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Lectures in Early Breast Cancer
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Lectures in Early Breast Cancer Part 1:
Overview and Assessment of Early Breast Cancer
Lectures in Early Breast Cancer
Adapted from American Cancer Society (2006) and Hulka et al. (2001).
Lectures in Early Breast Cancer
Accurate clinical staging for breast cancer has always been considered essential before surgery is undertaken (Sobin & Wittekind, 2002). However, it is important to remember
the clinical signs of breast cancer that would invalidate surgical attempts at cure. In these instances, initial referral to a clinical oncologist would be more relevant.
Lectures in Early Breast Cancer
The staging systems currently in use are based on the clinical size and extent of invasion of the primary tumour (T), the clinical absence or presence of palpable axillary lymph
nodes and evidence of their local invasion (N), together with the clinical and imaging evidence of distant metastases (M). *For T1–3: 'a' indicates no attachment to underlying
muscles; 'b' indicates attachment.
Adapted from Sobin & Wittekind (2002).
Lectures in Early Breast Cancer
The TNM classificatio has been subdivided into four broad categories by the Union Internationale Contre Cancer. *Many expert
groups include T2 tumors in stage I.
Adapted from Sobin & Wittekind (2002).
Lectures in Early Breast Cancer
Oestrogen plays an important role in regulating the growth and differentiation of normal, premalignant and malignant cell types, especially breast epithelial cells. The
biological effects of oestrogen are mediated by oestrogen receptors, which consist of two isoforms (ER-α and ER-β) that are transcribed from two genes.
AF, activation function region.
Reproduced with permission from Cui et al. (2005).
Lectures in Early Breast Cancer
cAMP, cyclic AMP; E2, oestrogen; 4-OH-E2, 4-hydroxyestradiol; ER, oestrogen receptor; EGFR, epidermal growth factor receptor; IGF-1, insulin-like growth factor; MAPK,
mitogen-actived protein kinase; mRNA, messenger RNA; PI3K, phosphoinositide 3-kinase; mtProteins, mitochrondrial proteins; Shc, Src homology 2 domain-containing
protein; pShc, phosphorylated Shc protein; Ras, GTP-binding protein; Raf, serine/threonine kinase; Src, protein tyrosine kinase. Dashed line arrows indicate putative
pathways.
Reproduced with permission from Yager & Davidson (2006).
Lectures in Early Breast Cancer
Oestrogens cause activation of various protein kinases, such as mitogen-activated protein kinases (MAPK), and increase levels of second messengers, such as cAMP.
EGF, epidermal growth factor; IGF-1, insulin-like growth factor 1; PI3K, phosphoinositide 3-kinase; ERK, extracellular signal-activated protein kinase; JNK, c-jun Nterminal kinase.
Reproduced with permission from Yager & Davidson (2006).
Lectures in Early Breast Cancer
The progesterone receptor is a nuclear transcription factor that mediates the biological actions of its ligand, progesterone. The progesterone receptor consists of two
isoforms (PR-A and PR-B) that are transcribed from a single gene using an alternative promoter and translation start site.
AF, activation function domain.
Reproduced with permission from Cui et al. (2005).
Lectures in Early Breast Cancer
Growth factor reduction of progesterone receptor (PR) via direct inhibition of PR gene transcription and induction of membrane-initiated oestrogen receptor (ER) signalling.
E2, oestradiol; ERK1/2, extracellular regulated kinase 1/2; HB-EGF, heparin-binding epidermal growth factor; HER, human epidermal growth factor receptor; IGF-IR, insulinlike growth factor-1 receptor; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; SERM, selective oestrogen receptor modulator; Tam, tamoxifen.
Reproduced with permission from Cui et al. (2005).
Lectures in Early Breast Cancer
Binding of epidermal growth factor (EGF) to the human epidermal growth factor receptor (EGFR) activates a cellular pathway, with induction of phosphorylation by
intracellular kinases, leading to nuclear signals that increase cell proliferation.
Based on Lo et al. (2006).
Lectures in Early Breast Cancer
Epidermal growth factor receptor (EGFR) family members are dysregulated in many human cancers, suggesting a pivotal role in tumorigenesis (Grünwald & Hidalgo, 2003).
Lectures in Early Breast Cancer
A tumour's hormone receptor status can be determined by immunohistochemistry. This photomicrograph demonstrates strong positive nuclear staining (brown or black)
for oestrogen receptors in an infiltrating ductal carcinoma.`
Reproduced with permission from Dietz J et al. Atlas of Cancer.
Lectures in Early Breast Cancer
Hormone receptors in breast tissue are measured semiquantitatively, using simple scoring systems such as the Allred score or H-score. The Allred score is a microscopic
method conveying the estimated proportion and intensity of positive tumour cells (range 0–8) (Allred et al, 1998).
