Organochlorines and breast cancer risk by receptor status, tumor size, and grade (Canada).

OBJECTIVE: We evaluated the association between organochlorines and breast cancer subtype defined by the tumor characteristics: estrogen receptor status, progesterone receptor status, tumor size, and grade. METHODS: A case-control study was conducted from 1995 to 1997 in Kingston and Toronto, Canada. Breast adipose tissue, taken from 217 cases and 213 biopsy controls frequency-matched on age, was analysed for 14 polychlorinated biphenyl (PCB) congeners and 10 pesticides. RESULTS: Adjusting for age, geometric means of several organochlorines differed by estrogen receptor status and tumor grade (p < 0.05). Odds ratios (ORs) for each organochlorine relative to the common control group for breast cancers of differing subtype were compared using polytomous logistic regression. Although the ORs did not differ significantly by subtype, the ORs of PCBs and p, p'-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) were higher with risk of estrogen receptor-negative breast cancer than estrogen receptor-positive breast cancer. One of the most extreme differences was with DDE, where the OR for the association with risk of estrogen receptor-negative breast cancer was 2.4 (95% confidence interval (CI) 1.0-5.4) in the uppermost tertile relative to the lowest, whereas the corresponding OR for risk of estrogen receptor-positive breast cancer was 1.1 (95% CI 0.6-1.9). PCBs also tended to be more strongly positively associated with risk of larger and higher-grade tumors. CONCLUSIONS: The association between organochlorines and breast cancer risk did not significantly differ by subtype, but many PCBs were more strongly associated with tumors of poor prognosis.

Mammographic density changes in perimenopausal and postmenopausal women: is effect of hormone replacement therapy predictable?

BACKGROUND: Mammographic density adversely affects diagnostic accuracy and may be a risk factor for breast cancer. Mammographic density is affected by hormone replacement therapy (HRT). OBJECTIVE: To assess mammographic density in postmenopausal women with and without HRT. METHOD: Part I. Mammographic density was determined in 1232 postmenopausal women attending a breast screening clinic. Density was compared between HRT users and nonusers in three age groups. When available, previous mammograms were assessed for interval density change. Part II. Density change in 162 women during transition from premenopause to postmenopause was recorded. HRT effect was assessed. RESULTS: Part I. There was no density difference between postmenopausal HRT-users and nonusers younger than age 55. Thereafter, the density was significantly less in nonusers. In the majority of HRT-users the density remained at pretreatment levels but density increased in 8% of women after HRT was started. Part II. Of 117 HRT nonusers followed over menopause 38% had a density decrease before age 55. Of those started on HRT, 80% had no density change, 18% decreased density and 2% increased density. CONCLUSIONS: The density decreases significantly after age 55 with the greatest change occurring between age 55 and 64. This decrease does not occur in the majority of HRT-users. Usually HRT maintains the density present at the time HRT is started. Density decreases after HRT is started in some women suggesting refractoriness to hormones. In fewer than 8% of women density increases commensurate with HRT. Any adverse effect of HRT may depend on the receptivity of the epithelial elements which, in turn, may be reflected by the mammographic density at the time HRT is started.

Breast adipose tissue concentrations of polychlorinated biphenyls and other organochlorines and breast cancer risk.

Numerous studies have examined the relationship between organochlorines and breast cancer, but the results are not consistent. In most studies, organochlorines were measured in serum, but levels in breast adipose tissue are higher and represent cumulative internal exposure at the target site for breast cancer. Therefore, a hospital-based case-control study was conducted in Ontario, Canada to evaluate the association between breast cancer risk and breast adipose tissue concentrations of several organochlorines. Women scheduled for excision biopsy of the breast were enrolled and completed a questionnaire. The biopsy tissue of 217 cases and 213 benign controls frequency matched by study site and age in 5-year groups was analyzed for 14 polychlorinated biphenyl (PCB) congeners, total PCBs, and 10 other organochlorines, including p,p'-1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene. Multiple logistic regression was used to assess the magnitude of risk. While adjusting for age, menopausal status, and other factors, odds ratios (ORs) were above 1.0 for almost all organochlorines except five pesticide residues. The ORs were above two in the highest concentration categories of PCB congeners 105 and 118, and the ORs for these PCBs increased linearly across categories (Ps for trend < or =0.01). Differences by menopausal status are noted especially for PCBs 105 and 118, with risks higher among premenopausal women, and for PCBs 170 and 180, with risks higher among postmenopausal women. Clear associations with breast cancer risk were demonstrated in this study for some PCBs measured in breast adipose tissue.

