Karen Titus
March 2024—Like identifying the shift in battle that leads to victory, or the battle that wins the war—let alone declaring a war’s ultimate victor—it’s hard to gauge the whens, ifs, and hows that mark progress in medicine. Just ask Henry V—or better yet, his son.
For those who are deeply rooted in bringing advances to testing in urothelial cancers, current research is flourishing and flummoxing. In early and late stage, both for bladder and upper tract disease, recently approved therapies are leading to better outcomes for patients. More immunotherapies and antibody-drug conjugates are on their way, and with them come new options for testing.
But as with any cancer, researchers follow numerous promising paths, knowing that some will dead-end and others will succeed primarily (albeit usefully) in raising more questions.
Nevertheless, they continue to rally the work forward, with multiple breaches, and Agincourt, ever in sight.
For experts such as David McConkey, PhD, director of the Johns Hopkins Greenberg Bladder Cancer Institute, progress will best be measured by how regularly precision makes its way into the clinical setting.
“We’ve done a lot of work evaluating pretreatment biomarkers for selecting patients for various therapies,” says Dr. McConkey, whose group works primarily with chemotherapy; other groups focus on immunotherapy. “The goal was to have precision medicine tests that would be used on the patient standing in front of you, to assign the patient” to a specific regimen.
But an advance in therapeutics can be matched by a retreat in diagnostics, as biomarker researchers well know. Says Dr. McConkey, “The big elephant in the room” is the recently approved drug combination of the antibody-drug conjugate enfortumab vedotin and the immune checkpoint inhibitor pembrolizumab.
Second of two parts on bladder cancer.
Part one in the February issue.
Like many elephants, this one is unwieldy. “We have very little information about predictive biomarkers for that regimen,” says Dr. McConkey. The companion diagnostic that was used in early studies—immunohistochemistry for Nectin-4—was eventually sidelined, he says, because the target has such strong clinical activity. “There’s a sense we don’t need biomarkers as much as we would for something less efficacious.”
True, says Sounak Gupta, MBBS, PhD, who suggests that wider use of antibody-drug conjugates might mean the field could be entering an era in which oncologists will treat bladder cancers without doing associated testing. At least for now, standard of care does not involve looking at Nectin-4 expression. The same is true for Trop2, another current bladder cancer target, says Dr. Gupta, associate professor of pathology; vice chair of oncology practice, Division of Laboratory Genetics and Genomics; and vice chair of research, Division of Anatomic Pathology, Department of Laboratory Medicine and Pathology, Mayo Clinic. “Initial studies suggested there’s a high level of expression in a lot of urothelial cancers. For better or for worse, current guidelines don’t require that you have a certain amount of expression” of Nectin-4 or Trop2.
Moreover, some treatments are given off-label. As guidelines evolve, “Maybe we’ll see criteria come into play,” Dr. Gupta says. As physicians wait for guidelines to catch up, most are operating on the assumption that high levels of one or the other are being expressed. At some point, it may be necessary to establish baselines and what level of expression might qualify a patient for treatment. “We need some of that data to become mature.”
If it’s easy to talk about reducing biomarker testing, it’s equally easy to envision how use of biomarkers could expand. Researchers have to be adept at considering both possibilities.
Andres Matoso, MD, professor of pathology, urology, and oncology at Johns Hopkins University School of Medicine, sees another reason Nectin-4 and Trop2 IHC testing might become useful. Even though these are not companion tests, higher levels of expression could be an indicator of a therapy’s likelihood of working, he says. “You don’t want to wait a few months for a response that’s not going to happen,” particularly in the metastatic setting.
And it’s possible that the drug combination is not ideal for every patient—another area worth exploring, says Dr. Matoso, whose research specialty is urologic pathology. “Some patients have specific situations where they do not tolerate conventional chemotherapy, and they need to jump into an alternative therapy right away. So that’s where I think this testing comes in handy.” He also notes he’s had consults for nonurothelial cancer, for which Nectin-4 is not approved because there is no clinical trial that supports its use. “But they’re just trying something because it’s a situation of clinical emergency.”
