Age at any birth and breast cancer in Italy

To provide quantitative information on the role of age at any birth for breast cancer risk, we analyzed data from a cooperative Italian case-control study conducted between 1991 and 1994 on 2,569 incident, histologically confirmed breast cancer cases and 2,588 controls in hospital for acute, non-neoplastic, non-gynecological conditions. A single logistic model was fitted, including terms for number of births, age at each birth and at menarche, plus age and center. Age at first birth was the strongest reproductive determinant of subsequent breast cancer risk, with an estimated increase of 4.6% per year of delay of first birth. This was similar to the influence of age at menarche (4.7% decrease in risk per year of delay of menarche). Ages at subsequent births had an independent effect on breast carcinogenesis, with an estimated 0.7% increase in risk per year of delay. Multiparity showed also an independent protection on breast cancer risk, and a protective effect of parity ≥3 was evident in all strata of age at first birth: the odds ratio was 0.81 for 3 births and 0.70 for ≥4 births. However, the effect of parity was determined by the age of occurrence of various births. © 1996 Wiley-Liss, Inc.     

Age at first birth, parity and risk of breast cancer in a Swedish population.

A case-control study was conducted over a period of 11 months in an area containing one-third of the Swedish population. One thousand and one patients participated, constituting 94% of all women newly diagnosed as having breast cancer within the area. They were compared with 1,001 age-matched, non-hospitalized controls without breast cancer, selected by paired sampling from a population register. The risk of breast cancer was slightly, but significantly, related to parity, the standardized relative risk (SRR) being 1.35 for nulliparous women as compared to ever parous. In the different parity groups a risk significantly lower than that for nulliparous women was found only for women with more than 2 children (SRR = 0.59) but the trend with parity was highly significant (P less than 0.001). Age at first birth was not found to be an important risk factor for breast cancer. SRR was lower than for nulliparous women in all groups of women with their first birth before the age of 35 years, but the difference was significant (P less than 0.05) only for those with the first birth between 20 and 24 (SSR = 0.69) and 25 and 29 (SRR = 0.69) years of age. The trend with age at first birth (P less than 0.05) disappeared after stratification for parity, suggesting that it was a confounding factor.     

Age at first birth and the risk of epithelial ovarian cancer

The relationships between age at first birth, parity, and the risk of ovarian cancer were evaluated in a case-control study of 272 women with histologically confirmed epithelial ovarian cancer and 544 age-matched controls with a spectrum of acute conditions unrelated to any of the established or potential risk factors for ovarian cancer. Late age at first birth was associated with increased risk: Compared to women who first had a child before the age of 22 years, the relative risks (RR) for those who first gave birth at ages 22-24, 25-27, and 28 or more were 2.7, 3.2, and 4.0, respectively. Nulliparous women showed increased RR (3.9) comparable to the RR among women who first bore a child at age 25 or more, regardless of the number of births. The elevated risk associated with later age at first birth was not accounted for by low parity. The risk of ovarian cancer, as expected, increased with decreasing parity: RR estimates for women having 5 or more, 3 or 4, and 1 or 2 children and for nulliparae were 1.0, 1.7, 1.9, and 2.6, respectively. However, the inverse association between parity and ovarian cancer could be accounted for largely by the importance of age at first birth, because when adjustment was made for that variable, the RR for 3 or 4 and 1 or 2 children decreased to 1.3 and 1.2, respectively. Thus the results of the present study show a strong independent effect of age at first birth on the risk of epithelial ovarian cancer, whereas the association with parity can be explained largely or totally in terms of a high correlation between total parity and age at first birth. The pattern of ovarian cancer risk that emerges from this study, therefore, is similar to the epidemiology of breast cancer. General evidence on this issue from various other studies, however, is rather controversial, and similar analysis of other data-sets would be useful.     

Age at first birth and breast atypia

The relation between age at first birth and the occurrence of fibrocystic breast disease of different atypia subtypes was evaluated using data from a cohort study of the health effects of oral-contraceptive use. Multivariate case-control analysis was performed on 218 parous women with biopsied fibrocystic disease and 928 parous controls. Fibrocystic breast disease, as a whole and as atypia subtypes, was found to be unrelated to age at first birth. Furthermore, the estimated effect of age at first birth did not vary from one atypia subtype to another. Women with high parity were found to be at decreased risk of fibrocystic breast disease compared to those with low parity. Age at completion of education, used as an indicator of socioeconomic status, was found to be moderately associated with fibrocystic breast disease. The estimated effect of parity and age at completion of education also did not vary among subtypes. More epidemiologic studies specific to histopathologic classifications of benign breast disease are called for.     

