Progesterone and estrogen receptors as prognostic variables in breast cancer.

Estrogen receptor (ER) and progesterone receptor (PR) levels have been measured in 374 tumors from patients with primary breast cancer and compared with axillary nodal status and other patient variables to determine their relationship to prognosis. Nodal status reliably predicted disease-free interval and overall survival, and both ER and PR status predicted overall survival both individually and within node-positive and node-negative subgroups. PR but not ER status was also able to predict disease-free survival both overall and in the node-positive subgroup. When the two receptor measurements were used in combination, a group of receptor-negative, (ER- and PR-negative), node-negative patients were identified with a significantly worse survival than that for an ER- and PR-positive group of node-positive patients. It is apparent that receptor status provides useful prognostic information in patients with early breast cancer and that ER and PR assays used in combination identify a subgroup of node-negative patients with poor prognosis who are likely to benefit from adjuvant therapy following mastectomy.

Seasonal change in the concentration of progesterone receptor in breast cancer.

There are conflicting reports of seasonal changes in steroid hormone receptor levels in breast cancer tissue. Estrogen receptor and progesterone (PR) receptor levels from 1132 tumors were thus grouped according to month of initial tumor detection or month of tissue sampling/surgery. There was a significant circannual variation in the mean monthly PR receptor concentration in patients grouped according to month of tissue sampling/surgery with peak PR levels in April (late summer-early autumn) and nadir values in August and September (late winter-early spring). There was no significant cyclic variation in estrogen receptor values. A significant annual variation in tumor PR concentration was also seen when receptor levels from individual tumors were grouped according to month of initial tumor detection, with peak PR levels found in January and February. The time interval between tumor detection and biopsy/surgery was 3.3 +/- 5.3 months (mean +/- SD) which was close to the interval between the peak PR concentration expressed by month of tumor detection compared with month of tissue sampling for receptor assay. There was also a significant seasonal variation in the month of initial tumor detection, with peak detection occurring in December (summer). The close synchrony between month of maximum tumor detection and month of peak PR concentration suggests that seasonal changes in detection of breast cancer may in part relate to seasonal changes in hormone responsiveness within tumor tissue.

Measurement of human IGF-II using Sephacryl extraction: a rapid and reliable assay method.

Measurement of insulin-like growth factor II (IGF-II) in human serum is complicated by the presence of IGF binding proteins and usually involves cumbersome extraction procedures followed by radioimmunoassay. We have utilized an extraction process developed for measuring insulin-like growth factor II in ovine serum using Sephacryl HR100, and have applied this to the extraction of human samples followed by radioimmunoassay for human IGF-II. The assay yielded 98% recovery of unlabelled IGF-II, parallelism between dilutions of eluate and the standard curve, complete removal of binding proteins and near-complete removal of IGF-I, and intra- and interassay coefficients of variation of 5% and 9%, respectively. The normal range for serum IGF-II in women was 490-1056 micrograms/L, and IGF-II levels were positively correlated with serum concentrations of insulin-like growth factor binding protein-3 (IGFBP-3) but not with IGF-I levels. Mean serum concentrations of IGF-II were reduced below normal in a number of hypopituitary patients and children with short stature and IGF-II concentrations in these subjects correlated positively with IGF-I and IGFBP-3. In acromegalic patients IGF-II levels were usually normal and were negatively correlated with IGF-I concentrations. From our experience with the above results the present assay appears particularly suitable for clinical measurements and research projects where high sample throughput is required.

Age and ethnicity as prognostic factors influencing overall survival in breast cancer patients in the Auckland region. Auckland Breast Cancer Study Group.

AIMS: to assess the effect of age at diagnosis and ethnicity on overall survival from breast cancer. METHODS: information was collected from 2706 breast cancer patients in the Auckland region, diagnosed between 1976 and 1985. Age at diagnosis was categorised into four groups: < 35 years, 35-49 years, 50-74 years and 75 years or older. Ethnicity was self reported in three categories: European, Maori and Pacific Island Polynesian. Independent effects were assessed by controlling for extent of disease, specifically metastases at presentation, nodal status and size of tumour. RESULTS: age and ethnic group were both significantly related to overall survival in univariate analyses. In multivariate analysis, age had an independent effect on survival mainly due to a significant survival difference between women aged less than 35 years and those aged 35 to 49 years (p < 0.0001; RR = 2.02). Survival was not significantly different between other age groups when adjustments were made for extent of disease. There was no significant effect of ethnicity on survival in the reduced dataset used for the multivariate analysis. Separate analyses suggested that ethnic differences in the extent of disease at diagnosis may be the cause of the apparent initial effect of ethnicity on survival. CONCLUSIONS: women < 35 years at diagnosis have a significantly poorer prognosis than women aged 35-49 years. Other differences between age groups were not significant when stage of disease was taken into account. Ethnicity was not an independent factor influencing survival after controlling for extent of disease but numbers in the Maori and Pacific Island groups were too small to conclusively evaluate any effect of ethnic group on prognosis.

