Urothelial Carcinoma Shows High Volume of Clinically Relevant Genomic Alterations

Greg Kennelty

A high number of clinically relevant genomic alterations (CRGAs) were found in patients with advanced urothelial carcinoma (UC) using a comprehensive genomic profile (CGP).

According to the study,1a cohort of 295 patients were assessed. The patients were classified as having high-grade and advanced-stage UC. Of the patients, 294 had at least 1 genomic alteration (GA) on their CGP, with a mean of 6.4 genomic alterations (GAs) per UC (61% substitutions/insertions/deletions, 37% copy number alterations, and 2% fusions). The study also states that 275 patients had at least one CRGA involving 75 individual genes with a mean of 2.

The cohort consisted of 75% male and 25% female patients. The mean age of the cohort was 66 years old.

In order to perform the study, ≥50 ng of DNA was taken from 40 µm of formalin-fixed, paraffin-embedded (FFPE) sections from all consecutive cases of recurrent/metastatic UC of each patient participating in the study. CGP was performed on hybridization-captured, adaptor ligation-based libraries to a mean coverage depth of 688X for all coding exons of 236 cancer-related genes plus 47 introns from 19 genes frequently rearranged in cancer, using process-matched normal control samples as a reference.

All FFPE samples were sequenced to high (average >600X), with uniform coverage where no exon was sequenced at less than 100X. All classes of genomic alterations including base substitutions (sub), small indels, copy number alterations (CNA), and rearrangements/fusions were determined and then reported for these patient samples.

CRGAs were defined in the study as GAs linked to treatments currently available on the market or currently under evaluation in mechanism-driven clinical trials.

According to the study, the most common CRGAs found in patients involved cyclin-dependent kinase inhibitor 2A (CDKN2A) at 34% of the cohort, fibroblast growth factor receptor 3 (FGFR3) at 24%, phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) at 20%, and ERBB2 at 17%. FGFR3 GA were diverse and included 10% fusions, ERBB2 GA were divided in half between amplifications CNA and SUB, and ERBB2 SUB were mostly found in the extracellular domain and showed particularly high levels of enrichment in the micropapillary UC subgroup.

"Using a CGP assay capable of detecting all classes of GA simultaneously, an extraordinary high frequency of CRGA were identified in a large series of patients with clinically advanced UC," wrote the authors in the conclusion of the study. "More than one-third of these relapsed/refractory cases of UC harbored alterations in NF2, FGFR3, and ERBB2, with selected patients showing active responses to targeted therapies. Continued evaluation of CGP for UC and the development of genomic-driven clinical trials designed to employ targeted agents potentially in combination with cytotoxic drugs for this challenging disease appears warranted."

"When cancer of the urinary bladder progresses to incurable metastatic disease, it is a major cause of morbidity and mortality around the world," wrote the authors.

"Although standard of care cytotoxic therapies can provide significant benefit, and new strategies of neoadjuvant chemotherapy have recently emerged. Despite significant success of targeted anticancer therapy in other common solid tumors, such as breast and lung cancer, patients with loco-regionally advanced and metastatic UC currently have limited therapy options, especially as chemoresistance develops to standard anticancer therapies."

Reference

  1. Ross J, Wang K, Khaira D, et al, Comprehensive genomic profiling of 295 cases of clinically advanced urothelial carcinoma of the urinary bladder reveals a high frequency of clinically relevant genomic alterations.http://onlinelibrarywileycom/. 2015. http://www.foundationmedicine.com/wp-content/uploads/2015/03/ASCO-GU_Bladder_Ross2_Final.pdf. Accessed December 21, 2015.