This is not widespread testing, obviously. Furthermore, says Dr. Matoso, “There is no consensus in the pathology community that this is the right approach. Nothing supports that. But occasionally, when a clinician wants to know, I do the testing,” especially since it may avoid unnecessary (and expensive) therapy.
IHC could also play an important role in cases of small cell carcinoma, which are aggressive but respond to a neuroendocrine-specific therapy, Dr. Matoso continues. “We now understand that there are three transcription factor-specific subtypes of small cell carcinoma, each with different expression of the receptors for those antibody-drug conjugates.”
Precision remains both alluring and elusive, as researchers are quick to point out.
Says Dr. McConkey, “With all these different regimens, we’re not satisfied that we have this kind of precision, that we can take a piece of tissue and do whatever we want with it, whether it’s RNA or DNA sequencing, spatial transcriptomics, or AI pathology, and say, ‘You need this regimen and not that regimen.’
“We’ve moved into a situation where it’s a bit more empirical,” he continues. While in metastatic settings it’s often possible to see on imaging studies whether a tumor is shrinking in response to therapy, that’s not always an option in the adjuvant setting. A patient may have received neoadjuvant therapy, and perhaps had a cystectomy, or, in the case of upper tract urothelial cancer, had their kidneys removed. “We don’t know whether to offer them more systemic therapy at that point. And the biomarkers aren’t robust enough for us to make the decision based on the pretreatment tissue.”
In response, researchers are turning to liquid biopsies.
In all cancers, Dr. McConkey says, there’s an appreciation that especially for advanced metastatic disease, tests—including next-generation sequencing—are now sufficiently sensitive to detect disease, even if it’s not visible on imaging.
The advantage for urothelial cancers in particular is the potential to use urine-based tests to detect disease presence. Specifically, researchers are employing machine learning to use the information gleaned from urine sequencing to estimate likelihood of a cancer recurring. In addition to serving as a readout for volume of disease locally, says Dr. McConkey, these urine tests are starting to become powerful prognostic tools—much better than urine cytology and other tools pathologists use routinely.
His group at Johns Hopkins, along with colleagues at SWOG, is working with a company called Convergent Genomics, which has a test that measures 60 common mutations and copy number variations across stages of bladder cancer. It also uses low-pass whole genome sequencing to measure copy number variations in aneuploidy. “We blinded them to the clinical outcome in similar trials,” says Dr. McConkey, and sent urine samples to the company. “The results they sent back to us have been astounding. So we’re excited about the possibility [of] maybe using both plasma and urine” in post-treatment testing, which might reduce concerns about the absolute accuracy of tissue-based predictions.
Such work is the focus of numerous clinical trials. One collaborator at Mount Sinai in New York, Matthew Galsky, MD, is overseeing one in which patients will receive adjuvant immunotherapy based on the presence or absence of circulating tumor DNA in plasma, Dr. McConkey says.
“The other big question is, how big a factor is tissue sampling in terms of estimating prognoses and predicting outcomes to therapy?” Dr. McConkey asks. Currently, much of the precision medicine for bladder cancer is based on, for example, activating FGFR3 mutations, he says. “This has allowed for any tissue that was available.” In some cases, therefore, patients with metastatic disease would be treated based on sequencing results from a biopsy or cystectomy sample taken months or years earlier, simply because of availability.
He mentions the work of David Solit, MD, at Memorial Sloan Kettering Cancer Center, who “did a really nice study where they looked at the accuracy of that, comparing tumor and plasma,” using the MSK-IMPACT targeted tumor-sequencing test. A newer platform, MSK-ACCESS, a plasma-based assay, should also advance this work, he says.
