Effect of Preventive Hormonal Therapy on Breast Density: A Systematic Qualitative Review

Table 4

Tamoxifen (TAM) studies: results: effect on BD and confounding factors of treatment interaction.

Authors	Change in BD			Confounding factors
	Treatment	Endpoint	P	At baseline	Interaction with treatment
Cuzick et al.; 2004 [32]	Tam; PLAC	Reduction in % density at 54 months; −13.7% (95% CI −12.3% to 15.1%); −7.3% (95% CI −6.1% to 8.4%)	0.001; 0.001	Statistically significant higher BD at baseline was associated with low BMI, age ≤ 55 y, no familial risk of BC, past breast biopsy, and never smoking	In MVA, greater reductions in BD were associated with treatment arm (Tam), BMI <25 kg/m^2 or less, stopping HRT during the study, smoking during the study, and higher BD at entry. Treatment effect statistically smaller in older and postmenopausal women^1
Decensi et al.; 2009 [33]		Reduction in % density at 24 months ^2		Statistically higher BD at baseline was associated with low BMI, younger age (details NA)	In MVA, BD at entry had no statistically significant interaction with treatment effect
	Tam	−19.6% (95% CI −26.3% to −12.9%)	0.003
	Fenretinide	−10.8% (95% CI −23.8% to 2.1%)
	Both	−21.6% (95% CI −29.0% to −14.3%)
	Placebo	−12.2% (95% CI −25.2% to 0.9%)
Chow et al.; 2000 [34]		Reduction in % density per year ^3		No statistically significant effect of age on BD	In MVA, age and menopausal status had no statistically significant interaction with treatment effect (P = NA)^4
	Tam	−4.3%	0.0007
	Control	No change
Brisson et al.; 2000 [35]		Reduction in % density ± SD posttreatment		No statistically significant effect of age on BD	In MVA, age, nulliparity, and history of breast biopsy had no statistically significant interaction with treatment effect
	Tam	−9.4%±12.0	0.010
	Plac	−3.6%±5.3
Atkinson et al.; 1999 [36]		Women with decreased BD: n (%)		NA	𝐍𝐌𝐓𝐀^5
	Tam	29 (33%)	0.0001
	Control	10 (5%)
Hong and Ki.; 1999 [37]		Women with decreased BD: n (%)		NA	In MVA, menopausal status had an interaction with treatment effect: decrease in BD (n): premenopause: 47/54 (87%); postmenopause: 14/48 (29.2%). (P = NA)
	Tam	61 (59.8%)	NA
	Group II	18 (36%)
	Group IIIl	2 (10%)
Konez et al.; 2001 [38]		Women with decreased BD: n (%)		NA	NMTA
	Tam	5/24 (21%); (within treatment: n: 3 and at end n: 2)
		Relative glandular density change per interval: 0.012±0.006	0.06^6
Meggiorini et al.; 2008 [39]		Women with decreased BD: n (%)		NA	In MVA, greater reduction of BD was statistically significantly associated with age <59 y (P = 0.035)
	Tam	14/68 (20.59%)	0.021
	Control	6/80 (7.50%)
Chen et al. 2011 [40]	Tam	Absolute reduction of %BD (Δ%BD) ^7; −5.8%±3.8% (95% CI: −3.7% to −7.8%)	0.001	NA	NMTA
Cuzick et al.; 2011 [41]		Reduction ≥ 10% in % density		Statistically significant higher BD; at baseline in women with atypical hyperplasia or LCIS	In MVA, atypical hyperplasia and LCIS had no significant interaction with treatment effect (P = 0.4), greater reduction in BD in women who had never taken HRT; (P = 0.03) ^9
	All patients (N in %)
	Tam	232/507 (45.7%)
	Placebo	140/558 (25%^8)
	Control subjects in Tam group	48%	<0.001
	Control subjects in Plac group	26%
	Case subjects in Tam group	29%
	Control subjects in Tam group	48%	0.01

1Using additional Student’s t-tests to determine whether the observed effects of tam on BD applied equally to all subgroups of women; in women ≤45 yr at entry, the net reduction with tam: 13.4% (95% CI −8.6% to 18.1%), whereas in women >55 y: 1.1% (95% CI −3.0% to 5.1%). MVA: multivariable analysis. ²Using analog mammograms only. ³Using digitized mammograms: SD ± 6.6%, range = −21.5 to 10.1. ⁴Because of the small numbers of patients in these groups, the power to detect mean differences (6–8% between them) is low. NMTA: no multivariable analysis of interaction with treatment effect available. ⁵There was too much missing data in order to assess the effect of previous use of HRT on change in BD. NA: data non available. ⁶Calculated in 27 cases. ⁷Evaluated by 3D MRI (magnetic resonance imaging). ⁸Personal calculation for percentages. LCIS: lobular carcinoma in situ. ⁹After adjusting for age and BD at IBIS-I entry, body mass index at IBIS-I entry, age at menarche, menopausal status at entry to IBIS-I, smoking, family history, benign breast disease (atypical hyperplasia or LCIS), and treatment arm, the mean reduction in breast density was smaller in women who started HRT during the study compared with those who had never taken HRT (4.3% versus 6.3%), mean difference in breast density reduction = 2.02%, 95% CI = 0.02% to 3.83%, 𝑃=0.03.