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Two studies have reported that young women with breast cancer face increased risk of early mortality if their first child was male rather than female. An immunological mechanism has been suggested. We sought to confirm these results in a larger, historical cohort study of 223 parous women who were aged <45 years at breast cancer diagnosis during 1983-1987. Subjects were identified through the Maine Cancer Registry. Follow-up data were obtained from hospitals, physicians, and death certificates. Reproductive history data were obtained from the next of kin of the deceased women, birth certificates, physicians, hospitals, and lastly, subjects. With a 7-year follow-up, multivariate modeling found a lower mortality risk in women with a male first child (hazard ratio [HR] 0.51, 95% confidence interval [CI] 0.32-0.81, log-rank comparison). The survival advantage remained for at least 13 years in women with a male firstborn. Thus, previous studies were not confirmed. Mortality risk in young women with breast cancer is not increased by having borne a male first child rather than a female first child.

Several reproductive factors have been found to be associated with breast cancer. Based on an immunologic rather than strictly hormonal interpretation of these observations, we hypothesized that, beyond the observed associations relating to pregnancy per se, multiple marriages would be found to protect women against breast cancer. We obtained cases and controls from linked records from the Utah Cancer Registry and genealogic records. A total of 2,414 women with newly diagnosed breast cancer and 9,138 individually matched controls were included. The unadjusted odds ratio for each marriage after the first was 0.81 [95% confidence interval (CI) = 0.68-0.97]. After adjustment for major reproductive factors, multiple marriages were still found to reduce the risk of breast cancer (odds ratio = 0.86; 95% CI = 0.72-1.03). The findings are consistent with the operation of an immunologic mechanism in the etiology of breast cancer and suggest that the gene/antigen responsible for this effect is quite common in males. Further empirical evaluation of the fetal antigen hypothesis seems warranted.

Background: Several studies have found that daughters born to older mothers have an elevated risk of breast cancer, and an endocrine hypothesis, among others, has been developed to explain these findings. Three recent studies have failed to find a consistent maternal age effect, indicating a need for further exploration of this issue., Purpose: We used Utah breast cancer records linked to genealogical records to investigate maternal and paternal age and other maternal reproductive factors in relationship to the daughter's risk of breast cancer., Methods: The study group consisted of 2414 breast cancer case patients and 9138 individually matched control subjects. Breast cancer diagnoses were ascertained through the National Cancer Institute's Surveillance, Epidemiology, and End Results Program. The case patients and control subjects were born between 1875 and the end of 1947, and the mean age at diagnosis of the case patients was 65.9 years., Results: No consistent effect for maternal or paternal age was found, except possibly among women who were firstborn children (odds ratio [OR] = 1.42 for a 10-year differential in maternal age; 95% confidence interval [CI] = 1.00-2.00). Further examination of the data indicated that mothers of case patients experienced long intervals between marriage and their first birth but not between subsequent births, and they went on to have fewer children. For each year of delay between the mother's marriage and first birth, the odds of breast cancer in the daughter increased 1.05-fold (95% CI = 1.01-1.10)., Conclusions: We found no evidence of a consistent maternal age effect with regard to breast cancer risk in the daughter, but we did find evidence that the mothers of women who go on to get breast cancer have a reproductive pattern that could suggest some form of underlying infertility., Implications: These findings widen the epidemiologic support for the fetal antigen hypothesis, which is an immunogenetic explanation for the relationships between reproductive factors and breast cancer risk. That hypothesis provides strategies for the identification of breast cancer genes and the eventual development of a breast cancer vaccine.

The fetal antigen hypothesis was proposed over a decade ago to explain the small, short-term promotional effect, as well as part of the long-term protective effect that pregnancy has on breast cancer risk. The hypothesis is based on immune interaction between mother and fetus, and postulates that breast cancer genes which a women's fetus inherits from her mate may be indirectly involved in protecting the woman against breast cancer. This article addresses new epidemiological data pertaining to the hypothesis plus the growing evidence that prenatal reproductive factors are important determinants of breast cancer risk. It also suggests that iso-immunization from pregnancy, similar to Rh iso-immunization, can produce immunity against breast cancer. The proposed mechanism provides a plan for development of a vaccine against breast cancer. If the fetal antigen hypothesis is valid for breast cancer, the mechanism behind it is likely to apply to other cancers, even cancers that are found in males, since males can be affected be the prenatal component of this mechanism.

We examined the relationship between the survival of women with breast cancer and the gender of their first children using a genealogy-based survival analysis. The study group consisted of 2,155 parous women diagnosed in Utah (United States) with first primary breast cancers (excluding in situ tumors). We calculated hazard rate ratios (HRR) which were adjusted for stage, median survival times, and proportions surviving for three-, five-, and 10-year intervals stratified by age at diagnosis. Median survival among women diagnosed under the age of 45 was 171 months if the first child was female, but only 66 months if the first child was male (HRR = 1.66, 95 percent confidence interval = 1.07-2.57, for male children). For women diagnosed at age 45 or older, all survival times were similar, although women whose first child was male had slightly longer median survival time. These findings suggest that the gender of the first child has a strong influence on survival among women diagnosed under 45 years of age, but not among those diagnosed later in life. Gender of the first offspring may be a useful clinical indicator of prognosis and survival and may provide insights into etiologic and promotional factors for breast cancer.

