Prognostic value of Bcl-2 in two independent populations of estrogen receptor positive breast cancer patients treated with adjuvant endocrine therapy

Figures & data

Table I. Odense cohort, association between Bcl-2 and DFS and determination of threshold values for Bcl-2 by univariate analysis.^a

Bcl-2^b	n	Period^c	HR	(95% CI)	p
1–49%	7		4.7	(2.0–11.1)	0.0003
≥50%/weak + mod	76	0–5 years	2.32	(1.40–3.85)	0.0011
		5–10 years	0.63	(0.31–1.27)	0.20
≥50%/strong	174		1.00	(reference)

CI, confidence interval; HR, hazard ratio; mod, moderate.

^aModel stratified by duration of allocated tamoxifen treatment (0.5 or 1, 2, and 5 years).

^bGlobal test for Bcl-2 (p < 0.0001).

^cTime-dependent variables. If nothing is mentioned the follow-up period is 0–10 years postsurgery.

Figure 1. Kaplan-Meier estimates of DFS according to level of Bcl-2 in the Odense cohort (n = 257).

Table II. Association between Bcl-2 and DFS in the Odense cohort by multivariable analysis.^a

Risk factor	p-value^b	Level	n	Period^c	HR	(95% CI)
Bcl-2	0.001	1–49%	7		4.14	(1.55–11.1)
		≥50%/weak + mod	76	0–5 years	1.62	(0.95–2.78)
				5–10 years	0.39	(0.19–0.82)
		≥50%/strong	174		1.00	(reference)
ER	0.32	1–79%	50		1.52	(0.67–3.46)
		80–100%	207		1.00	(reference)
Positive lymph nodes	<0.0001	0	22		0.90	(0.36–2.29)
		1–3	142		1.00	(reference)
		4–9	57		1.51	(0.92–2.47)
		10 +	36		4.67	(2.72–8.02)
Age	0.81	45–54	64		1.09	(0.66–1.79)
		55–64	114		1.00	(reference)
		65–74	79		0.91	(0.58–1.42)
Histological grade	0.09	Non-ductal	36		1.28	(0.74–2.22)
		Ductal grade I	61		0.54	(0.30–0.98)
		Ductal grade II	103		1.00	(reference)
		Ductal grade III	57		1.08	(0.66–1.77)
Tumor size	0.02	1–20 mm	105	0–5 years	0.71	(0.39–1.32)
				5–10 years	2.10	(1.15–3.84)
		21–50 mm	133		1.00	(reference)
		51 + mm	19		1.70	(0.88–3.27)
HER-2	0.16	Normal	238		1.00	(reference)
		Amplified	19		1.69	(0.81–3.51)

Bcl-2, ER and HER-2 were centrally assessed for the purpose of this study.

CI, confidence interval; ER, estrogen receptor; HER-2, human epidermal growth factor receptor 2; HR, hazard ratio.

^aModel stratified by duration of allocated tamoxifen treatment (0.5 or 1, 2, and 5 years).

^bP-value assessed by the Global test.

^cTime-dependent variables. If nothing is mentioned the follow-up period is 0–10 years post surgery.

Table III. Demographic characteristics of Danish patients randomized (n =1396) in the BIG 1-98 study.

