I dos Santos Silva

Fetal growth and subsequent risk of breast cancer: results from long term follow up of Swedish cohort

Abstract Objective: To investigate whether size at birth and rate of fetal growth influence the risk of breast cancer in adulthood. Design: Cohort identified from detailed birth records, with 97% follow up. Setting: Uppsala Academic Hospital, Sweden. Participants: 5358 singleton females born during 1915-29, alive and traced to the 1960 census. Main outcome measures: Incidence of breast cancer before (at age <50 years) and after (≥ 50 years) the menopause. Results: Size at birth was positively associated with rates of breast cancer in premenopausal women. In women who weighed ≥4000 g at birth rates of breast cancer were 3.5 times (95% confidence interval 1.3 to 9.3) those in women of similar gestational age who weighed <3000 g at birth. Rates in women in the top fifths of the distributions of birth length and head circumference were 3.4 (1.5 to 7.9) and 4.0 (1.6 to 10.0) times those in the lowest fifths (adjusted for gestational age). The effect of birth weight disappeared after adjustment for birth length or head circumference, whereas the effects of birth length and head circumference remained significant after adjustment for birth weight. For a given size at birth, gestational age was inversely associated with risk (P=0.03 for linear trend). Adjustment for markers of adult risk factors did not affect these findings. Birth size was not associated with rates of breast cancer in postmenopausal women. Conclusions: Size at birth, particularly length and head circumference, is associated with risk of breast cancer in women aged <50 years. Fetal growth rate, as measured by birth size adjusted for gestational age, rather than size at birth may be the aetiologically relevant factor in premenopausal breast cancer. What is already known on this topic There is some evidence that birth weight is related to risk of breast cancer The exact nature of any association and whether it differs at premenopausal and postmenopausal ages is unclear Few studies have examined the effect of other measures of birth size and of gestational age What this study adds There are strong positive associations between measures of birth size and rates of breast cancer at premenopausal ages that persisted after adjustment for adult risk factors For a given birth size, gestational age was inversely associated with risk, suggesting that the rate of fetal growth may be aetiologically relevant to premenopausal breast cancer There was no association between birth characteristics and rates of breast cancer at postmenopausal ages

Birthweight, childhood growth and risk of breast cancer in a British cohort

We have examined the relationship between birthweight and risk of breast cancer, taking into account growth in childhood, using data on a total of 2221 women born in 1946 and followed up to 1997. Thirty-seven breast cancers occurred during follow-up. There was evidence of greater risk of breast cancer with greater birthweight (rate ratio = 1.76 (95% CI: 0.92, 3.35) for birthweight ≥ 3.5 kg vs birthweight < 3.5 kg), which was more marked at pre-menopausal ages (RR = 2.31, 95% CI: 0.93, 5.74). The relation with birthweight was not substantially confounded by any of the measured adult risk factors. A significant interaction was observed between the effects of birthweight and height at age 7 years. Relative to those born lighter than 3.5 kg, women who were heavy at birth (≥ 3.5 kg) and short or average at 7 years (< 1.22 m) had a 21% increase in breast cancer rates (RR = 1.21; 95% CI = 0.49–2.99), while women who were heavy at birth (≥ 3.5 kg) but tall at 7 years (≥ 1.22 m) had a four-fold increase (RR = 4.01; 95% CI = 1.82–8.83). These results suggest that the effect of birthweight on breast cancer risk may be modulated by childhood growth.

A prospective study of serum insulin-like growth factor-I (IGF-I), IGF-II, IGF-binding protein-3 and breast cancer risk

The associations between serum concentrations of insulin-like growth factor-I (IGF-I), IGF-II and IGF-binding proteins (IGFBP)-3 and risk of breast cancer were investigated in a nested case–control study involving 117 cases (70 premenopausal and 47 postmenopausal at blood collection) and 350 matched controls within a cohort of women from the island of Guernsey, UK. Women using exogenous hormones at the time of blood collection were excluded. Premenopausal women in the top vs bottom third of serum IGF-I concentration had a nonsignificantly increased risk for breast cancer after adjustment for IGFBP-3 (odds ratio (OR) 1.71; 95% confidence interval (CI): 0.74–3.95; test for linear trend, P=0.21). Serum IGFBP-3 was associated with a reduction in risk in premenopausal women after adjustment for IGF-I (top third vs the bottom third: OR 0.49; 95% CI: 0.21–1.12, P for trend=0.07). Neither IGF-I nor IGFBP-3 was associated with risk in postmenopausal women and serum IGF-II concentration was not associated with risk in pre- or postmenopausal women. These data are compatible with the hypothesis that premenopausal women with a relatively high circulating concentration of IGF-I and low IGFBP-3 are at an increased risk of developing breast cancer.

