Abstract
BackgroundPlatinum (Pt)-based chemotherapy is the standard of care for muscle-invasive bladder cancer (MIBC). However, resistance is a major limitation. Reduced intratumoral drug accumulation is an important mechanism of platinum resistance. Our group previously demonstrated a significant correlation between tissue Pt concentration and tumor response to Pt-based neoadjuvant chemotherapy (NAC) in lung cancer. We hypothesized that increased Pt concentration in radical cystectomy (RC) specimens would correlate with improved pathologic response to Pt-based NAC in MIBC.MethodsA cohort of 19 clinically annotated, archived, fresh frozen RC specimens from patients with MIBC treated with Pt-based NAC was identified [ypT0 (pathologic complete response, pCR), N = 4; ≤ypT1N0M0 (pathologic partial response, pPR), N = 6; ≥ypT2 (minimal pathologic response/progression), N = 9)]. RC specimens from 2 patients with MIBC who did not receive NAC and 1 treated with a non-Pt containing NAC regimen were used as negative controls. Total Pt concentration in normal adjacent urothelial tissue and bladder tumors from RC specimens was measured by flameless atomic absorption spectrophotometry.ResultsTotal Pt concentration in normal urothelium differed by tumor pathologic response (P = 0.011). Specimens with pCR had the highest Pt concentrations compared to those with pPR (P = 0.0095) or no response/progression (P = 0.020). There was no significant difference in Pt levels in normal urothelium and tumor between pPR and no response/progression groups (P = 0.37; P = 0.25, respectively). Conclusions: Our finding of increased intracellular Pt in RC specimens with pCR following NAC for MIBC compared to those with residual disease suggests that enhanced Pt accumulation may be an important determinant of Pt sensitivity. Factors that modulate intracellular Pt concentration, such as expression of Pt transporters, warrant further investigation as predictive biomarkers of response to Pt-based NAC in MIBC.
Highlights
Muscle-invasive bladder cancer (MIBC) is a chemosensitive malignancy for which responses to cisplatin-based chemotherapy are seen in up to 50–60% of patients with advanced disease [1, 2]
Histology, nor number of cycles of neoadjuvant chemotherapy (NAC) (2, 3, or 4) were associated with Pt concentration in benign urothelial tissue (P = 0.47; P = 1.0; P = 0.49, respectively). This proof-of-principal study demonstrates that Pt concentration measured by flameless atomic absorption spectrophotometry (FAAS) in benign adjacent urothelial tissue correlates with muscle-invasive bladder cancer (MIBC) pathologic response following treatment with Pt-based NAC
Post-NAC cystectomy specimens with pathologic response following NAC (pCR) had higher Pt concentrations in the surrounding normal urothelium than cases with any degree of residual MIBC or dysplasia
Summary
Muscle-invasive bladder cancer (MIBC) is a chemosensitive malignancy for which responses to cisplatin-based chemotherapy are seen in up to 50–60% of patients with advanced disease [1, 2]. Expression of DNA repair proteins, such as excision repair cross complementing 1 (ERCC1) and breast cancer susceptibility gene 1 (BRCA1), have not consistently been associated with response to Pt-based chemotherapy in MIBC [5,6,7]. Alternative approaches to predict sensitivity to Pt-based therapy involving multigene expression profiling with the coexpression extrapolation (COXEN) platform and panels of multiple immunohistochemistry (IHC)-detected protein biomarkers are currently being studied in MIBC treated with Pt-based NAC [8, 9]. Platinum (Pt)-based chemotherapy is the standard of care for muscle-invasive bladder cancer (MIBC). We hypothesized that increased Pt concentration in radical cystectomy (RC) specimens would correlate with improved pathologic response to Pt-based NAC in MIBC
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