Showing papers on "Breast cancer published in 1984"

Estimates of the worldwide frequency of twelve major cancers.

Abstract: By examination of incidence mortality and relative frequency data an estimate has been made of the number of cancer cases in 12 common sites and of all cancers that occurred in 1975 and in the 24 areas of the world for which the UN publishes population data. While several cancers are of importance in localized areas or regions; e.g. cancer of the larynx these are infrequent on the world level and are not included here. While the relative importance of the selected sites varies from 1 area to another on a global basis the 1st 6 ranking cancer sites in males are lings stomach colon/rectum mouth/pharynx prostate and esophagus; in females they are breast cervix uteri stomach colon/rectum lung and mouth/pharynx. Cancers of these sites together with leukemias and cancers of the liver bladder and lymphatic tissues account for 75% of the estimated 5.9 million cancers that occurred in 1975. When the 2 sexes are combined stomach cancers are in 1st rank followed closely by lung; it is suggested that given current trends their rank order will soon be reversed. There are clear opportunities for cancer prevention by controlling tobacco smoking reducing infection by hepatitis B virus and curbing the excessive intake of alcohol. The increasing adoption of high fat diets may lead to more cancers of the large bowel breast and prostate. (authors modified)

Breast cancer: Relationship between the size of the primary tumour and the probability of metastatic dissemination

Abstract: The relationship between the size of the primary tumour upon initial treatment and the incidence of distant metastasis during the course of the disease was investigated using data from 2648 breast cancers treated at the Institut Gustave Roussy between 1954 and 1972. This analysis suggests the existence for each tumour of a critical volume (threshold) at which the first remote metastasis is initiated. The correlation between the size of the primary tumour and the probability of metastatic dissemination was assessed as well as the influence on this correlation of two prognostic indicators: histological grade and number of involved lymph nodes. It was found that the threshold volume is strongly correlated with the number of involved lymph nodes and the histological grading.

Pathologic predictors of early local recurrence in Stage I and II breast cancer treated by primary radiation therapy

Abstract: Thirty-four gross and histologic features of the primary tumor in 231 cases of clinical Stage I and II invasive breast cancer were reviewed in an attempt to identify features which might correlate with an increased risk of local recurrence within the breast following biopsy and primary radiation therapy. Local recurrence risk at 5 years was calculated for each feature studied. While results are reported in terms of 5-year actuarial local recurrence risk, not all patients were followed for 5 years (median follow-up period, 44 months). Patients with cases in which the biopsy was less than excisional had a considerably greater actuarial risk of local recurrence at 5 years than those in which the biopsy was excisional (36% versus 8%; P = 0.0005). Among 154 infiltrating ductal carcinomas treated by excisional biopsy prior to radiotherapy, histologic features associated with a significantly increased local recurrence risk at 5 years were the combination of extensive intraductal involvement by carcinoma and high nuclear grade and/or high mitotic index. Twenty-seven tumors demonstrated this constellation of features, and there was a 5-year actuarial local recurrence risk of 39% among this group. The local recurrence risk for the remainder of the population was only 4% (P less than 0.0001). Thus, through pathologic examination of the primary, the authors identified a subgroup of patients with a considerably increased risk of local recurrence following biopsy and primary radiotherapy.

Steroid‐hormone receptors in breast cancer

Abstract: An obvious problem for the surgeon or oncologist treating breast cancer has been to identify the patients likely to respond to endocrine manipulation. Until recently, clinical factors such as previous response to hormone therapy, disease-free interval, age and menopausal status, and location of the dominant metastatic lesion were the principal criteria for selecting therapeutic regimens for these women. Recently, the measurement of steroid hormone receptors has become an important laboratory test. Progress during the last decade has shown that: the most reliable methods of determining estrogen receptors (ER) and progestin receptors (PR) are multipoint titration analysis using dextran-coated charcoal, and sucrose density gradient centrifugation; 55% to 65% of primary breast tumors contain more than 10 femtomole/mg cytosol protein of ER; 45% to 55% of metastatic breast tumors contain more than 10 fmol/mg cytosol protein of ER; ER are present more often in tumors of postmenopausal women compared with those of premenopausal women; benign breast lesions such as fibrocystic disease and fibroadenomas usually contain less than 10 fmol/mg cytosol protein of ER; 90% of male breast carcinomas contain ER; approximately 55% of women with breast tumors containing ER respond objectively to endocrine therapy, either additive or ablative; less than 3% of women with breast tumors lacking ER respond objectively to hormone therapy. In addition, it has been suggested that the absence of ER in a breast tumor correlates well with an increased response to cytotoxic chemotherapy; 45% to 60% of primary or metastatic breast tumors contain PR. Also, the presence of both ER and PR in a breast tumor indicates a 75% to 80% likelihood that the patient will respond to endocrine manipulation, either additive or ablative; it has been suggested that the presence of the 8 Svedberg form of ER in a breast tumor (as detected by sucrose gradient centrifugation) improves the accuracy of selecting the patient likely to respond to endocrine therapy; and there appears to be a relationship between the quantity of ER in a breast tumor and a patient's response to endocrine therapy. The incidence of response to hormone therapy increases with increasing ER levels.

