FISH is known to detect recurrent bladder cancer before it is clinically evident by cystoscopy (i.e., molecular recurrence).17-19
Four prior studies have assessed the utility of FISH after intravesical BCG and found that a positive assay correlates with a higher risk of disease recurrence. However, the risk of progression has differed amongst these studies and remains in question.8-11
In this report, we build upon these previous findings and present results for 126 patients from our prospective clinical trial investigating the role of FISH in predicting response to intravesical BCG. We found that the results of FISH assays correlated with risk of tumor recurrence and progression. Notably, the risk of disease recurrence and progression increases with each additional positive FISH result, and the earlier a FISH result converts to positive from a negative baseline, the higher is the risk of recurrence and progression (a positive FISH result at 6 weeks indicated a 50% overall risk of recurrence and a 30% overall risk of disease progression). Our results suggest that FISH can be used as a surrogate marker to allow early identification of NMIBC patients who might be at high risk for tumor recurrence and progression so that alternative therapy may be offered while the potential for cure is high.20
FISH assays could potentially be used to develop a risk adapted and more efficient and cost-effective means of surveillance for patients with NMBIC.
Predictions can be made using not only the binary outcome of FISH analysis at a single time point but also the pattern of outcomes over time. For an individual patient, each additional positive FISH result correlates with an incremental increase in risk of recurrence and progression. Additionally, the earlier the conversion from a negative to positive FISH result, the higher the risk of disease recurrence. Thus, patients can be counseled with even greater accuracy based on their individual history of FISH results.
Our study has major strengths, the most important of which is that it is the largest cohort of patients recruited specifically to identify markers of response to intravesical BCG immunotherapy. In contrast to previous studies, we evaluated FISH assays at multiple time points throughout therapy and have the longest follow-up period reported to date. Our population includes the type of patients typical in BCG clinical trials – a large proportion had high-grade disease, and half had CIS as a secondary finding. Although we reported on the overall cohort because it is reflective of real-world patients treated with BCG, it is reassuring that the statistical power of FISH analysis to predict recurrence and progression persisted regardless of disease grade at study entry.
It is also important to point out that we incorporated what is still considered the standard of care today: patients with T1 and/or high-grade disease underwent a repeat TUR (to ensure there was no evidence of invasive disease), followed by induction and maintenance therapy with BCG. Even so, in the period under evaluation, 31% of patients developed recurrent disease and 14% experienced progression to muscle-invasive disease, which is reflective of the patients' high-risk status.
One limitation of our study, despite its large cohort population, is that it comes from a single center. Fortunately, external validation is ongoing in a multicenter prospective clinical trial that aims to recruit an estimated 134 patients. We recognize that it will be important to determine whether the predictive capability of FISH differs among sub-categories of tumors (Ta, T1, and Tis); such an analysis will be feasible only after a sufficient number of patients are pooled to avoid the small numbers that would otherwise result from sub-categorizing patients.