There are plenty of examples of discordance between the primary tumor and metastases, Dr. McConkey says. “As it turns out, a lot of our therapeutic targets are not truncal driver mutations; instead, they are subject to subclonality.” It’s not accurate, even with DNA, to predict outcome from a targeted therapy based on just any biopsy sample. “We’re moving more toward a plasma-based approach, where we ask about the target in the most proximal sample we can get, which is the blood sample in the patient right before therapy.”
In short, he says, “From a clinical biomarker perspective, I would say we’re a bit more skeptical of our pretreatment tissue-based biomarkers—certainly in my context, molecular subtypes.” While they continue to be used to design clinical trials, Dr. McConkey says, the limitations are becoming more evident. Even DNA-based tests, such as DNA damage repair mutations predicting cisplatin sensitivity, while significant and associated with outcomes, “are not 100 percent.”
And with immunotherapy, he says, “There is still a lot of buzz around using pretreatment tissues to look at certain immune features and predict response. But even these have proven to be less than perfect, so these liquid biopsies have entered in as complements to that.”
Researchers are also driven by the longed-for goal of diagnosing urothelial cancers earlier.
(See “Doing more, doing better in bladder cancer,” CAP TODAY, February 2024, page 1.)
Colleagues at Johns Hopkins, led by Bert Vogelstein, MD, are developing blood tests to detect not only the presence or absence of cancer, “but maybe even more importantly, the site of origin, just through routine blood screening,” Dr. McConkey says. Evidence shows that tumor DNA in plasma can anticipate clinical recurrence months or in some cases years before it happens.
More near-term, he says, both urine tumor DNA and plasma tumor DNA appear to be fairly powerful tools to detect the presence of cancer very early. “So the question is, which is the best test?” His early-detection preference, at least for now, would be a tumor DNA-based urine test for local disease, and a plasma-based test for metastatic disease.
A handful of companies are developing low-throughput, handful-of-biomarker types of tests, Dr. McConkey says, some of which involve proteins; most usually involve RNA; some might also have a few screening mutations. These tests are typically used in conjunction with conventional cystoscopy in patients with blood in their urine, to detect the presence of cancer. One test in particular, offered by Pacific Edge, “is getting to be so popular, and apparently robust, that there’s talk about using it to even replace” or reduce cystoscopy in certain settings, says Dr. McConkey. A negative test would be repeated at regular intervals until it’s positive, at which point the patient would get cystoscopy.
For his part, Dr. McConkey says the real power of using tumor genomics—and where many companies are exerting their energies—is not only to detect presence or absence of cancer but also to measure the potential aggressiveness of the cancer, like a molecular grading.
“I’m pretty enthusiastic about this,” he says. “As we gain more experience, we will see if our enthusiasm is justified.”
The approval of enfortumab vedotin in conjunction with pembrolizumab “has changed everything,” Dr. McConkey says. He reports that one of his colleagues, Jean Hoffman-Censits, MD, a medical oncologist who, along with urologist Nirmish Singla, MD, codirects the upper tract urothelial carcinoma program at Johns Hopkins, is about to start a clinical trial in which patients with upper tract cancer who might otherwise require definitive surgery and then go on dialysis will instead receive enfortumab vedotin plus pembrolizumab, with the goal of kidney preservation.
Dr. McConkey says he and his laboratory colleagues are building in both urine and plasma tumor DNA tests to ensure this course is indeed working. “And if it’s not—if we find a lot of tumor DNA in either place—we can revisit the decision to avoid surgery, to avoid dialysis.”
“I would say in general in urothelial cancer,” he adds, “there’s a feeling that this [drug] combination is going to move forward in clinical management to earlier stage disease, certainly of the muscle-invasive bladder cancer. As a result, there’s going to be more organ preservation, requiring more accurate tests to make sure the therapy eradicated local disease.” This is complicated by the fact that, as he acknowledged earlier, “we don’t have any robust biomarkers at this point to predict response.” The hope, he says, is that in most cases these would be conventional clinical tests. “But it will also be helpful to have some sort of sensitive molecular tests as companion diagnostics.”
