29. Established Risk factors For Breast cancer in Females: Risk factor High risk Low risk Relative risk Age old young >4.0 Socioeconomic status high low 2.0 – 4.0 Marital status Never married Ever married 1.1 – 1.9 Place of residence urban rural 1.1 – 1.9 Race > 45 years < 40 years white black 1.1 – 1.9 black white 1.1 – 1.9 Nulliparity yes no 1.1 – 1.9 Age of first full-term pregnancy > 30 y/o < 20 y/o 2.0 – 4.0 Oophorectomy premenopausally no yes 2.0 – 4.0 Age at menopause late early 1.1 – 1.9 Age at menarchy early late 1.1 - 1.9 Weight, postmenopausal women heavy thin 1.1 – 1.9 Hx of benign or cancer in one breast yes no 2.0 – 4.0 Hx of breast Ca 1 st degree relative yes no 2.0 – 4.0 Mother or sister w/ hx. Of breast CA yes no > 4.0 Hx. Of primary ovarian or endometrial CA yes no 1.1 – 9.0 Mammographic parenchymal patterns Dysplastic parenchyma Normal parenchyma 2.0 – 4.0 Radiation to chest Large doses Minimal doses 2.0 – 4.0
60. Survival Rates for patients w/ Breast Cancer Relative to Clinical Stage Clinical staging (American Joint Committee) Crude 5-yr survival (%) Range Survival (%) STAGE I Tumor < 2cm in diameter Nodes, if present, not felt to contain metastases w/o distant metastases 85 82 - 94 STAGE II Tumors > 5 cm in diameter Nodes, if palpable, not fixed w/o distant metastasis 66 47 – 74 STAGE III Tumor > 5cm in diameter Tumor any size w/ invasion of skin attached to chest wall Nodes in supraclavicular area Without distant metastases 41 7 – 80 STAGE IV With distant metastases 10 -
76. Mechanism of action of tamoxifen as an antitumor agent Local effects - independent of oestrogen receptor + - stromal cell Increase TGF β Anti-estrogen effects - blockage of estrogen receptor Decrease TGF α
77. Aromatase inhibition within the breast tumour cell ANDROGENS OESTROGENS P-450 Aromatase + NADPH-cytochrome P-450 reductase (Testosterone, androstenedione, 16-OH-testosterone) (Oestradiol, oestrone) Aromatase Inhibitors tumour growth
Ovarian production of oestrogen is under the influence of the gonadotrophins, follicle stimulating hormone (FSH) and luteinising hormone (LH), both produced by the pituitary gland Goserelin binds to LHRH receptors in the pituitary cell. Following an initial LH surge, there is ‘internalisation’ (or down-regulation) of LHRH receptors and LH synthesis is inhibited The reduction in LH production achieves suppression of oestradiol to levels comparable to those observed in postmenopausal women
Tamoxifen has i) an antioestrogenic effect via blockade of oestrogen receptors and ii) a local antitumour effect, independent of its effect upon oestrogen receptors Locally, tamoxifen decreases the secretion of stimulatory growth factors, such as transforming growth factor alpha (TGF α ). It also increases the secretion of an inhibitory growth factor, such as transforming growth factor (TGF β ) TGF β is also known to inhibit the growth of oestrogen-receptor-negative cells. It is believed that this is how tamoxifen can be effective in oestrogen-receptor-poor tumours Tamoxifen is thought to increase TGF β production in stromal cells in the tumour Tamoxifen may also act by other mechanisms including: i) affecting levels of sex hormones binding globulin ((SHBG) ii) preventing angiogenesis Reference Jordan VC. Tamoxifen. A guide for clinicians and patients. 1996. PPR, Inc. New York
Inhibition of aromatase activity can reduce the growth-stimulatory effects of oestrogens on tumours Whilst aromatase inhibitors are known to be effective in advanced breast cancer, the role of intra-tumoural aromatase activity still remains to be clarified
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