Early-Life Exposures and Age at Thelarche in the Sister Study Cohort

Mandy Goldberg; Aimee A. D'Aloisio; Katie M. O'Brien; Shanshan Zhao; Dale P. Sandler

Breast Cancer Res. 2021;23(111)

Abstract and Introduction

Abstract

Background: Early age at breast development (thelarche) has been associated with increased breast cancer risk. Average age at thelarche has declined over time, but there are few established risk factors for early thelarche. We examined associations between pre- and postnatal exposures and age at thelarche in a US cohort of women born between 1928 and 1974.

Methods: Breast cancer-free women ages 35–74 years who had a sister diagnosed with breast cancer were enrolled in the Sister Study from 2003 to 2009 (N = 50,884). At enrollment, participants reported information on early-life exposures and age at thelarche, which we categorized as early (≤ 10 years), average (11–13 years), and late (≥ 14 years). For each exposure, we estimated odds ratios (ORs) and 95% confidence intervals (CIs) for early and late thelarche using polytomous logistic regression, adjusted for birth cohort, race/ethnicity and family income level in childhood.

Results: Early thelarche was associated with multiple prenatal exposures: gestational hypertensive disorder (OR = 1.25, 95% CI 1.09–1.43), diethylstilbestrol use (OR = 1.23, 95% CI 1.04–1.45), smoking during pregnancy (OR = 1.20, 95% CI 1.13–1.27), young maternal age (OR 1.30, 95% CI 1.16–1.47 for < 20 vs. 25–29 years), and being firstborn (OR = 1.25, 95% CI 1.17–1.33). Birthweight < 2500 g and soy formula use in infancy were positively associated with both early and late thelarche.

Conclusions: Associations between pre- and postnatal exposures and age at thelarche suggest that the early-life environment influences breast development and therefore may also affect breast cancer risk by altering the timing of pubertal breast development.

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Breast Cancer Res. 2021;23(111) © 2021 BioMed Central, Ltd.
Copyright to this article is held by the author(s), licensee BioMed Central Ltd. This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original citation.

Abstract and Introduction
Background
Methods
Results
Discussion
Conclusions
References

Table 1. Distribution of age at thelarche by participant characteristics among 49,162 eligible women in the Sister Study cohort
	Age at thelarche
	Early (≤ 10 years)		Average (11–13 years)		Late (≥ 14 years)
	n	%	n	%	n	%
Number of participants	6613	13	34,030	69	8519	17
Participant characteristics
Birth cohort
1928–1939	613	10	4220	72	1045	18
1940–1949	2116	13	11,403	71	2607	16
1950–1959	2469	14	12,619	69	3186	17
1960–1974	1415	16	5788	65	1681	19
Race/ethnicity
Non-Hispanic White	5275	13	29,141	70	7015	17
Non-Hispanic African-American/Black	754	18	2,517	61	835	20
Hispanic/Latina	422	18	1,525	65	399	17
Others^a	162	13	847	66	270	21
Family income level growing up
Well off	436	14	2,194	70	507	16
Middle income	3863	13	20,597	70	4899	17
Low income	1739	14	8,693	68	2331	18
Poor	575	15	2,546	65	782	20
Maternal vital status at baseline
Alive	3198	14	15,788	69	4040	18
Deceased	3408	13	18,196	70	4465	17
Missing	7		46		14
Maternal pregnancy characteristics
Diabetes
Any (pre-pregnancy or gestational)	77	17	307	67	74	16
None	5816	13	30,259	69	7519	17
Missing	720		3464		926
Gestational hypertensive disorder
Any (gestational hypertension or pre-eclampsia)	285	17	1144	67	280	16
None	4708	13	24,505	69	6086	17
Missing	1620		8381		2153
DES use
Yes	181	16	770	67	191	17
No	5399	13	28,273	70	6969	17
Missing	1033		4987		1359
Smoking during pregnancy
Yes	2201	15	10,131	68	2546	17
No	4086	13	22,236	70	5553	17
Missing	326		1663		420
Farm exposure
Work and residence	770	13	3977	69	983	17
Work only	88	14	409	65	130	21
Residence only	269	13	1458	71	313	15
None	5263	13	27,132	69	6774	17
Missing	223		1054		319
Age at delivery
< 20 years	403	17	1544	66	387	17
20–24 years	1626	14	7916	69	1970	17
25–29 years	1904	13	10,189	69	2586	18
30–34 years	1419	13	7873	70	1916	17
35–39 years	854	13	4464	70	1096	17
≥ 40 years	314	13	1672	69	444	18
Missing	93		372		120
Birth and infancy characteristics
Firstborn
Yes	1699	15	7931	70	1664	15
No	4877	13	25,915	69	6814	18
Missing	37		184		41
Birthweight
< 2500 g	532	14	2505	67	692	19
2500–3999 g	4028	14	20,577	70	4900	17
≥ 4000 g	452	14	2331	70	555	17
Missing	1601		8617		2372
Multiple birth
Yes	182	12	1062	69	297	19
No	6430	14	32,963	69	8,221	17
Missing	1		5		1
Gestational age at birth
Born ≥ 1 month before due date	126	13	672	68	192	19
Born 2–4 weeks before due date	279	15	1324	70	301	16
Not born ≥ 2 weeks before due date	2784	14	13,773	69	3383	17
Missing	3424		18,261		4643
Ever breastfed
Yes	2993	13	15,608	70	3768	17
No	3147	14	15,923	69	4046	18
Missing	473		2499		705
Ever fed soy formula
Yes	179	15	797	67	219	18
No	5261	13	27,471	69	6827	17
Missing	1173		5762		1473

