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.
The INVIGOR-11 trial data should be applied carefully. A positive ctDNA result post-surgery indicates when to *initiate* adjuvant immunotherapy. However, if a patient on neoadjuvant therapy becomes ctDNA-negative, this signals treatment efficacy and is a reason to *continue* the planned course, not a justification for stopping it early.
For ctDNA-positive patients with high relapse risk, a clinical conflict arises. 'Purists' advocate for treatments with prospective trial data (single-agent immunotherapy), while 'pragmatists' argue for using the most effective therapy available (like EV pembro), treating ctDNA positivity as early metastatic disease, even without specific trial evidence in that setting.
Not all ctDNA clearance is equal. Data from KEYNOTE-361 shows chemotherapy clears ctDNA more frequently (40%) but with poor correlation to outcomes. In contrast, immunotherapy clears ctDNA less often (11%), but those patients who do clear it experience brilliant, more durable outcomes, suggesting a different biological mechanism of response.
Personalized, tumor-informed ctDNA approaches (like Signatera) are more specific and sensitive for bladder cancer than general panel-based assays. This is because bladder cancer has a distinct mutational landscape and because panel approaches can yield false positives from clonal hematopoiesis, making the personalized technique essential for accurate results in this disease.
The future of bladder cancer surveillance may involve using two types of liquid biopsies in tandem. A patient who is utDNA-positive but ctDNA-negative likely has a local, primary bladder issue. Conversely, a utDNA-negative but ctDNA-positive result suggests the cancer has already spread systemically, providing crucial information for treatment planning.