Adapted from American Cancer Society (2006) and Hulka et al. (2001)

Lectures in Early Breast CancerA PowerPoint slide set based on images from:Lectures in Early Breast Cancer Part 1:Overview and Assessment of Early Breast Cancer

Lectures inEarly Breast Cancer

Adapted from American Cancer Society (2006) and Hulka et al. (2001).


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.


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).


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).


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).


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).


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 N-terminal kinase.



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.



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, insulin-like growth factor-1 receptor; mTOR, mammalian target of rapamycin; PI3K, phosphatidylinositol 3-kinase; SERM, selective oestrogen receptor modulator; Tam, tamoxifen.



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).


Epidermal growth factor receptor (EGFR) family members are dysregulated in many human cancers, suggesting a pivotal role in tumorigenesis (Grünwald & Hidalgo, 2003).


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.


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.


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).


Endocrine responsiveness is an important prognostic marker in breast cancer. ER, oestrogen receptor.

Reproduced with permission from Hess et al. (2003).


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.



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).


*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).


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).


*ACI denotes a cross between August and Copenhagen-Irish strains and SENCAR sensitive to carcinogenesis.



Arrows indicate sites of conversion of androgen to oestrogen.

Reproduced with permission from Clemons & Goss ( 2001).


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).


Reproduced with permission from Bulun & Simpson (1994).

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.


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; PGE2, prostaglandin E2; TNF-α; tumour necrosis factor-alpha.

Reproduced with permission from Simpson (2000).


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).


Reproduced with permission from Smith & Dowsett (2003).

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).


Adapted from Lake & Hudis (2002).

ReferencesAllred DC, Harvey JM, Berardo M et al. Prognostic and predictive factors in breast cancer by immunohistochemical analysis. Mod Pathol 1998; 11:155-168.

American Cancer Society. Breast Cancer Facts & Figures 2005–2006. Atlanta: American Cancer Society, Inc, 2006. Available at www.cancer.org.

Bulun SE, Simpson ER. Competitive reverse transcription-polymerase chain reaction analysis indicates that levels of aromatase cytochrome P450 transcripts in adipose tissue of buttocks, thighs, and abdomen of women increase with advancing age. J Clin Endocrinol Metab 1994; 78:428–432.

Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med 2001; 344:276–285.

Colditz GA, Rosner BA, Chen WY et al. Risk factors for breast cancer according to estrogen and progesterone receptor status. J Natl Cancer Inst 2004;96:218–228.

Cui X, Schiff R, Arpino G et al. Biology of progesterone receptor loss in breast cancer and its implications for endocrine therapy.J Clin Oncol 2005; 23:7721–7735.

Dickson RB, Russo J. Biochemical control of breast development. In: Diseases of the Breast, 2nd edition. Edited by JR Harris, ME Lippman, M Morrowet al. Philadelphia: Lippincott, Williams and Wilkins, 2000;15–31.

Dietz J, Moore H, Crownover R et al. Atlas of Cancer. Edited by M Markman, J Crowe. Philadelphia, PA: Current Medicine LLC, 2002.

Grünwald V, Hidalgo M. Developing inhibitors of the epidermal growth factor receptor for cancer treatment. J Nat Cancer Inst 2003; 95:851–867.

Henderson BE, Bernstein L, Ross RK. Hormones and the etiology of cancer. In: Cancer Medicine, 5th Edn. Edited by RC Bast, DW Kufe, RE Pollack et al. Hamilton, ON: BC Decker, 2000. Hosted by www.ncbi.nlm.nih.gov/books/bv.fcgi?rid=cmed.chapter.3557

Hess KR, Pusztai L, Buzdar A et al. Estrogen receptors and distinct patterns of breast cancer relapse. Breast Cancer Res Treat 2003;78:105–108.

Hulka BS, Moorman PG. Breast cancer: hormones and other risk factors. Maturitas 2001; 38:103–113; discussion 113–116.

Lake DE, Hudis C. Aromatase inhibitors in breast cancer: an update. Cancer Control 2002; 9:490–498.

Lamarque J-L (Ed). Physiology and physiopathology. In: An Atlas and Text of the Breast: Clinical Radiodiagnosis. London: Wolfe Medical Publications,1984;29–38.

Lo HW, Hsu SC, Hung MC. EGFR signaling pathway in breast cancers: from traditional signal transduction to direct nuclear translocalization. Breast Cancer Res Treat 2006; 95:211–218.

Simpson ER. Role of aromatase in sex steroid action. J Mol Endocrinol 2000; 25:149–156.

Smith IE, Dowsett M. Aromatase inhibitors in breast cancer. N Engl J Med 2003; 348:2431–2442.

Sobin LH, Wittekind C (Eds). UICC’s TNM Classification of Malignant Tumours, 6th Edition. John Wiley & Sons, Ltd, 2002.

Yager JD, Davidson NE. Estrogen carcinogenesis in breast cancer. N Engl J Med 2006; 354:270–782.

Documents

Adapted from American Cancer Society (2006) and Hulka et al. (2001)