Urinary androgens and breast cancer risk: results from a long-term prospective study based in Guernsey.

Between 1961 and 1967 a cohort of over 5000 women volunteered for a prospective study to determine the relationship between the urinary androgen metabolites, androsterone (A) and aetiocholanolone (E), and risk of breast cancer. During the first 10 years of the study the concentration of urinary A and E was determined in 1887 of the urine specimens. In 1971 we reported that subnormal amounts of urinary A and E were associated with a significantly increased risk of breast cancer. The cohort has been followed regularly during the 37 years since inception of the study and, by May 1998, 248 women had been diagnosed with breast cancer. Urinary androgen metabolites had been measured in 116 of these cases. Analysis of these data confirmed that women diagnosed in the first decade of the study were more likely to have low levels of urinary androgen metabolites. In the following decades, however, those who developed breast cancer were more likely to have manifested an increased A and E excretion. The reversal in the relationship between androgen metabolite excretion and risk suggests that age, or probably more importantly, menopausal status at diagnosis is an important modifying factor. Dichotomizing at age 50 it was found that in the younger age group (predominantly premenopausal) the rate ratios in the lowest tertile of A or E excretion were two- to threefold greater than for those in the highest tertile (chi2(1) = 3.57; P = 0.06: chi2(1) = 4.70; P = 0.03 for A and E respectively). In contrast, in the older age group comprising predominantly post-menopausal women, the rate ratios associated with the lowest tertile of A or E were half that of those in the highest tertile (chi2(1) = 4.10; P = 0.04; chi2(1) = 8.72; P = 0.003 for A and E respectively). This suggests that there may be different endocrine promotional factors for pre-and post-menopausal breast cancer. Hormonal risk factors may vary during the lifetime of an individual woman and this may have profound consequences for prevention strategies.

Breast cancer risk is positively associated with height.

Inter- and intra-national epidemiological studies point to an association between socio-economic status and breast cancer risk. Although there is no direct evidence, the most favoured reason for this relationship is nutritional. An enhanced dietary status, especially during childhood, would be reflected in adult body build. It is, therefore, surprising that there is uncertainty in the literature concerning the association between height and breast cancer risk. In reviewing the publications on this topic it became apparent that case-control studies which found no association between height and risk tended to use self-reported height. In contrast reports claiming a significant, and positive, correlation tended to use heights which were measured by the investigators. In a prospective study we found in a cohort of 2731 ostensibly normal women that, although there was a highly significant linear correlation between self-reported and measured height, the shortest women over-estimated their height whilst the tallest volunteers under-estimated theirs. The significance of crude relative risk and height in this cohort was markedly attenuated when self-reported height was used compared to measured height. Such a systematic error could have a profound effect on the conclusions of studies in this field which relied on self-reporting and could explain the conflicting reports in the literature.

Ovarian irradiation and prednisone following surgery and radiotherapy for carcinoma of the breast.

Following mastectomy, patients aged 35 to 76 years with operable breast cancer underwent postoperative irradiation of the chest wall and regional lymph nodes. They were then assigned at random to receive no further therapy (NT), ovarian irradiation (R) 2000 rads in 5 days, or ovarian irradiation in the same dosage plus prednisone (R + P) 7.5 mg daily for up to five years. A total of 703 eligible patients received the randomly assigned treatment. The median follow up was 21 years with a range of 14 to 25 years. Overall, there was a delay in recurrence (p = 0.03) and survival was prolonged (p = 0.19) for patients who received R, but in neither case was the difference significant after adjusting for the multiplicity in our data. Overall, patients who received R + P experienced a significant delay in recurrence (p = 0.0003) and a significantly prolonged survival (p = 0.005), even after adjusting for multiple comparisons. In premenopausal patients who received R, the recurrence of breast cancer was delayed and survival prolonged, but not significantly. In premenopausal women aged 45 years or more, R + P therapy significantly prolonged survival (p = 0.0004), while the delay in recurrence although significant (p = 0.02) was only marginally so after allowance for multiple comparisons. No value was demonstrated for ovarian irradiation with or without prednisone therapy in postmenopausal patients. A new finding in this review was that contralateral breast cancer as the first failure was reduced by R + P compared to NT in the overall group.

The association of height, weight, menstrual and reproductive events with breast cancer: results from two prospective studies on the island of Guernsey (United Kingdom).

