Mammographic density parameters and breast cancer tumor characteristics among postmenopausal women

Figures & data

Table 1 Characteristics of study population

Variables^a		Cases (N=477) Mean (SD)/N (%)	Controls (N=588) Mean (SD)/N (%)
Age at study entry (years)		64.0 (7.7)	62.9 (7.9)
Age at mammogram (years)		60.9 (7.7)	63.0 (8.0)
Age at first mammogram (years)		47.7 (7.6)	47.0 (6.8)
Ethnicity	European	305 (63.9%)	465 (79.1%)
	East Asian	113 (23.7%)	61 (10.3%)
	Filipino	24 (5.1%)	20 (3.4%)
	South Asian	22 (4.6%)	23 (3.9%)
	Mixed/Other	13 (2.7%)	19 (3.3%)
Education	High school or less	197 (41.3%)	180 (30.6%)
	College/trade certificate	132 (27.7%)	169 (28.7%)
	Undergraduate degree	97 (20.3%)	121 (20.6%)
	Graduate/professional degree	51 (10.7%)	118 (20.1%)
BMI (kg/m^2) 2 years before study entry		26.3 (5.1)	25.1 (4.7)
Family history of breast cancer (%)		117 (24.5%)	90 (15.3%)
Age at menarche (years)		13.0 (1.6)	12.9 (1.5)
Ever been pregnant (yes)		370 (77.6%)	443 (75.3%)
Age at first pregnancy (years)^b		26.2 (5.5)	25.8 (4.9)
Parity^b		2.3 (1.1)	2.4 (1.0)
Ever breastfed^b (%)		367 (99.2%)	439 (99.1%)
Lifetime breastfeeding^b (months)		6.3 (5.1)	7.1 (5.0)
Oral contraceptive use (years)	Never	239 (50.1%)	249 (42.4%)
	<4.5 years	98 (20.5%)	133 (22.6%)
	4.5–10 years	90 (18.9%)	132 (22.4%)
	>10 years	50 (10.5%)	74 (12.6%)
HRT use (years)	Never	286 (60.0%)	343 (58.3%)
	<5 years	62 (13.0%)	85 (14.5%)
	5–12 years	84 (17.6%)	101 (17.2%)
	>12 years	45 (9.4%)	59 (10.0%)
Nonsteroidal anti-inflammatory drugs use (years)	Never	349 (73.2%)	399 (67.9%)
	<2.34 years	43 (9.0%)	70 (11.9%)
	2.34–8.5 years	46 (9.6%)	56 (9.5%)
	>8.5 years	39 (8.2%)	63 (10.7%)
Smoking (pack/years)		6.7 (13.7)	6.4 (12.4)
Alcohol consumption (drinks/week)		2.8 (5.1)	2.0 (5.0)
Dense area (cm^2)		20.68 (14.91)	15.80 (11.81)
Non-dense area (cm^2)		113.34 (62.76)	117.81 (62.28)
Percent dense area (%)		17.41 (10.94)	14.40 (11.89)

Notes:^aMissing values were present in the following variables: BMI (0.5% of cases and 0.1% of controls), age at first full-term pregnancy (0.8% of cases and 3.3% of controls), lifetime breastfeeding (1.4% of cases and 1.1% of controls), use of oral contraceptives (2.1% of cases and 1.9% of controls), family history of breast cancer (5.6% of cases and 3.1% of controls), HRT (2.3% of cases and 2.5% of controls), lifetime smoking (0.7% of cases and controls), and alcohol consumption (0.7% of cases and 3.3% of controls). ^bAmong parous women. Adapted by permission from Springer Nature: Breast Cancer Res Treat, Velásquez García HA, Sobolev BG, Gotay CC, et al, Mammographic non-dense area and breast cancer risk in postmenopausal women: a causal inference approach in a case–control study, 2018;170:159–168,³⁷ Copyright 2018.

Abbreviation: BMI, body mass index.