The Psychological Impact of Immediate Breast Reconstruction for Women with Early Breast Cancer

Abstract: Twenty-five patients were evaluated, 13 who had immediate breast reconstruction and 12 who had delayed breast reconstruction for early breast cancer. Data were elicited about the psychological impact of the cancer, the mastectomy, and the reconstruction. Our results support the conclusion that immediate breast reconstruction is accompanied by a lower incidence of psychological morbidity postoperatively, and we recommend that immediate breast reconstruction be offered as an alternative to women with early breast cancer.

Smoking and estrogen-related disease

Abstract: This review considers the possibility that female smokers have a modified risk of estrogen-related disease. The association of smoking with 2 estrogen deficiency states--early menopause and postmenopausal osteoporosis--is examined and data on possible negative relationships between smoking and cancers of the breast and endometrium are reviewed. Data were obtained through literature searches and consultations with investigators having unpublished results. Epidemiologic evidence strongly supports an association of smoking with early menopause. Toxic effects on the ovary enhancement of estrogen metabolism and effects on central nervous system hormone release have been proposed as the mechanism of this relationship but none has been fully investigated. Smoking also appears to be associated with osteoporotic fractures in postmenopausal women particularly among thin women not on estrogen. Although data are sparse and confounding questions exist female smokers appear to be at lower risk of endometrial cancer than nonsmokers. Ex-smokers may be at higher risk of breast cancer than current smokers perhaps reflecting hormonal changes associated with stopping smoking. The precise role of estrogens in breast cancer etiology remains undefined however. Data are insufficient to determine whether a smoking association with osteoporosis and breast and endometrial cancer arises through smokings association with early menopause. Overall the data suggest a smoking impact on estrogen-related phenomena. The mechanism of this association is probably extraovarian. It is noted that whatever protective effect smoking may have for estrogen excess disease smokers have a substantially higher overall mortality than nonsmokers.

Feature enhancement of film mammograms using fixed and adaptive neighborhoods.

Abstract: Digital techniques are presented for xerographylike enhancement of features in film mammograms. The mammographic image is first digitized using a procedure for gray scale dynamic range expansion. A pixel operator is then applied to the image, which performs contrast enhancement according to a specified function. The final transformation leads to either a positive or negative mode display as desired. We also present an adaptive neighborhood feature enhancement technique that enhances visibility of objects and details in an image. The availability of the enhanced images should aid diagnosis of breast cancer without requiring additional x-ray dose such as for xeromammography.

Plasma retinol, β -carotene and vitamin E levels in relation to the future risk of breast cancer

Abstract: Plasma retinol, β -carotene and vitamin E levels in relation to the future risk of breast cancer

Increased incidence of thromboembolism in stage IV breast cancer patients treated with a five-drug chemotherapy regimen

Abstract: We report an incidence of thrombosis of 17.6% in 159 patients treated with a five-drug chemotherapy regimen (cyclophosphamide, methotrexate, 5-fluorouracil, vincristine, and prednisone) for Stage IV breast carcinoma. Chi-squared analysis of risk factors for thrombosis (ambulatory status, obesity, family history, smoking, diabetes mellitus, hypertension, liver dysfunction, thrombocytosis, and previous endocrine therapy) showed no difference between the patients who had a thromboembolic event and those who did not. Statistical analysis revealed that a significantly higher incidence of thrombosis occurred during the chemotherapy regimen than when off this regimen (P less than 0.05). Detailed coagulation studies done prospectively on 10 patients receiving the five-drug chemotherapy regimen compared with 10 control patients showed a significantly elevated Factor VIII antigen:activity ratio in the group receiving the chemotherapy regimen compared with the control group and normals. These results implicate the chemotherapeutic regimen in the pathogenesis of the increased incidence of thrombosis. The pathophysiology of thrombosis in settings such as this awaits better in vitro tests defining the "hypercoagulable state."

