M. C. Pike

Epidemiology of soy exposures and breast cancer risk

Most of the early studies published on soy and breast cancer were not designed to test the effect of soy; the assessment of soy intake was usually crude and few potential confounders were considered in the analysis. In this review, we focused on studies with relatively complete assessment of dietary soy exposure in the targeted populations and appropriate consideration for potential confounders in the statistical analysis of study data. Meta-analysis of the 8 (1 cohort, 7 case–control) studies conducted in high-soy-consuming Asians show a significant trend of decreasing risk with increasing soy food intake. Compared to the lowest level of soy food intake (⩽5u2009mg isoflavones per day), risk was intermediate (OR=0.88, 95% confidence interval (CI)=0.78–0.98) among those with modest (∼10u2009mg isoflavones per day) intake and lowest (OR=0.71, 95% CI=0.60–0.85) among those with high intake (⩾20u2009mg isoflavones per day). In contrast, soy intake was unrelated to breast cancer risk in studies conducted in the 11 low-soy-consuming Western populations whose average highest and lowest soy isoflavone intake levels were around 0.8 and 0.15u2009mg per day, respectively. Thus, the evidence to date, based largely on case–control studies, suggest that soy food intake in the amount consumed in Asian populations may have protective effects against breast cancer.

Hormonal chemoprevention of cancer in women

The use of oral contraceptives in the United States during the past three decades has led to a dramatic decline in the incidence of cancers of the ovary and endometrium. The magnitude of these declines was predictable both from epidemiologic data and from the biologic effects of oral contraceptives on these tissues. Although the incidence of breast cancer has not been substantially affected by current oral contraceptives, it may be possible to develop alternative forms of contraception that provide protection against all three cancers. The major goal of hormonal chemoprevention of cancer is to reduce cell proliferation in the relevant epithelial tissue. New chemopreventive agents such as tamoxifen exemplify the application of this principle.

Serum oestrogen levels in postmenopausal women : comparison of american whites and japanese in Japan

Serum oestrone (E1), oestradiol (E2) and sex hormone binding globulin (SHBG) levels were studied in postmenopausal Japanese women in Japan (n = 91) and postmenopausal American white women (n = 38). The Japanese women were deliberately chosen to be from a rural agricultural area in order to get samples which represent as closely as possible the traditional Japanese lifestyle that gave rise to the low rates of breast cancer in Japan. E1 levels were 47%, and E2 levels 36%, greater in the American women; these differences were only reduced to 43% and 27% after adjustment for the lower weight of the Japanese. These results were all statistically highly significant. There was little difference in SHBG levels between the Japanese and the American women. These results for E1 and E2 could be an important part of the explanation why Japanese and American breast cancer rates continue to diverge further after the menopause.

An overview of menopausal oestrogen–progestin hormone therapy and breast cancer risk

Results from the Womens Health Initiative (WHI) trial support findings from observational studies that oestrogen–progestin therapy (EPT) use is associated with an increase in breast cancer risk. We conducted a meta-analysis using EPT-specific results from the Collaborative Group on Hormonal Factors in Breast Cancer (CGHFBC) pooled analysis and studies published since that report to obtain an overview of EPT use and breast cancer risk. We also assessed risk by histologic subtype of breast cancer, by schedule of the progestin component of EPT, and by recency of use. We estimate that overall, EPT results in a 7.6% increase in breast cancer risk per year of use. The risk was statistically significantly lower in US studies than in European studies – 5.2 vs 7.9%. There was a significantly higher risk for continuous-combined than for sequential EPT use in Scandinavian studies where much higher total doses of progestin were used in continuous-combined than in sequential EPT. We observed no overall difference in risk for lobular vs ductal carcinoma but did observe a slightly higher risk for current vs past EPT use.

Elevated levels of prolactin in nulliparous women.