There is, he says, talk of moving the regimen even earlier, though concerns about toxicities and expense could delay such a step. “There’s a lot of activity, led mostly by urologists, developing novel immunotherapy regimens for intravesical delivery into the bladder. So I think for the nonmuscle-invasive disease—the high-risk nonmuscle-invasive disease up to BCG-unresponsive disease—we’re going to see a lot of significant, very aggressive drug development efforts,” Dr. McConkey says.
Even the most enthusiastic researchers need to allow space for penciling in disappointments.
In 2016, in the realm of molecular subtypes, Dr. McConkey and colleagues were, he says, confident they had developed a robust predictive biomarker for treating patients with chemotherapy, with emerging evidence that it would also be robust for immunotherapy. Expectations were strong that molecular subtyping would inform treatment decisions in every disease state and with every therapy, and not just neoadjuvant chemotherapy.
Then the SWOG S1314 clinical trial weighed in, he says. “What we discovered was that while we were still reproducing our original observations to a certain extent, we weren’t seeing the same robust correlations between molecular subtypes and outcomes.”
RNA-related research has since moved on to the study of lineage plasticity. “Since then,” says Dr. McConkey, “we’ve developed great, new technologies that allow us to do things beyond bulk RNA sequencing.”
But that has also led to a cautionary note. Researchers led by John Sfakianos, MD, at Mount Sinai showed, using single-cell RNA sequencing, “that if you look at any bladder cancer, you can essentially find all the molecular subtypes in all of them,” says Dr. McConkey. They exist in different proportions; moreover, the observation that bulk RNA sequencing can call very robust subtypes still holds true. “But this suggested perhaps that not all the cells on a tumor that are assigned to a particular molecular subtype belong to that subtype.”
Down the rabbit hole the research goes, but it offers a glimpse into why experts in the field are filled with both excitement and caution, like finalists in a Miss America pageant.
Dr. McConkey and colleagues have also collaborated with a group at Columbia University that has isolated and created a panel of human bladder cancer organelles. “These are essentially human cells in tissue culture that are grown in three-dimensional spheres, in an extracellular matrix-containing environment,” Dr. McConkey says. They seem to preserve the characteristics of the original tumor, including histology, better than conventional cell lines. The plan is to use them for preclinical laboratory research studies.
But in the process of characterizing these organoids, he says, researchers discovered that some, perhaps even many, switched subtype. “Such that the original primary tumor in many cases was luminal, and the organoids, on passage outside the body, became basal.” This might be a consequence of some of the earliest genetic changes that happen in bladder as a result of field cancerization, Dr. McConkey says. “They lose chromatin-modifying enzymes that seem to control the terminal differentiation,” essentially making the cells much more plastic and enabling the switch between basal and luminal.
Other intriguing insights are based on work, done at MSK, that showed that histologic assessment of cystectomies showed widespread dysplasia and other features associated with abnormality in widespread regions of these cystectomies.
Since then, Dr. McConkey says, Bogdan Czerniak, MD, PhD, at the University of Texas MD Anderson Cancer Center, has been using a technique he calls whole organ histologic genomic mapping to measure the changes occurring not only in the cancer-containing areas of the urothelium but also in other areas of the organ that in some cases can look completely normal under the microscope.
“This work has been very informative of the fact that even in people who don’t smoke or presumably haven’t had exposure to major carcinogens—but just as a consequence of aging, anybody over 50 ends up having these mutations present in the bladder that are the same mutations in some cases that we see in cancer—they’re heavily enriched with a specific kind of mutation targeting these so-called chromatin-modifying enzymes,” Dr. McConkey says. “But there’s still controversy about whether you can also find really classic tumor mutations like [FGFR3] and p53.”