Flow-cytometric DNA analysis in primary breast carcinomas and clinicopathological correlations

Abstract: Flow-cytometric DNA analyses of single cell nuclei were performed on nuclear suspensions prepared from biopsies of primary breast carcinomas in 638 patients. Propidium-iodide-stained cell nuclei were analysed in an Ortho 50-H Cytofluorograph. The patients were staged by the TMN classification. Sixty percent of all the patients had aneuploid primary breast carcinomas; of size T1, T2, T3, and T4 tumors, 51%, 63%, 67%, and 75% were aneuploid, respectively. The proportions of aneuploid tumors in each of the tumor stages SI, SIl, SII1, and SIV were 47%, 62%, 67%, and 69%, respectively. This trend to increasing aneuploidy proportions with more advanced disease was significant in contrast to the degree of aneuploidy found in relation to axillary nodal tumor involvement. Multiple aneuploid cell populations were found in 109 (17%) tumors. With a mean follow-up time of 16 months, 92 patients have relapsed out of 540 completely staged patients with unilateral breast cancer with no distant metastases at the time of initial treatment. When the influence of various treatments and tumor stage are not considered, the recurrence rate was twice as high among patients with aneuploid primary tumors than among patients with euploid tumors. The differences in relapsing rates among patients with euploid and aneuploid primary tumors decreased with more advanced disease. Out of 170 patients with T1 tumors, 17 relapsed and 16 of these were aneuploid. No such difference in relapse rate in relation to ploidy was, however, found in patients with more advanced primary disease.

Epidermal growth factor receptors in human breast cancer

Abstract: The capacity for specific binding of125I-epidermal growth factor (EGF) was studied in crude membrane fractions from 95 human breast carcinomas. About 42% of the samples showed saturable, high affinity, specific binding of EGF. In 21% of the tumors we were able to demostrate high (above 10 fmoles/mg protein) binding capacity. Moreover, high EGF receptor values were associated with a low content of estradiol receptor. These studies are related to the definition of new biochemical markers in human breast cancer.

Androgen receptors in breast cancer.

Abstract: Androgen receptor assays have been performed on 1371 specimens of histologically confirmed primary and recurrent breast cancer. Forty-two patients who had received tamoxifen as treatment for advanced disease were assessed for objective response. Another 42 patients who had received chemotherapy were similarly studied. Patients with androgen receptor-negative tumors had a significantly poorer response rate to hormone therapy than those with receptor-positive tumors (P less than 0.05). This clinical correlation is supported by survival data of 1181 patients with primary breast cancer which showed that patients with androgen receptor-negative tumors had a highly significant trend toward shorter overall survival than those with receptor-positive tumors (P less than 0.001). Androgen receptor data added significantly to the information provided by estrogen receptor data both in terms of response to hormone treatment and survival.

Breast cancer in mothers given diethylstilbestrol in pregnancy.

Abstract: We compared the incidence of breast cancer in 3033 women who had taken diethylstilbestrol (DES) in pregnancy during the period from 1940 to 1960 with the incidence in a comparable group of unexposed parous women. We ascertained vital status in 95 per cent of the exposed women and in 93 per cent of the unexposed women and received completed questionnaires for 88 and 85 per cent, respectively. With over 85,000 woman-years of follow-up in each group, the incidence of breast cancer per 100,000 woman-years was 134 in the exposed group and 93 in the unexposed group, yielding a crude relative risk of 1.4 (95 per cent confidence interval, 1.1 to 1.9). The elevated incidence did not appear to be due to bias or to confounding by other risk factors measured in the study. Breast-cancer mortality was slightly higher in the exposed women (relative risk, 1.1) but not significantly so (95 per cent confidence interval, 0.7 to 2.0). We conclude that the incidence of breast cancer is moderately increased in women g...

