Bladder-sparing trimodality therapy is an acceptable alternative to radical cystectomy in well-selected patients with muscle invasive bladder cancer. It has a success rate of about 70% in well-selected patients; it consists of maximal TURBT, transurethral resection of a bladder tumour, followed by concurrent chemotherapy and radiation therapy. As I mentioned, the success rate is about 70%; the real question is how do we determine which patients will respond and will not respond to therapy. There's a real lack of molecular biomarkers that can tell us that exact question.

Several groups have now shown that bladder cancer can be subdivided into molecular subtypes based on their gene expression profiles. These are broadly grouped into basal subtypes and luminal subtypes, similar to breast cancer. Other groups have shown that these molecular subtypes can actually correspond to response to neoadjuvant chemotherapy prior to radical cystectomy. So we sought to perform gene expression profiling of bladder tumours from patients who were undergoing bladder-sparing trimodality therapy and to determine whether molecular subtypes and other gene expression profiles may correlate with response to therapy.

We analysed 139 patients who underwent bladder-sparing trimodality therapy at the Massachusetts General Hospital. The median follow-up was about seven years for alive patients and we performed transcriptome-wide gene expression analyses and that allowed us to explore a variety of different expression profiles. So one of the first things we looked at was molecular subtype and, interestingly, in this subgroup, in this cohort of patients, bladder molecular subtype actually did not play a significant role in prognosis of the patients. So that is different from the findings for neoadjuvant chemotherapy that had been described earlier. We then looked at several other markers; interestingly, we found that the molecular signature for what we call a double negative subtype, so that's actually missing markers for basal and luminal markers but are expressing p53 wildtype type markers, those tumours actually correlated with a worse prognosis for the patient after bladder-sparing trimodality therapy.

Then there are two other interesting findings. One is that we found several other markers that were correlated with good prognosis after bladder-sparing trimodality therapy. These include PPAR-γ as well as the DNA damage repair protein Mre11, or actually this is the gene expression, the RNA level of Mre11. Then finally we found that the presence of immune related signatures, in particular interferon gamma and several other signatures, were actually correlated with good prognosis after bladder-sparing trimodality therapy. So that suggests an interplay between the immunological microenvironment and chemoradiation therapy.

So, in summary, we found a number of interesting candidate biomarkers that correlate with both good prognosis and poor prognosis after trimodality therapy. Certainly these are promising biomarkers but we need to validate them in the context of prospective clinical trials before they can be considered for use in the clinic.

What are the potential implications of this?

The real summary is that we've shown that gene expression profiling can identify molecular signatures that correlate with good prognosis and bad prognosis after trimodality therapy. It will be interesting in the future to determine if these are true predictive signatures that predict for response after chemoradiation therapy but do not predict for response after surgery; that would help us really make this decision between trimodality therapy and radical cystectomy. Those studies still remain to be done and, really, all this needs to be validated in the context of clinical trials.

What do you want to look at next?

There's a real interest right now in the field of moving towards combining immunotherapy, in particular immune checkpoint inhibitors, with radiation therapy. There's real interest in combining that and looking at that in the context of bladder-sparing chemoradiation therapy. So one of the real interesting things that we'll follow-up on closely is this immune signature, this immune infiltrate signature that we found was correlated with good prognosis. Because if it's correlated with good prognosis with bladder-sparing trimodality therapy then it may be correlated with even better prognosis if you add an immune checkpoint inhibitor to that mix. So that will be a real area of future interest.