Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC).
BACKGROUND
Contrasting etiologic hypotheses about the role of endogenous sex steroids in breast cancer development among premenopausal women implicate ovarian androgen excess and progesterone deficiency, estrogen excess, estrogen and progesterone excess, and both an excess or lack of adrenal androgens (dehydroepiandrosterone [DHEA] or its sulfate [DHEAS]) as risk factors. We conducted a case-control study nested within the European Prospective Investigation into Cancer and Nutrition cohort to examine associations among premenopausal serum concentrations of sex steroids and subsequent breast cancer risk.


METHODS
Levels of DHEAS, (Delta4-)androstenedione, testosterone, and sex hormone binding globulin (SHBG) were measured in single prediagnostic serum samples from 370 premenopausal women who subsequently developed breast cancer (case patients) and from 726 matched cancer-free control subjects. Levels of progesterone, estrone, and estradiol were also measured for the 285 case patients and 555 matched control subjects who had provided information about the day of menstrual cycle at blood donation. Conditional logistic regression models were used to estimate relative risks of breast cancer by quartiles of hormone concentrations. All statistical tests were two-sided.


RESULTS
Increased risks of breast cancer were associated with elevated serum concentrations of testosterone (odds ratio [OR] for highest versus lowest quartile = 1.73, 95% confidence interval [CI] = 1.16 to 2.57; P(trend) = .01), androstenedione (OR for highest versus lowest quartile = 1.56, 95% CI = 1.05 to 2.32; P(trend) = .01), and DHEAS (OR for highest versus lowest quartile = 1.48, 95% CI = 1.02 to 2.14; P(trend) = .10) but not SHBG. Elevated serum progesterone concentrations were associated with a statistically significant reduction in breast cancer risk (OR for highest versus lowest quartile = 0.61, 95% CI = 0.38 to 0.98; P(trend) = .06). The absolute risk of breast cancer for women younger than 40 followed up for 10 years was estimated at 2.6% for those in the highest quartile of serum testosterone versus 1.5% for those in the lowest quartile; for the highest and lowest quartiles of progesterone, these estimates were 1.7% and 2.6%, respectively. Breast cancer risk was not statistically significantly associated with serum levels of the other hormones.


CONCLUSIONS
Our results support the hypothesis that elevated blood concentrations of androgens are associated with an increased risk of breast cancer in premenopausal women.
Kaaks
Rudolf
R
Nutrition and Hormones Group, International Agency for Research on Cancer (IARC-WHO), Lyon, France. kaaks@iarc.fr
Berrino
Franco
F
Key
Timothy
T
Rinaldi
Sabina
S
Dossus
Laure
L
Biessy
Carine
C
Secreto
Giorgio
G
Amiano
Pilar
P
Bingham
Sheila
S
Boeing
Heiner
H
Bueno de Mesquita
H Bas
HB
Chang-Claude
Jenny
J
Clavel-Chapelon
Françoise
F
Fournier
Agnès
A
van Gils
Carla H
CH
Gonzalez
Carlos A
CA
Gurrea
Aurelio Barricarte
AB
Critselis
Elena
E
Khaw
Kay Tee
KT
Krogh
Vittorio
V
Lahmann
Petra H
PH
Nagel
Gabriele
G
Olsen
Anja
A
Onland-Moret
N Charlotte
NC
Overvad
Kim
K
Palli
Domenico
D
Panico
Salvatore
S
Peeters
Petra
P
Quirós
J Ramón
JR
Roddam
Andrew
A
Thiebaut
Anne
A
Tjønneland
Anne
A
Chirlaque
Ma Dolores
MD
Trichopoulou
Antonia
A
Trichopoulos
Dimitrios
D
Tumino
Rosario
R
Vineis
Paolo
P
Norat
Teresa
T
Ferrari
Pietro
P
Slimani
Nadia
N
Riboli
Elio
E
D000328:Adult; D001943:Breast Neoplasms / Q000097:blood* / Q000453:epidemiology* / Q000209:etiology; D016022:Case-Control Studies; D016001:Confidence Intervals; D015986:Confounding Factors, Epidemiologic; D003687:Dehydroepiandrosterone / Q000097:blood; D019314:Dehydroepiandrosterone Sulfate / Q000097:blood; D005060:Europe / Q000453:epidemiology; D005260:Female; D012739:Gonadal Steroid Hormones / Q000097:blood*; D006801:Humans; D016015:Logistic Models; D008597:Menstrual Cycle; D008875:Middle Aged; D016017:Odds Ratio; D017697:Premenopause; D011446:Prospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism; D013739:Testosterone / Q000097:blood
D012739:Gonadal Steroid Hormones; D012738:Sex Hormone-Binding Globulin; D013739:Testosterone; D003687:Dehydroepiandrosterone; D019314:Dehydroepiandrosterone Sulfate