According to the International Agency for Research on Cancer (IARC), in-utero exposure to diethylstilbestrol, i.e., when a pregnant woman uses the drug, increases a female child’s risk of developing breast cancer.
The knowledge on the etiology of breast cancer has advanced substantially in recent years, and several etiological factors are now firmly established. However, very few new discoveries have been made in relation to occupational risk factors. The International Agency for Research on Cancer has evaluated over 900 different exposures or agents to-date to determine whether they are carcinogenic to humans. These evaluations are published as a series of Monographs.
For breast cancer the following substances have been classified as “carcinogenic to humans” (Group 1): alcoholic beverages, exposure to diethylstilbestrol, estrogen-progestogen contraceptives, estrogen-progestogen hormone replacement therapy and exposure to X-radiation and gamma-radiation (in special populations such as atomic bomb survivors, medical patients, and in-utero exposure). Ethylene oxide is also classified as a Group 1 carcinogen, although the evidence for carcinogenicity in epidemiologic studies, and specifically for the human breast, is limited.
The classification “probably carcinogenic to humans” (Group 2A) includes estrogen hormone replacement therapy, tobacco smoking, and shift work involving circadian disruption, including work as a flight attendant. If the association between shift work and breast cancer, the most common female cancer, is confirmed, shift work could become the leading cause of occupational cancer in women.
Full study (free access) : Risk Factors for Breast Cancer, Including Occupational Exposures, Saf Health Work, NCBI PubMed PMC3431884, 2011 Mar.
Systematic review and meta-analysis of current evidence, 2007
BACKGROUND Emerging evidence suggests an association between female prenatal experience and her subsequent risk of developing breast cancer. Potential underlying mechanisms include variation in amounts of maternal endogenous sex hormones and growth hormones, germ-cell mutations, formation of cancer stem-cells, and other genetic or epigenetic events. We reviewed and summarised quantitatively the available data on intrauterine exposures and risk of breast cancer.
METHODS We systematically searched for studies that assessed association between perinatal factors and risk of breast cancer. We reviewed separately each of the perinatal factors, including birthweight, birth length, parental age at delivery, gestational age, intrauterine exposure to diethylstilbestrol, twin membership, maternal pre-eclampsia or eclampsia, and other factors.
FINDINGS We identified 57 studies published between Oct 1, 1980, and June 21, 2007. Increased risk of breast cancer was noted with increased birthweight (relative risk [RR] 1.15 [95% CI 1.09-1.21]), birth length (1.28 [1.11-1.48]), higher maternal age (1.13 [1.02-1.25]), and paternal age (1.12 [1.05-1.19]). Decreased risk of breast cancer was noted for maternal pre-eclampsia and eclampsia (0.48 [0.30-0.78]) and twin membership (0.93 [0.87-1.00]). No association was noted between risk of breast cancer and gestational age at birth (0.95 [0.71-1.26]) or maternal diethylstilbestrol treatment (1.40 [0.86-2.28]).
INTERPRETATION The intrauterine environment contributes to the predisposition of women to breast cancer in adulthood. The in-utero mechanisms responsible for such predisposition need to be elucidated.
Intrauterine factors and risk of breast cancer: a systematic review and meta-analysis of current evidence, The Lancet Oncology, NCBI PubMed PMID: 18054879, 2007 Dec.
“Suggestions that risk of breast cancer in human beings might be affected by early-life exposures, or even intrauterine events and conditions, have been reported in published studies in the past four decades, …
… More direct evidence in support of a role of pregnancy oestrogens has been provided by the results from a unique cohort of womenin utero exposed to diethylstilbestrol, a synthetic oestrogen. These women were found to be at increased risk for breast cancer after the age of 40 years, when familial breast cancer becomes rare.”
Intrauterine exposures, pregnancy estrogens and breast cancer risk: where do we currently stand?
2006 Study Abstracts
Since 1990, when a hypothesis on intrauterine influences on breast cancer risk was published, several studies have provided supportive, indirect evidence by documenting associations of birth weight and other correlates of the prenatal environment with breast cancer risk in offspring. Recent results from a unique cohort of women with documented exposure to diethylstilbestrol in utero have provided direct evidence in support of a potential role of pregnancy oestrogens on breast cancer risk in offspring.
Since 1992, all US cohorts of DES-exposed persons for whom there was an appropriate comparison group of unexposed persons and for whom there was medical record documentation of exposure (or not) to this substance are being followed in a study supported by the US National Cancer Institute. Slightly more than 4800 women exposed in utero to DES and approximately 2070 unexposed women are included in this cohort. Results concerning breast cancer in offspring have been reported in three reports. The risk for developing breast cancer in the earliest report, when women exposed to DES in utero were still very young (38 years on the average), was barely 18% higher in exposed to nonexposed women. However, the increase became progressively greater with longer follow up.
In the most recent report, for breast cancer occurring at age 40 years or older the risk was significantly higher, by 91%, in women exposed to DES in utero than in those who were not exposed. For breast cancer at age 50 years or older the corresponding excess was 200%, which again was significant but with a wide confidence interval. The overall pattern does not come as a surprise because breast cancer among young women is known frequently to have genetic roots, so an excess risk on account of intrauterine exposure to oestrogens is likely to become more evident with advancing age.
