Researchers identified potential genetic alterations in penile cancer that could lead to targeted treatments for the disease. A complex landscape that could suggest clinical trials of targeted therapies and potential limitations in some patients was described in a report published in Cancer Research (10.1158/0008-5472.CAN-15-1004).

Surgery is the only treatment needed for many patients with penile cancer. But few therapeutic options exist for patients with aggressive forms of penile cancer, in particular targeted therapies.

“We saw that determining the best targeted therapies may be more complicated in penile cancer than in other cancers based on the combinations of genetic changes and variability between primary tumor and metastases,” said senior study author Scott A. Tomlins, MD, PhD, assistant professor of pathology and urology at the University of Michigan Medical School in Ann Arbor.

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Researchers performed next generation sequencing on 43 cases of penile squamous cell carcinoma. The cases varied in stage, grade, and subtype. Fourteen samples were matched to include the primary tumor and metastatic tissue.

The researchers found a common combination of alterations in the KRAS, HRAS, and NRAS genes, as well as alterations in the EGFR gene. Although tumors such as colon cancer are commonly treated with EGFR inhibitors, tumors with KRAS or NRAS mutations are resistant to EGFR inhibitors. However, planned clinical trials are using EGFR inhibitors for penile cancer based on anecdotal examples of clinical response.

“In colon cancer, there are so few HRAS mutations that they haven’t been tested for predicting resistance to EGFR inhibitors. But based on the biology of HRAS, NRAS, and KRAS, we would predict that they do cause resistance. As HRAS mutations are relatively common in penile cancer, this alteration may impact the tumor’s response to an EGFR inhibitor in this cancer type,” Tomlins said.

The researchers also found differences between the original primary tumor and metastases in the pelvic lymph nodes. In most cases, the best therapeutic targets are the same in primary tumors and metastases, suggesting that genetic changes occur early in disease development. These findings, however, indicate that aggressive forms of penile cancer mutate as they begin to spread, and more than 1 tumor area may need to be studied to identify the best therapeutic target for a patient.

“It may not be as simple as matching one drug with one mutation based on a single sample in penile cancer. We may need to take the genomic profile in total from 1 or more areas to determine best strategies,” Tomlins said.

Sequencing was done using the Oncomine Comprehensive Panel, a new assay that assesses the most common genetic variants across cancer types. The assay is filtered to include variants associated with potential therapies either approved or being studied in clinical trials. This assay is being used in the National Cancer Institute MATCH trial. It was developed and validated by researchers at the University of Michigan and Thermo Fisher Scientific.

Penile cancer represents approximately 17% of all cancers in men. Although penile cancer is a rare disease, the study revealed key similarities with other squamous cell cancers, such as lung cancer, head and neck cancer, and cervical cancer.

“This provides a roadmap to design better, more informed trials for penile cancer. We have some good leads for potential therapeutic approaches. This is the basic knowledge we need to open the door to more individualized trials and treatments in the future,” Tomlins said.