Survival of women with node negative breast cancer in the Auckland region.

AIMS: To assess the effect of prognostic factors on overall survival from node negative breast cancer. METHODS: Information was collected on 1138 node negative breast cancer patients in the Auckland region, diagnosed between 1976 and 1985. Prognostic variables investigated included oestrogen (ER) and progesterone (PR) receptor status, tumour grade, tumour size, body mass index, lactation history and parity. The effects of these variables on overall survival were assessed separately in pre and postmenopausal groups. RESULTS: Over a median follow up time of 10.2 years, improved survival was seen in premenopausal women with PR+ status (p = 0.0007), ER+ status (p = 0.03), positive lactational history (p = 0.03) and low tumour grade (p = 0.04). In postmenopausal women, only ER+ status (p = 0.01) and PR+ status (p = 0.02) were associated with improved survival. Multivariate analysis suggested that positive PR status combined with tumour size provided the best prognostic discrimination in premenopausal women, whereas ER status was the dominant prognostic variable in postmenopausal patients. CONCLUSIONS: For premenopausal node negative women, progesterone receptor status, considered either alone, or together with tumour size, provides the best prognostic prediction of survival. By comparison, oestrogen receptor status is the most important predictor of overall survival in postmenopausal women.

Detection of contralateral breast cancer by mammography in women with previous breast cancer and the impact of endocrine therapy.

AIMS: To determine the efficacy and extent of screening mammography for detection of contralateral breast cancer in a cohort of women with previous unilateral mammary carcinoma, and to assess the effect of endocrine therapy on the risk of developing cancer in the contralateral breast. METHODS: Women with previous breast cancer eligible for mammography were identified from the Auckland breast cancer data file and the extent and outcome of mammographic screening determined by questionnaire and survey of mammography reports. The extent of adjuvant hormonal therapy and development of contralateral breast cancer was ascertained from the ABCDF records. RESULTS: Of 703 eligible subjects, 59% had undergone screening mammography with a cancer detection rate of 17 per 1000 mammograms and a benign to malignant ratio was 1.7 to 1. Contralateral breast cancer developed in 2.9% of 1980 women with previous unilateral mammary tumours who did not receive endocrine therapy with 1.1% of 374 women who were given adjuvant hormonal treatment (p = 0.04). CONCLUSIONS: The efficacy of mammography in those screened was comparable to major overseas screening programs, but the proportion of women undergoing mammography in this high risk group was relatively low suggesting a need for greater promotion of mammography in Auckland. The use of adjuvant endocrine therapy significantly reduced the rate of development of contralateral breast tumours supporting the current development of formal trials of chemoprevention of breast cancer in women at high risk groups of the disorder.

Treatment of breast cancer in the Auckland region 1976-85.

AIM: A descriptive study of the treatment of breast cancer in Auckland between the years 1976 to 1985. METHODS: A database was constructed utilising information from all new breast cancer cases recorded in the Auckland region from September 1976 to September 1985. Details of treatment were obtained at the time of diagnosis and the database was updated every 9 months. Patient survival was measured and changes in the pattern of treatment were assessed. RESULTS: After a median follow up of 9 years 41% of patients were alive without evidence of breast cancer, 9% were alive with recurrence and 50% had died, 38% having died of breast cancer. Survival of node positive patients at 5 years of follow up who received adjuvant tamoxifen or adjuvant chemotherapy was 57 (SE 4)% and 63 (4)% respectively. The proportion of less than mastectomy surgical procedures increased over the study period, and local recurrence in these patients was reduced by postoperative radiotherapy. CONCLUSIONS: Between 1976 and 1985 there was an increasing rate of conservative surgery for breast cancer in Auckland. Overall survival of patients was comparable to that reported in international studies, with increasing use of adjuvant endocrine therapy but a decline in adjuvant chemotherapy over the duration of the study.

Incidence and clinical features of breast cancer in the Auckland region.

