Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing Breast Cancer

Victor G. Vogel; Joseph P. Costantino; D. Lawrence Wickerham; Walter M. Cronin; Reena S. Cecchini; James N. Atkins; Therese B. Bevers; Louis Fehrenbacher; Eduardo R. Pajon; James L. Wade; André Robidoux; Richard G. Margolese; Joan James; Carolyn D. Runowicz; Patricia A. Ganz; Steven E. Reis; Worta McCaskill-Stevens; Leslie G. Ford; V. Craig Jordan; Norman Wolmark

doi:10.1158/1940-6207.CAPR-10-0076

DOI: 10.1158/1940-6207.CAPR-10-0076 Published June 2010

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Fig. 1.
Cumulative incidences of invasive and noninvasive breast cancer.
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Fig. 2.
Cumulative incidences of invasive uterine cancer and thromboembolic events.

Table 1.

Characteristics at entry to the NSABP STAR Trial (P-2) for women included in the STAR-update analyses

Participant characteristics	Tamoxifen		Raloxifene
Participant characteristics	No.	%	No.	%
Age (years)
≤49	884	9.1	878	9.0
50–59	4,856	49.9	4,855	49.8
60–69	3,137	32.2	3,174	32.5
≥70	859	8.8	847	8.7
Race/ethnicity
White	9,105	93.5	9,115	93.4
African-American	233	2.4	243	2.5
Hispanic	192	2.0	193	2.0
Other	206	2.1	203	2.1
No. 1° relatives with breast cancer
0	2,838	29.1	2,791	28.6
1	5,046	51.8	5,135	52.6
2	1,532	15.7	1,561	16.0
≥3	320	3.3	267	2.7
History of hysterectomy
No	4,739	48.7	4,717	48.4
Yes	4,997	51.3	5,037	51.6
History of lobular carcinoma in situ
No	8,844	90.8	8,865	90.9
Yes	892	9.2	889	9.1
History of breast atypical hyperplasia
No	7,545	77.5	7,513	77.0
Yes	2,191	22.5	2,241	23.0
5-year predicted breast cancer risk (%)^*
≤2.00	1,055	10.8	1,102	11.3
2.01-3.00	2,993	30.7	2,893	29.7
3.01-5.00	3,042	31.2	3,086	31.6
≥5.01	2,646	27.2	2,673	27.4
Total	9,736	100.0	9,754	100.0

Abbreviation: NSABP STAR, National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene.

↵*Determined by the Gail model.

Table 2.

Annual rates of invasive breast cancer—NSABP STAR Trial (P-2)

Participant characteristic at baseline	Number of events		Rate per 1000			RR^*	RR (95% CI)
Participant characteristic at baseline	Tamoxifen	Raloxifene	Tamoxifen	Raloxifene	Difference^†	RR^*	RR (95% CI)
Age at entry (years)
≤49	10	15	1.84	2.80	−0.96	1.53	0.64–3.80
50-59	125	155	4.09	5.03	−0.94	1.23	0.97–1.57
≥60	112	140	4.47	5.48	−1.01	1.22	0.95–1.58
History of lobular carcinoma in situ
No	197	253	3.54	4.50	−0.96	1.27	1.05–1.54
Yes	50	57	9.14	10.34	−1.20	1.13	0.76–1.69
History of atypical hyperplasia
No	187	218	3.90	4.52	−0.62	1.16	0.95–1.42
Yes	60	92	4.58	6.79	−2.21	1.48	1.06–2.09
5-year predicted breast cancer risk (%)
≤3.00	61	81	2.39	3.21	−0.82	1.34	0.95–1.90
3.01-5.00	84	91	4.43	4.63	−0.20	1.05	0.77–1.42
≥5.01	102	138	6.13	8.17	−2.04	1.33	1.02–1.74
No. 1⁰ relatives with breast cancer
0	82	105	4.77	6.17	−1.40	1.29	0.96–1.75
1	112	135	3.51	4.10	−0.59	1.17	0.90–1.51
≥2	53	70	4.44	5.96	−1.52	1.34	0.93–1.96
Total	247	310	4.04	5.02	−0.98	1.24	1.05–1.47

Abbreviations: CI, confidence interval; NSABP STAR, National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene; RR, risk ratio.

