Multicenter prospective observational study to evaluate the clinical utility of rs61094339 SNP Kit in predicting response to intravesical Bacillus Calmette-Guérin therapy for highest-risk non-muscle-invasive bladder cancer: the PRECISE-BCG study

Japanese researchers have launched a multicenter prospective observational study, called PRECISE-BCG, to test whether a newly developed genetic test can predict which patients with the highest-risk form of non-muscle-invasive bladder cancer will benefit from intravesical Bacillus Calmette-Guérin therapy, the current standard of care for this disease. The study protocol, published in BMC Cancer on 28 August 2026, outlines a plan to enroll 120 patients across a network of Japanese hospitals and follow them for two years after treatment begins. The effort represents one of the more concrete attempts to bring pharmacogenomic-style prediction into the everyday management of a disease that has long been treated with a one-size-fits-all approach.

The clinical problem the study addresses is well known to urologic oncologists. Although intravesical BCG instillation remains the standard treatment for patients with highest-risk non-muscle-invasive bladder cancer, nearly 30 percent of such cases experience disease progression despite adequate treatment. Because BCG failure can carry serious consequences, identifying patients unlikely to respond before committing them to a lengthy course of instillations is a major unmet need in the field. Patients who progress after BCG often require radical cystectomy, a major operation with substantial morbidity, or face the possibility of muscle-invasive disease requiring systemic chemotherapy or, in some settings, additional aggressive interventions. The stakes of choosing the wrong initial strategy are therefore high for individual patients.

Bladder cancer itself is among the most common malignancies worldwide, and non-muscle-invasive disease accounts for the majority of new diagnoses. Standard risk stratification relies on pathological features assessed at transurethral resection of the bladder tumor, including tumor stage, grade, size, number, and the presence of carcinoma in situ. Patients classified as highest risk by these criteria are those in whom the probability of recurrence and progression is greatest, and clinical guidelines consistently recommend induction BCG followed by maintenance therapy for this group. Yet even within this carefully stratified category, individual responses to BCG differ dramatically, and the pathological variables that guide current decision-making do not capture that variability.

The test at the heart of the trial is built around a single nucleotide polymorphism, rs61094339, located on the X chromosome. Researchers led by Takashi Matsumoto and corresponding author Masaki Shiota of Kyushu University have previously identified this SNP as correlating with BCG response. A diagnostic kit based on the marker was newly developed by KUBIX Inc., a company based in Hakusan, Ishikawa, to stratify patients by their likelihood of responding to intravesical BCG therapy. According to the disclosure accompanying the protocol, Shiota holds a patent for rs61094339, while the other authors declared no competing interests. The use of a standardized commercial kit, rather than laboratory-specific assays, is notable because reproducibility across centers has historically been a barrier to moving biomarkers from discovery into clinical validation.

The design of PRECISE-BCG is straightforward. Patients with histologically confirmed highest-risk non-muscle-invasive bladder cancer who are scheduled to receive intravesical BCG therapy will be enrolled at participating centers. Before their first instillation, peripheral blood will be collected for genotyping with the rs61094339 SNP kit. Patients will then undergo a standard BCG regimen consisting of six weekly induction instillations, followed by maintenance therapy of three weekly instillations at three, six, twelve, and eighteen months. Each participant will be followed for two years. This treatment schedule reflects the maintenance approach widely adopted after clinical trials demonstrated that maintenance dosing improves outcomes compared with induction alone, and it aligns the study’s treatment framework with contemporary guideline-concordant care.

The primary endpoint of the study is event-free survival analyzed by SNP genotype, which will allow investigators to determine whether carriers of different genotypes experience meaningfully different outcomes on the same treatment. Secondary endpoints include progression-free survival, intravesical recurrence-free survival, and overall survival, providing a fuller picture of how genotype relates to the range of outcomes that matter to patients with this disease. Event-free survival, which captures a combination of recurrence, progression, and other treatment-related events, is increasingly used in trials of bladder cancer therapies because it reflects the totality of a patient’s clinical course rather than a single event type. By pairing this composite endpoint with the more granular secondary measures, the investigators aim to characterize the relationship between genotype and outcome in depth.

The study is being conducted by a team from Kyushu University’s Department of Urology, the Center for Clinical and Translational Research at Kyushu University Hospital, and KUBIX Inc. Participating institutions span much of Japan and include Hokkaido University Hospital, Akita University Hospital, Keio University Hospital, St. Marianna University Hospital, Kanazawa University Hospital, Osaka University Hospital, Kindai University Hospital, Nara Medical University Hospital, Kobe University Hospital, Tokushima University Hospital, the Hospital of the University of Occupational and Environmental Health, Harasanshin Hospital, Kagoshima University Hospital, and the University of the Ryukyus Hospital. This geographic breadth is intended to support the multicenter, prospective character of the validation effort. Including centers from Hokkaido in the north to Okinawa in the south also helps ensure that the enrolled cohort reflects the diversity of clinical practice settings across Japan, from large academic referral centers to community-adjacent hospitals, which strengthens the generalizability of the eventual findings within the studied population.

