Pathological prognostic factors in breast cancer

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Introduction

The management of patients with carcinoma of the breast has changed enormously in the last 20 years, for a variety of reasons. The number of therapeutic options has widened considerably for both local and systemic modalities. More and more women are opting for conservation and reconstructive surgery rather than mastectomy and radiotherapeutic techniques are constantly being improved and refined. These changes have been accompanied by an ever increasing range of systemic hormonal and cytotoxic drugs which can be used in both the adjuvant and the neoadjuvant setting. Increasing breast awareness amongst women, due to better health education should lead to earlier clinical detection and it is clear that population screening with mammography can achieve a significant improvement in survival [1] and even in the short-term will detect cancers which are substantially different in their biological behaviour from those which present symptomatically [2], [3].

All these developments highlight the increasing importance of prognostic factors in the management of patients with breast cancer [4], [5]. A major change in approach is required by both clinicians making therapeutic decisions and pathologists who provide the prognostic information. In a most perceptive review Clark [6] has addressed this question in the light of the increasing tendency for oncologists, especially in the USA, to adopt a strategy of advising the administration of adjuvant systemic therapy to all women with breast cancer, regardless of prognosis. He suggested that there are three major reasons for the use of prognostic factors. Firstly, to identify patients whose prognosis is so good that adjuvant systemic therapy after local surgery would not be ‘cost-beneficial’. Secondly, to identify patients whose prognosis is poor enough to warrant a more aggressive adjuvant approach to therapy. Thirdly, it is important to pick out those patients whose tumours are likely to be responsive or resistant to particular types of therapy.

The search for clinically relevant prognostic and predictive information has prompted an extensive industry devoted to the evaluation of a large number of putative factors, with differing degrees of significance. The current trend towards high technology has to a certain extent obscured the value of traditional histopathology in this area, despite the fact that the correlation between tumour morphology and degree of malignancy was described over 100 years ago. This is unfortunate because there is no doubt that careful histopathological examination of breast cancer specimens provides the great majority of the prognostic information required for therapeutic stratification [5]. The value of hormone receptors as a predictive factor for response to systemic endocrine therapy is also well-established [7], [8], [9]. Whilst a role for the newer molecular markers has yet to be determined, the aim of this review is to give a comparative account of these three groups of factors with particular emphasis on those which we believe are of most importance in the management of patients with breast cancer.

Section snippets

Traditional morphological factors

The diagnostic histopathologist is in an ideal position to supply clinical colleagues with a substantial amount of useful prognostic information from the routine examination of breast cancer specimens [5]. Most of the factors described below have a subjective element to their assessment and although relatively objective diagnostic criteria have now been provided [10], [11] the quality of reporting can be compromised seriously by poor specimen preparation. It is the responsibility of both

Hormone receptors

Some tumours, notably carcinoma of the breast and prostate, are often responsive to hormones, a property which has become exploited through endocrine surgery and more recently medically through drugs which influence hormonal levels or inhibit their effects on tumour cells.

Steroid hormones bind with high specificity and affinity to intracellular receptors. These steroid receptors belong to a ‘superfamily’ of proteins whose function is to control the transportation of a repertoire of other

Molecular markers

Apart from the hormone receptors referred to above an extensive range of novel variables have been proposed as putative prognostic factors. Most are associated, experimentally at least, with mechanisms of differentiation, invasion, metastasis or growth rate of neoplasms. They include expression of epithelial mucins including MUC1 [138], [139] growth factor receptors (e.g. epidermal growth factor receptor) [140], [141], oncoprotein expression such as c-erbB-2 [142], [143] and c-myc [144], [145],

Prognostic factors in patient management

Unfortunately, despite the evidence presented above, there is little general agreement on which factors should be used routinely in clinical practice and Hawkins [156], in a review of the literature, found a staggering range of findings and conclusions. In practice the only factor used consistently as a guide for therapy has been lymph node stage and this has also been true for patient stratification in clinical trials. Lymph node stage is a time-dependent factor; the longer the tumour has been

Conclusion

In summary, histopathological factors currently provide the most useful prognostic information available for the management of patients with primary operable carcinoma of the breast. In this respect the Nottingham Prognostic Index, based on careful assessment of tumour size, histological grade and lymph node stage is currently the most practical outcome measure available, and the only integrated index to have been confirmed in independent prospective studies [5], [159], [160]. Although of

Reviewers

This paper was reviewed by Vincenzo Eusebi, M.D., FRCPath, Sezione di Anatomia, Istologia e Citologia Pagologica ‘M. Malpighi’, Dipartimento di Oncologia, Università di Bologna, Ospedale Bellaria, Via Altura 3, 1–40139 Bologna, Italy; Dr James L. Conolly, Department of Pathology, Beth Israel Deaconess Medical Center, East Campus, 330 Brookline Avenue, Boston, MA 02215, USA and Prof Dr W. Böcker, Gerhard-Domagk-Institut für Pathologie, Westfälische Wilhelms-Universität Münster, Domagkstrasse 17,

Prof Christopher Elston, Dr Ian Ellis and Dr Sarah Pinder provide the histopathology service to the Nottingham Breast Unit. They form part of a multidisciplinary team with colleagues in breast surgery, imaging and medical and clinical oncology. The Nottingham Breast Unit is one of the largest in the United kingdom and, through its extensive research programme, makes a major contribution to our understanding of the biology of breast cancer and the management of patients with this disease.

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    Prof Christopher Elston, Dr Ian Ellis and Dr Sarah Pinder provide the histopathology service to the Nottingham Breast Unit. They form part of a multidisciplinary team with colleagues in breast surgery, imaging and medical and clinical oncology. The Nottingham Breast Unit is one of the largest in the United kingdom and, through its extensive research programme, makes a major contribution to our understanding of the biology of breast cancer and the management of patients with this disease.

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