The relation between multiple births and maternal risk of breast cancer.

Introduction: Hormonal exposure during pregnancy is believed to be associated with subsequent maternal risk of breast cancer, but so far limited epidemiological data are available. Study design: A case-control study (223 cases and 417 controls) was nested within the Northern Sweden Maternity Cohort to explore the associations between pregnancy concentrations of sex steroid hormones and insulin-like growth factor I (IGF-I) with maternal risk of breast cancer by hormone receptor (HR) expression of the tumors. The study included women who had donated a blood sample during the first trimester of their first full-term pregnancy. Most cases had HR-positive disease: 171 (77%) estrogen receptor-positive (ER+), 157 (70%) progesterone receptor-positive (PR+) and 152 (68%) ER+/PR+ tumors. Estradiol, estrone, progesterone and testosterone were measured by high-performance liquid chromatography tandem mass spectrometry. Sex hormone-binding globulin (SHBG) and insulin-like growth factor I (IGF-I) were measured by immunoassays. For each hormone, the difference (residual) between the actual assay value for each subject and the estimated mean determined for the day of gestation when the sample was drawn was computed by local linear regression. Conditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI). Results: For HR-positive tumors, a significant direct association was observed with circulating concentrations of testosterone (e.g. OR for ER+ in the top versus bottom tertile of 1.8 (1.1-3.0), p<0.02) and IGF-I (e.g. OR for ER+ in the top versus bottom tertile of 2.0 (1.2-3.3), p<0.01). For HR-negative disease, risk estimates for a doubling of estrogens, progesterone and SHBG concentrations were above unity, but did not reach statistical significance with the exception of progesterone for PR-negative tumors (OR 2.0 (1.0-3.9), p<0.04). In analyses limited to ER-negative tumors diagnosed up to age 50 (n=38), these associations were stronger, but only of borderline significance. For PR-negative tumors diagnosed up to age 50 (n=49), the associations were significant for estradiol (OR 1.8 (1.0-3.1), p<0.04), progesterone (OR 2.6 (1.1-6.1), p<0.03) and SHBG (OR 1.8 (1.0-3.0), p<0.04). Adjustments for maternal height, weight, smoking, hypertension during pregnancy, child's sex, weight and length had negligible effect on risk estimates. Associations were similar by combined ER/PR tumor status or when limited to cases diagnosed ≥10 years after blood donation. Conclusions: In this nested case-control study hormone concentrations during early pregnancy were associated with risk of maternal breast cancer but the associations differed by hormone receptor expression of the tumors. For hormones with placental contribution to circulating concentrations (estrogens and progesterone), there were indications for positive associations with risk of maternal HR-negative breast cancer. For hormones, with similar concentrations during early pregnancy and in the non-pregnant state (testosterone and IGF-I), direct associations with HR-positive breast cancer were observed, in line with most available epidemiological data in non-pregnant women. Larger studies are necessary to characterize the association of pregnancy hormones with risk of hormone-defined maternal breast cancer. Citation Format: Annekatrin Lukanova, Egle Tolockiene, Helena Schock, Kjell Grankvist, Hans Ake Lakso, Helja Marja Surcel, Goran Wadell, Anne Zelenuich-Jacquotte, Paolo Toniolo, Eva Lundin. Pregnancy hormones and maternal risk of hormone receptor-defined breast cancer. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr B75.

Pregnancy reduces maternal risk of breast cancer in the long term, but the biological determinants of the protection are unknown. Animal experiments suggest that estrogens and progesterone could be involved, but direct human evidence is scant. A case-control study (536 cases and 1,049 controls) was nested within the Finnish Maternity Cohort. Eligible were primiparous women who delivered at term a singleton offspring before age 40. For each case, two individually matched controls by age (± 6 months) and date of sampling (± 3 months) were selected. Estradiol, estrone and progesterone in first-trimester serum were measured by high-performance liquid chromatography tandem mass spectrometry and sex-hormone binding globulin (SHBG) by immunoassay. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. In the whole study population there was no association of breast cancer with any of the studied hormones. In analyses stratified by age at diagnosis, however, estradiol concentrations were positively associated with risk of breast cancer before age 40 (upper quartile OR, 1.81; CI, 1.08-3.06), but inversely associated with risk in women who were diagnosed ≥ age 40 (upper quartile OR, 0.64; CI, 0.40-1.04), p(interaction) 0.004. Risk estimates for estrone mirrored those for estradiol but were less pronounced. Progesterone was not associated with risk of subsequent breast cancer. Our results provide initial evidence that concentrations of estrogens during the early parts of a primiparous pregnancy are associated with maternal risk of breast cancer and suggest that the effect may differ for tumors diagnosed before and after age 40.