Table 2 Distribution of tumor characteristics on cases

Characteristic		N (%)
Invasiveness	In situ	107 (23.26)
	Invasive	370 (76.74)
Breast cancer stage	0	107 (22.43)
	I	189 (39.62)
	II	116 (24.32)
	III	41 (8.60)
	IV	7 (1.47)
	Unknown	17 (3.56)
Histology^a	Ductal	310 (83.78)
	Lobular	26 (7.03)
	Mixed	11 (2.97)
	Other	23 (6.22)
Tumor size^a	<1.1 cm 1.1–2.0 cm >2.0 cm	100 (27.03)
	1.1–2.0 cm >2.0 cm	145 (39.19)
	>2.0 cm >2.0 cm	106 (28.65)
	Unknown	19 (5.14)
ER status^a	Positive	287 (77.57)
	Negative	66 (17.84)
	Unknown	17 (4.59)
PR status^a	Positive	212 (57.30)
	Negative	141 (38.11)
	Unknown	17 (4.59)
HER2 status^a	Positive	88 (23.78)
	Negative	265 (71.62)
	Unknown	17 (4.59)
Phenotype group^a (ER|PR+ vs ER&PR-)	ER|PR+	290 (78.38)
	ER&PR-	63 (17.03)
	Unknown	17 (4.59)

Note:^aInvasive cases only.

Abbreviations: ER, estrogen receptor; PR, progesterone receptor.

Table 3 Associations of mammographic density parameters stratified by breast cancer tumor characteristics in postmenopausal women

