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Background: The goal of this prospective study was to determine (a) concentrations of the carbohydrate biomarkers Thomsen Friedenreich (TF) antigen and its precursor, Tn antigen, in nipple discharge (ND) collected from women requiring biopsy because of a suspicious breast lesion; and (b) if concentration levels predicted pathologic diagnosis., Methods: Adult women requiring biopsy to exclude breast cancer were enrolled and ND obtained. The samples from 124 women were analyzed using an anti-TF and anti-Tn monoclonal antibodies in direct immunoassay., Results: The highest median concentration in ND for TF and Tn was in women with ductal carcinoma in situ (DCIS). TF was higher in women with 1) cancer (DCIS or invasive) vs. either no cancer (atypia or benign pathology, p = .048), or benign pathology (p = .018); and 2) abnormal (atypia or cancer) versus benign pathology (p = .016); and was more predictive of atypia or cancer in post- compared to premenopausal women. Tn was not predictive of disease. High TF concentration and age were independent predictors of disease, correctly classifying either cancer or abnormal vs. benign pathology 83% of the time in postmenopausal women., Conclusions: TF concentrations in ND were higher in women with precancer and cancer compared to women with benign disease, and TF was an independent predictor of breast atypia and cancer. TF may prove useful in early breast cancer detection.

Background: Eukaryotic Initiation Factor 4E (eIF4E) plays a crucial role in translation control. High eIF4E increase in tumor specimens independently predicted recurrence by multivariate analysis. This prospective trial of node-negative only breast cancer patients was initiated to test the hypothesis that high eIF4E increase predicts cancer recurrence and death, independent of nodal status., Methods: The trial was powered to detect a 2.4-fold increase in relative risk for cancer recurrence in 240 node-negative patients on the basis of high versus low eIF4E increase in tumor specimens (type I error = .05, statistical power = .08). eIF4E level was quantified by using Western blot test. Treatment and surveillance regimens were standardized. Primary endpoints were cancer recurrence and cancer-related death., Results: Of the 242 patients accrued, 112 were in the low eIF4E group (<7.5-fold), 82 were in the intermediate eIF4E group (7.5- to 15-fold), and 48 were in the high eIF4E group (>15-fold). Patients in the high eIF4E group had a statistically significant higher rate of cancer recurrence and cancer-related death (P = .0001 and P < or = .0001, log rank test). The relative risk for cancer recurrence was 2.2-fold higher in the high eIF4E group (P = .001, Cox model), and 3.7-fold higher for cancer-related death (P = .0009)., Conclusions: In node-negative breast cancer, high eIF4E increase predicted a higher rate of cancer recurrence and death. High eIF4E patients had a >2-fold increase in relative risk for cancer recurrence and nearly a 4-fold increase in relative risk for death. This supports our hypothesis that high eIF4E is an independent predictor for breast cancer outcome independent of nodal status.

The discovery of 25,000 human genes from the Human Genome Project has had a dramatic impact on the translational landscape of human diseases. Nowhere is the impact more apparent than in the field of cancer, specifically breast cancer. Understanding of the malignant process at a molecular level, coupled with the discovery of novel molecular techniques, has shifted the paradigm of treating breast cancer from a clinical, population-based risk assessment model to one based on molecular classification of disease.

To investigate the role of genetics in the development of cancer, we developed a new approach to analyze data on prostate, breast, and colorectal cancer from the Swedish, Danish, and Finnish twin registries on monozygotic (MZ) and same-sex dizygotic (DZ) twins. In the spirit of a sensitivity analysis, we modeled genetic inheritance as either an autosomal recessive or dominant cancer susceptibility (CS) genotype that involves either a single gene, many genes with equal allele frequencies, or three genes with a ninefold range of allele frequencies. We also modeled the joint probability of cancer incidence among five age categories, conditional on the presence or absence of the CS genotype. The main assumptions are: (1) The joint distribution of unobserved environmental effects in a twin pair conditional on the presence or absence of the CS genotype is the same for MZ and DZ twins, (2) the probability of cancer conditional on the presence or absence of the CS genotype and the unobserved environmental effects (i.e., the gene-environment interaction) is the same for MZ and DZ twins, and (3) the probability of cancer is independent between twins with the CS genotype. Estimation was maximum likelihood via a search over allele frequency and two levels of EM algorithms. Models had acceptable or good fits. Variability was estimated using a bootstrap approach, but only 50 replications were feasible. The 94th percentile of bootstrap replications for the estimated fraction of cancers with the CS genotype ranged, over the various genetic models, from 0.16 to 0.45 for prostate cancer, 0.12 to 0.30 for breast cancer, and 0.08 to 0.27 for colorectal cancer. We conclude that genetic susceptibility makes only a small to moderate contribution to the incidence of prostate, breast, and colorectal cancer.