Liarozole fumarate (R85246): in the treatment of ER negative, tamoxifen refractory or chemotherapy resistant postmenopausal metastatic breast cancer.

Three phase II studies were conducted to determine the efficacy and tolerability of liarozole fumarate (R85246; liarozole), a retinoic acid metabolism blocking agent (RAMBA) and aromatase inhibitor. Additionally, animal experiments in the MNU-induced rat mammary tumor model and in immature ovariectomized rats were conducted to further elucidate liarozole's mechanisms of action. Patients were postmenopausal with either: ER negative disease in first relapse (Group 1: 1n = 16); ER positive or unknown disease refractory to tamoxifen (Group 2; n = 16); ER positive, negative or unknown disease resistant or refractory to chemotherapy (Group 3; n = 27). Treatment was liarozole (150-300mg) twice daily orally until disease progression. Response rates were: 25% in group 1 (95% CI 11.0-52.3%: median duration (MD) 20 months; range 2-36.5); 25% in group 2 (95% CI 11.0-52.3%; MD 6.5 months: range 3.5-38): 11% in group 3 (95% CI 4.2-29.2%; MD 7 months; range 3-8.5). No significant improvement in quality of life scores (FLI-C) was noted. Toxicities observed were predominantly dermatological (skin disorders: 88%; dry mouth/eyes/lips: 69%). Plasma estradiol decreased from mean pre-treatment levels of 72.7 pM (9.1-1,839 pM) to below detection (9.2 pM) after 1 month. Liarozole, but not vorozole, partially inhibited estradiol induced uterine hypertrophy and demonstrated dose-dependent anti-tumor effects in the rats, only partially overcome by coadministration of estradiol. The clinical responses observed, together with our preclinical results, confirm liarozole's dual mechanism of action and provide a rationale for further evaluation of RAMBAs in the treatment of breast cancer.

Mammographic density in women on postmenopausal hormone replacement therapy.

BACKGROUND: Studies have suggested that mammographic density and pattern are affected by hormone replacement therapy (HRT) and may influence breast diagnosis. Because 40% of breast cancers diagnosed at our center are mammographically detected while still clinically occult, mammographic sensitivity is crucial. For this reason we studied the effect of HRT on mammographic density. METHODS: During a period of 18 months we studied consecutive women older than 54 years attending for breast screening. We recorded HRT use and dosing regimes. A breast density score (BDS) was developed and applied to all mammograms. RESULTS: Mammograms of 148 HRT users were compared with those of 158 nonusers. HRT users had a significantly higher mean density score (4.7 versus 3.4; p < 0.001). Only 11% of non-HRT users had high scores compared with 37% among HRT users (p < 0.001). The significant difference remained when women were stratified by age. Duration of HRT (longer or shorter than 5 years) did not affect density scores. CONCLUSIONS: HRT is associated with a significant increase in breast density. In turn, density and mammographic sensitivity are related. The possibility that increased breast density will hamper mammographic diagnosis of clinically occult cancers is worrisome.

Changing emphasis in breast diagnosis: the surgeon's role in evaluating mammographic abnormalities.

