Predictive Biomarkers of Bacillus Calmette-Guérin Immunotherapy Response in Bladder Cancer: Where Are We Now?

Table 1

Tumour-associated markers predicting BCG treatment outcome. The markers are ordered from the most studied to the less, and, within each marker, the studies are ordered by quality score.

Marker	Author	Quality	n	Treatment scheme	Impact	Outcome
						Rec(P)	RFS; (P/HR (95% CI))	Prog(P)	PFS; (P/HR (95% CI))
p53
	Lopez-Beltran et al., [34]	8/8	51	iBCG	−	X	0.0332/NS^*	X	0.0041/1.003 (1.002–1.074)
	Park et al., [26]	7/8	61	iBCG	−	NS	NS	X	0.0495
	Zlotta et al., [22]	7/8	47	iBCG	None	NS	NS/NS^*	NS	NS/NS^*
	Lee et al., [35]	7/8	32	iBCG	−	X	0.0027/3.8 (1.3–11.4)^*	X	X
	Lacombe et al., [18]	7/8	98	iBCG	−	NS	X	X	0.0001/2.5 (1.1–5.5)^*
	Palou et al., [31]	6/8	92	iBCG	<PFS-M	NS	NS	X	NS/0.018^*
	Esuvaranathan et al., [30]	6/8	80	iBCG	None	NS	NS	X	NS
	Kyroudi-Voulgari et al., [27]	6/8	66	iBCG	None	NS	X	X	X
	Cormio et al., [32]	5/8	27	mBCG	−	NS	NS	NS	0.06
	Saint et al., [23]	5/8	102	iBCG/mBCG	−	NS	0.03/0.15 (0.06–0.42)^*	0.001	<0.0001
	Peyromaure et al., [24]	5/8	29	iBCG	None	NS	NS	NS	NS
	Caliskan and Türkeri [19]	5/8	30	iBCG	>Prog	NS/NSa	X	NS/NSa	0.04
	Pages et al., [25]	4/8	43	iBCG	None	NS	NS	X	X
	Okamura et al., [20]	4/8	38	mBCG	None	NS	X	X	X
	Moyano Calvo et al., [29]	3/8	51	iBCG	None	NS	X	X	X
	Moyano Calvoet al., [33]	3/8	71	iBCG	None	NS	X	NS	X
	Lebret et al., [21]	3/8	35	iBCG	None	NS	X	X	X
	Serdar et al., [28]	1/8	24	iBCG	None	NS	NS	X	X
Ki-67
	Lopez-Beltran et al., [34]	8/8	51	iBCG	−	X	0.0034/NS^*	X	0.0163/NS^*
	Park et al., [26]	7/8	61	iBCG	−	NS	NS	X	NS
>25%	Zlotta et al., [22]	7/8	47	iBCG	−	NS	0.02/NS^*	NS	NS/NS^*
	Lee et al., [35]	7/8	32	iBCG	−	0.0413	0.0164/NS^*	X	X
	Palou et al., [31]	6/8	92	iBCG	>Rec	0.015	NS	X	NS/NS^*
	Kyroudi-Voulgari et al., [27]	6/8	66	iBCG	−	<0.05	X	X	X
	Blanchet et al., [38]	5/8	57	iBCG	−	X	NS/NS^*	X	0.0001/4.61 (P < 0.04)
>20%	Lebret et al., [37]	5/8	25	iBCG	−	0.03	X	X	X
	Moyano Calvo et al., [33]	3/8	71	iBCG	None	NS	X	NS	X
	Moyano Calvo et al., [29]	3/8	51	iBCG	None	NS	X	X	X
pRB
	Park et al., [26]	7/8	61	iBCG	−	NS	NS	X	NS
+	Esuvaranathan et al., [30]	6/8	80	iBCG	None	NS	NS	X	NS
Altered exp	Cormio et al., [39]	5/8	27	mBCG	−	X	0.037	X	0.018
CD68
High TAM	Ayari et al., [41]	6/8	46	iBCG/mBCG	−	X	0.093/3.81 (1.32–11)b	X	X
High TAM	Takayama et al., [42]	6/8	41^1	iBCG	−	0.0023	0.0002/1.7 (1.48–5.03)^c	X	X
	Kitamura et al., [48]	4/8	30	iBCG	None	X	NS/NS^*	X	X
c-erbB2	Lee et al., [35]	7/8	32	iBCG	None	X	NS/NS^*	X	X
	Janane et al., [43]	5/8	84	iBCG	−	X	<0.01	X	X
	Morgan et al., [95]	5/8	82	iBCG	None	NS	X	X	X
E-Cadherin	Moyano Calvo et al., [29]	3/8	51	iBCG	None	NS	X	X	X
	Serdar et al., [28]	1/8	24	iBCG	None	NS	NS	X	X
bcl-2	Lee et al., [35]	7/8	32	iBCG	−	X	0.0112/NS^*	X	X
	Okamura et al., [20]	4/8	38	mBCG	+	0.044	X	X	X
p21	Lopez-Beltran et al., [34]	8/8	51	iBCG	None	X	NS/NS^*	X	NS/NS^*