Follicular-phase (Day 11) plasma prolactin, and plasma and urinary oestrogen levels of 70 nulliparous nuns were compared with those of 80 of their sisters, of whom 62 were parous. The nuns and their nulliparous sisters did not differ significantly in their prolactin and oestrogen levels. No differences in plasma oestrogens or urinary oestriol ratio were found between the parous and the nulliparous women. However, the mean prolactin level of the nuns and their nulliparous sisters was 35% higher than that of the parous women in the sample taken approximately 1 3/4 h after rising (p less than 0.0005), and 24% higher (P less then 0.01) in the 2nd sample taken 2 h later. The elevation was independent of age, weight, and age at menarché. Age at first full-term pregnancy, at least up to the age of 30, and second or subsequent full-term pregnancies had no further effect on prolactin level. This study suggests that the effect of early first full-term pregnancy in lowering breast cancer risk may be mediated, at least in part, by permanently lowering the level of circulating prolactin.

Hormone levels in older women: a study of post-menopausal breast cancer patients and healthy population controls.

Hormone concentrations in blood and total 12 h urine values were compared between 40 post-menopausal women with breast cancer and 40 control women in a study which carefully controlled for the possible confounding effects of age, weight and pregnancy history by individually matching cases and controls on these factors. Breast cancer cases had received only surgical treatment for their localised disease, which was diagnosed from 1 to 9 years before hormonal evaluation. Cases had 15% higher serum oestradiol levels (P = 0.02), 40% more urinary oestradiol (P = 0.03) and 44% more urinary oestriol (P = 0.04) than control women. Cases also had higher levels of serum and urinary oestrone, but these differences were not statistically significant. The percentages of serum oestradiol not bound to albumin or sex-hormone binding globulin did not differ between cases and controls, nor were there statistically significant differences in the serum levels of prolactin, sex-hormone binding globulin or dehydroepiandrosterone sulphate. These results provide further support for the hypothesis that breast cancer risk is determined in part by post-menopausal serum oestrogen concentration.

Progesterone receptor variation and risk of ovarian cancer is limited to the invasive endometrioid subtype: Results from the ovarian cancer association consortium pooled analysis

There is evidence that progesterone plays a role in the aetiology of invasive epithelial ovarian cancer. Therefore, genes involved in pathways that regulate progesterone may be candidates for susceptibility to this disease. Previous studies have suggested that genetic variants in the progesterone receptor gene (PGR) may be associated with ovarian cancer risk, although results have been inconsistent. We have established an international consortium to pool resources and data from many ovarian cancer case–control studies in an effort to identify variants that influence risk. In this study, three PGR single nucleotide polymorphisms (SNPs), for which previous data have suggested they affect ovarian cancer risk, were examined. These were +331 C/T (rs10895068), PROGINS (rs1042838), and a 3′ variant (rs608995). A total of 4788 ovarian cancer cases and 7614 controls from 12 case–control studies were included in this analysis. Unconditional logistic regression was used to model the association between each SNP and ovarian cancer risk and two-sided P-values are reported. Overall, risk of ovarian cancer was not associated with any of the three variants studied. However, in histopathological subtype analyses, we found a statistically significant association between risk of endometrioid ovarian cancer and the PROGINS allele (n=651, OR=1.17, 95% CI=1.01–1.36, P=0.036). We also observed borderline evidence of an association between risk of endometrioid ovarian cancer and the +331C/T variant (n=725 cases; OR=0.80, 95% CI 0.62–1.04, P=0.100). These data suggest that while these three variants in the PGR are not associated with ovarian cancer overall, the PROGINS variant may play a modest role in risk of endometrioid ovarian cancer.

LHRH agonists and the prevention of breast and ovarian cancer.