Data from a large case-control study of breast cancer were examined to test the hypothesis that maternal age at the birth of female offspring is related to the incidence of breast cancer in daughters. Participants were between the ages of 20 and 54 at the time of the study. Based on results for 2,492 parous women who were newly diagnosed with breast cancer and 2,687 parous controls from the general population, a 15-year increase in maternal age was found to be associated with a 29% increase in the risk of breast cancer in daughters. Adjustment for the daughter's age, her own reproductive history, and other potential confounding factors yielded an estimate of 25% for this increase in risk (95% CI, 8% to 46%). The corresponding increase among 499 nulliparous cases and 457 nulliparous controls was 7%, which was not statistically significantly different in magnitude from the increase among parous women. These findings provide evidence for perinatal influences on the subsequent incidence of breast cancer during adulthood. Although specific mechanisms cannot be inferred directly, the results are consistent with the hypothesis that mutations in the genes of the human egg or sperm play a role in the etiology of breast cancer in female offspring.

The effect of oral contraceptive (OC) use was examined among parous breast cancer cases diagnosed at less than or equal to 45 years of age, and in two different general population control groups of parous women. The primary analysis compared 278 cases with 520 controls. In the secondary analysis, a subgroup of 190 cases were compared with 190 controls from another reference group. In both analyses, ever use of OC, duration of OC use, and OC use prior to first pregnancy showed no significant association with breast cancer risk. Also in both analyses, in women with prior benign breast disease OC use increased the risk of breast cancer, although this finding was statistically significant only in the larger group used in the primary analysis.

We examined some characteristics of first pregnancy in 314 female breast cancer patients whose disease was diagnosed at < 45 years of age and who were identified through a population-based cancer registry in New York State and in 314 control women identified through birth records. Preeclampsia was reported less frequently on the birth records of the first recorded pregnancy in the cases than in those of the controls, with a relative risk of 0.28 (0.05 < p < 0.10, from logistic model). We examined this finding on preeclampsia with particular reference to immunologic mechanisms, but further studies are needed on larger samples. Twinning and maternal Rh factor, also relevant to immunologic factors, were not significantly associated with a higher risk of breast cancer. Among the women whose first pregnancy resulted in a live birth, length of gestation (which is correlated with maternal estriol levels) did not differ between the cases and controls.

Data from the Cancer and Steroid Hormone Study, a large nationwide population-based case-control study conducted in the United States in 1980-1982, were analyzed to investigate whether pregnancies ending in a multiple birth affect the risk of subsequent breast cancer. The cases were 3,918 parous women who were aged 20-54 years and newly diagnosed with breast cancer; controls were 4,047 parous women selected randomly from the same geographic areas as the cases. Multiple births were reported by 118 cases and 161 controls. After adjustment for other reproductive variables, having a multiple last birth was found to be protective against breast cancer (odds ratio (OR) = 0.60, 95% confidence interval (CI) 0.43-0.85), whereas having a multiple birth prior to the last birth was not (OR = 1.11, 95% CI 0.79-1.57). To the authors' knowledge, this study is the first investigation to report such a protective effect, and thus the finding warrants replication. One mechanism that might account for the effect involves the increased output of alpha-fetoprotein by multiple fetal livers.

Epidemiological data are presented to show that pregnancy is related to a short-term increase in breast cancer risk which precedes its well recognized lower rate for the remainder of life. The data confirm and extend related findings from several earlier studies, and suggest that the biological mechanism which produces the apparent protective effect resulting from pregnancy also produces a short-term adverse effect which is approximately proportionate to the protective effect. This phenomena seems important in terms of what it reveals about the natural history of breast cancer. It is proposed that the general biological mechanism underlying this effect is the immune tolerance during pregnancy which allows the female's immune system to tolerate a fetus whose genes and antigens are partially dissimilar to her own. It is further suggested that the specific mechanism responsible for the phenomena is either a mammary tumor virus or the woman's immune reaction to unidentified fetal antigens that are common to human fetal cells and mammary cancer cells.

In a study in upstate New York, incidence and survival rates of 317 young women (less than 45 years), diagnosed with breast cancer, were examined in relation to the sex of each woman's first offspring. While incidence of breast cancer was not found to be affected by the sex of the first child, prognosis was poorer when the first child was made (p less than 0.05). The authors examined the effect of stage at diagnosis, interval between first pregnancy and diagnosis and concurrent pregnancy at the time of diagnosis as factors other than sex of first offspring that might have an additional influence on survival. Among these, only interval had an effect, and it was of weak statistical significance (0.05 less than p less than 0.1). These findings regarding survival in relation to the sex of the offspring are opposite to those reported recently in France by Juret et al. (Lancet 1:415-416, 1978). Possible differences between the two studies which may account for the opposite findings are discussed.

We investigated the relationship between hypertension and breast cancer using data from a large case-control study of women younger than 55 years. Among nulliparous women, there was little evidence of an association between hypertension and breast cancer. Among parous women, hypertension reduced the risk of breast cancer if it had been diagnosed at any time in their lives before the end of the most recent pregnancy (odds ratio = 0.73; 95% confidence interval = 0.59-0.92). Several earlier studies indicate that there is an association between hypertension during pregnancy and elevated levels of maternal serum alpha-fetoprotein. Thus, our results are consistent with the hypothesis that maternal exposure to alpha-fetoprotein during pregnancy protects women against the subsequent occurrence of breast cancer.