>10%	Zlotta et al., [22]	7/8	47	iBCG	−	NS	0.02/NS^*	NS	NS/NS^*
p27	Lopez-Beltran et al., [34]	8/8	51	iBCG	+	X	0.0005/0.997 (0.995–0.999)^*	X	0.0161/NS^*
	Park et al., [26]	7/8	61	iBCG	−	NS	NS	X	NS
Cyclin D1	Lopez-Beltran et al., [34]	8/8	51	iBCG	−	X	0.0103/NS^*	X	<0.0001/1.009 (1.002–1.074)^*
Cyclin D3	Lopez-Beltran et al., [34]	8/8	51	iBCG	−	X	0.0332/NS	X	0.0041/1.003 (1.002–1.074)^*
PTEN	Park et al., [26]	7/8	61	iBCG	−	NS	NS	X	NS
FGFR3	Park et al., [26]	7/8	61	iBCG	−	NS	NS	X	NS
CD9	Park et al., [26]	7/8	61	iBCG	−	NS	NS	X	NS
hTERT
Pre-treat  >75%	Zachos, [96]	7/8	30	iBCG	−	X	0.05/NSc	NS/NSc	X
c-myc	Lee et al., [35]	7/8	32	iBCG	None	X	NS/NS^*	X	X
Cathepsin D	Lee et al., [35]	7/8	32	iBCG	−	X	0.0235/NS^*	X	X
CD83
High; CD83+	Ayari et al., [41]	6/8	53	mBCG	−	X	0.0001/9.81 (1.12–85.7)d	X	X
Ezrin	Palou et al., [31]	6/8	92	iBCG	−	0.041	0.06	X	0.009/0.031^*
NKp30	Yutkin, [46]	6/8	17	iBCG	<Rec	0.0026	X	X	X
NKp44	Yutkin, [46]	6/8	17	iBCG	<Rec	0.027	X	X	X
NKp46	Yutkin, [46]	6/8	17	iBCG	<Rec	0.044	X	X	X
PD-L1	Inman et al., [97]	5/8	44	iBCG/mBCG	None	NS	X	X	X
CD25	Honda et al., [98]	5/8	16	iBCG	None	NS	X	X	X
Cox-2	Kim et al., [45]	5/8	37	iBCG	−	X	0.0493	X	0.0272
VEGF	Morgan et al., [95]	5/8	82	iBCG	None	NS	X	X	X
TCR 𝛾/𝛿	Honda et al., [98]	5/8	16	iBCG	None	NS	X	X	X
HSP60	Lebret et al., [47]	4/8	33	iBCG	None	NS	X	NS	X
HSP90
Loss exp	Lebret et al., [47]	4/8	33	iBCG	−	0.0001	X	0.0001	X
CD4	Kitamura et al., [48]	4/8	30	iBCG	None	X	NS/NS^*	X	X
CD8	Kitamura et al., [48]	4/8	30	iBCG	None	X	NS/NS^*	X	X
HLA class I	Kitamura et al., [48]	4/8	30	iBCG	+	X	0.0394/0.06 (0.01–0.4)	X	X
CD20	Kitamura et al., [48]	4/8	30	iBCG	None	X	NS/NS^*	X	X
TIA-1	Kitamura et al., [48]	4/8	30	iBCG	None	X	0.0393/NS^*	X	X
S-100	Kitamura et al., [48]	4/8	30	iBCG	None	X	NS/NS^*	X	X
FOXP3	Kitamura et al., [48]	4/8	30	iBCG	None	X	NS/NS^*	X	X
PCNA	Okamura et al., [20]	4/8	38	mBCG	None	NS	X	X	X
HSP65	Ardelt et al., [99]	3/8	16	mBCG	None	NS	X	X	X
B-Catenin	Moyano Calvo et al., [29]	3/8	51	iBCG	+	<0.05	X	X	X

−: negative impact, marker associated with a poor BCG response.
+: positive impact, marker associated to a better BCG response.
Rec: recurrence; P value for recurrence.
RFS: recurrence-free survival; P value for log-rank test/HR: hazard ratio from Cox regression; (95% Cl): 95% confidence interval.
Prog: progression; P value for progression.
PFS: progression-free survival; P value for log-rank test/HR: hazard ratio from Cox regression; (95% Cl): 95% confidence interval.
iBCG: induction BCG scheme only.
mBCG: maintenance BCG scheme.
NS: no statistical significance.
X: not evaluated.
^*all analysed variables (independent prognostic factor).
aadjusted for grade and stage.
badjusted for age, gender, T stage and number of mBCG instillations.
cadjusted for age and gender.
dadjusted for age, gender, T stage.
¹only CIS patients.