What does this mean from a pathologic perspective? “There may be a lot more going on in areas of the bladder that used to be considered benign,” he says. In the realm of early detection, “It may be necessary for us to start thinking about intervening long before we would have otherwise.”
It also has implications for liquid biopsies, he says. Just as clonal hematopoiesis can make it difficult to discern between cancer and noncancer in plasma, “We don’t know yet quite how black and white the distinction between field cancerization and overt cancer is going to be.” As the field evolves, “It’s going to have dramatic implications for early intervention and prevention.”
Bladder cancer is also starting to turn a page that has already been written in lung and prostate neuroendocrine small cell cancers, Dr. McConkey says, in which some cancers can acquire neuroendocrine features, possibly associated with loss of p53 and Rb, and possibly PTEN, as well as certain transcriptomic changes. “We’re starting to see this with some molecular subtypes of bladder cancer as well.”
The fingers-crossed view of this situation is that “it may be possible to lock the cancers into a state that we can treat more easily,” he says. The head-in-hands viewpoint is that these subtypes are a moving target. “And it may be why we’re not seeing complete concordance between our predictions and our clinical outcomes.
“Most of us probably think this molecular subtype switching happens in maybe 20 to 25 percent of cases,” Dr. McConkey says. “We’re starting to learn some of the rules about what might be governing this switching. But having a test that’s only 75 or 80 percent accurate is not satisfying, and certainly not accurate enough to confidently assign a patient who’s standing in front of you to a given therapy based on that.”
In short, he says, “Molecular subtype plasticity has become a very important area of current research, and awareness of it has lowered our confidence somewhat in using molecular subtypes as predictive biomarkers for selecting therapy.”
As noted, the role of liquid biopsies has expanded in tumor sequencing, with additional uses likely as well.
Predicts Dr. McConkey: “I suspect as these tests get more sophisticated, the liquid biopsy’s going to tell us something about the presence or absence of subtypes or molecular grade to complement what pathologists are doing in conventional histology.”
Mayo Clinic’s Dr. Gupta too anticipates a shift from tissue-based testing to liquid biopsy-based testing. Moreover, he says, “I also think there’s a huge role for liquid biopsies in managing patients with bladder cancer. That’s an area that’s probably going to take off in the next few years.”
Like others, Surena Matin, MD, the Monteleone Family Foundation distinguished professor, Department of Urology, MD Anderson, is intrigued about emerging possibilities for liquid biopsy, especially in the realm of upper tract urothelial cancer. This field has had its own set of ebbs and flows.
UTUC therapeutics experienced a leap forward with the approval several years ago of the drug mitomycin hydrogel. “For the first time ever,” says Dr. Matin, “there is a drug—the only drug—that’s been approved for treatment of low-grade upper tract urothelial cancer.” The gel essentially acts as a slow-release formulation of mitomycin, a chemotherapy commonly used in the urinary tract.
For this, “You definitely want a biopsy that shows low-grade disease,” says Dr. Matin, who participated in the drug’s clinical trials. “We had several patients in whom it didn’t work, with a biopsy that showed low grade.” After patients were treated, they were subsequently found to have high-grade disease. It’s possible the high-grade disease was always present but wasn’t initially apparent, he says. When the drug eliminated the low-grade disease, it “basically exposed the high-grade component. I saw a fair amount of that happening.”
While urologists and pathologists need to do their due diligence to ensure presence of low-grade disease, he says, “we also use cytology, because we find that as an adjunctive test, it can help detect high-grade cancer sometimes. So a lot of us do both—the washing [with saline] and biopsy.”
In addition to using cytology in the context of mitomycin hydrogel therapy, it could be used for liquid biopsy, he suggests. “We have done this at a research level, helping to identify if they have particular mutations.” But researchers are also exploring whether this could be a lower-risk option for determining treatment strategies.
Mutational testing continues to exert a push-pull relationship on the field.
