Genomic Predictors of Response to Neoadjuvant Cisplatin-based Chemotherapy in Upper tract Urothelial Carcinoma (UTUC)
Use of neoadjuvant cisplatin-based chemotherapy (NAC) in UTUC is based on evidence of survival benefit in urothelial carcinoma (UC) of the bladder. However, concerns regarding toxicity and lack of efficacy have prevented its widespread adoption. We aim to analyze the genomic profiling data of UTUCs from patients who received NAC to identify predictors of chemo-sensitivity.
We reviewed data on all >=cT2anyNM0 high-grade UTUC patients who underwent genomic profiling prior to cisplatin-based NAC to identify somatic mutations that correlated with response, defined as =10%) identified by the MSK-IMPACT assay in a recently published study (FGFR3, KMT2D, KDM6A, KMT2C, STAG2, CDKN2A, TP53, CDKN2B, CREBBP, TSC1, PIK3CA, ARID1A, CCND1 and, HRAS). We also looked at ERCC2 and BCL2, which have been linked with response to chemotherapy in bladder UC. We assessed the association between alterations and pathologic response using univariate logistic regression.
In 678 patients who underwent NU, 62 (9.1%) received cisplatin-based NAC and 22 underwent MSK-IMPACT sequencing of pre-treatment tumor tissue. Of these patients, 16 (73%; 95% CI 50%, 89%) achieved
CCND1 amplification was found to be non-significantly associated with lack of response following cisplatin-based NAC. Similar findings in cancers of the head and neck, lung, breast and bladder suggest the importance of CCND1 as a prognostic marker and potential actionable target in cisplatin-resistant high risk UTUC; however larger studies are needed for confirmation.