Micrometastatic And Metastatic Disease

The main reason for using adjuvant therapy after surgery is to treat micrometastatic disease, and so prevent metastases occurring at a later date. Our ability to monitor patients for micrometastases and understand their significance is still more restricted to research than open clinical application. The introduction of sentinel node procedures has increased awareness of minimal spread (isolated tumor cells and micrometastases) to axillary lymph nodes, but its significance is still unresolved...

Reactivation of wildtype p53

In the majority of breast cancers where the p53 gene is not mutated, the p53 protein is often kept at very low levels by excessive negative regulation, even under cellular stress. Since MDM-2 binds to and inhibits p53 directly, it has been possible to screen for small molecules which disrupt this binding, leading to reactivated p53. Molecules capable of doing just this have been identified and include the Nutlins,94 potent p53-reactivating molecules, which have been shown to work in vivo by...

Detection Of Tumorspecific Alterations In Cellfree Dna In Plasmaserum

Stroun et al28 were the first to characterize circulating DNA from the plasma of cancer patients. They used a 32P-labeled human DNA probe to show that it was human in origin and comprised of double-stranded fragments of up to 21kb in length.28 Detectable amounts of circulating DNA were found predominantly in patients with advanced malignancies bearing a large tumor cell burden. They then went on to demonstrate that plasma DNA from cancer patients had decreased strand stability, in common with...

P53 as a predictor for treatment strategy or disease response

Endocrine therapy, systemic chemotherapy and breast radiotherapy have been shown to significantly reduce disease relapse and prolong survival in patients with breast cancer. However, it has not been possible to confidently identify the patients in whom treatment is of benefit or those for whom such treatments ought to be avoided. The function of a number of anticancer agents is directed towards inducing cell death or apoptosis. Loss of normal p53 function can potentially result in relative...

Background

The baseline evidence for the variation in breast cancer behavior comes from studies from many years ago of women who had no treatment and of those that were before the advent of systemic (i.e. adjuvant) treatment following surgery. Bloom et al1 reported on a series of 250 women seen at the Middlesex Hospital, London, UK between 1805 and 1933 74 had advanced (stage IV) disease at the time of admission but 18 of these were still alive at 5 years without any treatment. The number of patients is...

Immunotherapy and immunization

Vaccine strategies are being investigated as another method of targeting HER2 overex-pressing cancer cells. Patients with HER2-positive tumors have been shown to develop an immune response against the protein,114-116 which suggests that antireceptor vaccines may be successful in mounting an anticancer response. With a large difference in levels of expression between HER2-positive tumors and normal tissues, there exists a potential therapeutic window for such cancers with no residual autoimmune...

Gene Expression Profiling

In the first edition, gene expression profiling was referred to in the Introduction, but now merits a chapter. The initial publications were concerned with subcategorization of breast cancers,27-29 but soon the emphasis was on identifying expression profiles relating to prognosis and the prediction of response to endocrine therapy and chemotherapy, and these are discussed in Chapter 11. Genomic prognostic tests are now available. As the authors of Chapter 11 point out, no prospective randomized...

Strategies For Manipulation Of The P53 Pathway In The Treatment Of Breast Cancer

The insights provided by p53 laboratory research over three decades are now moving to clinical applications for enhanced diagnostic, prognostic, and therapeutic intervention. The detailed strategies for engaging and manipulating the p53 pathway have been comprehensively reviewed in the literature for a wide range of human cancers.5,10,86 For breast cancer, where not only p53 mutation but also aberrations of the p53 pathway occur commonly, many of these strategies hold promise.

Detection Of Circulating Nucleic Acids In Plasma Or Serum

The first description of DNA in plasma or serum was by Mandel and Metais in 1948.9 Using a perchloric acid precipitation method, they detected both DNA and RNA at a concentration of between 0.3 to 1.0mg l of plasma in healthy and sick individuals. This concentration is higher than that reported in more recent studies, probably reflecting both methodological and sample differences. It was not until the 1960s that the field was revisited when high levels of DNA were reported in the serum of...

Endocrine Therapies For Breast Cancer

Breast cancer is the most common female cancer in the Western world (accounting for 28 of all cancers) and the leading cause of death by cancer in women (approximately 20 ). Although the mortality rate has stabilized or decreased, the incidence of breast cancer is still rising in all European countries.1 Around two-thirds of breast cancers are hormone (estrogen)-dependent as they are positive for estrogen receptor alpha (ERa) and or progesterone receptor (PR). As estrogen is the principal...