The epidemiology of carcinoid tumours in England and Scotland

Relatively little is known about the epidemiology of carcinoid tumours in contrast to the extensive information available on their biochemical effects and natural history. Accordingly, we have used cancer registrations in England from 1979 to 1987, and in Scotland from 1980 to 1989, to estimate the incidence of carcinoid tumours in Britain. Age-standardised incidence rates for England, based on 3,382 registrations, were 0.71 (0.68-0.75) for men and 0.87 (0.83-0.91) for women, per 100,000 per year. The equivalent rates for Scotland, based on 639 registrations, were 1.17 (0.91-1.44) for men and 1.36 (1.09-1.63) for women. There was a consistent female excess of carcinoid tumours in the reproductive years, which was reversed after the age of 50. The female excess was most striking for gastrointestinal carcinoid tumours in women aged 15-19 years (F:M ratio = 2.14). The sex differences are probably due in part to incidental diagnosis of carcinoid tumours during abdominal procedures, which are more common in women than men at ages 15-49 years. However, there is some evidence to suggest a true sex difference in incidence, particularly the fact that the sex ratio for thoracic tumours varies with age in a similar way to that for gastrointestinal tumours. Hormonal factors may, therefore, be important in the aetiology of carcinoid tumours.

Thyroid cancer epidemiology in England and Wales: time trends and geographical distribution.

Thyroid cancer incidence has been increasing in many countries, whereas mortality has been falling due to better survival. Radiation is the best-established risk factor and there has been concern that recent rises in incidence might be related to fallout radiation from atmospheric nuclear weapon tests. We examined thyroid cancer time trends and geographical distribution in England and Wales and possible interpretations of these. During 1962-84, there were significant increases in incidence (P < 0.001) in each sex at ages under 45. Cohort analysis by single year of birth showed an overall increase in incidence risks in women aged 0-44 born since 1920, with a sudden rise in risk for the birth years 1952-55 followed by a lower risk for the more recent cohorts. In men, there was an overall increase in risk at ages 0-44 in successive birth cohorts, but the pattern was irregular. In each sex, the risk in persons aged 45 and over decreased slightly in successive generations. Geographically, highest incidence risks were in countries in North and Mid Wales, in which the risk was almost twice that in the rest of the country. This pattern was present only at ages 45 and over and was most clear in rural areas. The peak of thyroid cancer risk in women born in 1952-55 is consistent with a carcinogenic effect of fallout radiation, since these women were children in the late 1950s and early 1960s when fallout radiation was greatest in England and Wales. The focus of high thyroid cancer risks in Wales was in areas with high levels of fallout radiation. However, thyroid cancer risks in Wales were not high for more recent cohorts (the ones who were exposed to fallout early in life), and a focus on high risk of benign thyroid diseases was present in Wales well before nuclear weapons existed. The distributions of these benign thyroid diseases, or of factors causing them, seem more likely than fallout to explain the high risk areas for thyroid cancer in the country.

Ovulation-stimulation drugs and cancer risks: a long-term follow-up of a British cohort

To assess long-term health effects of ovarian-stimulation drugs we followed-up for over 20 years a British cohort of 7355 women with ovulatory disorders, 43% of whom were prescribed ovarian-stimulation drugs, and identified a total of 274 deaths and 367 incident cancers. Relative to the general population, the cohort experienced lower mortality from most causes, including from all neoplasms combined, and lower incidence of cervical cancer, but higher incidence of cancers of the breast (relative risk: 1.13; 95% CI 0.97, 1.30) and corpus uteri (2.02; 1.37, 2.87). There were, however, no significant differences in the risk of cancers of the breast, corpus uteri, ovary, or of any other site, between women who had been prescribed ovarian-stimulation drugs and those who had not. Further analyses by type of drug and dose revealed a dose–response gradient in the risk of cancer of the corpus uteri (P for linear trend=0.03), with women given ⩾2250 mg of clomiphene having a 2.6-fold (2.62; 0.94, 6.82) increase in risk relative to those who were not treated. These findings do not support strong associations between ovulation-stimulation drugs and cancer risks, but they indicate the need for continued monitoring to establish whether risks are elevated in certain subgroups of users.

Life-course body size and perimenopausal mammographic parenchymal patterns in the MRC 1946 British birth cohort

Dense mammographic parenchymal patterns are associated with an increased risk of breast cancer. Certain features of body size have been found to be associated with breast cancer risk, but less is known about their relation to breast density. We investigated the association of birth size, childhood growth and life-course changes in body size with Wolfe grade in 1298 perimenopausal women from a British cohort of women born in 1946. The cohort benefits from repeated measures of body size in childhood and adulthood. We obtained mammograms for 90% of women who at age 53 years reported having previously had a mammogram. We found no associations with birth weight or maximum attained height. Body mass index (BMI) at age 53 years and breast size were independently and inversely associated with Wolfe grade (P-value for trend <0.001 for both). Women who reached puberty later were at a greater odds of a higher Wolfe grade than women who had an earlier puberty (odds ratio associated with a 1 year delay in menarche 1.14, 95% CI: 1.01–1.27, adjusted for BMI and breast size at mammography). A higher BMI at any age during childhood or adult life was associated with a reduction in the odds of a higher Wolfe grade, after controlling for breast size and BMI at mammography, for example, standardised odds ratio for height at age 7 was 0.72 (95% CI: 0.64, 0.81). These findings reveal the importance of taking life-course changes in body size, and not just contemporaneous measures, into account when using mammographic density as an intermediate marker for risk of breast cancer.