↵*Risk ratio for women in the raloxifene group compared to women in the tamoxifen group.
↵^†Rate in the tamoxifen group minus rate in the raloxifene group.

Table 3.

Annual rates of noninvasive breast cancer and uterine disease/hysterectomy—NSABP STAR Trial (P-2)

Disease/uterine event type	Events, n		Rate per 1,000			RR^*	RR (95% CI)
Disease/uterine event type	Tamoxifen	Raloxifene	Tamoxifen	Raloxifene	Difference^†	RR^*	RR (95% CI)
Noninvasive breast cancer
DCIS	70	86	1.15	1.40	−0.25	1.22	0.88–1.69
LCIS	33	34	0.54	0.55	−0.01	1.02	0.61–1.70
Mixed	8	17	0.13	0.28	−0.15	2.11	0.86–5.64
Total	111	137	1.83	2.23	−0.40	1.22	0.95–1.59
Uterine disease and hysterectomy^‡
Invasive Cancer	65	37	2.25	1.23	1.02	0.55	0.36–0.83
Hyperplasia^§	126	25	4.40	0.84	3.56	0.19	0.12–0.29
Without atypia^§	104	21	3.63	0.70	2.93	0.19	0.11–0.31
With atypia^§	22	4	0.77	0.13	0.64	0.17	0.04–0.51
Hysterectomy during follow-up	349	162	12.08	5.41	6.67	0.45	0.37–0.54

Abbreviations: CI, confidence interval; DCIS, ductal carcinoma in situ; LCIS, lobular carcinoma in situ; NSABP STAR, National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene; RR, risk ratio.

↵*Risk ratio for women in the raloxifene group compared with women in the tamoxifen group.
↵^†Rate in the tamoxifen group minus rate in the raloxifene group.
↵^‡Women at risk were those with an intact uterus at entry (see Table 1).
↵^§Among women not diagnosed with uterine cancer.

Table 4.

Annual rates of site-specific invasive cancer cases other than breast and uterine cancer—NSABP STAR Trial (P-2)

Site of cancer	Events, n		Rate per 1000			RR^*	RR (95% CI)
Site of cancer	Tamoxifen	Raloxifene	Tamoxifen	Raloxifene	Difference^†	RR^*	RR (95% CI)
Adrenal gland	0	1	0	0.02	−0.02	—	—
Bone/cartilage/connective tissue	3	4	0.05	0.06	−0.01	1.32	0.22–8.98
Buccal cavity and pharynx	4	6	0.06	0.10	−0.04	1.48	0.35–7.13
Cervix	3	0	0.05	0	0.05	—	—
Colorectal	48	45	0.78	0.72	0.06	0.93	0.60 to 1.42
Esophagus	2	0	0.03	0	0.03	—	—
Eye	1	1	0.02	0.02	0	0.99	0.01–77.48
Gallbladder	5	2	0.08	0.03	0.05	0.39	0.04–2.41
Kidney	14	21	0.23	0.34	−0.11	1.48	0.72–3.15
Larynx	0	1	0	0.02	−0.02	—	—
Leukemia/other lymph/hemato	60	53	0.97	0.85	0.12	0.87	0.59–1.28
Liver	7	2	0.11	0.03	0.08	0.28	0.03–1.48
Lung, trachea, bronchus	57	64	0.92	1.02	−0.10	1.11	0.76–1.61
Nasal/middle ear/sinuses	1	1	0.02	0.02	0	0.99	0.01–77.48
Nervous system	9	10	0.15	0.16	−0.01	1.10	0.40–3.05
Other gyn	2	2	0.03	0.03	0	0.99	0.07–13.62
Ovary	21	34	0.50	0.79	−0.29	1.58	0.89–2.86
Pancreas	12	11	0.19	0.18	0.01	0.90	0.36–2.24
Retroperitoneum	7	4	0.11	0.06	0.05	0.56	0.12–2.22
Skin	25	24	0.40	0.38	0.02	0.95	0.52–1.73
Small intestine	0	2	0	0.03	−0.03	—	—
Spleen	0	2	0	0.03	−0.03	—	—
Stomach	5	1	0.08	0.02	0.06	0.20	0.004–1.76
Thyroid gland	18	32	0.29	0.51	−0.22	1.76	0.96–3.32
Urinary bladder	15	12	0.24	0.19	0.05	0.79	0.34–1.81
Site unspecified/unspecified nature	15	19	0.24	0.30	−0.06	1.25	0.60–2.64
Secondary/uncertain	4	5	0.06	0.08	−0.02	1.23	0.27–6.22

Abbreviations: CI, confidence interval; gyn, gynecologic; hemato, hematopoietic; lymph, lymphatic; NSABP STAR, National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene; RR, risk ratio.

