ASCO GU 2019: Penile Squamous Cell Carcinoma is Genomically Similar to Other HPV-Driven Tumors

San Francisco, CA ( Penile squamous cell carcinoma is a rare disease in the US with 2,030 new cases and 340 deaths each year. It is also a global health issue, particularly in developing countries. HPV is responsible for ~50% of penile squamous cell carcinomas; relapsed disease is fatal after first-line treatment failure, with a median survival of 5 months. While surgery and radiation may be used for patients with loco-regional disease, unfortunately, there are limited treatment options for patients with advanced penile squamous cell carcinoma. To date, there have been no published genome-wide studies on the genetic alterations of penile squamous cell carcinomas or on the differences between HPV (+) and HPV (−) tumors. At the GU ASCO session on improving outcomes in rare genitourinary malignancies, Jad Chahoud, MD presented results of the largest whole exon sequencing analysis among patients with penile squamous cell carcinoma.

For this study, the authors identified 34 patients with penile squamous cell carcinoma, at the MD Anderson Cancer Center. These patients had primary tumors or metastatic lesions sufficient for whole exon sequencing. Patient information, and tumor and surgical characteristics were available through the MD Anderson prospective registry. Genomic DNAs from both fresh frozen macrodissected tumors and paired-normal penile tissues were analyzed by whole exon sequencing.

The median age of patients meeting inclusion criteria was 61 years (range 39-83). The pathologic T and N stages were as follows: 
Fifty percent of patients had lymphovascular invasion and 50% had perineural invasion. Among 18 patients with HPV status (p16 IHC/ISH), 6 patients were positive. 53% of patients underwent a partial penectomy and 38% underwent a radical penectomy. The most common grade of tumor was grade 2 (53%). Eight of the most frequently mutated penile squamous cell carcinoma gene were NOTCH1 (35%), TP53 (35%), CDKN2A (24%), PIK3CA (21%), CASP8 (21%), FAT1 (18%), FBXW7 (15%) and EP300 (12%) were significantly mutated in other SCC tumor types. Compared to other squamous cell carcinoma tumors, all eight genes were mutated in head and neck squamous cell carcinoma and five were mutated in cervical squamous cell carcinoma. TP53 mutations were associated with HPV (-) penile squamous cell carcinoma and were absent in HPV (+) disease (p = 0.03). EP300 mutations were associated with advanced primary tumor stage. Interestingly, the authors did not identify unique mutations associated with lymph node status. NOTCH1 loss of function mutation was not thought to be a targetable entity, however, in this study loss function were related to PI3K/mTOR inhibition. This finding requires validation in future studies. 

Of note, this is the largest systematic analyses of penile squamous cell carcinoma genomics citing the involvement of multiple cancer genes that are likely to be contributing to tumor development. These include genes responsible for squamous differentiation, cell cycle, and chromatin regulation. Dr. Chahoud concluded with several take-home messages:

  • Whole genome sequencing of penile squamous cell carcinomas confirmed that the top altered genes include TP53, NOTCH1, CDKN2A, and PIK3CA
  • Penile squamous cell carcinomas are genomically similar to other HPV related squamous cell carcinomas
  • Tumor mutation burden in penile squamous cell carcinomas appears to be similar to HNSCC and lung squamous cell carcinoma, which could include a potential role in immunotherapy
  • NOTCH and PI3K/AKT/mTOR pathways could be of potential relevance for targeted therapy for this disease

Presented by: Jad Chahoud, MD, The University of Texas MD Anderson Cancer Center, Houston, TX

Co-Authors: Barrett Z. McCormick, Frederico Netto, Priya Rao, Curtis R. Pickering, Curtis Alvin Pettaway; University of Texas MD Anderson Cancer Center, Houston, TX; MD Anderson Cancer Center, Houston, TX; The University of Texas MD Anderson Cancer Center, Houston, TX; Department of Head and Neck Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX; UT MD Anderson Cancer Center, Houston, TX

Written By: Zachary Klaassen, MD, MSc – Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Twitter: @zklaassen at the 2019 American Society of Clinical Oncology Genitourinary Cancers Symposium, (ASCO GU) #GU19, February 14-16, 2019 - San Francisco, CA
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