Recent trends in incidence of and mortality from breast, ovarian and endometrial cancers in England and Wales and their relation to changing fertility and oral contraceptive use

Reproductive-related factors play a major role in the aetiology of cancers of the breast, ovary and endometrium. Pregnancy history influences the risk of each of these cancers, and oral contraceptive use modifies the risks of ovarian and endometrial cancers, although its effect on breast cancer risk is less certain. We analysed recent time trends in the incidence and mortality of these cancers in England and Wales and assessed whether they can be explained by changes in fertility and oral contraceptive use. During 1962-87, there were significant increases in the overall incidence of breast cancer (0.95% increase per annum) and ovarian cancer (0.76% per annum) but little increase in endometrial cancer (0.13% per annum). At young ages incidence of each of the cancers has declined in recent years, whereas at older ages there have been substantial increases. Mortality data show similar time trends. In analyses by birth cohort, incidence of each of the cancers increased steeply for successive cohorts born before the turn of the century, and more slowly for cohorts thereafter, reaching a maximum for those born in the 1920s, and decreased for those born subsequently. The increases in incidence for women born before the turn of the century paralleled marked declines in their fertility. The fall in risk for women born after the 1920s was not accompanied by significant increases in their fertility, but coincided with the introduction and increase in use of oral contraceptives. For ovarian and endometrial cancers this accords with strong evidence from person-based studies of the protective effect of oral contraceptives. For breast cancer, the reasons for the recent decline are not clear. It would accord with recent suggestions of a long-term protective effect of oral contraceptives, on which further studies are needed. It is also possible, however, that changes in other risk factors such as dietary fat intake and menarcheal age might have contributed to the recent declines in the risk of these cancers.

Is the association of birth weight with premenopausal breast cancer risk mediated through childhood growth

Several studies have found positive associations between birth weight and breast cancer risk at premenopausal ages. The mechanisms underlying this association are not known, but it is possible that it may be mediated through childhood growth. We examined data from a British cohort of 2176 women born in 1946 and for whom there were prospective measurements of birth weight and of body size throughout life. In all, 59 breast cancer cases occurred during follow-up, 21 of whom were known to be premenopausal. Women who weighed at least 4 kg at birth were five times (relative risk (RR)=5.03; 95% confidence interval=1.13, 22.5) more likely to develop premenopausal breast cancer than those who weighed less than 3 kg (P-value for linear trend=0.03). This corresponded to an RR of 2.31 (0.95, 5.64) per 1 kg increase in birth weight. Birth weight was also a predictor of postnatal growth, that is, women who were heavy at birth remained taller and heavier throughout their childhood and young adulthood. However, the effect of birth weight on premenopausal breast cancer risk was only reduced slightly after simultaneous adjustment for height and body mass index (BMI) at age 2 years and height and BMI velocities throughout childhood and adolescence (adjusted RR=1.94 (0.74, 5.14) per 1 kg increase in birth weight). The pathways through which birth weight is associated with premenopausal breast cancer risk seem to be largely independent of those underlying the relation of postnatal growth to risk.

The insulin-like growth factor system and mammographic features in premenopausal and postmenopausal women.

High levels of circulating insulin-like growth factor-I (IGF-I) and its major binding protein (IGFBP-3) at premenopausal ages have been associated with an increased breast cancer risk. We conducted a cross-sectional study (215 premenopausal women and 241 after natural menopause) nested within the Guernsey prospective studies to examine the relationship between the IGF system and mammographic features of the breast. The mammographically dense area in the breast increased with increasing serum levels of IGF-I (P for linear trend, Pt = 0.05), IGF-II (Pt = 0.08), and IGFBP-3 (Pt = 0.01) only in premenopausal women. IGF-II and IGFBP-3 serum levels were associated with increases in the mammographically lucent area in both premenopausal (Pt = 0.01 and 0.04, respectively) and postmenopausal women (Pt < 0.001 for both), but these associations were no longer statistically significant after adjustment for body mass index and waist circumference. Neither the IGF-I/IGFBP-3 nor the IGF-II/IGFBP-3 molar ratio was associated with any of these mammographic features. The number of A alleles at a polymorphic locus in the promoter region of the IGFBP-3 gene was associated with increasing mean IGFBP-3 levels in both premenopausal (Pt = 0.01) and postmenopausal (Pt <0.001) women but not with mammographically dense area. These results support the hypothesis that the IGF system may affect the amount of mammographically dense tissue in premenopausal women, possibly by promoting cell proliferation and inhibiting apoptosis in the fibroglandular tissue. The findings also show strong relations between IGF-II and IGFBP-3 levels and the amount of mammographically lucent tissue, reflecting the associations between body adiposity and amount of fat tissue in the breast and between body adiposity and circulating levels of these growth factors. (Cancer Epidemiol Biomarkers Prev 2006;15(3):449–55)