Dr. Matin is the first to say that in terms of mutations for UTUC, very little is highly clinically relevant right now. “But at a research level, we’re very interested in what’s going on.” UTUC tumors have a high rate of FGFR3 mutations, he says. He and colleagues will publish results from a recent clinical trial using these inhibitors in patients with nonmetastatic upper tract disease. “We saw dramatic responses,” he reports. Patients who initially had been candidates for organ removal were able to have kidney preservation instead.
Arlene Siefker-Radtke, MD, professor of genitourinary medical oncology, MD Anderson, sees the possible need for additional testing to identify whether mutations persist or evolve. While erdafitinib is the first-in-class agent approved in the setting of FGFR3 alterations, there are several current trials of smaller targeted therapies that might overcome some of the mutations of the FGF receptor that associate with resistance to agents like erdafitinib, she says. Some of these are gatekeeper mutations in the FGF receptor. Knowing this type of a mutation is present “could help us pick one of these next-generation, or smaller, agents that can still fit into that pocket despite the presence of a gatekeeper mutation. But those trials are still enrolling, and we don’t yet have data on how effective they are.”
In the meantime, she advocates for a more near-term change: early gene sequencing. “Most insurance plans are covering it for patients who have stage IV or surgically unresectable urothelial cancer,” she says, since these are patients who would qualify for standard-of-care treatment with erdafitinib. “I personally test any patient who has stage IV disease, and I test it early—as soon as they present to the clinic, so I can plan for the appropriate sequence.”
For all the intrigue of future developments, clinicians face the hard reality of patients in the here and now. “Patients’ tumors can progress quickly, so they often don’t have time to wait,” Dr. Siefker-Radtke says. “If we send a mutation late, we might not get the results back in time to intervene with a potentially effective therapy that potentially will extend a patient’s life.”
The same is true for UTUC, Dr. Matin says. “It can be a very insidious disease. I’ve had at-risk patients I was monitoring very closely who developed disease within three months of imaging.” Though it’s not common, “the aggressive subtypes can sneak right up—one minute it’s not there, and the next thing you know it’s a stage III.”
Slow-moving cases are equally deserving of molecular testing, Dr. Gupta suggests, but there’s no real clarity about how best to do this. “Many of these patients may have a long disease course, which makes bladder cancer one of the most expensive cancers.” Somebody may get diagnosed with a low-grade papillary lesion on year one, and 10 years later that progresses to more aggressive disease. And in the intervening period, the patient may have been screened with annual cytologies and intermittent biopsies, creating a huge number of surgical pathology specimens.
“At what point do you do the molecular testing?” Dr. Gupta asks. “Do you do it for your early, indolent-type tumors? Do you only do it for the aggressive tumors? Do you do it on the resection or on a liquid biopsy specimen? It’s difficult to come up with guidelines to say this must be done for all patients. So I think that’s part of the challenge here.”
“Being a molecular pathologist,” he continues, “I’m a big proponent of molecular profiling. But I also see the challenge in terms of cost and reimbursement. If access were not an issue, it’s inevitable that you’re going to have a lot more molecular profiling. And I think doing comprehensive testing just once, with a big panel, is probably the answer. Because you could get a representative specimen and know this patient’s status in terms of the most important biomarkers—FGFR alterations, microsatellite instability, TMB—and have it defined. It may not be required for patients with early, indolent tumors, but for patients with aggressive cancer.”
For now, says Dr. Gupta, there is a bit of a disconnect between basic science and diagnostic workup. “There is a lot of literature on molecular subtyping of bladder cancer, but none of that has made the transition to the clinical pathology report.” But it’s a brisk area of research and advocacy, “and I wouldn’t be surprised if we started doing a lot more molecular typing” in the not-too-distant future.
Dr. Matoso has a big ask for molecular pathology as well. In patients who have undergone a cystectomy, he says, “I would like to see a comprehensive panel of findings that could predict which one of the therapies the patient is most likely to respond to. Can we have a group of molecular testing, immunohistochemistry testing, and subcategories to be able to spare patients from chemotherapy who are not going to respond, and go directly to a more targeted therapy?”