BACKGROUND: The increasing number of mammograms performed has resulted in a substantial increase in surgical referral for mammographic abnormalities with or without clinically apparent change. This increase challenges surgeons to examine their criteria for biopsy. STUDY DESIGN: I performed a retrospective review of data from 2,936 women referred for breast assessment. Data from women younger or older than 50 years who were clinically normal or who had a clinically apparent lesion were evaluated to determine the effect of mammographic diagnosis on the biopsy rate, rate of carcinoma diagnosed per biopsy performed, and prevalence of carcinoma in the categories of mammographic results. RESULTS: Although the rates of biopsy and detection of carcinoma were different in younger and older women, the influence of mammographic diagnosis was similar. Regardless of age and presence or absence of a clinical abnormality, few breast carcinomas were detected in women whose mammograms showed normal breasts or benign lesions. Mammograms that showed malignant changes, even among women assessed as clinically normal, significantly influenced the rate of biopsy and the diagnoses of breast carcinoma. CONCLUSIONS: Women who are assessed as clinically normal and have mammograms that show benign lesions and women who have a breast problem judged clinically as benign and mammographic results that are normal or show a benign lesion can be observed with confidence that the risk of breast carcinoma is low. By careful selection, 40 percent of women who are assessed as clinically normal and younger than 50 years and 20 percent of women older than 50 years can be observed rather than undergo biopsy, even though the mammogram is considered to show malignant changes. A clinical abnormality combined with a mammographic finding of malignancy almost always requires performance of a biopsy. Because of the large number of women referred for surgical evaluations who have normal results on a mammogram or whose mammograms show a benign problem, a conservative approach is appropriate to reduce the number of biopsies performed in women of all ages.

Macromolecular interstitial clearance, tumour vascularity, other prognostic factors and breast cancer survival.

BACKGROUND: Clearance of large molecules from the interstitial space is an important function of lymphatics and is affected by local pathologic changes. OBJECTIVE: To determine if the clearance rate of interstitially injected albumin is correlated to tumour characteristics and outcome in women with invasive breast cancer. METHOD: In a consecutive series of women coming to biopsy for suspected breast cancer, technetium-tagged albumin was injected into the tissue adjacent to the palpable mass. The isotope disappearance rate was measured over two hours. Also assessed were the maximum vessel density (MVD-using Factor VIII polyclonal antisera), the proliferation rate (using Ki-67 antisera), node status, tumour size, histologic and nuclear grade, mitotic rate, and p53 and c-erbB-2 oncoproteins. All patients were followed until relapse and for a minimum of 10 years. RESULTS: In multivariate analysis, an association between relapse-free survival and isotope clearance rate was suggested (p = 0.024). The best outcome was seen in patients with the least isotope clearance. Node status, size, histologic and nuclear grade, and mitotic rate correlated with survival. MVD did not correlate with survival and was inversely related to the isotope clearance rate. Tumour proliferation rate, and the c-erbB-2 and p53 oncoproteins did not relate to outcome. CONCLUSION: The role of lymphatics in breast cancer is difficult to study. Measurement of interstitial clearance may be a useful technique and could be a prognostic factor.

Relation between clinical and mammographic diagnosis of breast problems and the cancer/biopsy rate.

OBJECTIVE: To determine the sensitivity of mammographic and clinical assessment of breast problems, independent of one another, on the ratio of cancers found to biopsies performed (cancer/biopsy rate). DESIGN: A review of diagnoses from prospectively recorded and independently assessed clinical and mammographic examinations. SETTING: The breast clinic in a university-affiliated hospital. PATIENTS: Patients were considered in two age groups--under 50 years and over; 1251 patients underwent breast biopsy between September 1976 and November 1994 after clinical assessment and mammography. MAIN OUTCOME MEASURE: The cancer diagnosis rate found on biopsy as a result of clinical and mammographic findings. RESULTS: In both age groups, mammography was significantly (p < 0.001) more sensitive than clinical assessment in cancer diagnosis but gave a significantly (p < 0.0001) higher rate of false-positive results. The cancer diagnosis rate was highest when lesions were assessed both clinically and mammographically as malignant but was of diagnostic benefit only to women in the under-50-year age group. The cancer rate was 12% when both assessments indicated a benign process and only 2% in women under age 50 years with clinically benign conditions who did not have mammography. Twenty-one percent of the biopsies were obtained in women with clinically normal breasts because of a mammographic abnormality and 17% of all the cancers found were clinically occult. CONCLUSIONS: The sensitivity of clinical assessment, particularly in premenopausal women is low and the false-positive mammography rate is high, but the cancer/biopsy rate is sufficiently high to warrant breast biopsy if either diagnostic modality suggests a cancer. When neither modality suggests cancer, the cancer/biopsy rate is 12% in both age groups.