The association with breast cancer of menstrual and reproductive events, family history of breast cancer, and body size have been studied on two cohorts of 6,706 volunteers on the island of Guernsey (United Kingdom), 168 of whom had breast cancer detected during follow-up. The median follow-up time of the non-cases was 21 years in the first study and 10 years in the second. A time-dependent Cox regression model was fitted to the data with age as the time-dependent variable in order to represent the effect of changing menopausal status. Other variables examined in the model were age at menarche, parity, age at first birth, family history of breast cancer, height, weight (both directly measured), relative weight (weight [kg]/height[m]), and Quetelet's body mass index (weight[kg]/height[m]2). Interactions between age and all other covariates also were examined. Family history was found to be the most important risk factor for women aged less than 51 years (relative risk [RR] = 3.5, 95 percent confidence interval [CI] = 2.0-6.0), and intervals between menarche and first birth longer than 14 years were found to increase significantly the risk of breast cancer in women older than 61 years (RR = 2.4, CI = 1.3-4.4). Height was the only indicator of body size which was associated significantly with risk of breast cancer, the estimated regression coefficient indicating an increase in risk of about 70 percent for women on the 90th centile of height relative to those on the 10th centile. A survey of the literature showed that the association between risk of breast cancer and height was found in those studies which used direct measurements of height but not in others which used self-reported values.

Copper in human mammary carcinogenesis: a case-cohort study.

In 1968-1975, a cohort of 5,100 ostensibly healthy women was established on the island of Guernsey, England, for investigation of the influence of hormonal factors on breast cancer. At the women's entry into the study, blood samples were drawn from each participant, and each woman completed a questionnaire that provided information on established risk indicators in human mammary carcinogenesis. Plasma copper levels were measured in 46 breast cancer cases diagnosed an average of 11 years (standard deviation (SD), 4) after entry into the study cohort and in an age-stratified random sample of 138 women drawn from the total initial cohort at risk. Plasma copper levels were 1.31 mg/liter (SD, 0.37) in the cases and 1.26 mg/liter (SD, 0.36) in the controls; the 95% confidence interval for the overall difference was -0.07 to 0.17. A U-shaped relation between premorbid plasma copper levels and the risk of developing breast cancer was seen. Adjusted odds ratios for breast cancer were 1.8, 1.0, 1.6, and 3.2, respectively, in the four quartiles of the copper distribution. No major changes in the risk estimates were observed when statistical evaluation was restricted to cases diagnosed more than 10 years after collection of blood samples.

Relationship of blood prolactin levels and the risk of subsequent breast cancer.

Between 1968 and 1976 a total of 5162 women volunteers were enrolled into a prospective study conducted on the Island of Guernsey. Up to February 1990 145 women subsequently developed breast cancer. Blood samples were taken at the time of enrollment and prolactin levels were known for 85% of the volunteers. In calculating the relationship between blood prolactin levels and subsequent breast cancer risk, women were excluded if they had a hysterectomy or an oophorectomy or had cancer at any site before enrollment. The final analysis was based on 2596 premenopausal and 1180 naturally postmenopausal women and, of these respectively, there were 71 and 40 volunteers who subsequently developed breast cancer. The total follow-up for these two groups was 49,941 and 22,360 woman-years, respectively. In assessing the relationship between blood prolactin levels and risk of subsequent breast cancer the cohort was divided into quintiles according to prolactin concentration and relative risks (RR) were estimated. In calculating these values possible confounding by age at entry, age at menarche, parity, age at first birth, years since menopause, body build, history of benign breast disease and family history of breast cancer were taken into consideration. There was no significant relation between risk of breast cancer and prolactin in either pre- or postmenopausal women. Hence prolactin appears not to be an important determinant of breast cancer risk.

Mastectomy or conservation for early breast cancer: psychological morbidity.

A consecutive series of 197 women under 70 years of age with operable breast cancer, randomised to treatment by a conservation technique in comparison to mastectomy, were assessed using structured interviews. The prevalence of cases of anxiety and depression was high before treatment commenced, there were fewer cases in the conservation group but no significant difference at 3 or 12 months in the number of new cases, social adjustment, or capacity to return to work. Attitudes to treatment showed significant differences between the groups, more women in the conservation group were able to wear their usual clothes and most women rated the cosmetic result highly. Patients were more likely to stop sexual intercourse completely after mastectomy. An effective conservation technique should be an attractive treatment choice available to selected women with early breast cancer.

