Our recent work showed that urothelial cancers harbor high rate of alterations in DDR (DNA damage repair and response) genes, with 25 – 29% rate of deleterious alterations and up to 25% with variants of unknown significance – considering the genomic complexity of urothelial cancers, it is not unreasonable to postulate that some of these variants of unknown significance might be functionally significant. We have also shown that DDR alterations are associated with higher likelihood of response to immune checkpoint inhibitors, an observation which was also commented upon by Necchi and colleagues in the neoadjuvant setting with pembrolizumab monotherapy (Nicchi et al, ASCO 2018). Furthermore, the FDA has approved pembrolizumab for treatment of tumors with deficient mismatch repair capacity or microsatellite instability, which is one of the DNA damage repair mechanisms – these collectively point towards a potential utility for DDR alterations to guide treatment.

Tumor mutation burden / load has been shown across different studies to be associated with treatment response with different immune checkpoint inhibitors as well. To further complicate matter, urothelial cancers on average harbor higher mutation load compared to other tumor types (Lawrence et al, Nature 2013); these are associated with alterations in DDR genes, and could also be associated with other non-DDR genomic events. At least in our analysis, presence of DDR alterations confers more statistical strength in association with clinical response, progression-free survival and overall survival, compared to tumor mutation burden. In summary, both DDR gene alterations and tumor mutation burden have potential as biomarkers of response to immunotherapy in urothelial cancers. Nevertheless, the field is evolving rapidly. A larger and more concerted effort is required to validate the clinical utility of DDR gene alterations and tumor mutation burden, along with other emerging biomarkers, before we could introduce it in clinical practice.