Data from a case-control study conducted in New York State during 1982-1984 were used to evaluate the relation between alcohol consumption and estrogen receptor-positive and estrogen receptor-negative breast cancers and alcohol and various histologic subtypes. The cases were women between 20 and 79 years of age with a diagnosis of primary breast cancer. A total of 794 estrogen receptor-positive and 358 estrogen receptor-negative breast cancer cases were available for study. Controls (n = 1,617) were selected from driver's license files of the New York State Department of Motor Vehicles. Information on estrogen receptor status and histology was obtained from hospital records. The risk of estrogen receptor-positive breast cancer was shown to increase with increasing amounts of alcohol consumption in grams per day (odds ratio (OR) = 1.18 (95% confidence interval (CI) 0.88-1.57) for < 1.5 g/day, 1.28 (95% CI 0.91-1.80) for 1.5-4.9 g/day, 1.28 (95% CI 0.96-1.70) for 5.0-14.9 g/day, and 1.35 (95% CI 0.99-1.85) for > or = 15.0 g/day). There was no relation between alcohol consumption and estrogen receptor-negative tumors (OR = 0.92 (95% CI 0.62-1.36) for < 1.5 g/day, 1.19 (95% CI 0.77-1.83) for 1.5-4.9 g/day, 0.94 (95% CI 0.64-1.35) for 5.0-14.9 g/day, and 1.05 (95% CI 0.70-1.59) for > or = 15.0 g/day). The risk for each of the histologic subtypes studied increased with increasing daily alcohol consumption. These findings suggest that alcohol may only increase a woman's risk of estrogen receptor-positive breast cancers.

The association between multiple births and subsequent maternal breast cancer risk was explored in a nested case-control study in Sweden encompassing 19,368 parous women with breast cancer diagnosed up to age 65 years, and 100,459 parous controls. Among cases and controls, there were 329 and 2,031 women, respectively, with a history of at least one live multiple birth. Compared with singleton mothers, breast cancer risk was 12 percent lower (odds ratio = 0.88, 95 percent confidence interval = 0.78-0.99) in women who had had a multiple birth. After stratification for age at diagnosis, evidence of a significant inverse association was found only in women aged 54 years or younger. Birth order of the multiple pregnancy had no apparent risk-modifying effect. Age at earliest multiple birth was unrelated to breast cancer risk. The inverse association between twinning and breast cancer risk may reflect protective physiological features of twin pregnancies. Further research is needed to investigate the role, if any, of increased levels of steroid hormone-binding globulins in mothers of twins and the proposed inhibitory effects of human chorionic gonadotropin and alpha-fetoprotein, both of which are increased during multiple gestations, on breast carcinogenesis. Breast feeding patterns in mothers of twins also may modify their risk of developing breast cancer.

Could Modification of Lifestyle Factors Prevent Second Primary Breast Cancers?

Maternal Risk of Breast Cancer and Birth Characteristics of Offspring by Time Since Birth

Although many studies have shown that higher weight increases the risk of postmenopausal breast cancer, some aspects of this association are unclear. In order to examine the risk associated with different patterns of weight change, we analyzed data from a large case-control study of postmenopausal breast cancer. Participants included women aged 50 79 years (n = 5031) who are newly diagnosed with invasive breast cancer in Massachusetts, New Hampshire, and Wisconsin. Similarly-aged population controls (n = 5255) were selected at random from driver's license files and Medicare beneficiary lists. Height, weight, and information on other breast cancer risk factors were ascertained by structured telephone interviews from 1992 to 1995, and logistic regression was used to estimate multivariable-adjusted odds ratios (OR) and 95% confidence intervals (CI). Women in the top quintile groups for height at age 20, recent weight, and recent body mass index had significantly increased risks of breast cancer. Among women who reached their highest adult weight at younger ages (<45 years), increasing weight loss since that age was associated with a reduced risk of postmenopausal breast cancer (OR 0.90, CI 0.84 0.98, per 5 kg). However, weight loss among women whose highest weight occurred after age 45 was not associated with risk (OR 1.00, CI 0.95 1.05, per 5 kg). Weight gain since the lowest adult weight increased risk by 8% for each 5 kg of gain (OR 1.08, CI 1.06-1. 11). Temporary weight cycling (weight loss followed by weight gain) was not associated with increased risk. Weight gain clearly increased risk of postmenopausal breast cancer. These data lend further support to efforts aimed at helping women avoid weight gain as they age.