Data on all new breast cancer cases in the Auckland area during the nine years September 1976 to September 1985 were used to obtain epidemiological information on breast cancer in the Auckland region. Breast tumours were found in 2706 women (300 per year), yielding a lifetime risk of breast cancer of one in 15. No significant difference in breast cancer incidence was detected between European, Maori and Pacific Island Polynesian women. Confidence limits for incidence were wide in the later groups. Fifty-one percent of women presented with intermediate sized (2-5 cm) tumours, and most (66%) were node negative. Eleven percent had evidence of metastatic disease at presentation. When the relationships between race, tumour size, nodal status and metastases were examined, Pacific Island women more frequently presented with large tumours and metastases, whereas Maori women were more frequently node positive. Eighty-five percent of tumours were invasive ductal carcinomas, 55% grade II, 35% grade III, and 10% grade I. Sixty-seven percent of tumours were oestrogen receptor positive (ER+ve) and ER status was significantly related to age; the proportion of ER+ve tumours was greater in older women. Fifty-seven percent of tumours were progesterone receptor positive (PR+ve), and PR distribution was bimodal with age. These data from the Auckland region are similar to breast cancer figures from other western countries, with some ethnic differences in tumour size and frequency of metastatic disease at presentation.

Determinants of vitamin D status in older men living in a subtropical climate.

INTRODUCTION: Previously we reported seasonal variation in 25-hydroxyvitamin D (25OHD) levels in postmenopausal women living in a subtropical climate. Because studies have suggested that there are gender differences in 25OHD levels, we sought to determine (1) the levels and determinants of 25OHD in men drawn from the same community, (2) whether seasonal variation of 25OHD occurs in men at this latitude (37 degrees S), and (3) whether these findings were comparable to those we previously observed in postmenopausal women. METHODS: Cross-sectional study of 378 healthy, middle-aged and older community-dwelling men in Auckland, New Zealand. RESULTS: The mean 25OHD (SD) level was 85 (31) nmol/l. We found significant seasonal variation in 25OHD levels (peak in autumn 103 nmol/l, nadir in spring 59 nmol/l). Vitamin D insufficiency (25OHD <50 nmol/l) was uncommon (prevalence in summer 0-17%, in winter 0-20%). The major determinants of 25OHD were month of blood sampling, fat percentage, physical activity, and serum albumin. Men had higher levels of 25OHD throughout the year than women did, a finding that persisted after adjusting for potential confounding factors. In men and women the determinants of 25OHD were similar. CONCLUSION: There is significant seasonal variation in 25OHD levels in men living in a subtropical climate. In contrast to postmenopausal women, men have low rates of suboptimal vitamin D status, even in winter. Routine vitamin D supplementation for this population of men is not warranted.

Steroid hormone receptors in breast tumours presenting during pregnancy or lactation.

Cytosol oestrogen receptor (ER) and progesterone receptor (PR) levels were measured in tumours from three patients with breast cancer during pregnancy and from three patients developing breast cancer while lactating. All lactating patients were ER-positive and two were PR-positive, whereas pregnant patients were uniformly ER-negative and PR-negative. Pregnant patients had a significantly shorter disease-free survival compared with matched nonpregnant women with breast cancer. Of five patients developing metastatic disease, one from the lactating group had a complete remission with chemotherapy and one had static disease with endocrine treatment, whereas all others had progressive disease despite a variety of treatments. Although numbers are too small to permit generalisation, these provisional data suggest that patients presenting with breast cancer during pregnancy may have mainly receptor-negative tumours, a short disease-free interval, and may be relatively resistant to treatment of metastatic disease. By comparison, patients with breast tumours during lactation have receptor-positive disease and metastases may respond to systemic therapy.

Does delay in diagnosis of breast cancer affect survival?

1675 breast cancer patients in the Auckland regional area have been divided into two major groups according to delay in diagnosis greater or less than six weeks. Overall there is no difference in survival although the variables tumour size, skin attachment, and nipple retraction are more common in the group with longer delay, and grade III tumours in those with short delay. Three important prognostic variables (the presence of tumour steroid receptors, positive axillary nodes, and distant metastases at diagnosis) are equally distributed and have a similar effect on survival within the two delay groups. However, in a subgroup of women with negative axillary nodes, short delay is associated with poorer survival, independent of tumour size. More tumours with grade III histology and a negative progesterone receptor status are found in this subgroup. Thus, short delay may constitute a new prognostic variable of some importance when in association with negative axillary nodes.

Seasonal changes in serum melatonin in women with previous breast cancer.