	Quartile	Controls	Dense area^a			Non-dense area^b			Percent dense area
			Cases	aOR (95% CI)	p-trend	Cases	aOR (95% CI)	p-trend	Cases	aOR (95% CI)	p-trend
Overall	1	147	86	Reference	<0.001	144	Reference	0.025	76	Reference	<0.001
	2	147	92	1.13 (0.75–1.71)		106	0.76 (0.51–1.12)		78	1.29 (0.84–1.99)
	3	147	107	1.34 (0.89–2.01)		112	0.75 (0.49–1.16)		154	3.09 (2.04–4.69)
	4	147	192	2.55 (1.74–3.73)		115	0.52 (0.31–0.85)		169	3.84 (2.48–5.95)
	Continuous	588	477	1.39 (1.25–1.54)^◊	<0.001		0.94 (0.91–0.97)^◊	<0.001		1.44 (1.26–1.64)^◊	<0.001
Invasiveness
In situ	1	147	23	Reference	0.075	46	Reference	0.022	15	Reference	0.001
	2	147	21	1.02 (0.50–2.07)		26	0.75 (0.40–1.39)		15	1.16 (0.51–2.62)
	3	147	26	1.12 (0.56–2.25)		16	0.39 (0.18–0.84)		34	2.81 (1.33–5.97)
	4	147	37	1.75 (0.92–3.36)		19	0.41 (0.17–0.98)		43	3.31 (1.51–7.29)
	Continuous	588	107	1.26 (1.06–1.49)^◊	0.010		0.91 (0.86–0.97)^◊	0.003		1.31 (1.07–1.61)^◊	0.010
Invasive	1	147	63	Reference	<0.001	98	Reference	0.148	61	Reference	<0.001
	2	147	71	1.21 (0.77–1.89)		80	0.78 (0.51–1.20)		63	1.38 (0.85–2.19)
	3	147	81	1.48 (0.94–2.31)		96	0.91 (0.57–1.46)		120	3.22 (2.05–5.06)
	4	147	155	2.84 (1.88–4.29)		96	0.59 (0.34–1.00)		126	4.08 (2.54–6.56)
	Continuous	588	370	1.43 (1.28–1.60)^◊	<0.001		0.95 (0.91–0.98)^◊	0.002		1.46 (1.27–1.68)^◊	<0.001
Invasiveness p-heterogeneity*			0.157 | 0.337			0.218 | 0.275			0.689 | 0.566
Histology (restricted to ductal and lobular invasive subtypes)
Ductal	1	147	56	Reference	<0.001	85	Reference	0.146	54	Reference	<0.001
	2	147	63	1.18 (0.74–1.90)		67	0.76 (0.48–1.20)		53	1.39 (0.85–2.28)
	3	147	61	1.27 (0.78–2.05)		78	0.84 (0.51–1.38)		97	2.99 (1.86–4.83)
	4	147	130	2.72 (1.76–4.19)		80	0.58 (0.32–1.02)		106	3.87 (2.34–6.38)
	Continuous	588	310	1.41 (1.25–1.58)	<0.001		0.94 (0.91–0.98)	0.002		1.45 (1.25–1.68)	<0.001
Lobular	1	147	3	Reference	0.008	7	Reference	0.921	4	Reference	0.006
	2	147	4	1.41 (0.28–7.16)		5	0.89 (0.24–3.27)		2	0.61 (0.10–3.85)
	3	147	5	2.04 (0.43–9.67)		8	1.20 (0.32–4.44)		9	3.67 (0.89–15.20)
	4	147	14	4.91 (1.24–19.56)		6	0.99 (0.21–4.76)		11	5.08 (1.13–22.80)
	Continuous	588	26	1.49 (1.12–1.98)^◊	0.006		0.98 (0.88–1.09)^◊	0.657		1.43 (1.01–2.04)^◊	0.044
Histology p-heterogeneity*			0.279 | 0.362			0.590 | 0.984			0.403 | 0.493
Tumor size (missing for 19 invasive cases)
<1.1 cm	1	147	23	Reference	0.094	22	Reference	0.336	25	Reference	0.179
	2	147	20	0.91 (0.45–1.83)		20	1.05 (0.50–2.21)		18	0.73 (0.36–1.52)
	3	147	20	0.93 (0.46–1.89)		29	1.49 (0.68–3.29)		31	1.58 (0.81–3.11)
	4	147	37	1.65 (0.87–3.12)		29	1.38 (0.57–3.37)		26	1.38 (0.66–2.92)
	Continuous	588	100	1.27 (1.05–1.52)^◊	0.011		1.00 (0.95–1.06)^◊	0.870		1.16 (0.92–1.45)^◊	0.213
1.1–2.0 cm	1	147	22	Reference	<0.001	41	Reference	0.139	20	Reference	<0.001
	2	147	26	1.39 (0.71–2.69)		27	0.60 (0.33–1.10)		22	1.77 (0.86–3.63)
	3	147	33	1.95 (1.02–3.72)		42	0.93 (0.50–1.72)		47	4.30 (2.20–8.40)
	4	147	64	3.46 (1.92–6.22)		35	0.46 (0.22–0.97)		56	6.95 (3.40–14.21)
	Continuous	588	145	1.50 (1.29–1.73)^◊	<0.001		0.92 (0.88–0.97)^◊	0.002		1.56 (1.29–1.87)^◊	<0.001
>2.0 cm	1	147	17	Reference	<0.001	26	Reference	0.247	16	Reference	<0.001
	2	147	20	1.61 (0.76–3.44)		26	0.90 (0.47–1.76)		20	2.36 (1.06–5.27)
	3	147	21	1.85 (0.86–3.97)		22	0.72 (0.34–1.55)		32	5.28 (2.38–11.71)
