ASCO 2017: Multiregion sequencing of penile cancer to reveal distinct patterns of heterogeneous actionable mutations

Chicago, IL ( Penile cancer, particularly in the first world, remains a rare oncologic condition. Indeed, metastatic penile cancer is even more rare. This makes large studies in this disease process difficult to initiate. However, with such a poor prognosis once it has metastasized even to regional lymph nodes, additional therapeutic options are in desperate need.

To that effect, these authors from the United Kingdom conduct the first study to assess intra-tumoral heterogeneity in penile cancer. By completing deep whole exome sequencing (DWES) on tissue from 8 patients – each patient had tumor tissue from 4 distinct regions of the tumor, as well as a matched normal and metastatic tissue, resulting in 48 samples total.

Following DWES, on average, 650 single nucleotide variants (SNVs) and insertion/deletion events were discovered per tumor sample. As suspected, there was extensive intra-tumor heterogeneity. HPV 16 was found in 75% of samples.

On further analysis, the authors found that there were two distinct patterns emerging: either the acquisition of mutations seen in the lymph node metastasis was an early event with a lower mutational load, or it was a later event with a high mutational load. The presence of HPV seemed to be associated with the patterns of presentation, as the two patients who were HPV negative had lymph node metastasis that evolved at a later date. However, in 5/6 cases of HPV+ patients infection, an early subclone developed which potentially led to the lymph node metastasis.

Looking at specific SNV’s and mutations, driver mutations in p53, cMET or FAT1 were found to be truncal early events in 80% of cases. Actionable mutations in PIK3CA, EGFR and ERBB4 were found to be subclonal in two further samples.

Limitations / Discussion Points:
1. Ultimately, this is a very small selected population in a disease process that it is rare to begin with. Validation is needed in additional cohorts to confirm these findings.

Take-home points / Discussion:
1) Intra-tumoral heterogeneity is significant within solid primary penile cancer. This heterogeneity may account for the variable progression of similarly staged penile primary cancers.
2) The main truncal drivers in penile cancer are cMET, FAT1 and p53.
3) Infection with HPV, a risk factor for penile SCC and SCC in general, is associated with a unique genomic signature.
4) Actionable mutations in PIK3CA and EGFR were found to be subclonal in origin. This may have profound effects on the clinical utility of targetable treatments such as tyrosine kinase inhibitors.

Presented By: Simon Rodney

Co-Authors: Miljana Tanic, James Barrett, Webster Philomena Amy, Patricia de Winter, Wei Shen Tan, Pramit Khetrapal, Liqin Dong, Sheida Rezaee, Alex Freeman, Raj Nigam, Peter Malone, Asif Muneer, Stephan Beck, Andrew Feber, John D Kelly
Institution(s): City of Hope Comprehensive Cancer Center, Duarte, CA; Fox Chase Cancer Center, Philadelphia, PA; Foudation Medicine, Inc., Cambridge, MA; The Warren Alpert Medical School of Brown University, Providence, RI; Albany Medical College, Albany, NY; Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston, MA

Written By: Thenappan Chandrasekar, MD, Clinical Fellow, University of Toronto, Princess Margaret Cancer Centre
Twitter: @tchandra_uromd

at the 2017 ASCO Annual Meeting - June 2 - 6, 2017 – Chicago, Illinois, USA