Using ctDNA Testing to Improve Postoperative Treatment Selection in Urothelial Cancer

Urothelial cancer affects the urinary tract, starting from the renal pelvis. Additional treatments, known as adjuvant therapy, are used in its management, particularly after radical cystectomy (complete removal of the bladder) or nephrectomy (removal of a kidney). Adjuvant treatment aims to destroy cancer cells that may remain after surgery.

Adjuvant Chemotherapy and Immunotherapy

Standards for Neoadjuvant Chemotherapy

Neoadjuvant cisplatin-based combination chemotherapy is standard practice in urothelial cancer; adding the immunotherapy nivolumab can improve its effectiveness. This treatment aims to shrink cancer before surgery and improve surgical success.

The POUT Study

The Peri-Operative Chemotherapy versus Surveillance in Upper Tract Urothelial Cancer (POUT) study showed that adjuvant chemotherapy (gemcitabine/cisplatin or gemcitabine/carboplatin) was superior to surveillance for disease-free survival. Adjuvant chemotherapy significantly prolonged disease-free survival (HR 0.45, 95% CI 0.30-0.68, p=0.0001), highlighting the importance of additional postoperative treatment.

The CheckMate 274 Study

CheckMate 274 showed that adjuvant nivolumab improved disease-free survival compared with placebo in patients with high-risk muscle-invasive urothelial cancer, leading to FDA approval in August 2021 . Median disease-free survival was 21 months with nivolumab and 10.9 months with placebo (HR 0.70, 95% CI 0.54-0.89, p=0.0006). This finding suggests that nivolumab may be an effective option for high-risk patients.

The AMBASSADOR Study

AMBASSADOR showed that adjuvant pembrolizumab was superior to observation. Median disease-free survival was 29 months in patients receiving pembrolizumab and 14 months in the observation group (HR 0.69, 95% CI 0.55-0.87, p=0.0013). These results support pembrolizumab as a potentially effective option in high-risk urothelial cancer.

The Role and Importance of ctDNA

Adjuvant Treatment and ctDNA

Adjuvant therapy is additional cancer treatment, usually given after surgery. In high-risk urothelial cancer, it aims to reduce recurrence risk. However, not every high-risk patient relapses despite receiving adjuvant treatment. Some patients may therefore be overtreated even though they do not actually have micrometastases. This is where ctDNA (circulating tumor DNA) comes in.

The Predictive Value of ctDNA

ctDNA consists of tumor DNA fragments circulating freely in the blood. Detecting these fragments may help predict the likelihood of cancer recurrence. Studies show that ctDNA has prognostic value both before and after radical cystectomy (bladder removal surgery). In particular, it has outperformed pathological staging and has been more effective in predicting how patients will respond to treatment.

How Effectively Does ctDNA Detect Metastatic Recurrence?

In IMvigor010, ctDNA assessment after radical cystectomy detected metastatic recurrence with 94% sensitivity and 98% specificity. This shows that ctDNA can identify patients at risk of recurrence with high accuracy. A recent systematic review of the literature confirmed its predictive role in patients treated with neoadjuvant and/or adjuvant chemotherapy and/or immunotherapy.

Data from IMvigor010

IMvigor010 demonstrates the potential of ctDNA to identify patients at risk of recurrence after surgery.

• Patient Population and Measurements:

  • The study included 581 patients who had undergone surgery and were evaluable for ctDNA.
  • Of these patients, 214 (37%) were positive at treatment initiation on the Sigratera ctDNA test .

• Efficacy and Predictive Ability:

  • The study found that ctDNA-positive patients had an unfavorable disease course (observation-arm hazard ratio = 6.3 (95% confidence interval: 4.45–8.92); P < 0.0001).
  • ctDNA-positive patients in the atezolizumab arm had better disease-free and overall survival than those in the observation arm (disease-free survival hazard ratio = 0.58 (95% confidence interval: 0.43–0.79); P = 0.0024; overall survival hazard ratio = 0.59 (95% confidence interval: 0.41–0.86)).

• Performance Assessment:

  • Sensitivity and specificity were calculated to assess how well ctDNA detected metastatic recurrence.
  • Sensitivity: This is the proportion of ctDNA tests that correctly detect metastatic recurrence. In this study, 94% was reported.
  • Specificity: This is the proportion of ctDNA tests that do not falsely identify metastatic recurrence (correctly identifying true negatives). In this study, 98% was reported.

Future Studies and Applications

Current data suggest that ctDNA may play an important role in treatment planning for high-risk urothelial cancer. In particular, patients with detectable ctDNA after radical cystectomy may benefit from additional treatment, and intensifying it may be appropriate. Further prospective treatment studies are needed to confirm these assumptions. Using ctDNA to reduce the side effects of additional treatment could increase recurrence risk in some patients.

Current and Future Studies

Several current and future clinical studies are examining ctDNA in treatment planning. They aim to establish its prognostic value for disease course and its potential to predict treatment response. Examples include:

• The TOMBOLA Study: This phase II study evaluates atezolizumab as additional treatment in patients with biochemical recurrence after radical cystectomy (NCT04138628).
• The IMvigor011 Study: This phase III study compares atezolizumab with placebo as additional treatment in ctDNA-positive patients with high-risk muscle-invasive bladder cancer after radical cystectomy (NCT04660344).
• The MODERN Study: In this phase II-III study, ctDNA-positive patients receive additional treatment with nivolumab plus relatlimab or nivolumab alone, while ctDNA-negative patients receive nivolumab or observation (NCT05987241).
• The ORACLE Study: This study uses the innovative Guardant ctDNA test in various solid tumors after neoadjuvant chemotherapy. Cohort 1 includes patients with muscle-invasive urothelial cancer, while Cohort 11 includes patients treated for high-grade stage II, III or limited stage IV renal cell carcinoma (NCT05059444).

Conclusion

ctDNA may improve the selection of patients with urothelial cancer for additional treatment and reduce overtreatment. Prospective clinical studies are nevertheless needed to refine patient selection using this technology. Greater participation in these studies could help improve its future application.

Sensitivity and Specificity

According to IMvigor010 data, ctDNA testing can predict metastatic recurrence after surgery with high sensitivity (94%) and specificity (98%). These rates indicate that ctDNA outperforms traditional pathological assessment and is a powerful tool for predicting disease course.