Table 1.
Emerging predictive molecular biomarkers of response to systemic therapies in urothelial carcinoma.
| Biomarker | Cohort | Source | Setting | Systemic therapy | Summary |
|---|---|---|---|---|---|
| DDR genes alterations | |||||
| ERCC2 | 50 | Tissue | NAC | Cisplatin-based | ERCC2 mutations correlate with pCR at RC [24]. |
| 48 | Tissue | NAC | Cisplatin-based | ERCC2 alterations confer vulnerability to cisplatin traducing in better OS [25]. | |
| 32 | Tissue | NAC | Gem-Cis | Deleterious ERCC2 alterations strongly predicted pDS and superior RFS [26]. | |
| ATM | 34 | Tissue | NAC | MVAC (discovery), Gem-Cis (validation) | ATM mutations predicted pCR and better OS/PFS in both sets [27]. |
| 24 | Tissue | NAC | MVAC (discovery), Gem-Cis (validation) | ATM mutations predicted better OS/DSS in both sets [28]. | |
| RB1 | 34 | Tissue | NAC | MVAC (discovery), Gem-Cis (validation) | RB1 mutations predicted pCR and better OS/PFS in both sets [27]. |
| 24 | Tissue | NAC | MVAC (discovery), Gem-Cis (validation) | RB1 mutations predicted better OS/DSS in both sets [28]. | |
| FANCC | 34 | Tissue | NAC | MVAC (discovery), Gem-Cis (validation) | FANCC mutations predicted pCR and better OS/PFS in both sets [27]. |
| 24 | Tissue | NAC | MVAC (discovery), Gem-Cis (validation) | FANCC mutations predicted better OS/DSS in both sets [28]. | |
| Driver mutations | |||||
| ERBB2 | 71 | Tissue | NAC | MVAC, Gem-Cis/Car (discovery/validation) | ERBB2 missense mutations predicted pCR and better CSS [33]. |
| 52 | Tissue | NAC | Gem-Cis | ERBB2 mutations were correlated with pDS [34]. | |
| FGFR3 | 52 | Tissue | NAC | Gem-Cis | FGFR3 mutations were correlated with pDS [34]. |
| 72 | Tissue | NAC | Gem-Cis | FGFR3 alterations were correlated with pNR and with worse RFS [36]. | |
| 74 | Tissue | AC | Gem-Cis | FGFR3 alterations were associated with worse RFS [36]. | |
| PIK3Ca | 52 | Tissue | NAC | Gem-Cis | PIK3Ca mutations were correlated with pDS [34]. |
| HUS1 | 23 | Tissue | NAC | Gem-Cis | Amplification of HUS1 predicted pNR and worse RFS [37]. |
| ABCA13 | 23 | Tissue | NAC | Gem-Cis | Amplification of ABCA13 predicted pNR and worse RFS [37]. |
| EGFR | 23 | Tissue | NAC | Gem-Cis | Amplification of EGFR predicted pNR and worse RFS [37]. |
| FIGNL1 | 23 | Tissue | NAC | Gem-Cis | Amplification of FIGNL1 predicted pNR and worse RFS [37]. |
| IKZF1 | 23 | Tissue | NAC | Gem-Cis | Amplification of IKZF1 predicted pNR and worse RFS [37]. |
| Liquid biopsy | |||||
| CTCs | 20 | Blood | NAC | MVAC or Gem-Cis | Patients with medium/high (cut-off 10 CTCs) count showed pNR [58]. |
| CTCs | 31 | Blood | Metastatic | MVAC | Patients with favorable CTCs trend showed better PFS and OS rates [59]. |
| ctDNA | 68 | Plasma | NAC/AC | Gem-Cis/Car; Car-Eto; Gem | Dynamics of ctDNA was associated with RFS and OS but not with pDS [70]. |
| ctDNA | 17 | Plasma | NAC | Cisplatin-based | Persistence of ctDNA detection during NAC predicted disease recurrence [72]. |
| NA | Urine | NAC | Cisplatin-based | ||
| miRs | |||||
| miR-886-3p | 30 | Tissue | AC/metastatic | MVAC or Gem-Cis | miR-886-3p was correlated with CR (RECIST) and better OS [76]. |
