Future possibilities in the prevention of breast cancer: Luteinizing hormone-releasing hormone agonists

The cyclic production of estrogen and progesterone by the premenopausal ovary accounts for the steep rise in breast cancer risk in premenopausal women. These hormones are breast cell mitogens. By reducing exposure to these ovarian hormones, agonists of luteinizing hormone-releasing hormone (LHRH) given to suppress ovarian function may prove useful in cancer prevention. To prevent deleterious effects of hypoestrogenemia, the addition of low-dose hormone replacement to the LHRH agonist appears necessary. Pilot data with such an approach indicates it is feasible and reduces mammographic densities

Ovarian cancer risk in premenopausal and perimenopausal women treated with Tamoxifen: a case–control study

As tamoxifen stimulates ovarian steroidogenesis in premenopausal women, induces ovulation and increases the incidence of benign ovarian cysts, there has been concern that it might also increase ovarian cancer risk in women treated premenopausally. In a national case–control study in Britain, treatment histories were collected for 158 cases of ovarian cancer after breast cancer diagnosed at ages under 55 years and 464 controls who had breast cancer at these ages without subsequent ovarian cancer. Risk of ovarian cancer was not raised for women overall who had taken tamoxifen (odds ratio (OR)=0.9, 95% confidence interval (CI) 0.6–1.3) or for those treated when premenopausal (OR=1.0, 95% CI 0.6–1.6) or perimenopausal (OR=0.7, 95% CI 0.2–2.4). There was also no relation of risk to daily dose, duration or cumulative dose of tamoxifen, or time since last use. There was, however, a significantly raised risk in relation to non-hormonal chemotherapy. The results suggest that tamoxifen treatment of premenopausal or perimenopausal women does not materially affect ovarian cancer risk, but that non-hormonal chemotherapy might increase risk

IL-1B drives opposing responses in primary tumours and bone metastases; harnessing combination therapies to improve outcome in breast cancer

Breast cancer bone metastasis is currently incurable, ~75% of patients with late-stage breast cancer develop disease recurrence in bone and available treatments are only palliative. We have previously shown that production of the pro-inflammatory cytokine interleukin-1B (IL-1B) by breast cancer cells drives bone metastasis in patients and in preclinical in vivo models. In the current study, we have investigated how IL-1B from tumour cells and the microenvironment interact to affect primary tumour growth and bone metastasis through regulation of the immune system, and whether targeting IL-1 driven changes to the immune response improves standard of care therapy for breast cancer bone metastasis. Using syngeneic IL-1B/IL1R1 knock out mouse models in combination with genetic manipulation of tumour cells to overexpress IL-1B/IL1R1, we found that IL-1B signalling elicited an opposite response in primary tumours compared with bone metastases. In primary tumours, IL-1B inhibited growth, by impairing the infiltration of innate immune cell subsets with potential anti-cancer functions but promoted enhanced tumour cell migration. In bone, IL-1B stimulated the development of osteolytic metastases. In syngeneic models of breast cancer, combining standard of care treatments (Doxorubicin and Zoledronic acid) with the IL-1 receptor antagonist Anakinra inhibited both primary tumour growth and metastasis. Anakinra had opposite effects on the immune response compared to standard of care treatment, and its anti-inflammatory signature was maintained in the combination therapy. These data suggest that targeting IL-1B signalling may provide a useful therapeutic approach to inhibit bone metastasis and improve efficacy of current treatments for breast cancer patients

Changes in magnetic resonance mammography due to hormone replacement therapy

BACKGROUND: The aim of the present article is to investigate effects of hormone replacement therapy (HRT) on contrast medium enhancement patterns in postmenopausal patients during magnetic resonance mammography (MRM). MATERIALS AND METHODS: Two hundred and fifteen patients receiving hormonal medication were divided into four groups: 150 patients with 1 MRM during HRT (group A), 13 patients with 2 MRMs under HRT (group B), 30 patients with 1 MRM during HRT and 1 MRM after HRT withdrawal (group C), and 22 women with 1 MRM after HRT withdrawal (group D). Dynamic MRM was performed at 1.5 Tesla. Signal intensity changes were characterized by five time curves: minimal enhancement (type I), weak continuous enhancement (type II), strong continuous enhancement (type III), and a steep initial slope followed by a plateau phenomenon (type IV) or a washout effect (type V). RESULTS: Of all 193 patients under HRT (group A + group B + group C), 60 patients (31.1%) showed curve type I, 88 patients (45.6%) showed type II and 45 patients (23.3%) showed type III. There were significant differences to 52 patients after HRT withdrawal (group C + group D) (P < 0.0001), with 42 patients (80.8%) for curve type I, 8 patients (15.4%) for type II, and 2 patients (3.8%) for type III. In both MRM sessions in group B, 69% of the patients showed identical curve types without significant differences (P = 0.375). In group C, 28 of 30 patients (93%) dropped to lower curve types with significant differences in curve types during and after HRT (P < 0.0001). CONCLUSION: The majority of patients receiving postmenopausal HRT showed bilateral symmetrical, continuous enhancement without evidence of a plateau phenomenon or a washout effect due to HRT in MRM. Hormonal effects could be proven and were reproducible and reversible

