Metastatic penile cancer remains a challenging entity due to poor long-term durable response to contemporary cisplatin based systemic regimens.1 Within this context, it has been suggested that chemoresistance in micrometastatic lesions may account for the diminished durable response rates in advanced disease, however, there are limited studies involving the identification of biomarkers that predict chemotherapy response in this patient population.2,3 Moreover, due to the rarity of penile cancer, studies evaluating the genetic underpinnings of tumor response to cisplatin are limited.4,5 Thus, our study was devised as a means of informing further study in this area.
In the study, we performed immunohistochemistry on surgical specimens obtained from the primary tumor, adjacent normal skin, metastatic inguinal lymph nodes, and normal inguinal lymph nodes in 51 patients treated for squamous cell carcinoma of the penis. We stained specimens for two proteins, ERCC1, and E2F1, known to be associated with cisplatin resistance in other disease types and penile cancer respectively, and evaluated their association with cisplatin response and pathologic features of metastatic potential. We found that elevated E2F1 staining was associated with poorly differentiated primary tumors, however, we were unable to demonstrate a link between cisplatin response and either protein.
In addition, we conducted next-generation sequencing on the transcriptome of surgical specimens obtained from 8 patients and reported differential expression patterns between primary tumors with matched metastatic lymph nodes and primary tumors without metastatic lymph node sites specifically related to metalloproteinase expression.
Our results provide insights for potential targeted therapeutics that may augment our current strategies for metastatic penile cancer such as the use of cobimetinib, a MEK inhibitor that has been shown to downregulate E2F1 expression and metalloproteinase inhibitors.6,7
Written by: Christine Ibilibor, MD, MSc, Assistant Professor, Division of Urologic Oncology, Department of Urology, University of Virginia
References:
- Graafland NM, Verhoeven RH, Coebergh JW, Horenblas S. Incidence trends and survival of penile squamous cell carcinoma in the Netherlands. Int J Cancer. 2011;128(2):426-432.
- Bermejo C, Busby JE, Spiess PE, Heller L, Pagliaro LC, Pettaway CA. Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol. 2007;177(4):1335-1338.
- Houede N, Dupuy L, Flechon A, et al. Intermediate analysis of a phase II trial assessing gemcitabine and cisplatin in locoregional or metastatic penile squamous cell carcinoma. BJU Int. 2016;117(3):444-449.
- Fenner F, Goody D, Protzel C, et al. E2F1 Signalling is Predictive of Chemoresistance and Lymphogenic Metastasis in Penile Cancer: A Pilot Functional Study Reveals New Prognostic Biomarkers. Eur Urol Focus. 2018;4(4):599-607.
- Kuasne H, Canto LMd, Aagaard MM, et al. Penile Cancer-Derived Cells Molecularly Characterized as Models to Guide Targeted Therapies. Cells. 2021;10(4):814.
- Gong S, Xu D, Zhu J, Zou F, Peng R: Efficacy of the MEK Inhibitor Cobimetinib and its Potential Application to Colorectal Cancer Cells. Cell Physiol Biochem 2018;47:680-693. doi: 10.1159/000490022
- Sparano JA, Bernardo P, Stephenson P, et al. Randomized phase III trial of marimastat versus placebo in patients with metastatic breast cancer who have responding or stable disease after first-line chemotherapy: Eastern Cooperative Oncology Group trial E2196. J Clin Oncol. 2004;22(23):4683-4690