Age at menarche,urine estrogens and breast cancer risk

In 511 nulliparous women aged 15–19 years and 347 aged 30–39, an analysis has been undertaken of the relationship of urine concentrations of the three principal estrogens to age, age at menarche and Quetelet's index of adiposity. The analysis was undertaken by means of multiple regression, controlling for each of the 12 centers from which the data originated, as well as for the other study variables. In the younger women, age was strongly and positively related to concentrations of El and E2 and less so to E3. In the age group 30–39, folluiar phase specimens showed positive relationships with age for all three fractions but luteal specimens did not. Age at menarche showed inverse relationships to levels of El and E2 which were significant in the younger but not in the older age group. The associations of estrogens with Quetelet's index were weak and not statistically significant. The data suggest that women whose menarche occurs early not only have a longer duration of exposure to estrogens during years which are probably important in the initiation of breast cancer but, in addition, their exposures are at a higher level during those years and probably at later ages also. These observations support the hypothesis that the mechanism of the association of early menarche with breast cancer risk is via the association of both with estrogen stimulus.     

Age at first birth and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers

An early age at first full-term birth is associated with a reduction in the subsequent development of breast cancer among women in the general population. A similar effect has not yet been reported among women who carry an inherited BRCA1 or BRCA2 mutation. We conducted a matched case–control study on 1816 pairs of women with a BRCA1 (n = 1405) or BRCA2 (n = 411) mutation in an attempt to elucidate the relationship between age at first full-term pregnancy and the risk of developing breast cancer. Information about the age at first childbirth and other pregnancy-related variables was derived from a questionnaire administered to women during the course of genetic counselling. There was no difference in the mean age at first full-term birth in the cases and controls (24.9 years vs. 24.8 years; P = 0.81, respectively). Compared to women whose first child was born at or before 18 years of age, a later age at first full-term birth did not influence the risk of developing breast cancer (OR = 1.00 per year; 95% CI 0.98–1.03; P-trend = 0.67). Stratification by mutation status did not affect the results. These findings suggest that an early first full-term birth does not confer protection against breast cancer in BRCA mutation carriers. Nonetheless, BRCA mutation carriers opting for a prophylactic oophorectomy as a breast and/or ovarian cancer risk-reducing strategy should complete childbearing prior to age 40 when this prevention modality is most effective. Other members of the Hereditary Breast Cancer Clinical Study Group—J. Garber, Dana Farber Cancer Center, D. Gilchrist, University of Alberta, M. Osborne, Strang Cancer Prevention Centre, New York, NY, USA, D. Fishman, Northwestern University, E. Warner, Toronto-Sunnybrook Regional Cancer Center, Toronto, ON, Canada, J. McLennan, University of San Francisco, W. McKinnon, University of Vermont, S. Merajver, University of Michigan Comprehensive Cancer Center, H. Olsson, Jubileum Institute, Department of Oncology, Lund University Hospital, Lund, Sweden, D. Provencher, University of Montreal, B. Pasche, Northwestern Medical Facility, Chicago, IL, USA, G. Evans, Regional Genetics Service, St. Mary’s Hospital, Manchester, UK, WS Meschino, North York General, North York, ON, Canada, E. Lemire, Division of Medical Genetics, Royal University Hospital and the University of Saskatchewan, Canada, A. Chudley, Children’s Hospital, Winnipeg, Manitoba, Canada, D. Rayson, Queen Elizabeth Health Sciences Centre, Halifax, Nova Scotia, Canada and C. Bellati, Dipartimento di Genetica, Biologia e Biochimica, Università di Torino, Italy.     