Full paper (free access) : Intrauterine exposures, pregnancy estrogens and breast cancer risk: where do we currently stand?, Breast Cancer Research, NCBI PubMed PMC1797035, 2006.
In 1971, the US Food and Drug Administration contraindicated its use in pregnancy when DES was associated with the development of vaginal clear cell adenocarcinoma (CCA) in daughters exposed in utero.
In daughters whose mothers took DES during pregnancy, the drug has been associated with congenital malformations of the reproductive tract, fertility problems, a possible increased risk of cervical carcinoma in situ, and a presumed lifetime risk of vaginal and cervical CCA.
DES mothers have an increased risk of breast cancer (RR = 1.3).
DES sons have an increased prevalence of urogenital anomalies, and a possible increased risk of testicular cancer.
DES exposure and the aging woman: mothers and daughters, Current women’s health reports, NCBI PubMed PMID: 12215312, 2002 Oct.
Intrauterine DES exposure and subsequent risk of breast cancer
1998 Study Abstract
The results from previous studies have provided evidence to support the hypothesised association between intrauterine oestrogen exposure and subsequent risk of breast cancer. Information has not been available to study this relationship for several perinatal factors thought to be related to pregnancy oestrogen levels.
Data collected from the mothers of women in two population-based case-control studies of breast cancer in women under the age of 45 years (510 case mothers, 436 control mothers) who were diagnosed between 1983 and 1992 in three western Washington counties were used to investigate further the relationship between intrauterine oestrogen exposure and risk of breast cancer.
A pregnancy weight gain of 25-34 pounds was associated with breast cancer risk (odds ratio [OR] = 1.5; 95% confidence interval [CI] 1.1, 2.0); however, women whose mothers gained 35 pounds or more were not at increased risk. Use of antiemetic medication in women with any nausea and vomiting (OR = 2.9; 95% CI 1.1, 8.1) and use of diethylstilboestrol (DES) (OR = 2.3; 95% CI 0.8, 6.4) appeared to be positively associated with breast cancer risk.
The results from this study provide limited support for the hypothesis that in utero oestrogen exposure may be related to subsequent breast cancer risk among young women.
Maternal factors and breast cancer risk among young women, Paediatric and perinatal epidemiology, NCBI PubMed PMID: 9805713, 1998 Oct.
There is increasing interest in the role of early life exposures in breast carcinogenesis, especially estrogen exposure in utero
1997 Study Abstract
Estrogen levels during pregnancy may be higher in twin pregnancies and among older women and slightly lower among smokers.
We analyzed early life risk factors in a population-based case-control study in the United States of 2,202 breast cancer cases and 2,009 controls under age 55 years. Twins were at an increased risk of breast cancer compared with singletons (relative risk = 1.62; 95% confidence interval = 1.0-2.7), particularly women with a twin brother (relative risk = 2.06), a finding consistent with the observation of high estrogen levels in dizygotic twin pregnancies. Little association was seen between maternal age at birth and breast cancer risk.
We carried out further analyses for 534 cases and 497 controls under age 45 years, using data from a questionnaire completed by their mothers relating to the daughters’ early life exposures. There was no evidence of an effect of smoking or diethylstilbestrol exposure during pregnancy on daughters’ breast cancer risk. A reduced breast cancer risk was seen among women who had been breastfed (relative risk = 0.74; 95% confidence interval = 0.6-1.0).
These findings indicate some effect of early life exposures on breast cancer risk, although the role of estrogen exposure may be less central than previously suggested.
Prenatal and perinatal risk factors for breast cancer in young women, Epidemiology, NCBI PubMed PMID: 9229211, 1997 Mar.
The most common cancer in US women and the 2nd leading cause of cancer death is breast cancer.
Between 1980-1987 in the US. age-adjusted incidence rates of breast cancer rose rapidly. They are also rising rapidly in several Asian countries (e.g., in Japan) which have the lowest incidence rates. These rapid increases may mean that environmental factors are responsible.
Incidence rates rise greatly with age until the late 40s. US women at highest risk of breast cancer are Jewish women, urban women, single women, and women living in the northern US. Women at lowest risk include Mormon and Seventh-Day Adventist women, Hispanic and Asian women, rural women, women living in the southern US, and married women.
Factors that have a relative risk greater than 2 are
mother and sister with history of breast cancer, especially if diagnoses at an early age;
atypical epithelial cells in nipple aspirate fluid;
nodular densities on the mammogram;
history of cancer in 1 breast;
mother or sister with history of breast cancer;
biopsy-confirmed benign proliferative breast disease;
hyperplastic epithelial cells without atypia in nipple aspirate fluid;
and radiation to chest in moderate to high doses.
Ovarian hormones appear to stimulate cell division in the breast, thus elevated levels may be risk factors.
Exogenous hormones may also increase the risk. Women are exposed to these exogenous hormones through
Postmenopausal obesity increases the risk while premenopausal obesity decreases the risk. A high fat diet in childhood and adolescence may increase the risk. Alcohol drinking may also increase the risk.
Older, white, and nulliparous women are more likely to have estrogen receptor-positive cancers.
Breast cancer in males tends to share the same risk factors as well as its own unique factors.
Prevention of postmenopausal obesity is the only established primary prevention effort. Screening is the only secondary prevention means.
Breast cancer epidemiology: summary and future directions, Epidemiologic reviews, NCBI PubMed PMID: 8405209, 1993.