The role of antiestrogen treatment of postmenopausal breast cancer patients with high risk of recurrent disease is evaluated in a nationwide, prospective trial conducted by the Danish Breast Cancer Cooperative Group (DBCG). After total mastectomy and postoperative radiotherapy (RT), 840 patients were randomized to treatment with tamoxifen (RT + TAM) for one year, and 824 were randomized to no further therapy (RT). The recurrenceree survival (RFS) after ten years of lifeable analysis is 31% in the RT + TAM treated group, and 28% in the RT group (p = 0.01). Survival is 38% and 34% in the two treatment groups, respectively (p = 0.04). The data were further analyzed with respect to prognostic factors such as age, number of positive nodes, tumour size, and degree of anaplasia. Survival is prolonged in nearly all subgroups of patients treated with RT + TAM. However, the prolongation is only significant in patients with four or more positive nodes, with tumours of less than 5 centimeters or with tumours of anaplasia grade II. Estrogen (ER) and progesterone receptor (PgR) concentrations were measured in tumours from 309 and 219 patients, respectively. Only patients with ER and PgR values above 100 fmol/mg cytosol protein seemed to have a prolongation of survival. In conclusion, a modest survival benefit is achieved with one year of adjuvant tamoxifen treatment. Nevertheless, this is the first example of a systemic treatment approach being able to change the fatal course of breast cancer in postmenopausal patients. By means of endocrine therapy, and in the context of a new randomized trial, the DBCG will try to improve the survival in these patients even further.
To examine how breast cancers found by mammographic screening differ from those found outside screening.
Comparative cohort study.
Turku, southwestern Finland.
126 women aged 40-74 years with breast cancer detected during the first round of mammographic screening in 1987-90 and 125 women within the same age range with breast cancer detected outside screening during the same period.
Primary tumour size, axillary nodal status, histological features, oestrogen and progesterone receptor concentrations, ploidy, and S phase fraction.
Compared with the controls women with cancers detected by screening had a smaller primary tumour (57 (46%) screened v 11 (10%) controls had tumours less than or equal to 11 mm in diameter, p less than 0.0001), and less often had axillary nodal metastases (104 (83%) screened v 71 (57%) controls node negative, p less than 0.0001). After adjustment for the smaller size of the primary tumour compared with control cancers, those cancers detected by screening were less likely to have axillary nodal metastases (odds ratio 0.44, 95% confidence interval 0.23 to 0.84), poor histological differentiation (0.20, 0.08 to 0.49), high mitotic counts (0.38, 0.15 to 0.97), tumour necrosis (0.45, 0.22 to 0.93) or to be of the ductal histological type (0.46, 0.22 to 0.95). They had low oestrogen receptor (0.29, 0.12 to 0.70) and progesterone receptor (0.35, 0.17 to 0.92) concentrations less often and had smaller S phase fractions (0.72, 0.55 to 0.96) than control cancers.
Even after adjustment for the smaller size of screen detected breast cancers, their histological and cytometric features suggest low malignant potential. They may also be less likely to metastasise to axillary lymph nodes than cancers found outside screening.
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BACKGROUND: Alcohol intake has been reported to be positively associated with an increased risk of postmenopausal breast cancer; however, the association with the estrogen receptor (ER) and progesterone receptor (PR) status of the breast tumors remains unclear. METHODS: Self-reported data on alcohol consumption were collected in 1987 and 1997 from 51,847 postmenopausal women in the population-based Swedish Mammography Cohort. Through June 30, 2004, 1188 invasive breast cancer case patients with known ER and PR status were identified during an average 8.3-year follow-up. We used Cox proportional hazards models to estimate multivariable relative risks (RRs) of breast cancer, adjusting for age; family history of breast cancer; body mass index; height; parity; age at menarche, first birth, and menopause; education level; use of postmenopausal hormones; and diet. Heterogeneity among groups was evaluated using the Wald test. All statistical tests were two-sided. RESULTS: Alcohol consumption was associated with an increased risk for the development of ER-positive (+) tumors, irrespective of PR status (highest intake [> or = 10 g of alcohol per day] versus nondrinkers, multivariable RR = 1.35, 95% confidence interval [CI] = 1.02 to 1.80; Ptrend
Comment In: J Natl Cancer Inst. 2005 Nov 2;97(21):1563-416264173
