Long-term follow-up of the randomized Stockholm trial on adjuvant tamoxifen among postmenopausal patients with early stage breast cancer

Figures & data

Figure 1.  Summary of trial design

Table I.  Distribution of patient characteristics by risk strata and allocated treatment

	Low-risk patients (%)		High-risk patients (%)		All patients (%)
Patient characteristic	TAM + ^1 (n = 886)	TAM − ^2 (n = 894)	TAM+(n = 488)	TAM−(n = 470)	TAM+(n = 1 374)	TAM−(n = 1 364)
Age (years)
< 50	0.9	1.7	1.6	2.6	1.2	2.0
50-59	33.4	35.9	41.8	37.0	36.4	36.3
60–69	62.0	58.7	54.7	55.7	59.4	57.7
≥ 70	3.7	3.7	1.8	4.7	3.1	4.0
Histopathological nodal involvement
N0	99.1	98.2	12.7	12.1	68.4	68.6
N1–3	0.1	0.8	54.1	58.5	19.3	20.7
N4 +	0.1	0.0	25.6	23.0	9.2	7.9
N? (unknown number of positive nodes)	0.0	0.0	7.0	5.7	2.5	2.0
Unavailable	0.7	1.0	0.6	0.6	0.7	0.9
Histopathological tumor size (mm)
< 10	31.6	30.5	6.6	6.0	22.7	22.1
11–20	46.5	47.9	37.3	36.4	43.2	43.9
21–30	18.5	17.1	29.5	30.2	22.4	21.6
31–50	0.1	0.6	20.5	23.0	7.4	8.3
> 50	0.0	0.0	3.9	2.3	1.4	0.8
Unavailable	3.3	3.9	2.3	2.1	2.9	3.3
Estrogen receptor status
Positive^3	67.2	65.8	69.5	70.4	68.0	67.4
Negative^4	16.0	17.2	19.5	20.2	17.3	18.3
Unavailable	16.8	17.0	11.1	9.4	14.8	14.4
Progesterone receptor status
Positive^3	34.2	32.1	29.9	32.8	32.7	32.3
Negative^4	33.4	37.0	40.2	39.2	35.8	37.8
Unavailable	32.4	30.9	29.9	28.1	31.5	29.9

¹Adjuvant tamoxifen. ²No adjuvant tamoxifen. ³≥0.05 fmol/µg DNA. ⁴<0.05 fmol/µg DNA.

Table II.  Analysis of first events and cause specific mortality among all patients

	Number of events (%)
Type of event	TAM −	TAM +	Hazard ratioa,c (95% confidence interval)	p-value^b,c
First events:
a. Loco-regional recurrence	205 (15.0)	151 (11.0)	0.66 (0.53–0.81)	<0.001
- Chest wall	133 (9.8)	87 (6.3)
- Axilla	37 (2.7)	39 (2.8)
- Supraclavicular fossa	35 (2.5)	25 (1.8)
b. Distant recurrence	290 (21.3)	256 (18.6)	0.78 (0.66–0.92)	0.004
c. Contra lateral breast cancer	100 (7.3)	70 (5.1)	0.62 (0.45–0.84)	0.002
d. Other cancer	94 (6.9)	164 (11.9)	1.53 (1.19–1.98)	<0.001
e. Intercurrent death	166 (12.2)	175 (12.7)	0.93 (0.75–1.15)	0.49
f. Any recurrence (a–e)	855 (62.7)	816 (59.4)	0.84 (0.77–0.93)	<0.001
Cause of death:
g. Breast cancer	463 (33.9)	375 (27.3)	0.76 (0.67–0.87)	<0.001
h. All intercurrent (i–j)	237 (17.4)	293 (21.3)	1.18 (0.99–1.40)	0.065
i. All cardiovascular	112 (8.2)	126 (9.2)	1.07 (0.83–1.39)	0.59
- Ischemic heart disease	57 (4.2)	54 (3.9)
- Other cardiovascular	55 (4.0)	72 (5.2)
j. Other causes	125 (9.2)	167 (12.2)	1.27 (1.00–1.60)	0.046
k. Any death (g–h)	700 (51.3)	668 (48.6)	0.90 (0.81–1.00)	0.055
Total number of patients	1364	1374

^a Hazard ratio and 95% confidence intervals. Tamoxifen versus control. ^bLog-rank test. ^cControlling for trial design by stratification.

