Table 3.

Comparison of baseline variables and outcomes in phase III trials of SERMs and AIs

StudyNSABP P-1: BCPTIBIS-IRoyal MarsdenItalian Tamoxifen TrialNSABP P-2: STARNCIC MAP.3
DrugTamoxifena vs. placebo (ref. 35)Tamoxifena vs. placebo (ref. 51)Tamoxifena vs. placebo (ref. 78)Tamoxifena vs. placebo (ref. 79)Raloxifeneb vs. tamoxifen (ref. 43)Exemestane vs. placebo (ref. 33)
Mean or median FU74-mo mean FU96-mo median FU13-y median FU11-y mean FU81-mo median FU35-mo median FU
Number randomized/ mean or median age at randomization13,388/NA7,145/50.7 y mean2,494/2,471 analyzed/47 y medianh5,408/51 y median19,747/58.5 y mean (postmenopausal)4,560/62.5 y median (postmenopausal)
Risk level of participants (% participants at given risk score level)5-y riskd: ≤2% (∼25%) 2.01%–3% (∼31%) 3.01%–5% (∼26.6%) ≥5% (∼17.3%)10-y riskf: <2% (∼1.5%) 2%–3% (∼3.5%) 35% (∼24%) 5%–10% (∼55%) >10% (∼16%)NAiNAjMean 5-y riskd: = 4.03%Median 5-y riskd: = 2.3%
Primary endpointcInvasive BC incidence: RR = 0.57 (95% CI, 0.46–0.70; P < 0.001)BC incidence (invasive + DCIS): RR = 0.73 (95% CI, 0.58–0.91; P = 0.004)Invasive BC: HR = 0.78 (95% CI, 0.58–1.04; P = 0.1)BC incidence: RR = 0.84 (95% CI, 0.60–1.17)Invasive BC incidence: RR = 1.24 (95% CI, 1.05–1.47; P = 0.01)Invasive BC: HR = 0.35 (95% CI, 0.18–.0.70; P = 0.002)
Secondary endpointsc
Noninvasive BCTotal noninvasive (DCIS + LCIS): RR = 0.63 (95% CI, 0.45–0.89; P = 0.008)NANANoninvasive: OR = 1.51 (95% CI, 0.54–4.24; P = 0.4)Total noninvasive (DCIS + LCIS + mixed): RR = 1.22 (95% CI, 0.95–1.59; P = 0.12)NA
DCISNARR = 0.63 (95% CI, 0.32–1.20)OR = 1.56 (95% CI, 0.67–3.61; P = 0.4)NARR = 1.22 (95% CI, 0.95–1.69)HR = 0.65 (95% CI, 0.28–1.51; P = 0.31)
Other groupings that include noninvasive BCNANAAny BC: HR = 0.84 (95% CI, 0.64–1.10; P = 0.2)NALCIS: RR = 1.02 (95% CI, 0.61–1.70) Mixed DCIS + LCIS: RR = 2.11 (95% CI, 0.86–5.64)ADH, ALH, LCIS: HR = 0.36 (95% CI, 0.11–1.12; P = 0.08); Invasive BC + DCIS: HR = 0.47 (95% CI, 0.27–0.79; P = 0.004)
BC ER status: ER-positiveRR = 0.38 (95% CI, 0.28–0.50)RR = 0.66 (95% CI, 0.50–0.87)HR = 0.61 (95% CI, 0.43–0.86; P = 0.005)RR = 0.77 (95% CI, 0.51–1.16)kRR = 0.93 (95% CI, 0.72–1.24)lHR = 0.27 (95% CI, 0.12–0.60; P < 0.001)
BC ER status: ER-negativeRR = 1.31 (95% CI, 0.86–2.01)RR = 1.00 (95% CI, 0.61–1.65)HR = 1.4 (95% CI, 0.7–2.6; P = 0.3)RR = 1.10 (95% CI, 0.59–2.05)kRR = 1.15 (95% CI, 0.75–1.77)lHR = 0.80 (95% CI, 0.21–2.98; P = 0.74)
Adverse events
Endometrial cancerInvasive: RR = 3.28 (95% CI,1.87–6.03) ≤49 y: RR = 1.42 (CI, 0.55–3.81) ≥50 y: RR = 5.33 (CI, 2.47–13.17) In situ: RR = 0.35 (CI, 0.01–4.36)RR = 1.55 (95% CI, 0.68–3.65)HR = 2.69 (95% CI, 0.96–7.55; P = 0.06)NARR = 0.55 (95% CI, 0.36–0.83; P = 0.003)NAm
Thromboembolic events: overall
Thromboembolic: pulmonary emboliRR = 2.15 (95% CI, 1.08–4.51)[DVT/PE: RR = 1.84 (95% CI, 1.21–2.82)]gNANARR = 0.80 (95% CI, 0.57–1.11)NA
Thromboembolic: DVTRR = 1.44 (95% CI, 0.91–2.30)[DVT/PE: RR = 1.84 (95% CI, 1.21–2.82)] 13)NANARR = 0.72 (95 % CI, 0.54–0.95)NA
Cardiovascular events and stroke or all CVA eventsStroke: RR = 1.42 (95% CI, 0.97–2.08) TIA: RR = 0.91 (95% CI, 0.54–1.52) Ischemic heart disease: RR = 1.03 (95% CI, 0.79–1.36)Stroke/CVA: RR = 1.25 (95% CI, 0.55–2.93) All cardiac events: RR = 0.99 (95% CI, 0.77–1.29)Stroke: OR = 0.74 (95% CI, 0.28–2.00; P = 0.6)Cerebrovascular events total: RR = 1.78 (95% CI, 0.70–4.52; CV events: RR = 1.04 (95% CI, 0.30–3.58); CV-arrhythmia: RR = 1.73 (95% CI, 1.01–2.98)NAStroke/TIA: OR = 1.19 (95% CI, 0.53–2.66; P = 0.7) CV events: OR = 0.96 (95% CI, 0.72–1.26; P = 0.78)
Bone: clinical skeletal fractureHip, spine, radius: RR = 0.68 (95% CI, 0.51–0.92)eAll fractures: RR = 1.02 (95% CI, 0.86–1.21)OR = 0.86 (95% CI, 0.46–1.59; P = 0.6)NARR = 0.92 (95% CI, 0.69–1.22)lOR = 1.05 (95% CI, 0.83–1.33; P = 0.72)
Bone: new osteoporosisNANANANANAOR = 1.24 (95% CI, 0.76–2.02; P = 0.39)
Musculoskeletal: arthritisNANANANANAOR = 1.19 (95% CI, 0.99–1.43; P = 0.01)
Joint painNANAOR = 1.18 (95% CI, 0.82–1.70; P = 0.4)NANAOR = 1.14 (95% CI, 1.00–1.30; P = 0.04)
Muscle pain or crampsNANAOR = 1.70 (95% CI, 0.96–3.01; P = 0.09)NANAOR = 0.75 (95% CI, 0.60–0.94; P = 0.01)
StudyNSABP P-1: BCPTIBIS-IRoyal MarsdenItalian Tamoxifen TrialNSABP P-2: STARNCIC MAP.3
DrugTamoxifena vs. placebo (ref. 35)Tamoxifena vs. placebo (ref. 51)Tamoxifena vs. placebo (ref. 78)Tamoxifena vs. placebo (ref. 79)Raloxifeneb vs. tamoxifen (ref. 43)Exemestane vs. placebo (ref. 33)
Hot flashes (often or extremely bothersome) or vasomotorNA in ref. 28; TAM: 45.7% vs. placebo: 28.7%e[Combined gynecologic and vasomotor: RR = 1.08 (95% CI, 1.06–1.10)]gOR = 1.99 (95% CI, 1.69–2.35; P < 0.001)RR = 1.78 (95% CI, 1.57–2.00)NAVasomotor symptoms in MENQOL: OR = 1.49 (95% CI, 1.31–1.69; P < 0.001)n
Vaginal/ gynecologic symptoms (moderately bothersome or worse)NA in ref. 28; Vaginal discharge: TAM: 29% vs. placebo: 13%e[Combined gynecologic and vasomotor: RR = 1.08 (95% CI, 1.06–1.10)]gVaginal discharge: OR = 2.23 (95% CI, 1.81–2.75; P < 0.001)Vaginal dryness: RR = 1.14 (95% CI, 0.97–1.34); vaginal discharge: RR = 3.44 (95% CI, 2.90–4.09)NAVaginal dryness: OR = 1.03 (95% CI, 0.88–1.22; P = 0.68)
  • Abbreviations: BC, breast cancer; BCPT, Breast Cancer Prevention Trial; CI, confidence interval; CV, cardiovascular; CVA, cerebrovascular accident; DVT, deep vein thrombosis; FU, follow-up; NA, not available; PE, pulmonary embolus; RR, relative risk or risk ratio; TAM. tamoxifen; TIA, transient ischemic attack.