Clinical features of breast cancer--Anglo-Japanese comparative study.

A comparative study was undertaken at Guy's Hospital in the UK and the Aichi Cancer Center in Japan of the clinical picture of breast cancer in the UK and Japan. Target patients were 221 UK and 200 Japanese primary operable patients who were recruited from April 1979 through August 1980. No difference was seen between the two countries in the side and site of the lesion and the size of the lesion. The localized tenderness of the tumor site was higher in Japanese patients than in UK patients (25.5% vs 0%). Difference was observed in tumor characteristics: breast cancers of the UK patients were irregular, ill-defined, and not so mobile, whereas those of the Japanese patients were round or oval, well-defined, and mobile. Skin fixation was higher in Japanese patients (71.0% vs 44.8%). Clinical node involvement was higher in UK patients (32.5% vs 19.0%).

Patterns of recurrence and relapse--Anglo-Japanese comparative study.

A prospective study was undertaken to compare the recurrent sites of breast cancer patients in Japan and the UK. The number of patients collected between April 1979 and August 1980 were 205 in the UK and 199 in Japan, of which those who had recurrence were 89 and 49 respectively. A comparison of the distribution of the first recurrence sites demonstrated that the Japanese patients had significantly higher rates of local recurrence in the supraclavicular fossa and distant metastasis to the lung than UK patients. When comparing the distribution of all recurrent sites seen in the study, Japanese patients showed a significantly higher incidence of metastasis to the supraclavicular fossa and the lung while the UK patients showed a significantly higher incidence of skin metastasis. Bone metastases were observed more often in Japanese patients and liver metastases in UK patients, but neither of the differences were statistically significant.

Recurrence and survival rates in British and Japanese women with breast cancer.

The biology of breast cancer in Japan appears to be changing in that, while post-menopausal Japanese patients have a better prognosis than comparable British women, no differences in recurrence or survival rates can now be found in pre-menopausal patients.

A comparison of epidemiological characteristics in breast cancer patients and normal women in Great Britain and Japan: results of a prospective study.

The epidemiological characteristics of normal women and women with early breast cancer in Great Britain were prospectively compared with similar subjects from Japan. The study consisted of 204 women with early breast cancer and 792 normal controls from Great Britain and 200 breast cancers and 335 Japanese controls. The risk factors examined were age, height and weight, menopausal status, age at menarche and menopause, parity, age at first birth, use of oral contraceptives, and family history of breast cancer. The cancers and cases were divided into pre- and postmenopausal groups. There was a striking trend for a protective effect of multiparity in both countries and a weak but inconstant protective effect of age at first birth. In premenopausal British women increase in body mass was significantly associated with a decreased risk of breast cancer but this association was not found for postmenopausal women or in the Japanese women. The results showed that the classical risk factors did not fully account for the differences in breast cancer risk between Great Britain and Japan. The possibility that aetiological factors might be changing warrants investigation.

Blood concentrations of estradiol and sex hormone-binding globulin in relation to age at menarche in premenopausal British and Japanese women.

In a cross-sectional study, serum estradiol (E2) and sex hormone-binding globulin (SHBG) concentrations were not significantly related to age at menarche in premenopausal British women in the luteal or follicular phases of the cycle. In Japanese subjects in the luteal phase, a marginally higher concentration of E2 was observed in those who had undergone an early rather than a late menarche. In British women, previous oral contraceptive users had significantly lower luteal phase E2 concentrations than never users.

Breast cancer in English and Japanese women: prognostic significance of sinus histiocytosis and germinal center hyperplasia in axillary lymph nodes.

A prospective study of comparable Japanese and British breast cancer patients treated by radical mastectomy confirmed previously reported findings that sinus histiocytosis and germinal center hyperplasia are more frequently seen in axillary lymph nodes from Japanese than in those from British patients. In Japanese, but not British, cases of either of these two morphologic findings had favorable prognostic significance for recurrence. Sinus histiocytosis also had favorable prognostic significance in Japanese cases for five year survival. In a separate review of axillary nodes from Japanese autopsy cases sinus histiocytosis was absent, suggesting that this finding in Japanese breast cancer cases was related to presence of the disease.

A comparison of mammographic parenchymal patterns in premenopausal Japanese and British women.

Normal premenopausal Japanese women have significantly more favourable mammographic parenchymal patterns (Wolfe Grades) than comparable British women. This finding is unaffected when the women are stratified by age, Quetelet's Index, age at menarche, age at first birth, and parity.

