ctDNA Points to the Future of Precision Medicine in Genitourinary Cancers

DNA image by [Kelly Carmack]/MJH Life Sciences using AI

Crafting precision medicine requires specific knowledge of the patient’s disease and what makes it unique. As physicians determine these specifics, they can match patients to the most effective treatment, but not every disease has the same number of biomarkers as seen in lung cancer, for example.¹ Nevertheless, the use of circulating tumor DNA (ctDNA) as a noninvasive liquid biopsy has become a new standard of care for patients with advanced solid tumors. One setting ctDNA is beginning to play a larger part in helping to make treatment decisions is patients with bladder cancer.

“It’s a significant buzzword in oncology these days,” said Alan Tan, MD, associate professor in the Department of Internal Medicine and director of GU medical oncology at Vanderbilt University Medical Center, in an interview with Peers & Perspectives in Oncology on the burgeoning use of ctDNA in genitourinary cancer. Tan explained that the mounting evidence for the measurement of ctDNA and minimal residual disease (MRD) to guide treatment decisions for other patients with solid tumors is exciting and paving the way for understanding its role in crafting treatment for patients with bladder cancer.

“The presence or absence of ctDNA after surgery is helping physicians and patients make informed decisions on whether there would actually be a benefit from the cytotoxic chemotherapy or not,” he said. “Historically, we have tended to overtreat more than half of these patients in favor of improving cure rates in the fraction of patients who have micrometastatic disease that we cannot detect on conventional imaging methods; so in essence de-escalation of treatment in the lowest-risk patients and intensification for the highest-risk patients.”

ctDNA in the Clinic

According to an article in the journal Cancer Research and Treatment, ctDNA is the portion of cell-free DNA in the blood of patients with cancer released from tumor cells due to apoptosis, necrosis, or active release.² Detection of ctDNA signals to the physician the growth of new disease or continuation of disease post treatment. Analyzing the patient’s samples for ctDNA can be done in a variety of ways and can reveal to the physician a variety of information, depending on what they’re looking for. Next-generation sequencing tests based on ctDNA are used as companion diagnostics with certain therapies to evaluate whether those patients will be a match for that targeted approach. For example, FoundationOne Liquid CDx has been approved as a companion diagnostic alongside rucaparib (Rubraca) to identify BRCA1 and BRCA2 gene mutations in patients with ovarian cancer and with alectinib (Alecensa) to identify ALK rearrangements in patients with non–small cell lung cancer.²

Where the use of ctDNA has expanded is in the detection of MRD in patients with solid tumors. As Tan said, this has historically been just a measurement for assessing where patients with hematologic malignancies stand with their disease, but the use of MRD to determine the patient’s prognosis has grown alongside clinical trials in patients with solid tumors. According to a literature review published in JCO Precision Oncology, studies across different types of cancer show that ctDNA-based MRD measurements predict disease recurrence with a high sensitivity and specificity.³ For instance, in the adjuvant setting for patients with colorectal cancer, ctDNA-based MRD detection predicted disease recurrence with a range of 82% to 100% sensitivity and 89% to 100% specificity in several studies. This accuracy has allowed physicians to better design clinical trials and screen patients to determine enrollment.

As in the colorectal cancer setting, the use of ctDNA has allowed physicians to stratify patients with bladder cancer based on risk. This was seen in a small analysis of 68 patients with advanced bladder cancer showing the prognostic power of ctDNA before these patients underwent chemotherapy (HR, 29.1; P = .001).⁴ Patients who were ctDNA positive after transurethral resection of a bladder tumor had an overall recurrence rate of 46% and a 12-month recurrence rate of 42%.⁴

Demonstrating the capability of ctDNA as a prognostic factor in this setting, physicians are also using it to guide treatments in the adjuvant setting. According to Tan, one such study is the phase 3 IMvigor011 trial (NCT04660344) looking at adjuvant atezolizumab (Tecentriq) for patients with high-risk muscle-invasive bladder cancer who are ctDNA positive after surgery. He highlighted early readings from the trial that showed the vast majority of patients who remained MRD negative had high rates of survival, which suggests that patients remaining MRD negative can be spared from adjuvant therapy and not be overtreated.⁵

“In the adjuvant setting there is, by definition, nothing to measure. You can only measure if [the] cancer comes back at some point, but you can’t measure anything shrinking or disappearing, because there’s nothing to measure,” explained Matthew Galsky, MD, professor of medicine, director of genitourinary medical oncology, and codirector of the Center of Excellence for Bladder Cancer and associate director for translational research at The Tisch Cancer Institute in New York, New York, in an interview with Peers & Perspectives in Oncology.

“That’s changed now with ctDNA testing, and, theoretically, you could measure if someone has microscopic cancer that’s eradicated with your treatment,” he added. “If you can do that, then that raises the possibility of doing smaller studies with shorter-term end points looking for [the] disappearance of that DNA in the blood, rather than doing huge randomized studies and waiting years for them to read out.”