Figure 2.  Overall and event-free survival among all patients according to allocated treatment. Relative hazard (HR) and logrank p-values are indicated.

Table III.  Analysis of events by period of follow-up

Period of follow-up (years)	Any recurrence	Breast cancer death Hazard ratio^1 (95% C. I.)	Any death
0–4	0.72 (0.62–0.83)	0.80 (0.65–0.99)	0.90 (0.74–1.09)
5–9	0.94 (0.77–1–15)	0.72 (0.57–0.91)	0.77 (0.64–0.94)
10–14	1.03 (0.81–1.30)	0.84 (0.61–1.17)	0.97 (0.77–1.21)
15–19	1.17 (0.86–1.60)	0.72 (0.43–1.21)	1.19 (0.89–1.59)
20 +	0.89 (0.46–1.73)	1.18 (0.45–3.06)	0.98 (0.58–1.67)

1: TAM+ versus TAM − 

Table IV.  Analyses of the interaction between ER-content and the effect of adjuvant tamoxifen

ER content (fmol/microg DNA)	TAM + Events/Patients	TAM − Events/Patients	HR (95% C. I.)	Log-rank p
<0.05	151/237	146/249	1.18 (0.94–1.48)	0.16
≥0.05	557/934	605/919	0.77 (0.69–0.86)	<0.001
				Test for interaction between TAM and ER: p = 0.001
0	81/128	77/137	1.22 (0.89–1.66)	0.22
0.01–0.04	70/109	69/112	1.11 (0.80–1.55)	0.53
0.05–0.09	29/46	53/65	0.57 (0.36–0.90)	0.01
0.10–0.50	139/240	153/261	0.89 (0.71–1.12)	0.33
0.51–1.59	208/329	184/283	0.85 (0.69–1.03)	0.10
>1.59	181/319	215/310	0.66 (0.54–0.80)	<0.001
				Test for interaction between TAM and ER: p = 0.003.
Total	708/1171	751/1168	0.83 (0.75–0.93)	0.001

Table V.  Effect of tamoxifen by ER and PgR-status according to assay technique

	Events/patients Hazard ratio^1 (95% confidence interval) Progesterone receptor status
Assay technique/ER status	Negative	Positive	Total
Isoelectric focusing:
Negative	196/317	22/44	218/361
	1.16 (0.88–1.54)	1.59 (0.67–3.78)	1.21 (0.93–1.58)
Positive	343/570	411/647	754/1217
	0.76 (0.62–0.94)	0.76 (0.63–0.93)	0.76 (0.66–0.88)
Subtotal	539/887	433/691	972/1578
	0.89 (0.75–1.05)	0.81 (0.67–0.97)	0.85 (0.75–0.97)
Enzyme immuno assay:
Negative	23/45	1/3	24/48
	1.38 (0.61–3.16)	−	1.18 (0.52–2.64)
Positive	38/75	97/196	135/271
	0.43 (0.22–0.83)	0.87 (0.58–1.29)	0.71 (0.51–1.00)
Subtotal	61/120	98/199	159/319
	0.67 (0.40–1.12)	0.84 (0.57–1.25)	0.77 (0.56–1.05)
All patients:
Negative	219/362	23/47	242/409
	1.18 (0.91–1.54)	1.31 (0.56–3.09)	1.21 (0.94–1.55)
Positive	381/645	508/843	889/1488
	0.72 (0.59–0.88)	0.78 (0.66–0.93)	0.76 (0.66–0.86)
Total	600/1007	531/890	1131/1897
	0.86 (0.74–1.01)	0.81 (0.68–0.96)	0.84 (0.75–0.94)

¹TAM+ versus TAM − 

Table VI.  Analysis of first events and cause specific mortality among ER positive patients