Five to ten percent of cases of breast cancer and colorectal cancer are familial. These families can be divided into high-risk families and moderate-risk families. Cancer in high-risk families can often be explained by dominant inheritance of a gene causing increased susceptibility to cancer. There is a great demand for genetic counseling in these families, and the structure of and experiences from a familial cancer clinic at Odense University Hospital is described. The establishment of a familial cancer clinic involves three steps: 1) Identification of families with increased cancer susceptibility; 2) Molecular tests to identify gene carriers; 3) Clinical examinations for early detection of tumors. Achievement of these three steps requires the involvement of several medical specialties to ensure patient care. Experience with familial cancer clinics is still limited and the involvement of genetic testing and clinical examination programs at risk individuals are insufficiently examined. The rapidly improving techniques for genetic testing make it urgent that it is implemented as part of already established clinical programs.

The Danish Twin Register consists of the total population of twin pairs born in Denmark during a certain period. Within this population were found 50 monozygotic (MZ) female twins belonging to 45 MZ pairs and 81 dizygotic (DZ) twins belonging to 77 DZ female pairs, of which at least 1 twin had breast cancer (BC) and both twins were alive at the time of the first BC diagnosis. In 5 MZ and 4 DZ pairs, both partners had BC. Pairwise concordance rates were not significantly different between the 2 groups of twins but were of the same magnitude as in a previous study. The heritability, evaluated by genetic determination, was estimated to be 0.30-0.40. The observed number of BC cases developing in the co-twins after the first BC diagnosis in the twin pairs was increased by a factor of nearly 6 in MZ co-twins and by a factor of about 2 in DZ co-twins. For cancer of other sites, the observed and expected numbers were nearly identical in both MZ and DZ co-twins. In 8 of 9 pairs concordant for BC, the lesion was found on the same side. The mean age at diagnosis showed no significant difference between the concordant and discordant pairs. In the 40 MZ pairs with only 1 twin affected, she was more often unmarried and/or nulliparous than her unaffected, genetically identical co-twin, but this finding was not significant. A general tendency for the twin with BC to have the first child at a later age than her unaffected twin sister could not be demonstrated.

The influence of postoperative radiation therapy on development of late arm lymphedema and shoulder joint disability following mastectomy was evaluated from a series of 57 women with operable carcinoma of the breast. The patients were divided into three groups. Common for all three groups was mastectomy and partial axillary dissection. In addition one group received postoperative irradiation plus systemic therapy and another group systemic therapy alone. The incidence of late arm lymphedema/impaired shoulder mobility was 11%/4% in the group of patients undergoing surgery alone, 46%/38% in the group of patients receiving adjuvant irradiation and 6%/12% in the group of patients receiving adjuvant systemic therapy. It is concluded that adjuvant irradiation to the axilla in patients with metastatic lymph nodes highly increases the risk of late physical sequelae following modified radical mastectomy. Adjuvant systemic therapy can be administered to high risk patients without increasing the risk of late arm lymphedema and shoulder disability.

The distribution of metastases at the first recurrence of breast cancer was studied in 57 estrogen receptor (ER) positive and in 23 ER negative patients, who constituted a subset of 460 patients with operable breast cancer. The pattern of metastases with respect to localization of metastases and the dominant site of first recurrence was similar in patients with ER positive and ER negative tumours. The recurrence-free survival (RFS) and the overall survival were associated with the ER status in the 460 patients. ER positive patients had both a significantly longer RFS (p = 0.0024) and survival (p = 0.0001) compared to ER negative patients. Survival after recurrence was prolonged in patients with soft tissue recurrences only, and the proportion of dead patients was highest in receptor negative patients with metastases to bone and viscera. In conclusion, we could not demonstrate that ER positive and negative tumours have a propensity for recurrence at specific sites.