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- Cancer Control
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Breast Cancer and Novel Therapeutic Treatments
European Oncological Disease, 2007;1(2):47-50
Breast cancer remains the most common malignancy among women, with an average lifetime risk of approximately 10%. Despite the continued rise in incidence of the disease, with almost half a million deaths annually worldwide, mortality rates have fallen over the past two decades. This is testimony to the success of interventional strategies such as screening and adjuvant systemic therapies that permit diagnosis of breast cancer prior to de novo formation of micrometastases or the obliteration of established foci of disease at distant sites. It is this burden of micrometastatic disease outside the breast that represents the most fundamental and challenging aspect of breast cancer treatment.
In accordance with Fisher’s hypothesis of biological predeterminism, these micrometastatic foci can remain dormant and be activated many years after initial diagnosis.1 It is now acknowledged that not all cases of early breast cancer are systemic at the outset with distant micrometastases pre-existent at presentation. Breast cancer is a heterogeneous disease with a variable and unpredictable natural history. We have entered a new era in breast cancer management where disease is ‘small’ and more likely to be confined to the breast and regional nodes.2 This ‘stage migration’ is attributable to a combination of heightened public awareness and screening programmes and has led to an increased proportion of smaller-sized (<2cm) node-negative tumours. Some of these tumours will behave in a Halstedian manner with minimal proclivity for haematogenous dissemination and the formation of micrometastases at an early stage in the neoplastic continuum. A spectrum, or intermediate paradigm, is emerging that encompasses elements of Fisher and Halsted but is less restrictive than either hypothesis in pure form.3
Modern methods of molecular profiling may permit tumours to be assigned to one group or another based on biological behaviour, with appropriate intensities of locoregional and systemic treatments. Those patients without micrometastatic disease at presentation do not require adjuvant systemic therapy and fewer than 10% of those receiving chemotherapy for node-negative disease derive any benefit. It may be surmised that as tumour size has fallen progressively in recent years, a lower proportion of patients will have micrometastases at the time of diagnosis and a correspondingly greater proportion will have disease limited to the locoregional tissues. For these patients, inadequate primary locoregional treatment will lead to higher rates of local recurrence, which under these circumstances represents a determinant of distant disease and can directly affect survival by acting as a source for micrometastases.4 The biphasic pattern of recurrence with peaks at one to two and four to five years suggests that dormant micrometastases may be stimulated by the act of primary surgery, which can remove sources of angiostatin with
initiation of microangiogenesis and the dissemination of tumour cells. Administration of antiangiogenic agents in a pre-surgical schedule may suppress this angiogenic kick-start and interrupt the ‘conversation’ between breast cancer and endothelial cells.5
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- Early Breast Cancer Trialists Collaborative Group (EBCTCG), Effects of radiotherapy and of differences in the extent of surgery for early breast cancer on local recurrence and 15-year survival: an overview of the randomised trials, Lancet, 2005;366:2087–2106.
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- Lyman GH, Guiliano AE, Somerfield MR, et al., The American Society of Clinical Oncology Guideline Recommendations for Sentinel Lymph Node Biopsy in Early Stage Breast Cancer, J Clin Oncol, 2005;23:7703–20.
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- MacMillan RD, Blamey RW, The case for axillary sampling, Advances in Breast Cancer, 2004;1:9–10.
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- American College of Surgeons Oncology Group – ACSOG – Z0011, A randomised study of axillary node dissection in women with clinical T1-2, N0, M0 breast cancer who have a positive sentinel node, www.acosog.org/studies/organ
- IBCSG 23-01 Protocol, www.ibcsg.org
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- Schipper H, Baum M, Turley EA, Breast cancer: should we control rather than kill cancer cells? In: Calvo F, Crepin M, Magdelenat H, (eds) Breast Cancer: advances in biology and therapeutics, 1996:235–43.
- Romond EH, Perez E, Bryant J, et al., Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer, N Engl J Med, 2005;353:1673–84.
- Rimawi MF, Mohsin K, Gutierrez MC, et al., Inhibiting the growth factor receptor (GFR) pathway preserves and enhances the expression of the estrogen receptor (ER) in HER-2/neu (HER2) overexpressing human breast tumors and xenografts. Breast Cancer Res Treat, 2005;94: abstract 8.
- Kim W, Serrero G, PC-cell derived growth factor (PCDGF/GP88, progranulin) stimulates HER-2 phosphorylation and confers herceptin resistance to HER-2 overexpressing breast cancer cells, Breast Cancer Res Treat, 2005;94: abstract 10.
- Miller K, Wang M, Gralow J, et al., A randomised phase III trial of paclitaxel versus paclitaxel plus bevacizumab as first-line therapy for locally recurrent or metastatic breast cancer: a trial co-ordinated by the Eastern Co-operative Oncology Group (E2100), Breast Cancer Res Treat, 2005;94: abstract 3.
- Guix M, Kelley MC, Reyzer M, et al., Short course of EGFR tyrosine kinase inhibitor erlotinib (OSI-774, Tarceva) reduces tumour cell proliferation and active MAPK in situ in untreated operable breast cancers: strategy for patient selection into phase II trials with signalling inhibitors, Breast Cancer Res Treat, 2004;88:(Suppl. 1).
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- Awada A, Cardosa F, Fontaine C, et al., A phase Ib study of the mTOR inhibitor RAD001 (everolimus) in combination with letrozole (Femara), investigating safety and pharmacokinetics in patients with advanced breast cancer stable or slowly progressing on letrozole, Breast Cancer Res Treat, 2004;88:1.
- Baum M, ATAC update, Are there now sufficient data to replace tamoxifen with anastrozole as first-line therapy for hormone receptor positive post-menopausal breast cancer, 27th San Antonio Breast Cancer Symposium, 2004.
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- Punglia RS, Kuntz KM, Winer E, et al., Optimising adjuvant endocrine therapy in post-menopausal women with early-stage breast cancers, J Clin Oncol, 2005;23:5178–87.
- Cuzik J, Sasieni P, Howell A, et al., Should aromatase inhibitors be used as initial treatment or sequenced after tamoxifen, Br J Cancer, 2006;94:460–64.
- Ingle JN, Goss PE, Tu D, et al., Analysis of duration of letrozole extended adjuvant therapy as measured by hazard ratios of disease recurrence over time for patients on NCIC CTG MA.17, Breast Cancer Res Treat, 2005;94:S11, abstract 17.
- Van't Veer LJ, Dai H, van de Vijver MJ, et al., Gene expression profiling predicts clinical outcome of breast cancer, Nature, 2002;415:530–36.
- Buyse M, Loi S, van't Veer L, et al., Validation and clinical utility of a 70-gene prognostic signature for women with nodenegative breast cancer, J Natl Cancer Inst, 2006;98:1183–92.