Spontaneous Necrosis of a High-Risk Bladder Tumor Under Immunotherapy for Concurrent Malignant Melanoma: Role of BRAF Mutations and PD-L1 Expression

<b>Background:</b> Bladder cancer (BC) is a heterogeneous malignancy, and predicting response to immune checkpoint inhibitors (ICIs) remains a challenge. Herein, we investigate a high-risk bladder tumor, which developed during anti-BRAF/MEK therapy for a concurrent advanced <i>BRAF-V600E</i>-positive malignant melanoma (MM) and subsequently underwent complete spontaneous necrosis following Nivolumab immunotherapy, only to recur thereafter while still under the same treatment. This unique scenario provided an opportunity to investigate the roles of <i>BRAF</i> gene mutations in BC pathogenesis, respectively, of PD-L1 expression in immunotherapy response prediction. <b>Methods:</b> We retrospectively analyzed BC specimens obtained via transurethral resection at two critical time-points: prior to the complete spontaneous necrosis under Nivolumab (prenecrosis) and after tumor recurrence postnecrosis (postnecrosis). The <i>BRAF</i> gene mutation status was evaluated using quantitative polymerase chain reaction (qPCR). PD-L1 expression was assessed by immunohistochemistry (IHC), quantified using the combined positive score (CPS), and a cutoff of ≥10 for positivity. <b>Results:</b> Neither pre- nor postnecrosis BC samples harbored <i>BRAF</i> gene mutations. Prenecrosis PD-L1 expression (CPS = 5) indicated a minimal likelihood of response to immunotherapy. However, complete spontaneous necrosis occurred under Nivolumab, followed by recurrence with further reduced PD-L1 expression (CPS = 1). <b>Conclusions:</b> The complete BC regression challenges the conventional role of PD-L1 as a sole predictive biomarker for immunotherapy. This study also highlights the potential role of BRAF/MEK inhibitors in BC oncogenesis and underscores the need for alternative biomarkers, such as tumor mutation burden (TMB) and circulating tumor DNA (ctDNA), to guide treatment selection in BC better.