Height and weight, mammographic features of breast tissue, and breast cancer risk

Abstract: A case-control study was conducted to evaluate the association of body size with morphologic features of breast tissue visible on mammograms, and to analyze the interrelations of these factors with breast cancer risk. The cases were 362 women with newly diagnosed breast cancer identified in 1978-1979 in three large hospital-based xeromammography units in Boston, Massachusetts, and one unit in Livingston, New Jersey. The controls were 686 women referred to these units in the same period for a "routine" mammogram. The parenchymal pattern (N1, P1, P2, DY) and the per cent of the breast showing nodular densities were the principal mammographic features assessed. Among controls, body weight was strongly but inversely associated with the per cent of women who had the high risk P2 or DY patterns and with the mean per cent of the breast showing nodular densities. Body weight and the amount of nodular densities were both directly related to breast cancer risk. The strengths of the relations of body weight and of nodular densities to risk were each increased when the other factor was taken into account.

Prognostic significance of estrogen receptor status in breast cancer in relation to tumor stage, axillary node metastasis, and histopathologic grading

Abstract: The value of estrogen receptor (ER) measurements for predicting recurrence and survival rates in primary breast cancer was examined in 121 women who were followed from 5 to 12 years after mastectomy with a median follow-up of 64 months. The prognostic significance of the ER status was evaluated independently and in association with tumor stage, axillary node metastasis, and histopathologic grade. The independent evaluation demonstrated no statistically significant difference in prognosis between women with ER-negative and ER-positive cancers, although the latter group tended to have a longer time to recurrence and longer survival. Multivariate analysis of the data by Cox's proportional hazard regression techniques revealed a synergistic effect of ER status on the risk associated with axillary node metastasis. Patients with nodal metastasis were at 2.8 times the risk of recurrence compared to patients without metastasis. For women with nodal metastasis whose primary cancer was ER-negative, this risk increased to 4.6 times compared to women without metastasis and ER-positive tumors (P = 0.0003). The risk of cancer-related death was 5.6 times more likely for poorly differentiated tumors than for highly differentiated tumors. Patients with poorly differentiated ER-negative tumors were at an even higher risk (7.0) of dying than women with highly differentiated ER-positive carcinomas (P = 0.009). In conjunction with tumor stage, axillary node metastasis and histopathologic grade ER determination is useful for identifying subpopulations at increased risk of tumor recurrence or mortality.

Mammographic features of "early" breast cancer

Abstract: Mammographic detection of breast cancer at the earliest possible stage requires optimal radiographic technique and a full knowledge of the subtle features with which very small cancers can present. Although some early cancers are identified as characteristic clusters of calcifications or as spiculated or multinodular (knobby) masses, others demonstrate less typical and sometimes much less obvious mammographic signs: the single dilated duct, focal architectural distortion, asymmetry, and the developing density sign. Although these indirect signs are nonspecific, they provide mammographers with the important opportunity to discover breast cancer at a very early stage, when the likelihood for cure is great.

Breast self-examination practices and breast cancer survival

Abstract: To determine the relation between breast self-examination and survival of breast cancer patients, the authors studied 1004 newly diagnosed invasive breast cancer patients in Vermont general hospitals from 1 July 1975 to 31 December 1982. More frequent breast self-examination was associated with a greater likelihood of the patient's detecting her own cancer, less delay from first symptom to histologic diagnosis, earlier clinical stage, smaller pathologic tumor size, and fewer axillary node metastases. At a median follow-up time of 52 months (maximum follow-up, 92 months), 14% of the breast self-examination performers had died of breast cancer versus 26% of the nonperformers (P less than 0.001 based on chi-square). The product limit survival curve for breast self-examination performers (N = 424) was significantly better (P less than 0.001 by log-rank test) than for breast self-examination nonperformers (N = 411). Survival at 5 years was 75% for breast self-examination performers versus 57% for the nonperformers. The significant survival differences persisted after adjusting for any combination of the covariates age, method of detection, family history of breast cancer, and delay in treatment (P less than 0.002). Lead-time would have to be at least 3 years to negate the apparent beneficial effects of breast self-examination on survival. The authors conclude that in this population of breast cancer patients, breast self-examination was related to earlier detection and improved survival.