Reproduced from www.breastcenter.tmc.edu/research/cores/path/services/er.htm.
Lectures in Early Breast Cancer
Tumours that express ER and/or PR are deemed to be endocrine responsive, while those expressing neither receptor are endocrine unresponsive. ER, oestrogen receptor;
PR, progesterone receptor; +, positive (Allred score ≥2); –, negative (Allred score <2); ?, unknown. *Calculated from the Nurses' Health Study (2096 incident breast cancer
cases during 1,029,414 person-years of follow-up).
Data from Colditz et al. (2004).
Lectures in Early Breast Cancer
Endocrine responsiveness is an important prognostic marker in breast cancer. ER, oestrogen receptor.
Reproduced with permission from Hess et al. (2003).
Lectures in Early Breast Cancer
All patients were treated with systemic endocrine therapy (tamoxifen in >90%). ER+, oestrogen receptor positive; ER–, oestrogen receptor negative; PR+, progesterone
receptor positive; PR–, progesterone receptor negative.
Reproduced with permission from Cui et al. (2005).
Lectures in Early Breast Cancer
Many hormones influence breast development and function, including oestrogens, progesterone, androgens, prolactin, and luteinising hormone-releasing hormone
(LHRH). FSH, follicle-stimulating hormone; LH, luteinising hormone; ACTH, adrenocorticotrophic hormone.
Based on Dickson (2000) & Russo and Lamarque (1984).
Lectures in Early Breast Cancer
*The relative risk was calculated with the low-risk group as the reference group. †There is no association between the risk of breast cancer and oophorectomy performed
at 35 years of age or older.
Reproduced with permission from Clemons & Goss ( 2001).
Lectures in Early Breast Cancer
Oestradiol and, to a lesser degree, other steroid hormones (e.g., progesterone) drive breast cell proliferation, which facilitates mutation, enhances fixation of mutations or
facilitates expression of genetic errors by loss of heterozygosity by defects in DNA repair. Germline mutations in relevant tumour-suppressor genes accelerate the
transformation to the malignant phenotype.
Reproduced with permission from Henderson et al. (2000).
Lectures in Early Breast Cancer
*ACI denotes a cross between August and Copenhagen-Irish strains and SENCAR sensitive to carcinogenesis.
Reproduced with permission from Yager & Davidson (2006).
Lectures in Early Breast Cancer
Arrows indicate sites of conversion of androgen to oestrogen.
Reproduced with permission from Clemons & Goss ( 2001).
Lectures in Early Breast Cancer
CYP11, 11-hydroxylase; CYP17, 17-βhydroxylase; CYP21, 21-hydroxylase; DHEA, dehydroepiandrosterone; E1, oestrone; E2, oestradiol; 3β-HSD, 3β-hydroxysteroid
dehydrogenase; 17β-HSD, 17β-hydroxysteroid dehydrogenase; 17-KSR, 17-ketosteroid reductase; P450, cytochrome P450; scc, side-chain-cleavage enzyme.
Reproduced with permission from Clemons & Goss (2001).
Lectures in Early Breast Cancer
With advancing age there is a progressive increase in the efficiency with which circulating androgens are converted to oestrogens. This is associated with two- to fourfold
increases in both aromatase activity and aromatase mRNA in adipose tissue from many body sites, including the buttocks, thighs and abdomen.
Reproduced with permission from Bulun & Simpson (1994).
Lectures in Early Breast Cancer
Paracrine and autocrine mechanisms establish a positive feedback loop, leading to the continuing growth and development of the tumour. cAMP, cyclic AMP; DEX,
dexamethasone; E2, oestradiol; IL, interleukin; LIF, leukaemia inhibitory factor; OSM, oncostatin M; PGE 2, prostaglandin E2; TNF-α; tumour necrosis factor-alpha.
Reproduced with permission from Simpson (2000).
Lectures in Early Breast Cancer
Aromatase is the final rate-limiting step in oestrogen biosynthesis, thus selective blockade of the cytochrome P450 aromatase enzyme (P450arom) has no effect on
upstream hormones. 17β-HSD, 17β-hydroxysteroid dehydrogenase; 17-KSR, 17-ketosteroid reductase.
Based on Clemons & Goss (2001).
Lectures in Early Breast Cancer
Aromatase inhibitors are described as first-, second- and third-generation according to the chronological order in which they were developed, and are further classified as
type 1 or type 2 according to their mechanism of action.
Reproduced with permission from Smith & Dowsett (2003).
Lectures in Early Breast Cancer
Reproduced with permission from Smith & Dowsett (2003).
Lectures in Early Breast Cancer
Adapted from Lake & Hudis (2002).
References
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