Row percentages are displayed. Percentages may not add up to 100 due to rounding. Missing are not included in percentages
^aIncludes non-Hispanic Asian-Americans and Pacific Islanders (25%), non-Hispanic American Indians and Alaska natives (7%), and non-Hispanic race not specified (68%)

Table 2. Associations between early-life exposures and timing of thelarche in the Sister Study cohort ( N = 49,162)
	N	Early thelarche (≤ 10 years)^a,b		Late thelarche (≥ 14 years)^a,b
	N	OR	95% CI	OR	95% CI
Maternal pregnancy characteristics
Diabetes
Any	458	1.20	0.93, 1.54	0.91	0.70, 1.17
Gestational diabetes	215	0.79	0.52, 1.21	0.87	0.60, 1.25
Pre-pregnancy diabetes	223	1.72	1.24, 2.38	0.88	0.60, 1.29
None	43,594	1	Ref	1	Ref
Gestational hypertensive disorder
Any	1709	1.25	1.09, 1.43	0.96	0.84, 1.10
Pre-eclampsia	887	1.32	1.10, 1.58	0.99	0.83, 1.19
Gestational hypertension	626	1.12	0.90, 1.40	0.80	0.64, 1.01
None	35,299	1	Ref	1	Ref
DES use
Yes	1142	1.23	1.04, 1.45	1.02	0.86, 1.19
No	40,641	1	Ref	1	Ref
Smoking during pregnancy
Yes	14,878	1.20	1.13, 1.27	1.02	0.97, 1.08
No	31,875	1	Ref	1	Ref
Farm exposure
Work and residence	5730	1.00	0.92, 1.09	0.94	0.87, 1.02
Work only	627	1.06	0.84, 1.33	1.21	0.99, 1.48
Residence only	2040	0.98	0.86, 1.12	0.86	0.76, 0.98
None	39,169	1	Ref	1	Ref
Age at delivery
< 20 years	2334	1.30	1.16, 1.47	0.93	0.82, 1.05
20–24 years	11,512	1.09	1.01, 1.17	0.97	0.91, 1.03
25–29 years	14,679	1	Ref	1	Ref
30–34 years	11,208	0.95	0.88, 1.02	0.95	0.89, 1.01
35–39 years	6414	0.99	0.90, 1.08	0.94	0.87, 1.02
≥ 40 years	2430	0.95	0.83, 1.08	1.00	0.89, 1.12
Birth and infancy characteristics
Firstborn
Yes	11,294	1.25	1.17, 1.33	0.84	0.79, 0.89
No	37,606	1	Ref	1	Ref
Birthweight
< 2500 g	3729	1.06	0.96, 1.17	1.15	1.05, 1.25
2500–3999 g	29,505	1	Ref	1	Ref
≥ 4000 g	3,338	1.00	0.90, 1.11	0.99	0.90, 1.09
Multiple birth
Yes	1541	0.87	0.74, 1.02	1.11	0.98, 1.27
No	47,614	1	Ref	1	Ref
Gestational age at birth
Born ≥ 1 month before due date	990	0.91	0.75, 1.11	1.16	0.99, 1.37
Born 2–4 weeks before due date	1904	1.06	0.92, 1.21	0.93	0.81, 1.06
Not born ≥ 2 weeks before due date	19,940	1	Ref	1	Ref
Ever breastfed
Yes	22,369	0.98	0.93, 1.04	0.95	0.90, 1.00
No	23,116	1	Ref	1	Ref
Ever fed soy formula
Yes	1195	1.10	0.93, 1.30	1.07	0.92, 1.25
No	39,559	1	Ref	1	Ref