BACKGROUND: A full-term pregnancy is associated with a reduced risk of breast cancer, but the underlying biologic mechanism has not been elucidated. During pregnancy, maternal serum levels of alpha-fetoprotein, an estradiol-binding protein, rise sharply. In culture, alpha-fetoprotein inhibits the growth of estrogen-sensitive cells, including estrogen-sensitive breast cancer cells. Thus, we investigated whether a high level of alpha-fetoprotein in maternal serum during pregnancy is associated with a reduced risk of breast cancer. METHODS: From a population-based cohort of 42057 pregnant women in Denmark, enrolled in an alpha-fetoprotein-screening program from 1978 through 1996, we obtained a complete reproductive history, vital status, and a possible diagnosis of breast cancer (in 117 women) to the end of follow-up on September 1, 1998. RESULTS: During pregnancy, women with an alpha-fetoprotein level greater than or equal to the median value had a 41% lower risk of breast cancer than women with an alpha-fetoprotein level below the median value (relative risk [RR] = 0.59; 95% confidence interval [CI] = 0.41-0. 85). RRs for breast cancer by mother's age at childbirth were as follows: 29 years or younger, RR = 0.21 (95% CI = 0.08-0.56); 30-34 years, RR = 0.61 (95% CI = 0.32-1.14); 35-37 years, RR = 0.96 (95% CI = 0.49-1.89); and 38 years or older, RR = 0.71 (95% CI = 0.29-1. 75) (P for trend =.02). Further analyses suggested that high levels of alpha-fetoprotein were associated with a reduced incidence of aggressive disease. The most striking finding was that women with high levels of serum alpha-fetoprotein, compared with women with low levels of serum alpha-fetoprotein, showed a particularly reduced incidence of large tumors (>2 cm; RR = 0.24 [95% CI = 0.11-0.50]). CONCLUSION: A high level of alpha-fetoprotein in maternal serum during any pregnancy is associated with a low overall incidence of breast cancer and, in particular, with a low incidence of advanced breast cancer at diagnosis. This association appears particularly strong for a pregnancy occurring at a young age.
In the interval between screening examinations, some cases of breast cancer are invariably detected clinically in patients whose mammogram was considered to be normal at the earlier screening. During the first interval in the Stockholm study, 60 interval cancers were detected, giving a rate of 1.8 cases/1000 examinations/24 months. About half of these interval cases (31/60) were true interval tumours in that no sign of them could be found on the first mammogram; the other half, non-true, were possible to trace on the first mammogram. It is mainly women under 50 who feature in the interval group, above all in the sub-group of true interval cancers (p less than 0.05). The incidence of interval cancer rises, as expected, with the length of the interval (Fig. 1). In the final six months of the 2-year interval the incidence of interval cancers had risen to 88 per cent of the cancers detected in the control group in the same period of time. The cumulative incidence of interval cancers supports the hypothesis that the distribution of sojourn time in the interval 0-2 years is approximately rectangular. This means that shortening the interval by one-half would halve the number of interval cases. If mammography becomes a wide spread screening method for early detection of breast cancer, the number of non-true interval cancers could be a feed back on the effectiveness of the screening.(ABSTRACT TRUNCATED AT 250 WORDS)
The role of antiestrogen treatment in high risk postmenopausal patients with primary breast cancer is currently evaluated in a nationwide, prospective randomized trial conducted by the Danish Breast Cancer Cooperative Group. The primary treatment is total mastectomy and radiotherapy. As of February 1, 1982, 720 women were randomized to treatment with tamoxifen (30 mg daily for 1 year) and 691 women were randomized to no further therapy. Life-table analysis after 36 months shows a difference in recurrence rates of 9% (p = 0.19) in favor of the tamoxifen-treated patients. The material has been analyzed with respect to established prognostic factors such as age, degree of anaplasia, tumor size, and number of positive nodes. The rates of recurrent disease are lower in all subsets of patients treated with tamoxifen, but are only statistically significant in patients 50-59 years of age or with 4 or more positive lymph nodes. Regardless of treatment, ER negative patients have a 23% higher recurrence rate than ER positive patients after 18 months of analysis (p = 0.0033); this represents an approximate doubling of risk, and is independent of age, degree of anaplasia, tumor size, or lymph node status. With regard to PgR status, there is 11% higher recurrence rate in the PgR negative than in the PgR positive patients (p = 0.097).
