Case 3: Molecular Testing in Bladder Cancer

EXPERT PERSPECTIVE VIRTUAL TUMOR BOARD

Arlene O. Siefker-Radtke, MD:When are you testing? Are you waiting for progressive metastases, first-line mets [metastases], earlier? What do you prefer?

Tian Zhang, MD:As they are getting their cystectomy—after muscle-invasive disease we’ve given them neoadjuvant chemotherapy and the surgeon, Dr Gordon’s colleague, has taken out their bladder—I’m sending the high-risk patients right at that point. So as we’re thinking about adjuvant trials in that setting, I’m also getting their molecular testing so that if and when they do recur, I have that information to drive the next decision making.

And if we’re not seeing them until that metastatic point, then if I’m seeing them with a new diagnosis of either de novo or recurrent metastatic disease, then I’m grabbing the archival tissue and sending it off at that first office visit.

Arlene O. Siefker-Radtke, MD:When you say “high risk” following surgery, what would you define as high risk when molecular testing is indicated?

Tian Zhang, MD:I think of T4 disease, for example. And a lot of our women with vaginal or uterine involvement, I think of lymph node involvement, right? A couple of lymph nodes at the time of surgery is micro-metastatic disease, in my mind, and we really need to send that tissue off quickly.

Arlene O. Siefker-Radtke, MD:OK. For node-positive or T4a or T4b tumors, you would do molecular testing right away without waiting for relapse.

Tian Zhang, MD:Absolutely.

Arlene O. Siefker-Radtke, MD:What about you Betsy?

Elizabeth R. Plimack, MD:I think we are moving toward that. The one issue that gives me pause, Bishoy Faltas, MD, published really beautiful data on clonal evolution of bladder cancer, and it doesn’t stay the same. There’s reason to believe that as disease progresses through years of therapy, or through the metastatic process, that the marker has changed. And so part of me always would wonder if we’re using the bladder that’s out of the patient, are we really getting information that’s relevant to the tumor that’s in the patient, which is what we want to treat?

So I’ve been trying to time it where I do it right before I think I’m going to need it, like one line of therapy before I think I’m going to need it. In the case of a patient who got platinum chemotherapy and then immunotherapy, probably before the immunotherapy, we would send it off to be prepared. But it’s tricky because I think probably in a perfect world we would be able to quickly biopsy the metastatic lesion right before making a treatment decision and have that information in a few days. We’re not quite there yet. And so it’s sort of a balance between timing and delaying therapy versus getting the most relevant information, which I do believe is probably a metastatic site at the time of initiation of erdafitinib.

Tian Zhang, MD:I absolutely agree. And the only caveat is in my metastatic lesions, sometimes we don’t get enough tissue for Foundation Medicine or Caris Life Sciences next-generation testing on the tissue itself. Sometimes we’ve been depending on circulating tumor DNA tests, for example, to try to pick up on these rare allele frequency mutations. Sometimes it picks it up, other times it doesn’t. I think the tissue is still gold standard if we can get enough of it.

Arlene O. Siefker-Radtke, MD:How are we doing liquid biopsies in patients?

Elizabeth R. Plimack, MD:I have started to do them in patients who don’t have amenable biopsy-able lesions. I would preferentially lean on those results again over a remote cystectomy sample, for instance. But it’s early days and I think we don’t know exactly how to interpret that. Or, more importantly to me, whether we’re missing anFGFRmutation in a patient who could benefit from erdafitinib; that would make me a little bit uneasy.

Arlene O. Siefker-Radtke, MD:That’s an interesting point that you raised. I don’t know if you’re aware, but there was some liquid biopsy data presented from the erdafitinib trial. Now the erdafitinib trial itself required tissue confirmation. So all patients enrolled had the mutation detected in tissue, and this was mostly archival tissue.

The trial also collected tumor from doing the liquid biopsy, looking for circulating free DNA, and Ademi Santiago-Walker, MD at GU ASCO [the Genitourinary Cancers Symposium, American Society of Clinical Oncology], I think it was this last year or maybe the year before since time flies, she looked at the liquid biopsies. And when she detected the presence of the mutation and the circulating free DNA component, the response rate was actually over, I think it was over 60% of patients had a response, which speaks to that tumor heterogeneity that you were referring to, with having to be present to achieve the benefit.

But intriguingly, even when she couldn’t detect it, and again, these were patients preselected by archival tissue, the response rate was still around 30%. So that tells me there’s heterogeneity, but there are also limitations in the assay where we still cannot detect, or I’m guessing we still cannot detect, a very small amount of active disease.

So I think circulating DNA is certainly a promising strategy. Archival tissue remains the gold standard. We’re testing it earlier now rather than later, and the trial did allow people to have it tested at any point prior to needing therapy, so they could easily sequence on to their next line. But I’m curious in the urology setting. Are you doing any mutation testing or testing any of the tissues in superficial or even neoadjuvant patients?

Gordon Brown, DO:We’ve tried to make it standard operating protocol, quite honesty, with our pathology department at the time of diagnosis. That, to be honest, has been met with a little resistance because of some of the infrastructure demands, etcetera. So we’ve been trying to be selective in whom we request that analysis for. I think you’re absolutely correct, in those patients who have node-positive disease at time of cystectomy, those patients who have T4 disease. Especially if you’re looking to accrue them to a clinical trial in the adjuvant setting, those patients are ripe for testing at that point.

In the earlier stage of the disease and trying to risk stratify who may best benefit either from trial inclusion, or from off-label kind of indications and use of that, then the question really becomes, we only can go back to the insurance well so many times, to be quite honest with you, from a practical perspective, right?

So if it’s really going to make a difference I try to get them on trial preferentially because all of their costs are going to be covered by the trial, and if they required additional testing as their disease evolved, should it, then we can obtain analysis at that point, based on their current insurance. The logistics are a little bit different in terms of disease state, whether they’re on trial or off trial, in terms of how we utilize it.

Transcript edited for clarity.