Cellfree

Circulating cell-free RNA has also been found in the plasma and serum of healthy individu-als,64 with increased levels detected in cancer patients,65-67 including breast cancers.68 Fewer studies have been published than for circulating DNA, in part due to RNA stability problems in stored and freeze-thawed samples,69 and reproducibility problems with RNA analyses.70 Silva et al71 used nested RT-PCR to detect the presence of cytokeratin 19 (CK19) and mammoglobin RNA in plasma as markers of tumor...

Endocrine Resistance And Biology Of The Estrogen Receptor Function

As resistance to endocrine therapy is one of the main challenges in the treatment of ERpositive breast cancer, understanding such processes is of major importance. In particular, deciphering the biology of the ER function, and the proteins which participate in estrogen signaling, it is hoped to improve our knowledge of the events which cause a response to endocrine therapy and thus identify accurate predictive markers for responsiveness to treatment. In early studies, ER was identified as a...

Cellcell adhesion

Epithelial cells mediate intercellular adhesion primarily through adherens junctions, desmo-somes, and gap junctions. The molecules involved in these adhesive complexes - classical cadherins, desmosomal glycoproteins and connexins, respectively - have all been shown to exhibit altered expression in breast cancers. The classical cadherins include E-cadherin, P-cadherin and N-cadherin, and of these the major focus in breast cancer has been E-cad-herin. E-cadherin mediates homophilic...

The Prognostic Impact Of Nodal Micrometastases

Nodal status is generally considered an important prognostic factor. Several studies have highlighted that the volume of metastatic nodal load also represents a prognostic parameter beyond the node-positive versus node-negative status. At one end of the spectrum, metastasis in a large number of lymph nodes is associated with a worse prognosis than the involvement of a few lymph nodes,52,53 or the involvement of a larger proportion of the examined lymph nodes is worse than a lower ratio of...

Morphological Factors Tumor size

The prognostic importance of tumor size is well recognized patients with larger invasive breast carcinomas have a poorer outcome than those with smaller lesions.3-6 Many years ago, Rosen and Groshen4 predicted 20-year relapse-free survival rates for women with tumors < 10mm, 11-13mm, 14-16mm and 17-22 mm in diameter of 88 , 73 , 65 and 59 , respectively. However, the clinical evaluation of tumor size is inaccurate, clinical-pathological agreement is seen in only 54 of cases.7 Radiological...

The stressactivated mitogenactivated protein kinases JNK and p38

As stated above, significant influences on ER and AP-1 signaling may also occur following phosphorylation of the SAPK members Jun kinase (JNK) and p38. While the endpoints of such signaling are likely to be as diverse as for ERK1 2 MAP kinase, as stated above, significant in vitro associations with negative growth regulation in breast cancer cells have been reported for JNK and p38.16,17,53 If represented in clinical breast cancer, therefore, JNK and p38 signaling would perhaps be predicted to...

References

Natural history of untreated breast cancer (1805-1933). Br Med J 1962 2 213-21. 2. Fisher B, Slack NH, Bross IDJ et al. Cancer of the breast size of neoplasm and prognosis. Cancer 1969 24 1071-80. 3. Adair F, Berg J, Joubert L, Robbins GF. Long-term follow-up of breast cancer patients the 30-year report. Cancer 1974 33 1145-50. 4. Nemoto T, Vana J, Bedwani RN et al. Management and survival of female breast cancer results of a national survey by the American...

Contributors

University Medical Center Lapeyronie Hospital Montpellier France Department of Pathology Stavanger University Hospital Stavanger Norway Edinburgh Cancer Research Centre Western General Hospital Edinburgh Scotland Dept of Medical Oncology Imperial College London Hammersmith Hospital London Bacs-Kiskum County Teaching Hospital Division of Radiation Oncology Netherlands Cancer Institute Amsterdam The Netherlands Dept of Histopathology Nottingham University Hospitals Nottingham United Kingdom...

Growth Factorinduced Mitogenactivated Protein Kinase Signaling

The MAP kinase signal transduction pathways are highly conserved signaling cascades which exert a profound effect on cell physiology.5-7 MAP kinase pathways can be activated by a variety of different stimuli, including growth 3S35SS8 BSSSS S S5SSS55 J iS55SS MEKK1-5, MLKs, TAOs, TPL-2, ASK, TAK1 MEKK1-5, MLKs, TAOs, TPL-2, ASK, TAK1 Figure 10.1 The mitogen-activated protein MAP kinase pathways. AP-1, Activator protein 1 ASK, apotosis signal regulating kinases ERK, extracellular signal-regulated...