-year survival rate of ESCC remains dismal despite improvements in treatments such as surgical resection and adjuvant chemoradiation, and current clinical staging approaches are limited in their ability to effectively stratify patients for treatment options. The aim of the present study, therefore, was to develop an immunohistochemistry-based prognostic model to improve clinical risk assessment for patients with ESCC.MethodsWe developed a molecular prognostic model based on the combined expression of axis of epidermal growth factor receptor (EGFR), phosphorylated Specificity protein 1 (p-Sp1), and Fascin proteins. The presence of this prognostic model and associated clinical outcomes were analyzed for 130 formalin-fixed, paraffin-embedded esophageal curative resection specimens (generation dataset) and validated using an independent cohort of 185 specimens (validation dataset).ResultsThe expression of these three genes at the protein level was used to build a molecular prognostic model that was highly predictive of ESCC survival in both generation and validation datasets (P = 0.001). Regression analysis showed that this molecular prognostic model was strongly and independently predictive of overall survival (hazard ratio = 2.358 [95% CI, 1.391–3.996], P = 0.001 in generation dataset; hazard ratio = 1.990 [95% CI, 1.256–3.154], P = 0.003 in validation dataset). Furthermore, the predictive ability of these 3 biomarkers in combination was more robust than that of each individual biomarker.ConclusionsThis technically simple immunohistochemistry-based molecular model accurately predicts ESCC patient survival and thus could serve as a complement to current clinical risk stratification approaches.

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“…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). Nevertheless, we failed to identify a signal of prolonged OS associated with the use of cetuximab in our study cohort.…”

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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Epidermal Growth Factor Receptor (EGFR)-RAS Signaling Pathway in Penile Squamous Cell Carcinoma

Cited by 42 publications

References 32 publications

Identification of somatic gene mutations in penile squamous cell carcinoma

Identification of somatic gene mutations in penile squamous cell carcinoma

A Molecular Prognostic Model Predicts Esophageal Squamous Cell Carcinoma Prognosis

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

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