	4	147	48	4.22 (2.11–8.41)		32	0.61 (0.26–1.43)		38	7.58 (3.30–17.42)
	Continuous	588	106	1.51 (1.29–1.77)^◊	<0.001		0.95 (0.90–1.00)^◊	0.071		1.53 (1.25–1.88)^◊	<0.001
Tumor size p-heterogeneity*			0.638 | 0.353			0.379 | 0. 306			0.044 | 0.163
Breast cancer stage (missing for 17 cases)
Stage 0	1	147	23	Reference	0.075	46	Reference	0.022	15	Reference	0.001
	2	147	21	1.02 (0.50–2.07)		26	0.75 (0.40–1.39)		15	1.16 (0.51–2.62)
	3	147	26	1.12 (0.56–2.25)		16	0.39 (0.18–0.84)		34	2.81 (1.33–5.97)
	4	147	37	1.75 (0.92–3.36)		19	0.41 (0.17–0.98)		43	3.31 (1.51–7.29)
	Continuous	588	107	1.26 (1.05–1.49)^◊	0.010		0.91 (0.85–0.97)^◊	0.003		1.31 (1.07–1.61)^◊	0.010
Stage I	1	147	38	Reference	0.001	47	Reference	0.737	37	Reference	<0.001
	2	147	35	0.96 (0.55–1.68)		36	0.74 (0.42–1.29)		30	0.97 (0.54–1.76)
	3	147	40	1.23 (0.71–2.14)		54	1.02 (0.57–1.83)		64	2.67 (1.55–4.59)
	4	147	76	2.15 (1.30–3.54)		52	0.76 (0.39–1.49)		58	2.74 (1.52–4.94)
	Continuous	588	189	1.34 (1.17–1.53)^◊	<0.001		0.96 (0.92–1.00)^◊	0.081		1.33 (1.12–1.58)^◊	0.001
Stage II	1	147	19	Reference	<0.001	29	Reference	0.285	19	Reference	<0.001
	2	147	23	1.55 (0.76–3.16)		31	1.09 (0.57–2.05)		24	2.01 (0.97–4.17)
	3	147	22	1.55 (0.74–3.21)		22	0.78 (0.37–1.68)		29	3.25 (1.54–6.86)
	4	147	52	3.80 (1.98–7.29)		34	0.66 (0.28–1.51)		44	5.99 (2.79–12.83)
	Continuous	588	116	1.52 (1.30–1.78)^◊	<0.001		0.95 (0.90–1.00)^◊	0.075		1.54 (1.26–1.88)^◊	<0.001
Stage III and IV	1	147	5	Reference	<0.001	14	Reference	0.298	5	Reference	<0.001
	2	147	9	2.17 (0.64–7.30)		7	0.42 (0.15–1.23)		7	2.96 (0.79–11.03)
	3	147	12	3.74 (1.14–12.19)		17	1.01 (0.39–2.65)		17	8.69 (2.53–29.76)
	4	147	22	5.14 (1.72–15.33)		10	0.36 (0.10–1.27)		19	12.64 (3.42–46.64)
	Continuous	588	48	1.55 (1.25–1.92)^◊	<0.001		0.93 (0.85–1.01)^◊	0.082		1.56 (1.17–2.07)^◊	0.002
Breast cancer stage p-heterogeneity*			0.349 | 0.488			0.338 | 0.451			0.516 | 0.390
ER status (missing for 17 invasive cases)
Negative	1	147	11	Reference	0.004	15	Reference	0.634	13	Reference	0.005
	2	147	15	1.60 (0.67–3.82)		12	0.97 (0.29–2.38)		9	0.97 (0.37–2.54)
	3	147	11	1.32 (0.52–3.35)		20	1.45 (0.59–3.59)		23	2.99 (1.27–7.03)
	4	147	29	3.15 (1.41–7.02)		19	1.11 (0.38–3.22)		21	2.92 (1.15–7.40)
	Continuous	588	66	1.44 (1.19–1.73)^◊	<0.001		0.97 (0.90–1.04)^◊	0.354		1.40 (1.10–1.80)^◊	0.007
Positive	1	147	51	Reference	<0.001	75	Reference	0.184	48	Reference	<0.001
	2	147	52	1.13 (0.69–1.84)		62	0.77 (0.49–1.23)		52	1.43 (0.86–2.38)
	3	147	63	1.50 (0.93–2.43)		73	0.92 (0.55–1.51)		87	3.10 (1.89–5.08)
	4	147	121	2.74 (1.76–4.28)		77	0.60 (0.34–1.07)		100	4.23 (2.52–7.10)
	Continuous	588	287	1.43 (1.27–1.61)^◊	<0.001		0.95 (0.92–0.99)^◊	0.009		1.44 (1.24–1.68)^◊	<0.001
ER status p-heterogeneity*			0.639 | 0.835			0.224 | 0.707			0.281 | 0.631
PR status (missing for 17 invasive cases)
Negative	1	147	20	Reference	<0.001	46	Reference	0.098	18	Reference	<0.001
	2	147	23	1.14 (0.57–2.28)		28	0.62 (0.34–1.12)		20	1.74 (0.82–3.70)
	3	147	34	1.89 (0.98–3.65)		35	0.75 (0.40–1.42)		46	4.75 (2.35–9.60)
	4	147	64	3.34 (1.82–6.11)		32	0.45 (0.20–0.99)		57	6.58 (3.15–13.77)
	Continuous	588	141	1.51 (1.31–1.75)^◊	<0.001		0.92 (0.87–0.97)^◊	0.002		1.59 (1.32–1.91)^◊	<0.001
Positive	1	147	42	Reference	<0.001	44	Reference	0.938	43	Reference	<0.001