↵*Risk ratio for women in the raloxifene group compared with women in the tamoxifen group.
↵^†Rate in the tamoxifen group minus rate in the raloxifene group.

Table 5.

Rates of thromboembolic events, cataracts, and cataracts surgery—NSABP STAR Trial (P-2)

Type of event	Events, n		Rate per 1,000			RR^*	RR (95% CI)
Type of event	Tamoxifen	Raloxifene	Tamoxifen	Raloxifene	Difference^†	RR^*	RR (95% CI)
Thromboembolic events	202	154	3.30	2.47	0.83	0.75	0.60–0.93
Pulmonary embolism	84	68	1.36	1.09	0.27	0.80	0.57–1.11
Deep-vein thrombosis	118	86	1.93	1.38	0.55	0.72	0.54–0.95
Cataracts and Cataract Surgery
Developed cataracts during follow-up^‡	739	603	14.58	11.69	2.89	0.80	0.72–0.89
Developed cataracts and had cataract surgery^‡	575	462	11.18	8.85	2.33	0.79	0.70–0.90

Abbreviations: CI, confidence interval; NSABP STAR, National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene; RR, risk ratio.

↵*Risk ratio for women in the raloxifene group compared to women in the tamoxifen group.
↵^†Rate in the tamoxifen group minus rate in the raloxifene group.
↵^‡Women at risk were those with no prior history of cataracts at entry (8,341 and 8,336 tamoxifen and raloxifene participants, respectively).

Table 6.

Distribution of Deaths - NSABP STAR Trial (P-2)

Cause of death	Deaths, n
Cause of death	Tamoxifen	Raloxifene
Cancer	101	86
Bladder	1	3
Bone, articular cartilage and connective tissue	1	1
Brain	6	4
Breast	11	4
Colon	4	3
Endocrine gland	0	1
Gallbladder	2	1
Kidney	1	1
Liver	7	1
Lung	25	28
Lymphatic/hematopoietic	12	11
Oral	2	1
Ovary	8	7
Pancreas	7	5
Peritoneum	2	0
Skin	2	0
Spleen	0	1
Stomach	2	1
Thyroid	1	0
Uterus	2	2
Other, uncertain, and unspecified sites	5	11
Circulatory/vascular disease	42	42
Aortic	1	2
Atherosclerosis	0	1
Cerebrovascular disease, unspecified	1	0
Hypertensive disease	1	4
Ischemic heart disease	13	8
Other heart disease	9	14
Peripheral vascular disease, unspecified	0	1
Polyarteritis nodosa	0	1
Pulmonary embolism	3	2
Primary pulmonary hypertension	1	0
Stroke	13	9
Other	93	74
Accident, auto	3	4
Accident, fire	1	0
Alcohol dependence syndrome	1	1
Asphyxiation and strangulation	1	0
Complications of surgery	0	1
Dementia	0	1
Diabetes	1	3
Disorders of metabolism	1	0
Emphysema	1	0
Injury, intracranial	2	2
Injury, other	1	0
Interferon toxicity	0	1
Intestinal infectious disease	0	1
Other conditions of the blood	0	2
Other conditions of the brain/neurological system	7	3
Other diseases of the digestive system	7	6
Other Diseases of the urinary system	2	1
Other respiratory disease	13	7
Pneumonia	2	4
Poisoning	2	0
Septicemia	4	3
Skin infections	0	1
Symptoms, signs, and ill-defined conditions	2	3
Unknown	42	30
Total deaths (rate per 1,000)	236 (3.81)	202 (3.22)
Risk ratio (95% CI)	0.70–1.02)