Age at menarche,probability of ovulation and breast cancer risk

An analysis is undertaken of the frequency of ovulation in 17 groups of women aged 15 to 19 who had been the subjects of other studies. A urine specimen of at least 8 h accumulation had been provided on the 20th or 21st day of a menstrual cycle by 681 women. Analysis is restricted to 431 specimens which had been collected between 11 and 3 days prior to the onset of the subsequent menstrual period. A pregnanediol concentration of less than 1 mg per litre in such a specimen was taken as evidence that the cycle was anovular. The probability of a cycle being anovular was inversely and significantly related to the number of years since menarche, and, with years since menarche held constant, was positively but not significiantly associated with age at menarche. This observation indicates that women with early menarche do not have a longer duration of exposure to anovular cycles than do those whose menarche is delayed, and that variation in the duration of exposure to post-menarcheal anovular cycles does not explain the association of breast cancer risk with early age at menarche. The 17 groups of women were classified into four categories according to ethnic origin and breast cancer incidence in the populations from which they derived. Anovular cycles were not more common in the high-risk groups; indeed, the two centers in the lowest risk category had the highest proportion of anovular cycles.     

Size at birth and risk of breast cancer: prospective population-based study

It has been hypothesized that birth size is positively associated with breast cancer risk in adulthood. We studied birth length, birth weight and head circumference at birth and subsequent risk for breast cancer in a cohort of 16,016 women in Norway. Birth length was positively associated with risk (p trend = 002), and women who were 53 cm or longer had a relative risk of 1.8 (CI = 1.2-2.6) compared with women who were shorter than 50 cm, after adjustment for birth year, length of gestation, birth order, maternal age, maternal marital status and socioeconomic status at childbearing. Mutual adjustment for birth weight did not influence the results, and further adjustment for maternal height and adult factors (age at first birth and parity) in a subset of the cohort did not change the results. For birth weight, women in the highest category (>/= 3,840 g) had an adjusted relative risk (RR) of 1.5 (CI = 1.0-2.2) compared to women in the lowest (< 3,040 g), but mutual adjustment for birth length attenuated this association (RR = 1.1; CI = 0.7-1.8). Head circumference at birth showed a similar association as birth weight, with attenuation after mutual adjustment for birth length. The positive association with birth length was stronger among women whose mothers were relatively tall (median or taller, p trend = 0.001) compared to women whose mothers were relatively short (below median, p trend = 0.67) at childbearing. The results provide evidence that intrauterine factors influence future breast cancer risk. The positive association related to birth length suggests that factors that stimulate intrauterine longitudinal growth are particularly important.     

Age at first birth, dietary practices and breast cancer mortality in various Italian regions

Breast cancer death certification rates in Italy showed a consistent geographic variation, with approximately a 2-fold ratio between the highest rates registered in Northern (and richer) regions, and the lowest ones in the South. This variation in breast cancer mortality was positively and strongly correlated with mean age at first birth (r = + 0.73). This positive correlation could not be totally explained by several other economic or dietary variables considered, though some of them substantially reduced the strength of the association. Breast cancer mortality rates were found to be positively correlated with milk, meat and sugar consumption, and negatively with pasta, thus confirming previous studies on national or international scales. These correlation coefficients, however, were considerably reduced after controlling for mean age at first birth. Further, when allowance was made for economic variables and age at first birth, only the correlation coefficients for milk and cheese remained significantly positive. Thus, the evidence from this study suggests that the Italian geographical correlations between breast cancer mortality and dietary variables may be largely explained in terms of reproductive factors, though there may be some effect of dietary variables on breast cancer risk as well.     

Age at first birth, parity and risk of breast cancer: a meta-analysis of 8 studies from the Nordic countries

Several large epidemiological studies in the Nordic countries have failed to confirm an association between age at first birth and breast cancer independent of parity. To assess whether lack of power or heterogeneity between the countries could explain this, a meta-analysis was performed of 8 population-based studies (3 cohort and 5 case-control) of breast cancer and reproductive variables in the Nordic countries, including a total of 5,568 cases. It confirmed that low parity and late age at first birth are significant and independent determinants of breast-cancer risk. Nulliparity was associated with a 30% increase in risk compared with parous women, and for every 2 births, the risk was reduced by about 16%. There was a significant trend of increasing risk with increasing age at first birth, women giving first birth after the age of 35 years having a 40% increased risk compared to those with a first birth before the age of 20 years. Tests for heterogeneity between studies were not significant for any of the examined variables. In the absence of bias, this suggests that several individual Nordic studies may have had too little power to detect the weak effect of age at first birth observed in the meta-analysis.     