	Number of events (%)
Stratum/type of event	TAM −	TAM +	Hazard ratio^a,c (95% confidence interval)	p-value^b,c
All patients:	919	934
First events:
a. Loco-regional recurrence	149 (16.2)	93 (10.0)	0.52 (0.40–0.67)	<0.001
- Chest wall	102 (11.1)	52 (5.6)
- Axilla	22 (2.4)	24 (2.6)
- Supraclavicular fossa	25 (2.7)	17 (1.8)
b. Distant recurrence	201 (21.9)	174 (18.6)	0.72 (0.59–0.88)	0.001
c. Contralateral breast cancer	76 (8.3)	42 (4.5)	0.46 (0.31–0.67)	<0.001
d. Other cancer	61 (6.6)	118 (12.6)	1.59 (1.16–2.16)	0.003
e. Intercurrent death	118 (12.8)	130 (13.9)	0.92 (0.71–1.18)	0.50
f. Any recurrence (a–e)	605 (65.8)	557 (59.6)	0.76 (0.68–0.85)	<0.001
Cause of death:
g. Breast cancer	328 (35.7)	247 (26.5)	0.69 (0.58–0.81)	<0.001
h. All intercurrent (i–j)	165 (18.0)	207 (22.2)	1.18 (0.96–1.45)	0.12
i. All cardiovascular	76 (8.3)	86 (9.2)	1.09 (0.80–1.49)	0.58
- IHD	35 (3.8)	38 (4.1)
- Other cardiovascular	41 (4.5)	48 (5.1)
j. Other causes	89 (9.7)	121 (13.0)	1.25 (0.95–1.65)	0.11
k. Any death (g–h)	493 (53.6)	454 (48.6)	0.85 (0.75–0.97)	0.013
Low risk patients:	588	595
Any recurrence	342 (58.2)	302 (50.8)	0.75 (0.64–0.87)	<0.001
Any death	252 (42.9)	234 (39.3)	0.89 (0.75–1.06)	0.20
High risk patients:	331	339
Any recurrence	263 (79.5)	255 (75.2)	0.78 (0.65–0.93)	0.005
Any death	241 (72.8)	220 (64.9)	0.81 (0.67–0.97)	0.024

^a Hazard ratio and 95% confidence intervals. TAM+ versus TAM−. ^bLog-rank test. ^cControlling for trial design by stratification.

Figure 3.  Overall and event-free survival among ER positive, high risk risk patients according to allocated treatment.

Figure 4.  Overall and event-free survival among ER positive, low risk risk patients according to allocated treatment.

Table VII.  Analysis of first events and cause specific mortality among patients randomly allocated to 2 versus 5 years of tamoxifen

	Number of events (%)
Type of event	5 years TAM	2 years TAM	Hazard ratio^a,c (95% confidence interval)	p-value^b,c
1st events:
a. Loco-regional recurrence	26 (6.5)	25 (6.3)	1.04 (0.60–1.81)	0.89
- Chest wall	16 (4.0)	14 (3.5)
- Axilla	7 (1.8)	7 (1.8)
- Supraclavicular fossa	3 (0.8)	4 (1.0)
b. Distant recurrence	52 (13.0)	62 (15.7)	0.93 (0.64–1.34)	0.68
c. Contralateral breast cancer	14 (3.5)	24 (6.1)	0.54 (0.28–1.05)	0.065
d. Other cancer	54 (13.5)	47 (11.9)	1.11 (0.75–1.64)	0.61
e. Intercurrent death	47 (11.8)	51 (12.9)	0.85 (0.57–1.26)	0.41
f. Any recurrence (a–e)	193 (48.3)	209 (52.8)	0.92 (0.75–1.12)	0.38
Cause of death:
g. Breast cancer	67 (16.8)	76 (19.2)	0.94 (0.68–1.32)	0.73
h. All intercurrent (i–j)	74 (18.5)	87 (22.0)	0.78 (0.60–1.07)	0.12
i. All cardiovascular	34 (8.5)	38 (9.6)	0.82 (0.51–1.31)	0.41
- Ischemic heart disease	12 (3.0)	17 (4.3)
- Other cardiovascular	22 (5.5)	21 (5.3)
j. Other causes	40 (10.0)	49 (12.4)	0.75 (0.49–1.14)	0.17
k. Any death (g–h)	141 (35.3)	163 (41.2)	0.85 (0.68–1.07)	0.17
Total number of patients	400	396