	2	147	44	1.29 (0.76–2.19)		46	0.99 (0.58–1.70)		41	1.31 (0.76–2.25)
	3	147	40	1.32 (0.76–2.27)		58	1.23 (0.69–2.17)		64	2.59 (1.52–4.41)
	4	147	86	2.64 (1.61–4.30)		64	0.89 (0.47–1.69)		64	3.26 (1.86–5.73)
	Continuous	588	212	1.39 (1.21–1.58)^◊	<0.001		0.97 (0.94–1.01)^◊	0.175		1.33 (1.13–1.58)^◊	0.001
PR status p-heterogeneity*			0.215 | 0.051			0.190 | 0.113			0.071 | 0.016
HER2 status (missing for 17 invasive cases)
Negative	1	147	43	Reference	<0.001	67	Reference	0.135	43	Reference	<0.001
	2	147	49	1.29 (0.78–2.17)		61	0.82 (0.51–1.32)		43	1.46 (0.85–2.50)
	3	147	59	1.71 (1.03–2.85)		61	0.78 (0.46–1.33)		90	3.83 (2.29–6.39)
	4	147	114	3.21 (2.01–5.14)		76	0.61 (0.33–1.10)		89	4.88 (2.82–8.44)
	Continuous	588	265	1.47 (1.30–1.66)^◊	<0.001		0.95 (0.92–0.99)^◊	0.013		1.49 (1.28–1.74)^◊	0.001
Positive	1	147	19	Reference	0.018	23	Reference	0.645	18	Reference	0.009
	2	147	18	0.99 (0.47–2.07)		13	0.66 (0.30–1.44)		18	1.21 (0.58–2.56)
	3	147	15	0.91 (0.42–1.98)		32	1.60 (0.76–3.35)		20	1.63 (0.75–3.50)
	4	147	36	2.02 (1.05–3.90)		20	0.83 (0.33–2.12)		32	2.63 (1.22–5.65)
	Continuous	588	88	1.31 (1.10–1.57)^◊	0.002		0.96 (0.90–1.02)^◊	0.174		1.30 (1.05–1.62)^◊	0.015
HER2 status p-heterogeneity*			0.175 | 0.242			0.332 | 0.891			0.112 | 0.443
Phenotype group (ER|PR+vs ER&PR-) (missing for 17 invasive cases)
ER&PR -	1	147	11	Reference	0.004	15	Reference	0.881	13	Reference	0.002
	2	147	13	1.37 (0.55–3.56)		12	0.92 (0.37–2.25)		7	0.73 (0.26–2.05)
	3	147	11	1.31 (0.51–3.55)		17	1.12 (0.44–2.85)		22	2.95 (1.24–7.02)
	4	147	28	3.07 (1.36–7.60)		19	0.99 (0.34–2.89)		21	3.09 (1.21–7.91)
	Continuous	588	63	1.45 (1.20–1.76)^◊	<0.001		0.96 (0.89–1.03)^◊	0.247		1.46 (1.13–1.88)^◊	0.003
ER|PR +	1	147	51	Reference	<0.001	75	Reference	0.221	48	Reference	<0.001
	2	147	54	1.18 (0.72–1.92)		62	0.78 (0.49–1.23)		54	1.51 (0.91–2.49)
	3	147	63	1.51 (0.93–2.45)		76	0.96 (0.58–1.59)		88	3.11 (1.90–5.09)
	4	147	122	2.77 (1.77–4.32)		77	0.61 (0.34–1.09)		100	4.20 (2.50–7.03)
	Continuous	588	290	1.42 (1.26–1.61)^◊	<0.001		0.95 (0.92–0.99)^◊	0.011		1.43 (1.23–1.67)^◊	<0.001
Phenotype group p-heterogeneity*			0.680 | 0.999			0.371 | 0.959			0.420 | 0.932

Notes:^‡All models adjusted for BMI, age, BMI by age interaction, education, ethnicity, age at menarche, parity, age at first full-term pregnancy, lifetime breastfeeding, lifetime use of oral contraceptives, family history of breast cancer, lifetime use of hormone replacement therapy, lifetime smoking, and alcohol consumption. ^aAdjusted for ^‡ +dense area. ^bAdjusted for ^‡ +non-dense area.

*Categorical | Continuous. ^◊ Estimate per 10-unit change in mammographic density parameter (continuous).  Bold values in this table correspond to statistically significant p-values (<0.05).

Abbreviations: aOR, adjusted odds ratio; ER, estrogen receptor; PR, progesterone receptor; HER2, human epidermal factor receptor 2.

Velásquez GarcíaHA, SobolevBG, GotayCC, et al. Mammographic non-dense area and breast cancer risk in postmenopausal women: a causal inference approach in a case–control study. Breast Cancer Res Treat. 2018;170:159–168. doi:10.1007/s10549-018-4737-729516373

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Data availability

The analyzed datasets are available from the corresponding author on reasonable request.