Women who were younger at their first live birth have a reduced breast cancer risk. Other pregnancy characteristics, including complications, also may affect risk but because they are rare, require large datasets to study. The association of pregnancy history and breast cancer risk was assessed in a population-based study including 22,646 cases diagnosed in Washington State 1974 to 2009, and 224,721 controls, frequency matched on parity, age, calendar year of delivery, and race/ethnicity. Information on prediagnosis pregnancies derived from linked birth certificate and hospital discharge databases. Adjusted odd ratios (ORs) and 95% confidence intervals (CI) were calculated. Multiple gestation pregnancies were associated with decreased breast cancer risk (OR, 0.65; 95% CI, 0.57-0.74) as was prepregnancy obesity (OR, 0.76; 95% CI, 0.65-0.90). Infant birth weight was positively associated (6% per 1,000 g; 95% CI, 3%-9%). The ORs for first trimester bleeding (OR, 3.35; 95% CI, 1.48-7.55) and placental abnormality/insufficiency (OR, 2.24; 95% CI, 1.08-4.67) were increased in women diagnosed at age 50+ years and 15+ years after the index pregnancy. Results were similar in analyses restricted to first pregnancies, those closest to diagnosis, and when excluding in situ disease. These data suggest that multiple gestation pregnancies are protective, whereas delivering larger infants increases risk for later development of maternal breast cancer. Placental abnormalities that result in bleeding in pregnancy also may reverse the long-term protection in postmenopausal women associated with parity. Certain pregnancy characteristics seem to be associated with later maternal breast cancer risk.

Discrete windows of susceptibility to toxicants have been identified for the breast, including in utero, puberty, pregnancy, and postpartum. We tested the hypothesis that polychlorinated biphenyls (PCBs) measured during the early postpartum predict increased risk of maternal breast cancer diagnosed before age 50. We analyzed archived early postpartum serum samples collected from 1959 to 1967, an average of 17 years before diagnosis (mean diagnosis age 43 years) for 16 PCB congeners in a nested case–control study in the Child Health and Development Studies cohort (N = 112 cases matched to controls on birth year). We used conditional logistic regression to adjust for lipids, race, year, lactation, and body mass. We observed strong breast cancer associations with three congeners. PCB 167 was associated with a lower risk (odds ratio (OR), 75th vs. 25th percentile = 0.2, 95 % confidence interval (95 % CI) 0.1, 0.8) as was PCB 187 (OR, 75th vs. 25th percentile = 0.4, 95 % CI 0.1, 1.1). In contrast, PCB 203 was associated with a sixfold increased risk (OR, 75th vs. 25th percentile = 6.3, 95 % CI 1.9, 21.7). The net association of PCB exposure, estimated by a post-hoc score, was nearly a threefold increase in risk (OR, 75th vs. 25th percentile = 2.8, 95 % CI 1.1, 7.1) among women with a higher proportion of PCB 203 in relation to the sum of PCBs 167 and 187. Postpartum PCB exposure likely also represents pregnancy exposure, and may predict increased risk for early breast cancer depending on the mixture that represents internal dose. It remains unclear whether individual differences in exposure, response to exposure, or both explain risk patterns observed.

Discrete windows of susceptibility to toxicants have been identified for the breast, including in utero, puberty, pregnancy, and postpartum. We tested the hypothesis that polychlorinated biphenyls (PCBs) measured during the early postpartum predict increased risk of maternal breast cancer diagnosed before age 50. We analyzed archived early postpartum serum samples collected from 1959 to 1967, an average of 17 years before diagnosis (mean diagnosis age 43 years) for 16 PCB congeners in a nested case–control study in the Child Health and Development Studies cohort (N = 112 cases matched to controls on birth year). We used conditional logistic regression to adjust for lipids, race, year, lactation, and body mass. We observed strong breast cancer associations with three congeners. PCB 167 was associated with a lower risk (odds ratio (OR), 75th vs. 25th percentile = 0.2, 95 % confidence interval (95 % CI) 0.1, 0.8) as was PCB 187 (OR, 75th vs. 25th percentile = 0.4, 95 % CI 0.1, 1.1). In contrast, PCB 203 was associated with a sixfold increased risk (OR, 75th vs. 25th percentile = 6.3, 95 % CI 1.9, 21.7). The net association of PCB exposure, estimated by a post-hoc score, was nearly a threefold increase in risk (OR, 75th vs. 25th percentile = 2.8, 95 % CI 1.1, 7.1) among women with a higher proportion of PCB 203 in relation to the sum of PCBs 167 and 187. Postpartum PCB exposure likely also represents pregnancy exposure, and may predict increased risk for early breast cancer depending on the mixture that represents internal dose. It remains unclear whether individual differences in exposure, response to exposure, or both explain risk patterns observed.