Ovarian cysts in women receiving tamoxifen for breast cancer

Tamoxifen is a nonsteroidal anti-oestrogen with gynaecological side-effects. Only recently, ovarian cyst formation during tamoxifen treatment has been reported. The present study aimed to evaluate patient-related parameters that determine ovarian cyst formation in women using tamoxifen for breast cancer. A cross-sectional study was performed in 142 breast cancer patients using tamoxifen. Forty-five patients were also examined prior to tamoxifen treatment. Gynaecological assessment, transvaginal ultrasonography (TVU) and serum oestradiol (E2) and follicle stimulating hormone (FSH) analysis were performed. Follow-up assessments were performed twice a year. Uni- or bilateral ovarian cysts were detected by TVU in 24 tamoxifen-using patients and in one patient before tamoxifen treatment. Multiple regression analysis showed that cyst development is related (multiple R = 0.73) to high E2 (P < 0.001), younger age (P < 0.001) and absence of high-dose chemotherapy (P = 0.007). Patients with ovarian cysts had higher serum E2 levels compared to patients without cysts (1.95 vs 0.05 nmol l−1; P < 0.001). All patients after high-dose chemotherapy or older than 50 years had E2 < 0.10 nmol l−1 and/or amenorrhoea > 1 year and did not develop ovarian cysts. Patients still having a menstrual cycle during tamoxifen had a high chance (81%) of developing ovarian cysts. Breast cancer patients receiving tamoxifen only develop ovarian cysts if their ovaries are able to respond to FSH stimulation as shown by E2 production. © 1999 Cancer Research Campaig

MUC1 Contributes to BPDE-Induced Human Bronchial Epithelial Cell Transformation through Facilitating EGFR Activation

Although it is well known that epidermal growth factor receptor (EGFR) is involved in lung cancer progression, whether EGFR contributes to lung epithelial cell transformation is less clear. Mucin 1 (MUC1 in human and Muc1 in animals), a glycoprotein component of airway mucus, is overexpressed in lung tumors; however, its role and underlying mechanisms in early stage lung carcinogenesis is still elusive. This study provides strong evidence demonstrating that EGFR and MUC1 are involved in bronchial epithelial cell transformation. Knockdown of MUC1 expression significantly reduced transformation of immortalized human bronchial epithelial cells induced by benzo[a]pyrene diol epoxide (BPDE), the active form of the cigarette smoke (CS) carcinogen benzo(a)pyrene (BaP)s. BPDE exposure robustly activated a pathway consisting of EGFR, Akt and ERK, and blocking this pathway significantly increased BPDE-induced cell death and inhibited cell transformation. Suppression of MUC1 expression resulted in EGFR destabilization and inhibition of the BPDE-induced activation of Akt and ERK and increase of cytotoxicity. These results strongly suggest an important role for EGFR in BPDE-induced transformation, and substantiate that MUC1 is involved in lung cancer development, at least partly through mediating carcinogen-induced activation of the EGFR-mediated cell survival pathway that facilitates cell transformation

Percentage density, Wolfe's and Tabár's mammographic patterns: agreement and association with risk factors for breast cancer

INTRODUCTION: The purpose of this report was to classify mammograms according to four methods and to examine their agreement and their relationship to selected risk factors for breast cancer. METHOD: Mammograms and epidemiological data were collected from 987 women, aged 55 to 71 years, attending the Norwegian Breast Cancer Screening Program. Two readers each classified the mammograms according to a quantitative method (Cumulus or Madena software) and one reader according to two qualitative methods (Wolfe and Tabár patterns). Mammograms classified in the reader-specific upper quartile of percentage density, Wolfe's P2 and DY patterns, or Tabár's IV and V patterns, were categorized as high-risk density patterns and the remaining mammograms as low-risk density patterns. We calculated intra-reader and inter-reader agreement and estimated prevalence odds ratios of having high-risk mammographic density patterns according to selected risk factors for breast cancer. RESULTS: The Pearson correlation coefficient was 0.86 for the two quantitative density measurements. There was moderate agreement between the Wolfe and Tabár classifications (Kappa = 0.51; 95% confidence interval 0.46 to 0.56). Age at screening, number of children and body mass index (BMI) showed a statistically significant inverse relationship with high-risk density patterns for all four methods (all P < 0.05). After adjustment for percentage density, the Wolfe classification was not associated with any of the risk factors for breast cancer, whereas the association with number of children and BMI remained statistically significant for the Tabár classification. Adjustment for Wolfe or Tabár patterns did not alter the associations between these risk factors and percentage mammographic density. CONCLUSION: The four assessments methods seem to capture the same overall associations with risk factors for breast cancer. Our results indicate that the quantitative methods convey additional information over the qualitative methods

Breast cancer chemoprevention: beyond tamoxifen

A large number of new potential chemoprevention agents are available that target molecular abnormalities found in estrogen receptor (ER)-negative and/or ER-positive precancerous breast tissue and have side effect profiles that differ from tamoxifen. Classes of agents currently undergoing evaluation in clinical prevention trials or those for which testing is planned in the near future include new selective ER modulators, aromatase inactivators/inhibitors, gonadotrophin-releasing hormone agonists, monoterpenes, isoflavones, retinoids, rexinoids, vitamin D derivatives, and inhibitors of tyrosine kinase, cyclooxygenase-2, and polyamine synthesis. New clinical testing models will use morphological and molecular biomarkers to select candidates at highest short-term risk, to predict the response to a particular class of agent, and to assess the response in phase II prevention trials. If validated, morphological and molecular markers could eventually replace cancer incidence as an indicator of efficacy in future phase III trials