He too brings it back to the need for personalized care. More uniformity in testing and in classifying patients with metastatic disease would be a huge advancement, he says. And it may well be within reach: “There has been a lot of progress in the last five years. And yes, I could see more coming up in the next five years or so.”
It should be clear by now that research advances are more of a field guide to possibilities rather than actual practice. But the bridge between the two supports quite a bit of traffic.
Dr. Gupta leads the solid tumor practice for Mayo’s molecular testing laboratory. “We do a lot of test development,” he says, fielding requests from Mayo pathologists and oncologists as well as those outside the institution. “At any given point in time, we have over 100 requests to develop tests.” While they look at every disease state, “Recently we have built quite a few tests specifically for bladder cancer.”
Two groups order these tests: pathologists ordering diagnostic testing, and oncologists needing tests for therapeutic or prognostic indications. The former tend to be single-gene assays. One gene alteration, though not specific for bladder cancer, is enriched for the disease: mutations in the promotor region of the TERT gene. “Often we struggle with a very poorly differentiated aggressive tumor and are trying to decide, is this urothelial or not?” The other struggle is trying to discern, usually on a tiny biopsy, whether a lesion represents benign proliferative-type changes or is malignant (such as the nested variant of urothelial carcinoma, which appears cytologically bland). “So in those contexts, testing for TERT promoter mutations has become very popular,” Dr. Gupta says. There are several approaches to doing this, including sequencing this gene as part of a large panel or single-gene sequencing; Mayo uses digital droplet PCR. “You need very little material—you can even have one or two unstained slides,” he says. “It’s also relatively inexpensive.”
Bladder cancer can have multiple variants, he notes. The micropapillary variant is very aggressive, and often it will have HER2 amplification. “So we also get requests for that.”
On the oncology side, where testing for FGFR alterations is common, this may be a more focused assay to look for FGFR alterations alone, or as part of a 500-gene panel.
Microsatellite instability is also relevant to bladder cancer. “I think we probably undertest for that,” says Dr. Gupta, noting it’s not part of current screening protocols. Upper tract tumors in particular are often enriched for MSI; many of these patients will have Lynch syndrome.
Dr. Gupta reports that some recent studies suggest HER2 amplification might not be restricted to micropapillary bladder cancer—that some other conventional types of bladder cancer also have HER2 amplification. But to date there has not been widespread adoption of HER2-targeted therapies for bladder cancer.
Dr. Matoso has observed a slight uptake in requests for HER2 testing in urothelial cancer. “We follow the breast methodology. But there is not a urothelial-specific consensus in terms of reporting it. That is a need,” he acknowledges. “We need some sort of reporting system that would be specific for bladder. GI has it, and breast has it, but for bladder there is no consensus.”
More clinical trials will help sort this out, Dr. Siefker-Radtke says. “We now have clinical trials that are showing clinical activity of HER2-targeting antibody-drug conjugates. So recognizing HER2 overexpression I believe is going to be important. At the moment we don’t yet know if it needs to be IHC 3 versus [IHC] 2, or even some IHC 1 responding. We are waiting for larger clinical trials of these HER2-targeting agents to see which patient population benefits the most.”
For Dr. McConkey, the field is moving tantalizingly closer to using classifiers that might inform that prediction of metastases in urothelial cancers. He and colleagues are involved in numerous clinical trials, including one that looks at standard versus extended lymph node sections, and several focused on nonmuscle-invasive bladder cancer to test a number of systemic and adjuvant intravesical therapies.
“It’s an exciting area of investigation, for biomarker folks like myself but also pathologists.”
And? “We also don’t know for sure where all this is going,” he concedes.
Karen Titus is CAP TODAY contributing editor and co-managing editor.