(Urotoday.com) The 2023 American Society of Clinical Oncology Genitourinary (ASCO GU) cancers symposium held in San Francisco, CA between February 16th and 18th was host to a prostate cancer and urothelial carcinoma poster session. Dr. Ralph Wirtz presented an analysis of predictors of response to neoadjuvant chemotherapy in patients with muscle invasive bladder cancer by molecular subtyping and radioligand target quantitation.
Patients with muscle invasive urothelial carcinoma achieving pathological complete responses (pCR) following neoadjuvant chemotherapy (NAC) have demonstrated improved prognoses.
The various molecular subtypes of bladder cancer demonstrate significant heterogeneity with regards to cisplatin-based chemotherapy sensitivity and harbor varying degrees of FGFR expression. It has previously been demonstrated that luminal tumors have a superior response to neoadjuvant chemotherapy, whereas FGFR1 expression is associated with increased chemotherapy resistance.1 The objective of this study was to evaluate whether radioligand therapy may be a potential treatment option for patients with chemo-resistant tumors, with the hope that results of this study could be used to subsequently justify prospective validation studies within the "Bladder BRIDGister".
This study included 36 patients who had received neoadjuvant chemotherapy. Formalin fixed paraffin embedded (FFPE) tissues from transurethral resections (TUR) samples prior to chemotherapy and cystectomy samples (post-NAC) were retrospectively collected. RNA from FFPE tissues were extracted using commercial kits. Relative gene expression of subtyping markers (KRT5, KRT20, FGFR1) and radioligand target genes (CXCR4, FAP) were analyzed by standardized RT-qPCR systems (STRATIFYER Molecular Pathology GmbH, Cologne).
Spearman correlation, hierarchical clustering, Kruskal-Wallis, chi square and contingency tests were done by JMP 9.0.0 (SAS software).
The median patient age was 69.0 years, and 84% were male. 92% of patients had pathologically node negative disease. When comparing pretreatment TUR with post-treatment cystectomy specimens:
- The median expression of KRT20 dropped 128-fold
- FGFR1, CXCR4 and FAP mRNA expression increased 6.8, 1.9 and 2.9-fold, respectively.
FAP was positively associated with KRT5, FGFR1 and CXCR4 in treatment naïve TUR biopsies (r=0.4051 p=0.0141, r=0.6458 p<0.0001 and r=0.7586 p<0.0001, respectively), but negatively associated with KRT20 (r=-0.3879 p=0.0194). Consistent with prior reports, FGFR1 was negatively associated with pCR (r=-0.6418 p<0.0001). Similarly, CXCR4 and FAP trended to be negatively associated with pCR (r=-0.3181 p=0.0586; r=-0.3072 p=0.0684).
Hierarchical clustering revealed that CXCR4 and FAP are elevated in stromal rich, KRT5 & KRT20 negative tumors not responding to neoadjuvant chemotherapy. Elevated FAP above median mRNA expression was significantly associated with resistance to neoadjuvant chemotherapy (chi2 4.314 p=0.0378). Combining elevated FAP and CXCR4 mRNA expression did identify 28% of the patients to be at high risk of neoadjuvant chemotherapy resistance (90%).
The authors concluded that expression of the radioligand targets CXCR4 and FAP are associated with basal/stromal enriched tumors and resistance to neoadjuvant chemo. Theranostic targeting of CXCR4 and FAP before neoadjuvant chemotherapy might increase response towards neoadjuvant chemotherapy in this poor prognosis group.
Presented by: Ralph M. Wirtz, PhD, STRATIFYER Molecular Pathology GmbH, Max Delbruck Center for Molecular Medicine in Berlin, Berlin, Germany
Reference:
- Ecke TH, et al. Molecular Diagnostic and Prognostication Assays for the Subtyping of Urinary Bladder Cancer Are on the Way to Illuminating Our Vision. Int J Mol Sci 2022;23(10):5620.