Ethical oversight and patient protections are built into the protocol. The Institutional Review Board of Kyushu University Hospital approved the study under approval number 25224, and written informed consent will be obtained from all participants before enrollment. The work is supported by a grant, 25ck0106008h0001, from the Japan Agency for Medical Research and Development, a national funding agency that supports translational medical research in Japan. AMED support for the project signals institutional confidence in the translational pathway from the Kyushu University team’s biomarker discovery work to a commercially manufactured diagnostic assay intended for bedside use.

The significance of the effort lies in the broader push toward precision oncology in bladder cancer. Non-muscle-invasive bladder cancer occupies a middle ground in urothelial malignancy: it has not invaded the bladder muscle, but in its highest-risk form it behaves aggressively enough that recurrence and progression are common concerns. BCG, an attenuated live bacterium originally developed as a tuberculosis vaccine, is instilled directly into the bladder to provoke an immune response against tumor cells. The treatment works not through direct toxicity but by recruiting the patient’s own immune system, which helps explain why individual genetic variation might shape therapeutic response. Yet the response to this immunotherapy varies considerably between individuals, and clinicians currently lack a validated, easily deployable tool to predict who will respond before treatment starts. Molecular and genomic predictors have been explored extensively in retrospective cohorts, ranging from immune-signature expression panels to host germline polymorphisms, but none has achieved routine clinical adoption.

If the PRECISE-BCG study succeeds in prospectively validating the predictive performance of the SNP-based assay, the authors suggest the kit could serve as a precision-medicine tool to guide individualized therapy for non-muscle-invasive bladder cancer. Specifically, such a test could help identify candidates for early radical cystectomy, the surgical removal of the bladder, which is often considered when BCG fails or is expected to fail. It could also help pinpoint patients who might be better served by novel treatments rather than conventional BCG, at a time when new intravesical and systemic therapies are being developed for BCG-unresponsive disease. The therapeutic landscape for this patient group has expanded in recent years, with novel intravesical agents, targeted therapies, and checkpoint inhibitor immunotherapy now available in various settings, making the timely identification of likely BCG non-responders increasingly consequential for treatment planning.

Because the marker resides on the X chromosome, its biology warrants particular attention. Males carry a single X chromosome, while females carry two, and patterns of X-inactivation can complicate the interpretation of genotype effects in women. Bladder cancer is substantially more common in men, so the enrolled cohort is expected to be predominantly male, a factor that will shape how the results can be applied and may limit the study’s ability to draw firm conclusions about the marker’s performance in women.

As with any observational validation study, the design carries inherent limitations that the field will weigh when interpreting results. Because all patients receive standard BCG therapy rather than being randomized to alternative treatments, the study can demonstrate an association between genotype and outcome but cannot directly compare the kit-guided approach against alternative management strategies. Demonstrating that a biomarker predicts outcome is a distinct step from demonstrating that using the biomarker to guide decisions improves patient outcomes, and the latter typically requires interventional testing. The sample size of 120 patients, while substantial for a prospective biomarker study of a relatively uncommon disease, will constrain the precision of subgroup analyses. The two-year follow-up period may also be shorter than the full horizon over which bladder cancer recurrence and progression can occur, and results in a Japanese cohort will need replication in other populations before broad adoption, since both the frequency of genetic variants and the characteristics of bladder cancer can vary across ancestries and regions.

Nevertheless, the prospective, multicenter structure of PRECISE-BCG represents a meaningful step beyond retrospective biomarker discovery. Many candidate biomarkers for BCG response have been proposed over the years, but few have advanced to prospective testing in a real-world treatment setting. The field’s experience with premature enthusiasm for unvalidated markers has made investigators and clinicians appropriately cautious, and prospective designs such as this one are widely regarded as the necessary proving ground for any test hoping to enter practice. By collecting blood before treatment begins, applying a standardized commercial genotyping kit, and tracking clinically meaningful endpoints such as event-free, progression-free, recurrence-free, and overall survival, the study is structured to generate evidence that regulatory bodies and clinical guidelines can act upon.

The protocol was published as an open-access study protocol, received by the journal on 9 March 2026 and accepted on 26 August 2026, allowing the research community to follow the trial’s conduct and eventual results. Open publication of study protocols has become an important mechanism for transparency in clinical research, as it pre-specifies the design, endpoints, and analysis plan before results are known and reduces the risk of selective reporting. Its findings, expected after enrollment and two-year follow-up are complete, will determine whether rs61094339 genotyping can move from a research observation into routine clinical practice for patients facing the highest-risk form of non-muscle-invasive bladder cancer.

For patients, the potential value of such a test is straightforward: a simple blood draw before starting therapy could spare unlikely responders months of instillations unlikely to succeed, while giving likely responders greater confidence in committing to the full BCG course. For health systems, better upfront prediction could reduce the downstream costs associated with managing disease progression, including major surgery and advanced systemic therapy. Whether those benefits materialize now depends on the answer PRECISE-BCG delivers, and the urologic oncology community will be watching the results closely.