Miscellaneous And Molecular Factors

Extensive tumor necrosis appears to be associated with an aggressive clinical course.54 However, where strict criteria have been applied, and multivariate analysis performed, an association with tumor size, histological grade and proliferation, as well as lymph node status, has been described, but there has been no independent prognostic value to this feature.55 There is some evidence that the presence and relative size of fibrotic areas in breast carcinoma can be correlated with an early relapse.56,57 However, whether these morphological features are robust enough to be included in a routine histopathology dataset remains controversial.

Many molecular markers have been assessed by groups and reported to be potential prognostic markers in invasive breast carcinoma. C-erbB-2/HER2-/neu is an oncogene and member of the epidermal growth factor receptor (EG-FR) family.58 Amplification of the gene is one of the commonest genetic abnormalities occurring in breast carcinoma, although in a small proportion of cases (approximately 5%) overexpression appears to be the result of increased transcription.58 In terms of prognostic significance, amplification of this gene appears to be associated with an aggressive phenotype, i.e. high histological grade, estrogen and progesterone negativity, and reduced overall and metastasis-free survival.58,59 The significance of HER2 assessment, and the need for strict quality assurance methodology, now largely relates to the development of targeted monoclonal antibody therapies such as Herceptin (trastuzumab),60 and this is discussed in Chapter 13.

Overexpression of EGFR correlates with estrogen receptor negativity and resistance to tamoxifen,6 and clinical trials are underway to assess its therapeutic potential. Although there are some promising data from results of trials of the dual HER2 and EGFR tyrosine kinase inhibitor, lapatinib, in HER2-positive breast cancer, to date some other EGFR inhibitors have proven somewhat disappointing. In particular, there are difficulties with methodology for selection of those patients most likely to respond to these new drugs.61

Other molecular markers have been widely described. For some, changes are common in invasive breast cancer; p53 is mutated in nearly one-third of breast carcinomas and an association with an aggressive clinicopathological pheno-type has long been recognized (see Chapter12).6 Evaluation of proliferation markers MIB1/Ki67 antigen,62,63 proliferating cell nuclear antigen (PCNA) and S-phase fraction have shown a correlation with prognosis (see Chapter 3). Other molecular markers whose over- or underexpression have been reported as showing a correlation with prognosis include, not exclusively, transforming growth factor alpha, bcl-2, p16INK4a, parathyroid hormone-related protein, metalloproteinases, inte-grins, E-cadherin, pS2 and cathepsin-D.6,64-70 However, validation of their robustness as independent prognostic factors is disputed, and many have not withstood close scrutiny and repeat analysis.

But, most recently researchers have begun to examine invasive breast carcinomas with more advanced methodologies such as gene expression profiling and other "omics" techniques (see Chapter 11). There has been increasing recognition that breast carcinoma is not a single disease but a biological (as well as morphological) heterogeneous group of lesions, and using such approaches molecular methods of subclassification have been described. Gene expression profiling utilizing microarray analysis has identified breast cancer signatures which appear to be related to prognosis and potentially for treatment. Different molecular subtypes, designated luminal (either 2 or 3 groups), normal-like, HER2+/ER-, and basal-like have been proposed. Interestingly, such groupings have been confirmed with more commonly available immuno-histochemical techniques, and confirmed to have prognostic value.72 At present, there is increasing interest in the overlap between the "basal-type" of invasive breast carcinoma and the so-called "triple negative" (i.e. ER-negative, PR-negative and HER2-negative) breast cancers, partly because of the poor prognosis of these patients and partly because of the therapeutic conundrum they present clinically.

However, differences in design of study, patient groups included, array technology/ different platforms, and methods of analysis make correlation and interpolation of many of the omics study's results difficult.74 Nevertheless, there are now a large number of studies which report, albeit differing, prognostic gene signatures. Indeed, clinical trials based on such signatures are planned and underway, although not without significant logistically and interpretive difficulties, as recognized by the trial group concerned.74

It is clear that breast cancer is a complex and heterogeneous disease, clinically and biologically. Although in the recent past a myriad of putative prognostic and predictive markers of breast cancer have been examined, very few have proven useful. Studies which have found a variable to be of independent importance have not generally been replicated by other groups. At present, the variables which have been shown repeatedly, and by different groups, to be of independent prognostic significance remain those routine histological factors which can be assessed using H&E stains. Such "routine" variables should not, however, be dismissed as "simple" biologically. Such histological features are a complex combination of time and tumor-dependent factors. For example, the presence of lymphovascular invasion or metastatic disease is likely to be a result of interaction of features involving cell-cell and cell-matrix adhesion, degradation/ infiltration, cell proliferation, tumor surface markers, and other specific genetic abnormalities.

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