	Study population		Excluded		Total
Characteristic	N	(%)	N	(%)	N	(%)	p^a
All	1191	(100.0)	205	(100.0)	1396	(100.0)
Age at randomization, y
45–54	136	(11.4)	36	(17.6)	172	(12.3)	0.053
55–64	658	(55.2)	107	(52.2)	765	(54.8)
65–75	397	(33.3)	62	(30.2)	459	(32.9)
Tumor size, mm
0–20	568	(47.7)	116	(56.6)	684	(49.0)	0.068
21–50	585	(49.1)	84	(41.0)	669	(47.9)
≥51	38	(3.2)	5	(2.4)	43	(3.1)
Histological type
Inv Ductal	999^b	(83.9)	170	(82.9)	1169	(83.7)	0.89
Inv Lobular	160	(13.4)	29	(14.1)	189	(13.5)
Other	32	(2.7)	6	(2.9)	38	(2.7)
Tumor grade
I	249	(20.9)	61	(29.8)	310	(22.2)	0.020
II	619	(52.0)	98	(47.8)	717	(51.4)
III	164	(13.8)	18	(8.8)	182	(13.0)
Unknown	159	(13.4)	28	(13.7)	187	(13.4)
Positive lymph nodes
0	416	(34.9)	89	(43.4)	505	(36.2)	0.010
1–3 +	516^b	(43.3)	64	(31.2)	580	(41.5)
4–9 +	166	(13.9)	32	(15.6)	198	(14.2)
10 +	93	(7.8)	20	(9.8)	113	(8.1)
ER
<1%	0	(0.0)	23	(11.2)	23	(1.6)	0.65^c
1–79%	207	(17.4)	16	(7.8)	223	(16.0)
80–100%	984	(82.6)	66	(32.2)	1050	(75.2)
Unknown	0	(0.0)	100	(48.8)	100	(7.2)
HER-2
Normal	1077	(90.4)	83	(40.5)	1160	(83.1)	0.85^d
Amplified	109	(9.2)	7	(3.4)	116	(8.3)
Unknown	5	(0.4)	115	(56.1)	120	(8.6)

ER, estrogen receptor; HER-2, human epidermal growth factor receptor 2.

^aComparison of study population and excluded patients by Fisher's exact test.

^bIncluding one observation with missing value.

^cUnknown and <1% was excluded from analysis. ER was centrally assessed for this study.

^dUnknown excluded from analysis. HER-2 was centrally assessed for this study.

Figure 2. Kaplan-Meier estimates of DFS according to level of Bcl-2 in Danish Cohort of BIG1-98 (n = 1191).

Table IV. Association between Bcl-2 and DFS in the Danish Cohort of BIG 1-98 by univariate analysis.^a

Bcl-2^b	n	Period^c	HR	(95% CI)	p
0–9%	37		2.90	(1.83–4.61)	0.0001
10–49%	32		1.23	(0.65–2.34)	0.52
≥50%/weak + mod	234	0–5 years	1.41	(1.06–1.90)	0.02
		5–10 years	0.49	(0.23–1.02)	0.06
≥50%/strong	888		1.00	(reference)

CI, confidence interval; HR, hazard ratio; mod, moderate.

^aModel stratified by randomization option, allocated treatment and age at randomization.

^bGlobal test for Bcl-2 (p =0.0002).

^cTime-dependent variables. If nothing is mentioned the follow-up period is 0–10 years postrandomization.

Table V. Association between Bcl-2 and DFS in the Danish Cohort of BIG 1-98 by multivariable analysis.^a

Risk factor	p-value	Level	n	Period^b	HR	(95% CI)
Bcl-2	0.004	0–9%	37		2.11	(1.30–3.42)
		10–49%	32		0.79	(0.41–1.53)
		≥50%/weak-mod	234	0–5 years	1.20	(0.89–1.63)
				5–10 years	0.44	(0.21–0.93)
		≥50%/strong	888		1.00	(reference)
ER	0.82	1–79%	207		1.03	(0.78–1.38)
		80–100%	984		1.00	(reference)
Tumor grade	0.004	Not known	159		1.22	(0.70–2.12)
		Grade I	249		0.72	(0.52–1.00)
		Grade II	619		1.00	(reference)
		Grade III	164		1.47	(1.09–2.00)
Positive lymph nodes	0.0001	0	416		0.70	(0.53–0.93)
		1–3	516		1.00	(reference)
		4 +	166		1.13	(0.82–1.57)
		10 +	93		3.05	(2.18–4.27)
Histological type	0.25	Ductal	999		1.00	(reference)
		Non-ductal	192		0.73	(0.43–1.24)
Tumor size	0.001	1–20 mm	568		0.69	(0.54–0.89)
		21–50 mm	585		1.00	(reference)
		≥51 mm	38		1.62	(1.01–2.61)
HER-2	0.034	normal	1082		1.00	(reference)
		amplified	109		1.47	(1.03–2.06)

CI, confidence interval; ER, estrogen receptor; HER-2, human epidermal growth factor receptor 2; HR, hazard ratio.

^aModel stratified by randomization option, allocated treatment and age at randomization.

^bTime-dependent variables. If nothing is mentioned the follow-up period is from 0 years after randomization.