Thermography. Its relation to pathologic characteristics, vascularity, proliferation rate, and survival of patients with invasive ductal carcinoma of the breast.

BACKGROUND: The reason for the thermal abnormality associated with some breast cancers is unclear. We previously reported that a thermographic abnormality is associated with tumor size and lymph node involvement. Despite this association, we were unable to demonstrate an independent association between an abnormal thermogram and survival. METHODS: To expand our previous findings, we assessed patients undergoing liquid crystal (contact) thermography (LCT) to identify a basis for the thermal abnormality and its relationship to survival. We assessed 420 women with invasive ductal carcinoma (IDC) followed for a mean of 6.2 years. In a consecutive series of 181 patients from the overall group, vascularity was assessed using a Doppler ultrasound (US) and microvessel density (MVD) by immunohistochemical staining with Factor VIII-related antigen. The tumor proliferation rate was measured immunohistochemically using Ki-67 monoclonal antibody. RESULTS: An abnormal thermogram was found in 18.6% of patients with IDC. A significant association was demonstrated between an abnormal LCT and age, stage, lymph nodal status, size, grade, and estrogen receptor status. We found no association between a LCT abnormality and MVD or proliferation rate. There was a significant relationship with US-demonstrated vascularity. In multivariate analysis, we found that LCT abnormality was not an independent prognostic variable for either overall or disease free survival. CONCLUSIONS: An abnormal thermogram is associated with large tumor size, high grade, and lymph node positivity but not proliferation rate or MVD. It also may be associated with relatively large regional vessels that can be identified by US. However, thermography is not an independent prognostic indicator.

Localization of platelet-derived growth factor beta receptor expression in the periepithelial stroma of human breast carcinoma.

Platelet-derived growth factor (PDGF) BB is secreted by most human breast carcinoma cells; however, only recently have PDGF beta receptors been demonstrated in malignant breast tissue. In the present study, the tissue localization of PDGF beta receptor expression was studied in human breast carcinoma and nonmalignant breast tissues stained using both immunofluorescence and immunoperoxidase techniques. We examined a total of 29 cases of breast carcinomas, which showed both in situ and invasive components. PDGF beta receptor staining was localized in the periepithelial stroma and was particularly intense in regions immediately adjacent to carcinoma in situ components in all tumors examined. A diffuse low level of PDGF beta receptor staining was seen throughout the stroma of eight nonmalignant breast tissues as well as of nonmalignant regions of tumor tissues. Image analysis was used to assess the coincidence of staining of PDGF beta receptor with epithelial or stromal cells in 13 of the 29 tumor tissues studied. Less than 5% of malignant ductal epithelium or myoepithelium showed PDGF beta receptor staining. Analysis with stromal cell type-specific markers indicated significant localization of PDGF beta receptor primarily within alpha smooth muscle actin-staining cells (32%) and vascular endothelial cells (41%) in the periepithelial stroma. PDGF beta receptor positivity was strongly associated with periepithelial stromal cells adjacent to the basement membrane surrounding regions of carcinoma in situ but was less intense in regions of invasive carcinoma where basement membrane was degraded. The absence of PDGF beta receptors on carcinoma cells and their presence in the surrounding stroma suggest a paracrine stimulation of adjacent stromal tissue by malignant epithelial cells in human breast tumors.

Coexpression of hepatocyte growth factor and receptor (Met) in human breast carcinoma.