| miR-923 | 30 | Tissue | AC/metastatic | MVAC or Gem-Cis | miR-923 was correlated with CR (RECIST) and better OS [76]. |
| miR-944 | 30 | Tissue | AC/metastatic | MVAC or Gem-Cis | miR-944 was correlated with CR (RECIST) and better OS [76]. |
| miR-138 | 30 | Tissue | AC/metastatic | MVAC or Gem-Cis | Decreasing miR-138 increased the in vitro Cis-sensitivity [76]. |
| miR-27a | 30 | Tissue | AC/metastatic and in-vitro analysis | MVAC or Gem-Cis | miR-27a overexpression increased the in vitro Cis-sensitivity [76]. |
| 354 | Tissue | Cisplatin-based | miR-27a increased the in vitro Cis-sensitivity through SLC7A11 axis [77]. | ||
| miR-642 | 30 | Tissue | AC/metastatic | MVAC or Gem-Cis | miR-642 overexpression increased the in vitro Cis-sensitivity [76]. |
| miR-101 | NR | Tissue | In-vitro analysis | Cisplatin-based | miR-101 downregulation induced Cis-resistance through COX-2 axis [78]. |
| miR-193a-3p | NR | Tissue | In-vitro analysis and in-vivo analysis | Cis, Pa, Ad, Epi | miR-193a-3p promotes the multi-chemoresistance [114]. |
| miR-203 | 108 | Tissue | AC | MVAC or Gem-Cis | Low miR-203 expression was correlated with worse PFS and OS [115]. |
| miR-372 | 83 | Tissue | Metastatic | MVAC or Gem-Cis | High miR-372 expression was associated with worse PFS [79]. |
| miR-21 | 83 | Tissue | Metastatic | MVAC or Gem-Cis | High miR-21 expression was associated with a shorter PFS [79]. |
| miR-34a | 20 | Tissue | NAC and in-vitro analysis | Cisplatin-based or Epi | Increased miR-34a expression mediated in-vitro Cis-sensitivity [116]. |
| miR-34a overexpression resulted in increased in-vitro Epi-sensitivity [117]. | |||||
| miR-101-3p | 89 | Tissue | In-vitro | Gem-Cis | miR-101-3p overexpression increased chemosensitivity through EZH2 [80]. |
| Cdr1as | NR | Tissue | In-vitro | Cisplatin-based | Cdr1as increased Cis-sensitivity through miR-1270/APAF1 axis [81]. |
ABCA13, ATP binding cassette subfamily A member 13; AC, adjuvant chemotherapy; Ad, adriamycin; ATM, ataxia telangiectasia mutated 1; APAF1: apoptotic protease-activating factor 1; Car, carboplatin; CR, complete response; CSS, cancer-specific survival; CTCs: circulating tumor cells; DDR, damage response and repair; DSS: disease-specific survival; EGFR, epidermal growth factor receptor; Epi, epirubicin; ERBB2, Erb-B2 receptor tyrosine kinase 2; ERCC2, excision repair cross complementing 2; Eto, etoposide; FANCC, FA complementation Group C; FGFR2–3, fibroblast growth factor receptor 2–3; FIGNL1, Fidgetin-like protein 1; Gem-Cis, gemcitabin–cisplatin; HUS1, HUS1 checkpoint clamp component; ICIs, immune checkpoint inhibitors; IKZF1, IKAROS family zinc finger 1; MVAC, methotrexate, vinblastine, doxorubicin, and cisplatin; NAC, neoadjuvant chemotherapy; OS, overall survival; Pa, paclitaxel; pCR, pathologic complete response; pDS, pathologic downstaging; PFS, progression-free survival; PIK3CA, phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α; pNR, pathologic non-response; RB1, RB transcriptional corepressor 1; RC: radical cystectomy; RECIST, response evaluation criteria in solid tumors; RFS, recurrence-free survival; VAF, variant allele frequency; Vin, vinflunine; NA, no available; NR, not report.