Age at first and second births and breast cancer risk in biparous women

The role of age at first and at second birth on subsequent breast cancer risk was analyzed using pooled data from 2 hospital-based case-control studies conducted in Italy, for a total of 1,200 biparous cases and 987 controls. Compared with women who gave birth for the first time below age 20, the relative risks were above unity for those with later first birth, even after allowance for age at second birth, although the trend was inconsistent across subsequent strata. A similar direct trend in risk was observed in relation to age at second birth: compared with less than 25 years and after allowance for age at first birth, the point estimates were 1.2, 1.4 and 1.4 for 25-29, 30-34 and greater than or equal to 35 (p for linear trend = 0.04). The results for age at first and at second birth were similar in the 2 studies pooled in this analysis. A significant interaction with age was observed in relation to age at first and at second birth. In younger women (below age 50) a strong and direct association with age at first birth was found, while no apparent protection was conveyed by earlier second birth. Among older women (aged 50 or over), there was no apparent relationship with age at first birth after allowance for age at second, but the role of age at second birth was independent and statistically significant. Thus, our study confirms an independent and significant role of age at second birth in biparous women, after allowance for age at first birth, and indicates that, after reciprocal allowance, the role of first and second birth was not apparently different. The relative risks for both variables were quantitatively moderate, and may be influenced by age or other temporal variables.     

Weight at birth and adolescence and premenopausal breast cancer risk in a low-risk population

We assessed breast cancer risk in relation to weight at birth and adolescence. In-person interviews were completed with the biological mothers of women aged 45 years and younger who participated in the Shanghai Breast Cancer Study in 1996-98 (288 cases, 350 controls). After adjustment for confounding, women who were 4000 g or more at birth were not at increased risk of breast cancer (odds ratio=0.7; 95% confidence interval 0.4-1.4) relative to women whose birth weight was 2500-2999 g. Compared with women of average perceived weight at age 15 years, no relation was apparent for heavier than average weight based on maternal report (odds ratio=0.7; 95% confidence interval 0.5-1.2) or self-report (odds ratio=1.0; 95% confidence interval 0.7-1.6). Perceived adolescent weight and height did not modify the association of birth weight with breast cancer risk. These results suggest that weight early in life is not related to premenopausal breast cancer risk in this low-risk population.     

Preterm birth, birth weight, and subsequent risk of female breast cancer

We have previously found an increased risk of breast cancer among women born preterm. To confirm or refute the results, an enlarged study was conducted. The results from this study do not confirm the initial findings and suggest that preterm birth can be ruled out as a risk factor for breast cancer.     

Season of birth and breast cancer risk in Sweden.

Recent research suggests that intrauterine exposures, perhaps factors that influence birth weight and other indicators of fetal growth, may affect future breast cancer risk. Because birth weight shows seasonal variation in Sweden, we assessed whether risk for breast cancer is associated with month of birth. The analyses included all 115,670 women, born between 1858 and 1968, who were reported to the Swedish Cancer Registry in 1958-89 as having breast cancer. Poisson regression models were used to examine the data. After adjustment for seasonality of number of live births in the population at risk, a significant seasonal pattern was identified for women born between 1880 and 1920. Women born in June had a 5% higher risk of breast cancer than those born in December. By contrast, there was no evidence of birth seasonality among 440,948 women with cancer at other sites. Exposures relevant to breast cancer risk later in life are unlikely to be related to month of birth. Thus, prenatal or early post-natal factors influence breast carcinogenesis, but the seasonal variation in these factors must have decreased over time.     

