Comparative Analysis of ISM-1 and B7-H3 Expression in Castration-Resistant Prostate Adenocarcinoma: Associations with Tumor Aggressiveness and Resistance Dynamics

<i>Background and Objectives</i>: Prostate cancer exhibits substantial biological heterogeneity. Although several biomarkers reflecting aggressive tumor behavior have been identified, molecular indicators related to biological adaptation to androgen deprivation remain limited. This study aimed to comparatively evaluate ISM-1 and B7-H3 expression in localized prostate cancer (LPC) and the pre-CRPC group (pre-treatment diagnostic biopsy tissue from patients who subsequently developed CRPC), and to investigate their clinicopathological associations in the pre-CRPC group. <i>Materials and Methods</i>: This retrospective study included 30 surgically treated LPC cases and 32 pre-CRPC cases with available prostate tissue samples obtained prior to the development of castration resistance. ISM-1 and B7-H3 expression levels were evaluated immunohistochemically using the H-score method (intensity 0-3 × proportion score 0-3 [0%, 1-19%, 20-50%, >50%]). Expression patterns were compared between LPC and pre-CRPC groups. Within the pre-CRPC group, associations with clinicopathological parameters were evaluated using H-scores as continuous variables, and time to castration resistance was analyzed using Cox regression. <i>Results</i>: ISM-1 expression was generally low in LPC cases, with a median H-score of 0, whereas pre-CRPC biopsy tissues demonstrated a marked increase in ISM-1 expression. B7-H3 expression was higher and more homogeneous in the pre-CRPC group compared with LPC. In the pre-CRPC group, ISM-1 and B7-H3 H-scores showed a strong positive correlation. No statistically significant associations were identified between ISM-1 or B7-H3 expression levels and most conventional clinicopathological parameters; however, both markers differed significantly across Grade Groups. Neither marker showed a statistically significant association with time to castration resistance, although ISM-1 demonstrated a non-significant trend toward a longer time to resistance. <i>Conclusions</i>: ISM-1 and B7-H3 exhibit distinct expression patterns across different stages of prostate cancer but show associated expression profiles in the pre-CRPC group. While B7-H3 appears to reflect aggressive tumor biology, the independent expression pattern of ISM-1 and its non-significant trend toward a longer time to resistance suggest a potential role in the clinical trajectory toward castration resistance. Combined assessment of ISM-1 and B7-H3 may contribute to a better understanding of tumor biology in patients who subsequently develop CRPC. These findings are descriptive and hypothesis-generating.