Breast cancer

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Australian New Zealand Breast Cancer Trials Group and International Breast Cancer Study Group, Sydney, New South Wales.


Abstract

Breast cancer and its treatment have changed enormously over the last four decades. Most newly diagnosed patients will not die of breast cancer, and the burdens of treatment are substantially less than formerly. Biological understanding of breast cancer has increased at an exponential rate, and has yielded many new therapeutic options. Clinical trials, to which Australian groups have made major contributions, provide the evidence base to utilise these discoveries to provide more effective, less onerous therapies.


Biology

Many of the changes in breast cancer management stem from understanding of its biology. Jensen’s discovery of the oestrogen receptor explained the previous empirical use of endocrine ablative surgery and additive natural hormones and led to the therapeutic application of tamoxifen,1 undoubtedly the single most important drug in breast cancer during the last 40 years. Over-expression and/or amplification of the HER2 (erb-B2) oncogene led to a major impact of trastuzumab in advanced disease, and adjuvant therapy.24 Classification of breast cancers into intrinsic subtypes, based on assays of gene expression and whole genome sequencing, have added to the depth of our understanding, if not always to the clarity of its therapeutic implications.4,5

Early detection

When I commenced practice, breast cancer usually presented as a palpable mass, not infrequently involving adjacent structures such as the skin and chest wall, and in most cases having spread to the draining lymph nodes. Increased awareness and mammographic screening have contributed to a steadily decreasing stage at presentation. In screened populations, many patients present with disease which cannot be palpated, and a minority show nodal metastases. Randomised clinical trials have established that population-based mammographic screening reduces breast cancer mortality.6,7 Though debate continues about the optimal target age-group, mammographic screening is now widely adopted in Western countries.

Surgery

As a surgical houseman only a little over 40 years ago, I was taught the Urban super-radical mastectomy.8 Expertise in this procedure was judged by the completeness of removal of all soft tissue down to the rib cage, and by the transparency of the skin flaps. Not surprisingly, when (and if) such flaps healed, the transparency was all too apparent. Surgical research since that time has demonstrated the safety of breast conservation,9,10 and if mastectomy is performed, immediate oncoplastic reconstruction.11 Similarly, sentinel node biopsy has reduced the indications for axillary dissection,1215 reducing the risk of lymphoedema without compromising efficacy.

Therapy

Local control of disease is enhanced by postoperative irradiation, and recent data shows that this is accompanied by a later reduction in breast cancer mortality.16 Refinements in radiotherapy technique have reduced late adverse effects due to radiation damage of adjacent vital structures, particularly the heart.17 Radiation is indicated after breast conservation,18 while indications for radiation after mastectomy appear to be increasing. Intraoperative radiotherapy delivered using ortho-voltage or electron techniques limits radiation to normal tissues and appears promising.19,20
More than half of all breast cancers contain oestrogen receptor, a marker of sensitivity to endocrine therapy. Oophorectomy, ovarian suppression and tamoxifen1, 20,21 remain important tools in premenopausal patients,23,24,25 while more recently the aromatase inhibitors have provided incremental benefit over tamoxifen among postmenopausal patients.22,23 Ongoing research is examining the optimal timing and duration of these agents.

Forty years ago, the cytotoxic armamentarium consisted of 5-fluorouracil,24 methotrexate, the alkylating agents and little else. Today, a wide variety of drugs and combinations offer palliation in advanced disease.25 Studies have shown that such treatment should be continued in the absence of disease progression or unacceptable toxicity.26 Chemotherapy also improves survival in the adjuvant setting.27 No single drug or combination has established itself as superior to others. Meta-analyses suggest overall improvement with the inclusion of anthracyclines and taxanes,27 but the contribution of each of these classes may depend on the subtype of the tumour. The threshold indications for adjuvant cytotoxic therapy undergo recurrent review.28,29

Undoubtedly the most exciting area of developmental therapeutics in breast cancer centres on the evaluation of agents targeting specific molecular changes in the cancer cell. In addition to the archetypal targeted agent,  tamoxifen,1 and more recently trastuzumab,30 agents targeting multiple intracellular metabolic aberrations are in various phases of clinical trial.

Clinical trials

Breast cancer was in the forefront of the evaluation of therapy by randomised clinical trials, perhaps the first being the Manchester radiotherapy trial commenced in the first half of last century.31 Successive trials have established the safety and efficacy of lesser surgery,10,32 adjuvant endocrine therapy,33 adjuvant cytotoxic therapy,34,35 and in appropriate patients trastuzumab.2,3 The Early Breast Cancer Trialists Collaborative Group, led by Sir Richard Peto, has since 1994 brought together virtually all the randomised evidence from trials in early breast cancer, providing an invaluable evidence base for treatment selection.21,27,36,37 Today’s patients owe an enormous debt to their sisters who participated in these clinical trials.

Quality of life

All treatments have adverse effects. In order to assess the net effect of the benefits and harms of treatment, patient self-evaluation of quality of life using scales feasible for use in the clinical trial setting,38 has been used to demonstrate the benefit of chemotherapy in metastatic disease both in terms of survival and quality of life.25 In the adjuvant setting, similar studies demonstrated that the adverse effects of chemotherapy were perceived as modest, transient and fully reversible.39

An important corollary of the high survival rate of breast cancer patients has been the emergence of organised, knowledgeable and vocal groups of breast cancer survivors. These groups contribute to better service delivery, and to the design and conduct of clinical trials.40 Australia can claim to be at the forefront of this movement, with bodies such as the Breast Cancer Network of Australia and the Consumer Advisory Panel of the Australian New Zealand Breast Cancer Trials Group. Importantly, patient advocates can argue to regulatory bodies to reduce bureaucratic impediments to research, to  facilitate trial participation and to promote academic independence from the pharmaceutical industry,41  roles in which the professional researcher is often regarded with suspicion.

Conclusion

Both the disease and its management today are radically different from their equivalents of 40 years ago. Most patients now present with early, frequently impalpable disease, receive vastly less mutilating local treatments, increasingly effective systemic adjuvant therapy, and go on to join the increasing number of long-term breast cancer survivors.

References

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