Expression of hepatocyte growth factor (HGF) and HGF receptor (HGFR, product of the met proto-oncogene) mRNA were examined by nonisotopic in situ hybridization in a spectrum of benign and malignant human breast tissues. mRNA for both HGFR and HGF was detected in benign ductal epithelium. Epithelial expression of HGF mRNA was particularly intense in regions of ductal epithelial hyperplasia. Positive expression of HGF (but not HGFR) mRNA was also found in adipocytes, endothelial cells, and to varying degrees in stromal fibroblasts. In 12 of 12 cases of ductal carcinoma in situ and infiltrating ductal carcinoma, carcinoma cells showed a heterogeneous pattern of expression for both HGFR and HGF mRNA. In infiltrating ductal carcinomas, intense expression of HGFR mRNA was not restricted to ductular structures but as also seen in non-duct-forming carcinoma cells. The same zones of the tumors (most commonly at the advancing margins) that expressed strongly HGFR mRNA often were also strongly positive for HGF mRNA, suggesting a possible autocrine effect. The expression pattern of HGFR protein in 25 cases including the same series of tissues used for in situ hybridization analysis was similar to that of HGFR mRNA, as determined by an immunoperoxidase technique. The finding that HGFR is expressed by both benign and malignant epithelium, and its not restricted to duct-forming structures, suggests that, although the potential for HGF/HGFR binding is maintained in malignancy, the response to ligand binding at the level of the receptor or the cellular response to receptor activation may change at some point during progression.

Vascularity demonstrated by Doppler ultrasound and immunohistochemistry in invasive ductal carcinoma of the breast.

BACKGROUND: Vascularity is an important determinant of a tumour's ability to grow and disseminate. Breast tumour vascularity can be determined with doppler ultrasound (US) and by counting the vessels microscopically (microvascular density-MVD). The biologic characteristics of tumours based on their vascularity have not been extensively studied. METHOD: Preoperative US was performed on 207 patients with invasive ductal breast carcinomas (IDC). MVD was assessed immunohistochemically using polyclonal antisera against factor VIII and the proliferation rate was measured with Ki-67 polyclonal antisera. Histologic tumour characteristics and oestrogen receptor (ER) status were determined. Thermography was performed on 174 of the patients. RESULTS: Twenty-five percent of IDC demonstrated US-vascularity. US-vascular tumours were more likely to be node positive, and had a higher mitotic rate than avascular cancers. US-vascularity was more common in tumours with MVD greater than 80 vessels/250x field than those with fewer vessels. The proliferation rate, histologic grade III, and nuclear grade III were higher and ER positivity lower, but the differences were not statistically significant. US-vascular cancers were associated with significantly more thermographic abnormalities. The cancer recurrence rate at three years was higher in patients with vascular cancers although the difference was not statistically significant. CONCLUSION: US appears to be a simple, non-invasive method of identifying vascular cancers associated with factors indicating a poor prognosis.

The abnormal mammogram in women with clinically normal breasts.

OBJECTIVES: To assess the impact of unnecessary referrals to breast surgeons as a result of abnormal mammograms in women with clinically normal breasts and to determine measures to make the management of such women more efficient. DESIGN: A case study. SETTING: A breast clinic in a university-affiliated hospital. PATIENTS: From among 6477 women referred for surgical breast assessment, 475 with asymptomatic, clinically normal breasts were referred solely on the basis of an abnormal mammogram. INTERVENTIONS: Mammography and breast biopsy. MAIN OUTCOME MEASURES: Need for surgical assessment as a result of mammographic findings, number of biopsies and the diagnosis of cancer. RESULTS: Clinically a breast abnormality was evident in 63 (13%) women and a malignant lesion in 14 of them (2.9% of the total). Of the 412 women who were confirmed as having clinically normal breasts, only 139 (33.7%) had mammograms originally reported as suspicious for cancer. After the mammograms were reviewed, 79% of women with such a suspicious mammogram underwent mammographic localization and biopsy: a malignant lesion was confirmed in 36.4% of these. Of the 475 women referred for assessment, only 202 (42.5%) had a significant clinical or mammographic abnormality. Of the 412 women with clinically normal breasts only 110 (26.7%) required a biopsy and only 40 (9.7%) had cancer. CONCLUSIONS: Most women referred because of an abnormal mammogram have no significant problem or have one that can be resolved without surgical referral. Screening efficiency can be improved, patient anxiety controlled and cost controlled by a number of recommended measures.