Gestational age at birth and risk of testicular cancer

Most testicular germ cell tumors originate from carcinoma in situ cells in fetal life, possibly related to sex hormone imbalances in early pregnancy. Previous studies of association between gestational age at birth and testicular cancer have yielded discrepant results and have not examined extreme preterm birth. Our objective was to determine whether low gestational age at birth is independently associated with testicular cancer in later life. We conducted a national cohort study of 354,860 men born in Sweden in 1973-1979, including 19,214 born preterm (gestational age < 37 weeks) of whom 1,279 were born extremely preterm (22-29 weeks), followed for testicular cancer incidence through 2008. A total of 767 testicular cancers (296 seminomas and 471 nonseminomatous germ cell tumors) were identified in 11.2 million person-years of follow-up. Extreme preterm birth was associated with an increased risk of testicular cancer (hazard ratio = 3.95; 95% confidence interval = 1.67-9.34) after adjusting for other perinatal factors, family history of testicular cancer and cryptorchidism. Only five cases (three seminomas and two nonseminomas) occurred among men born extremely preterm, limiting the precision of risk estimates. No association was found between later preterm birth, post-term birth or low or high fetal growth and testicular cancer. These findings suggest that extreme but not later preterm birth may be independently associated with testicular cancer in later life. They are based on a small number of cases and will need confirmation in other large cohorts. Elucidation of the key prenatal etiologic factors may potentially lead to preventive interventions in early life.     

Histologic specificity of the effect of age at birth of first child on breast cancer risk

Slides of 531 breast cancers from Glamorgan, Wales, were classified according to the presence or absence of each of three histologic characteristics: stromal infiltration by linear strands of tumor cells, areas of intraductal carcinoma, and areas of lobular carcinoma in situ. The proportion of tumors with each of these characteristics was positively associated with age at first child-birth. Increasing age at first birth had a strong positive effect on the incidence risk of tumors with any of these features, but only a small effect on risk of tumors with none. For porous women, the rate of breast cancer with or without linear strands, with or without areas of intraductal cancer, and without areas of lobular carcinoma in situ was lower than for nulliparous women. Parity appeared not to reduce the risk of tumors with areas of lobular carcinoma in situ.     

Age at menarche and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers

Age at menarche is a strong and consistent predictor of breast cancer risk in the general population, but has not been well studied in women with a family history of breast cancer. We conducted this study to examine whether the presence of a deleterious BRCA1 or BRCA2 mutation influences age at menarche and to investigate whether or not there is an association between age at menarche and the risk of breast cancer in BRCA1 or BRCA2 mutation carriers. The presence of a deleterious BRCA1 or BRCA2 mutation did not appear to influence a woman’s age at menarche. A matched case–control study was conducted on 1311 pairs of women who have been identified to be carriers of a deleterious mutation in either the BRCA1 (n = 945 pairs) or the BRCA2 gene (n = 366 pairs). Information about age at menarche was derived from a questionnaire routinely administered to carriers of a mutation in either gene. Among women who carried a deleterious BRCA1 mutation, age at menarche was inversely associated with the risk of breast cancer (p trend = 0.0002). This association was not observed among BRCA2 mutation carriers (p trend = 0.49). Compared with BRCA1 carriers whose age at menarche was ≤11 years, women with a menarcheal age between 14 and 15 years old had a 54% reduction in risk (OR = 0.46; 95% CI 0.30–0.69). This study implicates early age at menarche as a determinant of breast cancer among women with a BRCA1 mutation. * Address correspondence to: Steven A. Narod, Centre for Research in Women’s Health, University of Toronto, 790 Bay Street, Room 750, 7th Floor, Women’s College Hospital, Toronto, Ontario, M5G 1N8, Canada. Ph.: +1-416-351-3765; Fax: +1-416-351-3767; E-mail: steven.narod@swchsc.on.ca     

Heightened perception of breast cancer risk in young women at risk of familial breast cancer

The objective of this study was to explore the factors that influence perceived personal risk of developing breast cancer (BC) in younger women (<35) who are considering or have undergone bilateral prophylactic mastectomy (BPM). Qualitative interviews guided by interpretative phenomenological analysis were conducted with 46 women who had a strong family history of BC and had either undergone (n?=?26) or were considering (n?=?20) BPM. Participants were recruited from Australia and New Zealand via hospitals, a genetics clinic, a research cohort, a registry and online. Three main themes were identified: information that increases fear of BC and death, underlying anxiety and fear and screening anxiety. A further two themes: relief following surgery and confusion about residual risk following surgery were identified. Younger women (<35) appeared to have heightened and sometimes inaccurate perceptions of their BC risk. They appeared less relieved of anxiety and fear of developing BC by BPM surgery, in comparison to previous research with older women (>40). Those who had undergone BPM seemed more anxious about their risk of developing BC than those who were still considering surgery. This research has important implications for practice, particularly improving communication of accurate risk statistics. Future research should examine why some women interpret information differently and explore the benefits of psychological consultation for very anxious women.