^aHazard ratio and 95% confidence intervals. 5 years versus 2 years of tamoxifen. ^bLog-rank test. ^cControlling for trial design by stratification

Table VIII.  Analysis of first events and cause specific mortality among patients randomly allocated to 2 or 5 years of tamoxifen, and concurrent patients allocated to no adjuvant endocrine therapy

	Number of events (%) Duration of TAM:			Hazard rate ratio^a,c (95% CI)
	0 years^d	2 years	5 years	2 vs 0 years	5 vs 0 years	P-value^b,c
Type of event
1^stevents:
a. Loco-regional recurrence	94 (10.2)	25 (6.3)	26 (6.5)	0.57 (0.36–0.88)	0.58 (0.38–0.90)	0.006
b. Distant recurrence	153 (16.6)	62 (15.7)	52 (13.0)	0.79 (0.59–1.07)	0.73 (0.53–1.00)	0.083
c. Contralateral breast cancer	64 (6.9)	24 (6.1)	14 (3.5)	0.81 (0.50–1.30)	0.45 (0.25–0.80)	0.020
e. Other cancer	68 (7.4)	47 (11.9)	54 (13.5)	1.46 (1.01–2.12)	1.61 (1.12–2.30)	0.020
d. Intercurrent death	115 (12.5)	51 (12.9)	47 (11.8)	0.91 (0.65–1.27)	0.82 (0.59–1.16)	0.53
f. Any event (a–d)	494 (53.5)	209 (52.8)	193 (48.3)	0.87 (0.74–1.02)	0.81 (0.69–0.96)	0.028
Cause of death:
g. Breast cancer	225 (24.4)	76 (19.2)	67 (16.8)	0.70 (0.54–0.91)	0.65 (0.50–0.86)	0.001
h. All intercurrent (i–j)	159 (17.2)	87 (22.0)	74 (18.5)	1.23 (0.94–1.60)	1.01 (0.76–1.33)	0.28
i. All cardiovascular	65 (7.0)	38 (9.6)	34 (8.5)	1.32 (0.89–1.98)	1.12 (0.74–1.71)	0.39
-Ischemic heart disease	36 (3.9)	17 (4.3)	12 (3.0)
-Other CV	29 (3.1)	21 (5.3)	22 (5.5)
j. Other cause	94 (10.2)	49 (12.4)	40 (10.0)	1.16 (0.82–1.64)	0.93 (0.64–1.34)	0.55
k. Any death (g–h)	384 (41.6)	163 (41.2)	141 (35.3)	0.91 (0.76–1.10)	0.80 (0.66–0.97)	0.072
Total number of patients	924	396	400

^aHazard rate ratio and 95% confidence interval. Tamoxifen for 2 or 5 years versus 0 years. ^bLog-rank test. ^cControlling for trial design by stratification.

^dThe control group consists of concurrent, disease-free patients initially randomised to no tamoxifen [TAM-] in the trial.

Table IX.  Number of new cancers (other than contralateral breast cancer) diagnosed as first events by allocated treatment

Site/type of cancer	TAM−(n = 1 364)	TAM+(n = 1 374)
Head & neck	3	3
Esophagus	0	5
Stomach	3	6
Colorectal	15	22
Liver	3	5
Pancreas	4	3
Lung	4	21
Cervix uteri	1	2
Endometrium	4	33
Uterus, other	3	2
Ovary	8	7
Urinary tract	12	15
Skin	10	14
Lymphoma, leukemia	10	10
Misc.	14	16
All sites	94	164

Figure 5.  Cumulative incidence of endometrial cancer according to allocated treatment among all patients (left panel), and among those included in the randomized comparison of 2 versus 5 years of tamoxifen (right panel). Note that in the latter trial, the starting point for the curves is at 2 years after the initial entry into the trial. Number of patients at risk, relative hazards, and logrank p-values are indicated.