ctDNA is not a simple positive/negative binary test. Like PSA in prostate cancer, the quantitative level of ctDNA correlates with patient outcomes. Higher levels indicate a worse prognosis and a faster time to relapse, allowing for more nuanced risk stratification beyond a simple presence or absence of the biomarker.

Circulating tumor DNA (ctDNA) is a powerful tool in bladder cancer. A positive result post-surgery is a strong indicator for initiating adjuvant therapy. However, a negative result does not guarantee a cure, as a notable percentage of these patients still relapse, making clinicians cautious about withholding treatment based on a single negative test.

Circulating tumor DNA (ctDNA) is a powerful biomarker for identifying high-risk bladder cancer patients. However, its imperfection presents a new clinical dilemma: with a ~12% relapse rate even in ctDNA-negative patients, clinicians must decide whether to withhold adjuvant therapy and accept that risk, or overtreat the 88% who are likely cured.

Upcoming trials like RETAIN and IMVigor011 are using circulating tumor DNA (ctDNA) to guide complex treatment choices in muscle-invasive bladder cancer. This biomarker-driven approach aims to personalize therapy, potentially enabling bladder preservation for some patients and identifying others who need additional adjuvant treatment.

In adjuvant bladder cancer trials, ctDNA status is both prognostic and predictive. Patients with positive ctDNA after surgery are at high risk of relapse but benefit from immune checkpoint inhibitors. Conversely, ctDNA-negative patients have a lower risk and derive no benefit, making ctDNA a critical tool to avoid unnecessary, toxic therapy.

In muscle-invasive bladder cancer, patients whose cell-free DNA remains positive after surgery almost uniformly experience disease relapse. This makes ctDNA a powerful prognostic tool, akin to PSA in prostate cancer, for identifying patients at the highest risk.

Beyond a simple positive/negative result, the quantitative level of ctDNA is highly prognostic in bladder cancer. Similar to PSA in prostate cancer, higher ctDNA levels correlate with a significantly worse prognosis, offering a more nuanced risk assessment tool than a binary test.

A positive ctDNA result post-surgery in an immunotherapy-naive patient warrants starting treatment. Conversely, if a patient received neoadjuvant immunotherapy and remains ctDNA positive after surgery, it signals resistance, making continuation of the same therapy illogical and creating a clinical paradox.

The control arm relapse rate in the SUNRISE 2 trial was only ~20%, while in the EV-303/KEYNOTE-905 trial it was ~60%. This huge discrepancy highlights that current clinical staging and selection criteria are poor at identifying patient risk, signaling an urgent need for better stratification tools like ctDNA for more effective clinical trials.