Examining ctDNA to Guide Immunotherapy Decisions

As one of the lead researchers behind the biomarker-integrated MODERN trial (NCT05987241), Galsky explained that the trial is looking to test whether clinicians should escalate treatment in patients with urothelial cancer based on their ctDNA status.⁶ After surgery to remove the bladder, patients will be tested for ctDNA using Signatera, an MRD assay that uses ctDNA, and their results will determine which arm of the trial they move to.

“One of the main things we’re trying to accomplish is to establish clinical utility. These tests are commercially available… but showing that there is a correlation between a test and a clinical outcome and demonstrating that clinical decision-making based on that test result will improve patient outcomes are 2 different things,” he said. “So we want to establish clinical utility, we want to show that making a decision based on this test matters to patients and their outcomes, so that we can justify its routine use in clinical care.”

Patients with detectable tumor DNA in the blood will be randomly assigned to receive either adjuvant nivolumab or the experimental combination of nivolumab and relatlimab (Opdualag). According to Galsky, MODERN is a seamless phase 2/3 study gated on the ctDNA clearance end point first, and then researchers will have the opportunity to expand the study further to look at an overall survival end point. This is to help mitigate the risk of undertaking a large phase 3 study without an early indication that there may be a treatment benefit. Further, the secondary end points on this study include disease-free survival and assessing the incidences of adverse events from both cohorts.

The study is enrolling approximately 1000 patients across 300 or more sites who have histologically confirmed muscle-invasive urothelial carcinoma of the bladder.⁶ These patients need to have had radical cystectomy and lymph node dissection 12 weeks prior to preregistration and have no gross cancer at the surgical margins.⁷ Patients enrolled on this trial will be at a high risk of recurrence and will have an ECOG performance status of 0 to 2. Importantly, these are patients who historically would be exposed to enough adjuvant therapy to make their treatment challenging in this setting. By being able to personalize their treatment and de-escalate, outcomes can be improved in terms of both survival and due to toxicities.⁷

“Just from a patient advocacy standpoint, I think this is a huge win,” said Tan. “[Previously, we never had a way to tell when] we could de-escalate treatment for patients who were just cured surgically…but now we have such a sensitive biomarker in ctDNA that can help inform patients, their caregivers, and their treating physicians on whether they’re doing the right thing or not.”

Although this approach with ctDNA has inherent advantages, such as using a less invasive liquid biopsy compared with other approaches, there are still challenges to its use. In particular, clinical utility needs to be better proven, as Galsky and his fellow researchers are setting out to do, and there can be other issues like slow turnaround time and high costs to the patient and practice. Other physicians may point out that any given plasma sample may not have enough genomic equivalents to decisively show a negative result is fully free of ctDNA.⁸ Further, these concepts are in the very early stages for use in the bladder cancer space, and more research is needed to fully understand the role ctDNA plays in crafting a unique treatment for these patients.

“The scientific challenges are that we’re testing a lot of new concepts. We need to test new concepts because these are some of the more important concepts in terms of the historical limitations to the field,” said Galsky. “And by the very nature of when you test new concepts, there’s a risk that they won’t pan out, but that’s what clinical trials are all about.”

REFERENCES:

1. Saman H, Raza A, Patil K, Uddin S, Crnogorac-Jurcevic T. Non-invasive biomarkers for early lung cancer detection. Cancers (Basel). 2022;14(23):5782. doi:10.3390/cancers14235782

2. Kim H, Park KU. Clinical circulating tumor DNA testing for precision oncology. Cancer Res Treat. 2023;55(2):351-366. doi:10.4143/crt.2022.1026

3. Kasi PM, Fehringer G, Taniguchi H, et al. Impact of circulating tumor DNA-based detection of molecular residual disease on the conduct and design of clinical trials for solid tumors. JCO Precis Oncol. 2022;6:e2100181. doi:10.1200/PO.21.00181

4. Christensen E, Birkenkamp-Demtröder K, Sethi H, et al. Early detection of metastatic relapse and monitoring of therapeutic efficacy by ultra-deep sequencing of plasma cell-free DNA in patients with urothelial bladder carcinoma. J Clin Oncol. 2019;37(18):1547-1557. doi:10.1200/JCO.18.02052

5. Natera announces positive surveillance analysis from the randomized phase III IMvigor011 trial in muscle-invasive bladder cancer. Natera. News release. April 5, 2024. Accessed May 22, 2024. https://tinyurl.com/46ss4d8t

6. Natera and Alliance for Clinical Trials in Oncology announce activation of Alliance A032103 (MODERN): a randomized, phase II/III adjuvant trial in urothelial cancer. Natera. News release. April 1, 2024. May 22, 2024. https://tinyurl.com/5t3f8mnd

7. Testing the role of DNA released from tumor cells into the blood in guiding the use of immunotherapy after surgical removal of the bladder for bladder cancer treatment, MODERN study. ClinicalTrials.gov. Updated May 21, 2024. Accessed May 22, 2024. https://tinyurl.com/2b9rvfxr

8. Dang DK, Park BH. Circulating tumor DNA: current challenges for clinical utility. J Clin Invest. 2022;132(12):e154941. doi:10.1172/JCI154941