A seasonal variation in the month of initial detection of breast cancer has been previously observed in pre-menopausal women, and it has been proposed that this may be due to cyclic changes in tumour growth mediated by the effects of melatonin on ovarian function. To investigate this possibility serum melatonin concentrations have been measured every 2 h for 24 h at the summer and winter solstice in 20 pre-menopausal women with previous breast cancer and nine controls. Twelve women had detected their tumour in winter and eight in summer. Overall melatonin secretion assessed by either amplitude of the nocturnal melatonin pulse or the area under the 24 h melatonin curve (AUC) was not different between breast cancer women or controls. However, the amplitude and AUC fell in winter in breast cancer patients (summer to winter 93.6 to 77.5 pg ml-1, P less than 0.002 and 743 to 634 AUC units, P less than 0.005 for amplitude and AUC respectively), whereas the winter minus summer values were significantly positive in controls compared with cancer patients. The abnormal fall in winter values in the women with previous breast cancer was confined to the group of women who had been winter detectors (mean summer to winter levels 94.9 to 72.6 pg ml-1, P less than 0.01 and 775 to 637 AUC units, P less than 0.05 for amplitude and AUC respectively) whereas there was no significant seasonal alteration in these measurements in summer detectors. The acrophase of the nocturnal pulse of serum melatonin was significantly advanced in both groups of women with previous breast cancer (change in acrophase winter to summer from 0210 h to 0140 h in summer detectors, P less than 0.01, 0330 h to 0210 h in winter detectors, P less than 0.05) with a similar although nonsignificant trend in control women. The abnormal reduction of serum melatonin seen in wintertime in winter detectors of breast cancer could promote tumour growth at this season and so contribute to the decreased survival previously observed in this group compared with summer detectors. The relatively normal seasonal profile of melatonin observed in summer detectors could allow increased ovarian steroidogenesis in spring/summer with a resulting increase in tumour growth and consequent rise in tumour detection rate at this time.

Influence of height, weight, and obesity on breast cancer incidence and recurrence in Auckland, New Zealand.

The relationship between obesity and breast cancer has been investigated in 1281 Auckland breast cancer patients. Using a definition of obesity as a Body Mass Index (BMI) of greater than or equal to 28 kg/m2, 179 (14%) breast cancer patients were classified as obese. The heights, weights, and BMI of 822 breast cancer patients aged 35-64 compared to 518 randomly selected Auckland women of similar age showed no significant difference. Within the breast cancer patients, there was no variation in nodal status or estrogen and progesterone receptor status between obese and non-obese women. However, tumours greater than 5 cm occurred significantly more often in obese patients. Time to recurrence was reduced in obese women with tumours less than or equal to 5 cm, no tumour in the axillary nodes, positive estrogen or progesterone receptor, and without metastases at the time of presentation of the disease. Although obesity has not been shown to influence breast cancer incidence, an effect on tumour recurrence is seen in patients with less advanced disease. This is similar to other reports which suggest that obesity is a weak but positive risk factor for recurrence.

The relationship of urinary and plasma androgens to steroid receptors and menopausal status in breast cancer patients and their influence on survival.

The relationships between urinary 11-desoxy-17-oxo steroids (11-DOS), the ratio of 11-DOS to urinary 17-hydroxycorticosteroids (urinary discriminant ratio), plasma levels of the adrenal androgens dehydroepiandrosterone (DHA), DHA sulphate (DHAS), and 7 alpha-hydroxy DHA (7 alpha DHA), and tumour oestrogen receptor (ER) and progesterone receptor (PR) status were examined in pre, peri-, and postmenopausal women with breast cancer. Androgenic steroids and their metabolites decreased with age in women with breast cancer. In perimenopausal women there was a significant association of PR positive tumours and high androgen levels, whereas in postmenopausal women high androgen levels were associated with ER negative tumours. Survival was significantly related to plasma DHA level and tumour steroid receptor status. Thus, adrenal androgen levels below the group mean were associated with significantly decreased survival in women with postmenopausal receptor-positive tumours, and the association was particularly apparent in those who were axillary node negative. Since the number of patients studied was small these results should be regarded as provisional in nature. Nonetheless, the identification of this subgroup of node negative breast cancer women with reduced survival may be important when considering node negative patients for adjuvant therapy.

Estrogen receptors in bilateral breast cancer.

Estrogen receptor status, tumor histology, and the interval between the development of tumors were assessed in 99 patients with bilateral breast cancer. Tumors were first grouped into those simultaneously detected in both breasts or within 12 months of each other (synchronous bilateral breast cancer, of which there were 64) and second, those detected within more than 12 months of each other (asynchronous bilateral breast cancer, of which there were 35). Nineteen percent of all tumors were lobular carcinomas. Overall, the rate of receptor discordance between the two tumors was not significantly different from that previously reported between biopsies of primary tumor and metastases in patients with unilateral breast cancer. Synchronous receptor-positive tumors occurred significantly more frequently than expected, suggesting that the development of the two tumors was influenced by a common mechanism. In patients with asynchronous bilateral breast cancer there was a significantly longer interval between tumors if both were receptor-positive compared with concordant receptor-negative tumors and tumors with discordant receptor status. There was a significant discordance in the receptor status of asynchronous tumors when the histology also differed, indicating that the tumors in this group were likely to be separate primary tumors.