Early age at natural menopause or bilateral ovariectomy substantially reduce a womans lifetime risk of breast cancer. Reversible bilateral ovariectomy can now in effect be achieved by high-dose luteinising hormone releasing hormone (LHRH) agonists (LHRHAs). The harmful effects of such medical reversible bilateral ovariectomy, in particular the increased risks of coronary heart disease and osteoporosis, can in all likelihood be obviated by low-dose oestrogen replacement therapy (ERT), specifically 0.625 mg of conjugated equine oestrogens (CEE) for 21 days in each 28-day treatment cycle, and such ERT use will only negate to a relatively small extent the beneficial effect of such bilateral ovariectomy on breast cancer risk. We calculate that such an LHRHA plus low-dose ERT regimen given to a premenopausal woman for 10 years will, in addition to being a most effective contraceptive, decrease her lifetime risk of breast cancer by more than 50%. We calculate that such a 10-year regimen will also decrease her risk of ovarian cancer by two-thirds. This regimen should leave endometrial cancer risk and bone metabolism unaltered, and may reduce the risk of heart disease. The addition of a low-dose progestogen to the regimen for 12 days in each 28-day treatment cycle would be beneficial to the endometrium, but it will adversely affect risk factors for heart disease and it may significantly reduce the benefit of the regimen as regards breast cancer. A satisfactory compromise may be to add a low-dose progestogen for 12 days at less frequent intervals. Another possibility may be to deliver a progestogen solely to the endometrium with an intra-uterine device; the benefits of such a regimen would be a significant reduction in the incidence of breast, ovarian and endometrial cancer.

Prospective Study of Alcohol Drinking, Smoking, and Pancreatitis: The Multiethnic Cohort.

Objectives We conducted a prospective analysis of 145,886 participants in the multiethnic cohort to examine the relationship of alcohol drinking and smoking with pancreatitis. Methods Pancreatitis cases were categorized as gallstone-related acute pancreatitis (GSAP) (N = 1,065), non-GSAP (N = 1,222), and recurrent acute (RAP)/chronic pancreatitis (CP) (N = 523). We used the baseline questionnaire to identify alcohol intake and smoking history. Associations were estimated by hazard ratios (HRs) and 95% confidence intervals (CIs) using Cox models. Results Cigarette smoking was associated with non-GSAP and RAP/CP. Moderate alcohol intake was inversely associated with all types of pancreatitis in women (HRs, 0.66 to 0.81 for <1 drink per day), and with RAP/CP in men (HR, 0.57; 95% CI, 0.41–0.79 for <2 drinks per day). The risk of non-GS pancreatitis associated with current smoking was highest among men who consumed more than 4 drinks per day (HR, 2.06; 95% CI, 1.28–3.30), whereas among never smokers, moderate drinking was associated with a reduced risk (HR, 0.70; 95% CI, 0.51–0.96). In women, drinking less than 2 drinks per day was associated with a reduced risk of GSAP among never smokers (HR, 0.61; 95% CI, 0.46–0.80). Conclusions Smoking is a risk factor for non-GS pancreatitis. Moderate alcohol intake is protective against all types of pancreatitis in women and against RAP/CP in men.

Estrogens, Progestins, and Risk of Breast Cancer

Obesity is associated with a decreased risk of breast cancer in premenopausal women but an increased risk in postmenopausal women, an effect that increases with time since menopause. Analysis of these effects of obesity shows that there is a ceiling to the carcinogenic effect of estrogen on the breast; increases in nonsex hormone-binding globulin-bound estradiol (non-SHBG bound E2) exceeding approximately 10.2 pg/ml have no further effect on breast cancer risk; this ceiling is lower than the lowest level seen during the menstrual cycle. This suggests that the effects of menopausal estrogen therapy (ET) and menopausal estrogen-progestin therapy (EPT) on a womans breast cancer risk will greatly depend on her body mass index (BMI; weight in kilograms/height in meters squared, kg/m2) with the largest effects being in slender women. Epidemiological studies confirm this prediction. Our best estimates, per 5 years of use, of the effects of ET on breast cancer risk is a 30% increase in a woman with a BMI of 20 kg/m2 decreasing to an 8% increase in a woman with a BMI of 30 kg/m2; the equivalent figures for EPT are 50% and 26%. The analysis of the effects of estrogen also shows that even reducing the dose of estrogen in ET and EPT by as much as a half will have little or no effect on these risks. Reducing the progestin dose is likely to significantly reduce the risk of EPT: this is possible with an endometrial route of administration.