  • a Tamoxifen was approved by the FDA in October 1998.

  • b Raloxifene was approved by the FDA September 13, 2007.

  • c Values for OR, RR, and HR refer to comparisons of the hormonal intervention arm with the control arm.

  • d Five-year Gail model risk score. The Gail model score calculates breast cancer risk based on known clinical and demographic factors, including age, age at first period, age at first birth, family history of breast cancer (first-degree relative: mother, sister, or daughter), number of past breast biopsies, and number of breast biopsies that showed atypical hyperplasia. The Gail model risk assessment tool is available at http://www.cancer.gov/bcrisktool/.

  • e These rates reflect 69 months of follow-up and were obtained from the first publication of NSABP P-1:BCPT (see ref. 40).

  • f Predicted absolute 10-year risk in placebo group based on family history and other risk factors. These numbers were obtained from the first publication of IBIS-I (see ref. 80).

  • g Brackets indicate a repeat entry for categories listed separately in this table but combined in the original reference.

  • h Data from Powles et al. (81).

  • i Risk based primarily on family history, not on Gail model score.

  • j Participants were not selected for study based on their risk of developing breast cancer. All participants had had a hysterectomy; the majority (53%) had hadboth ovaries removed during hysterectomy and were therefore at slightly less than normal risk of breast cancer.

  • k Data from Veronesi et al. (ref. 79, Supplementary Table S1).

  • l These values for ER status and fracture rates are from the initial analysis of NSABP P-2:STAR (see ref. 42). ER status and fracture rates are not addressed in the 2010 Update of STAR (see ref. 43).

  • m Endometrial cancers are not addressed in this paper (33). However, the Supplementary Table S2 lists “gynecological cancers” as exemestane (5/2,240) vs. placebo (8/2,248).

  • n Data from Goss et al. (ref. 33, Supplementary Table S3, MENQOL assessment).