Immunohistochemical characteristics of human milk-fat globule antibodies in predicting chest wall and distant metastasis after mastectomy for localized cancer of the breast.

Because postoperative radiation reduces chest wall metastasis after mastectomy, it is important to identify patients in whom it might develop. Pathologic and immunohistochemical features in 59 patients with chest wall metastasis were compared with characteristics in disease-free patients and patients with systemic metastases without chest wall metastasis. Immunohistochemical studies with human milk-fat globule (HMFG)-2 were not predictive, but a membrane reaction with HMFG-1 was associated with fewer systemic metastases and tumors, in which most of the cells reacted with the antibody had significantly decreased likelihood of chest wall metastasis. Antigenic concordance between the primary breast cancer and the chest wall metastasis was demonstrated. Neither tumor size nor axillary node metastasis predicted development of chest wall metastasis, but systemic metastases were less common when fewer than four nodes were involved, the primary tumor was well differentiated, and estrogen receptors were positive.

Age-related breast diagnosis.

Of the three commonest symptoms found in 3294 patients referred to a specialty breast clinic--mass, nodularity and pain--only nodularity was age related. Only 30% of the patients had a clinically localized abnormality, and only 19% of these abnormalities were suggestive of carcinoma. The majority of suggestive lesions were in women over 55 years of age. Of the patients seen because of a breast lump, 46% were found to have a significant mass. Most abnormalities were found in patients presenting with a mass or nipple discharge, and the significance was age related. Symptoms associated with the lowest rate of positive biopsies were nodularity, pain and skin or nipple changes. The biopsy and cancer rates were significantly age related. The cancer rate in women 40 years of age and under was 0.8%, between 41 and 55 the rate was 5%, and in those over 55 it was 21%. The predominant finding in young women was a fibroadenoma. In the middle age range fibrocystic change was most common, and in postmenopausal women most of the lesions were malignant.

Immunohistochemical reaction to human milk fat globule antibodies and breast cancer differentiation.

Immunohistochemical studies of human breast cancers using human milk fat globule (HMFG) antibodies are divergent regarding the association with histologic differentiation. To clarify this association 392 tumors were assessed using two antibodies, HMFG-1 and HMFG-2. In half the tumors studied the tissue reaction to both antibodies was the same and in 63% the site of reaction was identical. Using both univariate and multivariate statistics, a highly significant association was recorded between membrane staining and well differentiated cancers and cytoplasmic staining and poor differentiation. Well differentiated tumors contained significantly more reactive cells. Complementing these findings was the association between age at diagnosis, tumor stage, and estrogen receptor status and differentiation. It is possible that immunohistochemical analysis with HMFG antibodies will provide better characterization of tumor differentiation than morphologic interpretation.

Prognostic significance of the immunohistochemical reaction to human milk fat globule antibodies in node-negative and node-positive breast cancer.

The status of axillary lymph nodes in patients with breast cancer is important prognostically but does not identify all patients who will have long or short survival. To determine if the immunohistochemical reaction of tumor cells to human milk fat globule (HMFG) antibodies will define prognosis more specifically, we examined patients with node-negative disease and patients with more than three positive nodes, the extremes of the prognostic spectrum. In both node-negative and node-positive groups, patients who relapsed were matched by age at diagnosis, tumor size, histologic type, and receptor status, with patients who remained disease-free for a minimum of 48 months. Patients with poor survival had a higher proportion of poorly differentiated cancers. The ability to generate antigens recognized by HMFG antibodies was decreased in patients with recurrent disease, but this was significant only in patients with node-positive tumors. Tumors of patients who remained disease-free were more likely to have a pattern of membrane staining, while cytoplasmic staining was more frequent in those who relapsed. The results suggest that immunohistologic response to HMFG antibodies may assist in identifying cancers with poor prognosis, supplementing the prediction derived from node status.