Amplification of 7p12 Is Associated with Pathologic Nonresponse to Neoadjuvant Chemotherapy in Muscle-Invasive Bladder Cancer

Abstract

Pathologic downstaging (pDS) to neoadjuvant chemotherapy (NAC) is one of the most important predictors of survival in muscle-invasive bladder cancer (MIBC). The use of NAC is limited as pDS is only achieved in 30% to 40% of cases and predictive biomarkers are still lacking. We performed a comprehensive immunomolecular biomarker analysis to characterize the role of immune cells and inhibitory checkpoints, genome-wide frequencies of copy number alterations, mutational signatures in whole exome, and tumor mutational burden in predicting NAC response. Our retrospective study included 23 primary MIBC patients who underwent NAC, followed by radical cystectomy. pDS to NAC was a significant prognostic factor for better recurrence-free survival (P < 0.001), with a median time to recurrence of 41.2 versus 5.5 months in nonresponders. DNA damage repair alterations were noticed in 38.1% (n = 8), confirming a positive correlation with high tumor mutational burden (P = 0.007). Chromosomal 7p12 amplification, including the genes HUS1, EGFR, ABCA13, and IKZF1, predicted nonresponse in patients with a sensitivity, a negative predictive value, and a specificity of 71.4%, 87.5%, and 100%, respectively. Total count of CD3+ T cells/mm2 tumor was a significant predictor of NAC response. In conclusion, 7p12 amplification may predict nonresponse to NAC and worse survival in MIBC. Multicenter, prospective trials with sufficient statistical power may further fortify these findings. Pathologic downstaging (pDS) to neoadjuvant chemotherapy (NAC) is one of the most important predictors of survival in muscle-invasive bladder cancer (MIBC). The use of NAC is limited as pDS is only achieved in 30% to 40% of cases and predictive biomarkers are still lacking. We performed a comprehensive immunomolecular biomarker analysis to characterize the role of immune cells and inhibitory checkpoints, genome-wide frequencies of copy number alterations, mutational signatures in whole exome, and tumor mutational burden in predicting NAC response. Our retrospective study included 23 primary MIBC patients who underwent NAC, followed by radical cystectomy. pDS to NAC was a significant prognostic factor for better recurrence-free survival (P < 0.001), with a median time to recurrence of 41.2 versus 5.5 months in nonresponders. DNA damage repair alterations were noticed in 38.1% (n = 8), confirming a positive correlation with high tumor mutational burden (P = 0.007). Chromosomal 7p12 amplification, including the genes HUS1, EGFR, ABCA13, and IKZF1, predicted nonresponse in patients with a sensitivity, a negative predictive value, and a specificity of 71.4%, 87.5%, and 100%, respectively. Total count of CD3+ T cells/mm2 tumor was a significant predictor of NAC response. In conclusion, 7p12 amplification may predict nonresponse to NAC and worse survival in MIBC. Multicenter, prospective trials with sufficient statistical power may further fortify these findings. In muscle-invasive bladder cancer (MIBC) with clinical stages T2 to T4a, cN0M0, cisplatin-based neoadjuvant chemotherapy (NAC) followed by radical cystectomy (RC) is currently the gold standard in cisplatin-fit patients.1Witjes A.J. Lebret T. Compérat E.M. Cowan N.C. De Santis M. Bruins H.M. Hernández V. Espinós E.L. Dunn J. Rouanne M. Neuzillet Y. Veskimäe E. van der Heijden A.G. Gakis G. Ribal M.J. Updated 2016 EAU guidelines on muscle-invasive and metastatic bladder cancer.Eur Urol. 2017; 71: 462-475Abstract Full Text Full Text PDF PubMed Scopus (1072) Google Scholar The absence of residual cancer (pT0) and pathologic downstaging (pDS) after NAC (ypT0 to ypT1) at RC specimens is a strong predictor of survival.2Zargar H. Zargar-Shoshtari K. Lotan Y. Shah J.B. van Rhijn B.W. Daneshmand S. Spiess P.E. Black P. Collaborators Final pathological stage after neoadjuvant chemotherapy and radical cystectomy for bladder cancer: does pT0 predict better survival than pTa/Tis/T1?.J Urol. 2016; 195: 886-893Crossref PubMed Scopus (57)