The extent of apoptosis and the expression of Bcl-2 was investigated in tumor samples from 165 women who underwent surgery for primary breast carcinoma between 1989 and 1990 in South-East Sweden. Apoptosis was assessed by a DNA fragmentation assay for flow cytometry. Bcl-2 protein expression was analyzed with immunocytochemistry. Bcl-2 immunoreactivity correlated with estrogen receptor (ER) and progesterone receptor (PgR) positivity and was inversely correlated with p53 accumulation. Apoptosis increased with patient age and a high degree of apoptosis was negatively associated with Bcl-2 immunostaining. Apoptosis showed no significant correlation with any of the other variables studied, including prognosis. The group with Bcl-2-positive tumors tended to have a lower risk of distant recurrence than others, but the association of Bcl-2 with recurrence was different in groups divided by ER and PgR status. Whereas Bcl-2 positivity indicated a low recurrence rate among PgR-negative patients, in the PgR-positive group, those with Bcl-2-positive tumors showed a non significantly higher recurrence rate than Bcl-2-negative cases. In the PgR-positive group, Bcl-2-positive tumors also appeared more frequently to be lymph node positive and DNA aneuploid. The results suggest that hormone receptor status is of importance for the prognostic role of Bcl-2. Likewise, patient age merits consideration when apoptosis is studied in human cancer.
We investigated the association between the risk of locoregional recurrence (LRR) and biological subtypes defined by hormonal receptors (HR) and HER-2 status in women with invasive breast cancer (BC). A total of 618 newly diagnosed BC patients were identified from a cancer registry within a single institution with standardized methods of tumor assessment for estrogen receptor (ER), progesterone receptor (PR), and HER-2. Patients were stratified based on surgical treatment, breast-conserving therapy (BCT) versus modified radical mastectomy (MRM), as well as biological subtypes: HR+/HER-2- (ER-positive or PR-positive, HER-2-negative), HR+/HER-2+ (ER-positive or PR-positive, HER-2-positive), HR-/HER-2+ (ER-negative and PR-negative, HER-2-positive) and TN (ER-negative, PR-negative and HER-2-negative). The association between clinicopathological factors, biological subtype and LRR was evaluated with univariate and multivariate Cox analysis. With a median follow-up of 4.8 years, the rate of LRR was 7.5%. On multivariate analysis, TN, tumor size =2 cm and lymph node (LN) positivity were associated with increased risk of LRR (P = 0.023, P = 0.048, and P = 0.0034, respectively). In BCT group, HR-/HER-2+ and LN positivity were associated with increased risk of LRR (HR 11.13; 95% CI 2.78-44.53; P = 0.0007 and HR 5.40; 95% CI 1.67-17.43; P = 0.0048, respectively). In MRM group, TN subtype and LN positivity were associated with increased risk of LRR (HR 4.72; 95% CI 1.53-14.52; P = 0.0069 and HR 3.23; 95% CI 1.44-7.29; P = 0.0047, respectively). Compared to HR+/HER-2-, HR-/HER-2+ treated by BCT and TN treated by MRM showed a significant decrease of 5-year LRR free survival (P = 0.0002 and P = 0.002, respectively). Tumor profiling using ER, PR, and HER-2 biomarkers is a promising tool to identify patients at high risk of LRR based on surgical treatment. Our findings suggest a different follow-up and locoregional treatment for patients with HR-/HER-2+ and TN subtypes.
Long-term exposure to oestrogens is a well-recognised risk factor for breast cancer, whereas little is known about the influence of polymorphisms of genes involved in oestrogen biosynthesis and metabolism. A candidate, containing a single bp polymorphism, T-->C, (designated, A2 allele), might be the CYP17 gene, which codes for an enzyme involved in oestrogen synthesis. This polymorphism creates an additional Sp1-type promoter site (CCACC box), which has been shown to be associated with increased serum oestrogen levels. We performed a case-control study, to evaluate association of the CYP17 gene polymorphism with risk of breast cancer in young women (younger than 37 years). We found a statistically significant increased risk in carriers of at least 1 A2 allele [odds ratio (OR), 2.0; 95% confidence interval (CI), 1.1-3.5, p = 0.027], and a trend toward a gene-dose effect illustrated by a slightly higher risk for A2-homozygous subjects (OR, 2.8) than for heterozygous women (OR, 1. 9). Furthermore, when we investigated the CYP17 genotype in relation to tumour characteristics, breast cancer patients with 1 or 2 A2 alleles tended to have lower oestrogen receptor levels (risk ratio, 0.70; CI, 0.41-1.2, p = 0.44). Our findings suggest that CYP17 gene polymorphism influences breast carcinogenesis in young women. Int. J. Cancer (Pred. Oncol.) 84:350-353, 1999.
The vitamin D3 receptor gene (VDR) contains a TaqI RFLP that is associated with increased VDR mRNA stability, increased serum levels of 1alpha,25-dihydroxyvitamin D3 (1,25-D3), and decreased risk for prostate cancer. Determination of the TaqI genotype, in a group of young women with breast cancer (n = 111; age,