Selenium in human mammary carcinogenesis: a case-cohort study.

In a prospective study conducted on the island of Guernsey a cohort of 5162 ostensibly healthy women was enrolled between 1967 and 1976. Blood samples were drawn from each participant, who also completed a questionnaire, which provided information on established risk indicators in human mammary carcinogenesis. Plasma selenium levels were measured in 46 breast cancer cases diagnosed a mean of 11 (S.D. 4) years after entry into the study cohort and in an age-stratified sample of 138 women drawn from the study base. Plasma selenium level in the cases was 109 (28) micrograms/l and in the base sample 103 (22) micrograms/l (95% confidence interval for the overall difference, -2 to 14 micrograms/l). The adjusted relative risk of developing breast cancer in the different quartiles of the selenium distribution was 0.80, 0.79, 0.72 and 1.00, respectively. Thus, in the present study selenium was not a strong indicator of human breast cancer risk.

Relationship of mammographic parenchymal patterns with breast cancer risk factors and risk of breast cancer in a prospective study.

A prospective study has been conducted on 4954 female volunteers from the Island of Guernsey between 1977 and 1985 to examine risk factors for breast cancer and their relationship to mammographic parenchymal patterns as assessed by Wolfe's method of grading. Up to September 1988, 69 women had developed breast cancer, 11 of whom were prevalent cases being diagnosed within six months of mammography. The remaining incident cases were diagnosed six to 126 months (median 65 months) after entry to the study. Univariate analysis showed that the distribution of Wolfe grades in the population was significantly associated with menopausal status, age, parity, adiposity, age at menarche, age at first childbirth and use of oral contraception, but not with a family history of breast cancer. Multivariate analysis of the data for these variables from either pre- and/or post-menopausal women indicated that age, parity and adiposity were significantly related to Wolfe grade pattern. Age had an opposite effect in pre- compared with postmenopausal women thus the probability of either a P2 or DY pattern increased with increasing age in premenopausal but decreased in postmenopausal women so that incidence peaked around the menopause. Other variables did not achieve significance in the multivariate analysis. Odds ratios (ORs) were calculated for women with P2 or DY patterns using those with N1 or P1 grades as the reference group. The ORs were determined at two censoring times; one at five years and the other to include the most recent follow-up of this cohort. The ORs were adjusted for years of follow-up, age and adiposity and in postmenopausal women adjustment was also made for age at menarche.(ABSTRACT TRUNCATED AT 250 WORDS)

Influence of radiotherapy on the dose of adjuvant chemotherapy in early breast cancer.

399 patients with early breast cancer were randomly allocated to treatment by either modified radical mastectomy or lumpectomy and radiotherapy. 169 had histologically involved axillary nodes and were randomised to receive either adjuvant cytotoxic chemotherapy (76 patients) or no systemic adjuvant treatment (93 patients). Chemotherapy comprised a combination of oral cyclophosphamide and intravenous methotrexate and 5-fluorouracil (CMF) for 12 cycles over one year. Patients in the mastectomy group received a significantly higher percentage of the planned chemotherapy dose compared with those in the radiotherapy group (median 85% v. 71% p less than 0.05). Patients treated with radiotherapy were more frequently nauseated and developed more severe alopecia, but these differences were not statistically significant. At median follow-up of 37 months the relapse-rate and pattern of relapse were similar in both groups of patients receiving CMF.

Locally advanced breast cancer: the contribution of cytotoxic and endocrine treatment to radiotherapy. An EORTC Breast Cancer Co-operative Group Trial (10792).

Patients with locally advanced carcinoma of the breast were randomized to receive either radiotherapy alone, radiotherapy + endocrine therapy, radiotherapy + chemotherapy or radiotherapy + endocrine therapy + chemotherapy. In 363 evaluable patients, time to first progression was delayed significantly by both endocrine treatment and chemotherapy, the greatest effect being achieved by the combination of endocrine treatment and chemotherapy. This effect was almost entirely due to a major effect of systemic treatment on time to loco-regional progression, for which the result is highly significant, rather than time to distant metastasis in which only a non-significant trend was observed. For survival, a trend was seen in favour of the combination of hormone treatment and chemotherapy, but this effect did not achieve statistical significance. This trial suggests that current endocrine and cytotoxic treatments are only of marginal value in improving the prognosis in locally advanced breast cancer.