Pathologic findings from the national surgical adjuvant breast project (protocol no. 4): XI. Bilateral breast cancer

Abstract: Sixty-six confirmed instances of clinically metachronous second breast cancers were encountered over a 10-year period in 1578 women with invasive breast cancer enrolled in Protocol 4 of the National Surgical Adjuvant Breast Project (NSABP). Seven of the second cancers were in situ, yielding an incidence of 3.7% invasive and 0.5% noninvasive cancers. Except for a peak of 1.75% in the second postoperative year, the annual incidence based on patients at risk was constant and less than 1%. Ninety-three percent of the second cancers occurred within 7 years and 80% within 5 years following mastectomy for the initial primary. All of the second cancers were regarded as being primarily of mammary origin exhibitng either: (1) an in situ component; (2) dissimilar but well-recognized patterns of primary breast cancers; or (3) the appearance of scar cancer, a recently described morphologic feature characteristically observed in some primary breast cancers. A search for factors that might be predictive of bilaterality was performed. Thirty-eight pathologic and eight clinical factors were assessed, including family history. Although the latter was 1.5 to 2 times more frequent in patients with bilateral disease, this estimate was not statistically significant. On the other hand, a statistically significant association with bilateral disease was found when the initial tumor measured more than 2.0 cm, was associated with invasive cancer or proliferative fibrocystic disease, nipple involvement, absent nodal sinus histiocytosis, lobular carcinoma in situ in the vicinity of the dominant mass, or was of the lobular invasive or tubular types. However, the degree of risk of these discriminants was no greater than 2 to 3:1. Despite the clinical scrutiny imposed by the NSABP protocol second tumors measured only 1 cm less than the first, measuring on average 2.4 cm, which reflects the difficulty attendant on the clinical detection of so-called early breast cancers. Yet, no significant difference in pathologic nodal status was noted between the first and second cancers or that of patients with unilateral disease. Furthermore, there was no difference in survival rate between patients who developed a second cancer and those with unilateral disease. These data, when considered with those of previous reports, indicate that: (1) the incidence as well as annual accrual per patients at risk of bilateral cancers is low; (2) most second cancers, although clinically metachronous, are probably biologically synchronous; (3) a second cancer does not influence the expected survival of patients who develop such an event; (4) the incidence of contralateral metastases from breast cancer is extremely rare and their distinction from a second primary depends principally if not exclusively on histologic assessment rather than on the somewhat empirical considerations often used in the past; (5) the influence of predictive characteristics for the development of bilateral disease that have been enumerated are relatively weak; and (6) it is justifiable to follow the contralateral breast of patients with breast cancer by careful physical and mammographic examinations rather than contralateral biopsies or mastectomies.

Do hormones cause breast cancer

Abstract: The evidence that various endogenous and exogenous sex hormones play a role in the etiology of breast cancer is reviewed. It is hypothesized that prolonged exposure to normal levels of ovarian estrogens and cyclic progesterone resulting from early menarche and late menopause, and primarily willful nulliparity and late childbearing, act at an early stage in the development of breast cancer by promoting excessive proliferation of normal epithelial stem cells. Excess endogenous or exogenous estrogens can enhance risk by stimulating proliferation of epithelial cells that have undergone partial malignant transformation. The breast, however, is much less responsive to the tumor-promoting effects of estrogens than the endometrium, and estrogens probably play a less important role in the later stages of mammary than endometrial carcinogenesis.

A Stochastic Numerical Model of Breast Cancer Growth That Simulates Clinical Data

Abstract: A new stochastic numerical model of breast cancer growth is developed. First, the model suggests that Gompertzian kinetics does apply but that from time to time, in random fashion, there occurs a spontaneous change in the growth rate or rate of decay of growth, such that the overall growth pattern occurs in a stepwise fashion. According to the model, the average time for the tumor burden to increase from one cell to detection is probably in the range of 8 years. Secondly, the model suggests that there is a linear relationship between the number of axillary lymph nodes positive for metastasis at diagnosis and the number of other metastatic sites. This can be described mathematically by the equation S = 0.24 + 0.35N where S is the number of other metastatic sites and N is the number of positive lymph nodes. The model has been verified by simulating three data sets: (a) the survival times of untreated breast cancer patients as described by Bloom et al. [Br. Med. J., 2: 213–221, 1962]; (b) the growth rates of breast cancers immediately prior to diagnosis as described by Heuser and Spratt [Cancer (Phila.), 43: 1888–1894, 1979]; and (c) the disease-free survival time postmastectomy as described by Fisher et al. [Surg. Gynecol. Obstet., 140: 528–534, 1975]. This model could have implications concerning the overall treatment rationale for breast cancer.