Overall survival from breast cancer in women pregnant or lactating at or after diagnosis. Auckland Breast Cancer Study Group.

The effect of concurrent or subsequent pregnancy or lactation has been studied in women with breast cancer to determine if these variables influence prognosis. Information was collected from 382 women potentially capable of bearing children, aged less than 45 years, in the Auckland Breast Cancer Study Group data file, a consecutive series of women diagnosed with breast cancer from 1976 to 1985, with a median follow-up of 10.2 years. The prevalence of both pregnancy at diagnosis and lactation at diagnosis was 2.6%. The incidence of pregnancy subsequent to diagnosis was 3.9%. Women pregnant at the time of breast cancer diagnosis had significantly more advanced disease than non-pregnant patients, and there was a similar trend for women lactating at diagnosis. Overall survival in these women was poor compared with the non-pregnant and non-lactating groups; only 2 of 10 pregnant patients and 0 of 10 lactating patients survived more than 12 years. The adverse outcome for women lactating at diagnosis of their breast cancer persisted despite allowance for nodal status, tumour size and age. However, survival was similar between pregnant and non-pregnant patients when these variables were taken into account. No significant differences in survival were found between those women who had pregnancies subsequent to diagnosis of breast cancer and breast cancer patients who did not become pregnant.

Characteristics of the menstrual cycle at the time of surgery for breast cancer.

Hormone measurements during the menstrual cycle were assessed in six premenopausal women undergoing breast cancer surgery and ten controls to determine whether the stress of diagnosis and surgery influenced cycle characteristics. There was hormonal evidence for normal ovulation in all cancer and control women, although the length of the luteal phase of the cycle was prolonged because of a delay in menstruation in two cancer patients. The timing of surgery in the cycle did not influence the hormonal data. The hormonal characteristics of the menstrual cycle thus appear to be normally preserved in women during the month in which breast cancer surgery is performed.

Estrogen receptor status, adrenal androgens and 7 alpha-hydroxydehydroepiandrosterone in breast cancer patients.

Plasma concentrations of dehydroepiandrosterone (DHA), DHA-sulphate (DHAS) and 7 alpha hydroxy-DHA (7 alpha OHDHA) were measured and compared with tumor estrogen receptor (ER) status in 33 postmenopausal patients with breast cancer. Although the plasma concentrations of DHA, DHAS and 7 alpha OHDHA were not different between the ER-positive (ER+) and ER-negative (ER-) patient groups, the ratios of 7 alpha OHDHA/DHAS and of DHA/DHAS were significantly higher (P less than 0.001 and P less than 0.001 respectively) in the ER- group. Nine women (normal or with benign breast disease) of similar age and menopausal status had values for plasma 7 alpha OHDHA/DHAS and DHA/DHAS between those of ER+ and ER- patient groups. The measurement of these steroid ratios in the plasma of breast cancer patients thus provides an indirect estimate of ER status. Since DHA and 7 alpha OHDHA are major metabolites of precursor DHAS in mammary tumor tissues, changes in their relative quantities in plasma may reflect the influence of receptor-mediated events on mammary steroid metabolism. Alternatively, the relative increase in tumor metabolism of androgens inferred from high 7 alpha OHDHA/DHAS and DHA/DHAS ratios in the ER- group may disrupt the hormonal microenvironment of the estrogen receptor. These events may, in turn, predispose toward ER status and a poor response to endocrine therapy.

Season of initial discovery of tumour as an independent variable predicting survival in breast cancer.

The month of initial detection of tumour was recorded in 2,245 patients with breast cancer and correlated with survival over a follow-up period of 1.5-10 years. Women who initially detected their breast cancer in spring/summer had a significantly longer survival than those detecting their tumour at other times of the year. Overall, this relationship was independent of nodal status, tumour size and hormone receptor status. However, when patients were divided into groups the survival advantage was significantly associated with receptor status and age. Women aged greater than or equal to 50 years with ER-positive and PR-positive tumours who discovered their initial tumour in spring/summer had significantly better survival than those detecting their tumours at other times of the year. Survival was also longer in women aged less than 50 years with receptor-negative tumours who initially found their tumours in spring/summer compared with the rest of the year. This study suggests that the season of first detection of a breast cancer relates significantly to the later behaviour of the tumour, and may reflect seasonal changes in hormone dependent growth.