The relation between body size and breast cancer remains uncertain, particularly with regard to differences between pre- and postmenopausal women. The authors examined whether height, weight, body mass index, and weight change were associated with breast cancer risk among pre- and postmenopausal women. This population-based case-control study included women aged 20-74 years (n = 6,548) who were diagnosed with invasive breast cancer during 1988-1991 in Maine, Massachusetts, New Hampshire, and Wisconsin. Similarly aged control women (n = 9,057) were selected at random from driver's license files and Health Care Financing Administration files. Height, weight, and information on other breast cancer risk factors were ascertained by telephone interview, and logistic regression was used to estimate multivariate-adjusted odds ratios and 95% confidence intervals. Among premenopausal women, the adjusted odds ratio for the upper quintile group of height relative to the lowest was 1.36 (95% confidence interval (CI) 1.05-1.76). The heaviest premenopausal women had a lower risk (odds ratio (OR) = 0.87, 95% CI 0.70-1.10). Among postmenopausal women, the adjusted odds ratios were higher for the upper quintile categories of both height (OR = 1.27, 95% CI 1.11-1.45) and weight (OR = 1.57, 95% CI 1.37-1.79). Weight gain since ages 18 and 35 years was associated with increased postmenopausal breast cancer risk, and risk was lower in women who had lost weight. These findings suggest that programs to avoid weight gain merit study as a means to reduce risk of postmenopausal breast cancer.

The protective effect of full-term pregnancy against breast cancer is thought to be induced by two placental hormones: human chorionic gonadotropin and human chorionic somatotropin hormone (CSH) produced by the placental trophoblastic cells. We hypothesized that variants in placental genes encoding these hormones may alter maternal breast cancer risk subsequent to pregnancy. We conducted a case-control study to examine the association between polymorphisms in a woman's placental (i.e., her offspring's) homologous chorionic gonadotrophin beta5 (CGB5) and CSH1 genes and her post-pregnancy breast cancer risk. A total of 293 breast cancer cases and 240 controls with at least one offspring with available DNA were selected from the New York site of the Breast Cancer Family Registry. Three single nucleotide polymorphisms (SNP) in CGB5 and CSH1 genes were genotyped for 844 offspring of the cases and controls. Overall, maternal breast cancer risk did not significantly differ by the offspring's carrier status of the three SNPs. Among women with an earlier age at childbirth (younger than the median age of 26 years), those with a child carrying the variant C allele of CGB5 rs726002 SNP had an elevated breast cancer risk [odds ratio (OR), 2.09; 95% confidence interval (95% CI), 1.17-3.73]. Among women with a later age at childbirth, breast cancer risk did not differ by offspring's carrier status of CGB5 rs726002 SNP (OR, 0.90; 95% CI, 0.53-1.51; P for interaction=0.04). The findings suggest that placental CGB5 genotype may be predictive of maternal post-pregnancy breast cancer risk among women who give birth early in life.

There is growing evidence that perinatal factors associated with altered gestational hormones may influence subsequent breast cancer risk in the mother. Events occurring during the first pregnancy may be particularly important. In this matched case-control study, we investigated the relation between characteristics of a woman's first pregnancy and her later breast cancer risk using linked records from the New York State birth and tumor registries. Cases were 2,522 women aged 22 to 55 diagnosed with breast cancer between 1978 and 1995 and who had also completed a first pregnancy in New York State (NY) at least 1 year prior to diagnosis. Controls were 10,052 primiparous women not diagnosed with breast or endometrial cancer in NY and matched to cases on county of residence and date of delivery. Information on factors characterizing the woman's first pregnancy was obtained from the pregnancy record of each subject. The association of these factors to breast cancer risk was assessed using conditional logistic regression. Extreme prematurity (< 32 weeks gestational age) was associated with elevated maternal breast cancer risk [adjusted odds ratio (OR)=2.1, 95% confidence interval (CI) 1.2,3.9], as were abruptio placentae (OR = 1.8, CI 1.1,3.0) and multifetal gestation (OR=1.8, CI 1.1,3.0). Preeclampsia was associated with a marked reduction in breast cancer risk among women who bore their first child after age 30 (OR=0.3, CI 0.2,0.7) and in the first 3 years after delivery (OR=0.2 (0.1-0.9). These findings suggest that certain perinatal factors influence maternal breast cancer risk and offer indirect support for a role of gestational hormones, and particularly gestational estrogens, in the etiology of breast cancer.

Hormone Levels in Pregnancy and Subsequent Risk of Maternal Breast and Ovarian Cancer: A Systematic Review.

1394P - The Relationship Between Preeclampsia, Pregnancy-Induced Hypertension and Maternal Risk of Breast Cancer: a Meta-Analysis