Noncontraceptive Estrogen Use and the Risk of Breast Cancer

Abstract: The relation between the risk of breast cancer and the use of noncontraceptive estrogens was investigated in a hospital-based study of 1,610 women with breast cancer and 1,606 with other conditions. The overall relative risk estimate for conjugated estrogens first taken at least 18 months before admission, compared with never-use of any noncontraceptive estrogens, was 0.9 (95% confidence interval, 0.7 to 1.1). For other estrogens first taken at least 18 months before admission, the estimate was 0.8 (0.6 to 1.1). The results were similar when known risk factors for breast cancer were taken into account. Among postmenopausal women, conjugated estrogens did not appear to increase the risk of breast cancer, even when taken for many years or in the distant past. There was no evidence of an increased risk due to conjugated estrogen use among subgroups of women defined according to various risk factors for breast cancer. The results of this study suggest that noncontraceptive estrogens do not increase the risk of breast cancer. ( JAMA 1984;252:63-67)

Cowden's disease: Analysis of fourteen new cases

Abstract: Fourteen new patients with Cowden's disease from the Netherlands were analyzed and compared with the sixty-nine previously reported patients. The full clinical spectrum of the disease can now be fairly well delineated. Mucocutaneous lesions, especially facial trichilemmomas and other follicular malformations, acral keratoses, and oral papillomas, remain the most constant findings. The incidence of each of these mucocutaneous findings was slightly higher than reported previously, probably reflecting increasing experience with this condition. Also our patients tended to have more extensive acral keratoses and perhaps less extensive facial lesions. In one family there was an extremely high incidence of lipomas. Breast cancer was seen in three of our twelve female patients, reflecting the trend toward a lower incidence of breast cancer in the recent literature. Gastrointestinal polyps in one family were much more common than previously reported, occurring in five of seven patients. Thyroid disease was found in about two thirds of the patients and abnormalities of the female reproductive system in slightly more than half of the patients, both incidences being approximately the same as in the literature. With increased awareness of the condition it is likely that many more cases will be recognized in the future.

Precancerous and cancerous breast lesions during lifetime and at autopsy. A study of 83 women.

Abstract: Among 83 consecutive, unselected female autopsy cases, 6 had been treated for invasive breast carcinoma (IBC) during lifetime. At autopsy, of these six women, two had IBC in the contralateral breast, and another two had in situ carcinoma. Among the 77 women without previous clinical breast cancer, one case of IBC and 14 cases of in situ carcinoma were found at autopsy. Thus, the total occurrence of primary malignant breast lesion was as high as 25.4%. Assuming that all IBCs evolve from in situ forms and that in situ carcinomas do not undergo total regression, our results seem to indicate that about one third of all in situ carcinomas develop into IBC.

The immunocytochemical detection of axillary micrometastases in breast cancer.

Abstract: The histological detection of tumour metastases in axillary lymph nodes from cases of breast carcinoma is of major prognostic significance, but may be difficult when metastases are of microscopic size. We have therefore investigated whether immunohistological techniques can increase the accuracy of metastasis detection in axillary lymph nodes. Forty-five cases of breast carcinoma were studied, in all of whom the axillary lymph nodes had been reported as free of metastases. Paraffin sections from these cases were stained by immunoenzymatic techniques, using monoclonal antibodies directed against human milk fat globule membrane antigen ("anti-EMA") and against epithelial intermediate filaments ("anti-keratin"). In 4/12 cases of lobular carcinoma and in 3/33 cases of ductal carcinoma, previously unsuspected micrometastases were revealed by immunohistological staining, representing an overall increase in detection rate of 15% (and of 33% for the lobular carcinoma cases). In addition to this group of 45 histologically "negative" biopsies, 12 samples were studied in which only a proportion of the nodes had been reported as containing tumour. In 5 of these cases immunostaining revealed previously undetected metastases. These findings suggest that immunohistological analysis may have a routine role to play in the staging of breast carcinoma. It is noted that the 15% increase in diagnostic accuracy achieved in the present study is comparable to the proportion of breast carcinoma patients in whom disseminated disease develops despite their axillary lymph nodes being reported as tumour-free at the time of surgery.