Australian New Zealand Breast Cancer Trials Group and International Breast Cancer Study Group, Sydney, New South Wales.
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.
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.2–4 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
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.
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,12–15 reducing the risk of lymphoedema without compromising efficacy.
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.
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.
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.
- Cole MP, Jones CT, Todd ID. A new anti-oestrogenic agent in late breast cancer. An early clinical appraisal of ICI46474. Br J Cancer.1971; 25:270-275.
- Piccart-Gebhart MJ, Procter M, Leyland-Jones B et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med. 2005;353(16):1659-1672.
- Romond EH, Perez EA, Bryant J et al. Trastuzumab plus Adjuvant Chemotherapy for Operable HER2-Positive Breast Cancer. N Engl J Med. 2005;353(16):1673-1684.
- Banerji S, Cibulskis K, Rangel-Escareno C et al. Sequence analysis of mutations and translocations across breast cancer subtypes. Nature. 2012;486(7403):405-409.
- Ellis MJ, Ding L, Shen D et al. Whole-genome analysis informs breast cancer response to aromatase inhibition. Nature 2012;486(7403):353-360.
- Kalager M, Zelen M, Langmark Fy, Adami HO. Effect of Screening Mammography on Breast-Cancer Mortality in Norway. N Engl J Med. 2010;363(13):1203-1210.
- Tabar L, Vitak B, Chen HH et al. The Swedish Two-County Trial twenty years later. Updated mortality results and new insights from long-term follow-up. Radiol Clin North Am 2000;38(4):625-651.
- URBAN JA, BAKER HW. Radical mastectomy in continuity with en bloc resection of the internal mammary lymph-node chain; a new procedure for primary operable cancer of the breast. Cancer 1952;5(5):992-1008.
- Veronesi U, Saccozzi R, Del VM et al. Comparing radical mastectomy with quadrantectomy, axillary dissection, and radiotherapy in patients with small cancers of the breast. N Engl J Med. 1981;305(1):6-11.
- Fisher B, Bauer M, Margolese R et al. Five-year results of a randomized clinical trial comparing total mastectomy and segmental mastectomy with or without radiation in the treatment of breast cancer. N Engl J Med. 1985;312(11):665-673.
- Urban C, Lima R, Schunemann E, Spautz C, Rabinovich I, Anselmi K. Oncoplastic principles in breast conserving surgery. Breast 2011;20 Suppl 3:S92-5.:S92-S95.
- Giuliano AE, Kirgan DM, Guenther JM, Morton DL. Lymphatic mapping and sentinel lymphadenectomy for breast cancer [see comments]. Ann . 1994;220(3):391-398.
- Veronesi U, Paganelli G, Galimberti V et al. Sentinel-node biopsy to avoid axillary dissection in breast cancer with clinically negative lymph-nodes. Lancet 1997;349(9069):1864-1867.
- Giuliano AE, Hunt KK, Ballman KV et al. Axillary Dissection vs No Axillary Dissection in Women With Invasive Breast Cancer and Sentinel Node Metastasis. JAMA: The Journal of the American Medical Association 2011;305(6):569-575.
- Galimberti V, Botteri E, Chifu C et al. Can we avoid axillary dissection in the micrometastatic sentinel node in breast cancer? Breast Cancer Res Treat 2012;131(3):819-825.
- Early Breast Cancer Trialists’ Collaborative Group. 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(9503):2087-2106.
- Dayes I, Rumble RB, Bowen J, Dixon P, Warde P. Intensity-modulated radiotherapy in the treatment of breast cancer. Clin Oncol (R Coll Radiol ) 2012;24(7):488-498.
- Early Breast Cancer Trialists’ Collaborative Group. Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10GÇê801 women in 17 randomised trials. The Lancet. 2011;(0).
- Vaidya JS, Joseph DJ, Tobias JS et al. Targeted intraoperative radiotherapy versus whole breast radiotherapy for breast cancer (TARGIT-A trial): an international, prospective, randomised, non-inferiority phase 3 trial. Lancet 2010;376(9735):91-102.
- Veronesi U, Orecchia R, Luini A et al. Intraoperative radiotherapy during breast conserving surgery: a study on 1,822 cases treated with electrons. Breast Cancer Res Treat 2010;124(1):141-151.
- Early Breast Cancer Trialists’ Collaborative Group. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. The Lancet 378, 771-784. 27-8-2011.
- Buzdar AU, Jonat W, Howell A et al. Anastrozole versus megestrol acetate in the treatment of postmenopausal women with advanced breast carcinoma: results of a survival update based on a combined analysis of data from two mature phase III trials. Arimidex Study Group. Cancer 1998;83(6):1142-1152.
- Dowsett M, Cuzick J, Ingle J et al. Meta-Analysis of Breast Cancer Outcomes in Adjuvant Trials of Aromatase Inhibitors Versus Tamoxifen. J Clin Oncol 2010;28(3):509-518.
- Heidelberger C. Fluorinated pyrimidines. Prog Nucleic Acid Res Mol Biol 1965;4:1-50.
- Coates AS, Gebski V, Bishop JF et al. Improving the quality of life in advanced breast cancer. A comparison of continuous and intermittent treatment strategies. N Engl J Med 1987;317:1490-1495.
- Gennari A, Stockler M, Puntoni M et al. Duration of Chemotherapy for Metastatic Breast Cancer: A Systematic Review and Meta-Analysis of Randomized Clinical Trials. J Clin Oncol 2011;29(16):2144-2149.
- Early Breast Cancer Trialists’ Collaborative Group. Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. Lancet 2011.
- Goldhirsch A, Wood WC, Coates AS et al. Strategies for subtypes – dealing with the diversity of breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011;22(8):1736-1747.
- Regan MM, Pagani O, Walley B et al. Premenopausal endocrine-responsive early breast cancer: who receives chemotherapy? Ann Oncol 2008;19(7):1231-1241.
- Vogel C, Cobleigh MA, Tripathy D et al. First-line, single-agent Herceptin(trastuzumab) in metastatic breast cancer: a preliminary report. Eur J Cancer 2001;37 Suppl 1:S25-9.:S25-S29.
- Jones JM, Ribeiro GG. Mortality patterns over 34 years of breast cancer patients in a clinical trial of post-operative radiotherapy. Clin Radiol 1989;40(2):204-208.
- Veronesi U, Cascinelli N, Mariani L et al. Twenty-Year Follow-up of a Randomized Study Comparing Breast-Conserving Surgery with Radical Mastectomy for Early Breast Cancer. N Engl J Med 2002;347(16):1227-1232.
- Baum M, Houghton J, Riley D. Results of the Cancer Research Campaign adjuvant trial for perioperative cyclophosphamide and long-term tamoxifen in early breast cancer reported at the tenth year of follow-up. Cancer Research Campaign Breast Cancer Trials Group. Acta Oncol 1992.
- Fisher B, Carbone P, Economou SG et al. 1-Phenylalanine mustard (L-PAM) in the management of primary breast cancer. A report of early findings. N Engl J Med 1975;292(3):117-122.
- Bonadonna G, Brusamolino E, Valagussa P et al. Combination chemotherapy as an adjuvant treatment in operable breast cancer. N Engl J Med 1976;294(8):405-410.
- Early Breast Cancer Trialists’ Collaborative Group. Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy. 133 randomised trials involving 31,000 recurrences and 24,000 deaths among 75,000 women (i). Lancet 1992;339:1-15.
- Early Breast Cancer Trialists’ Collaborative Group. Favourable and unfavourable effects on long term survival of radiotherapy for early breast cancer: an overview of the randomised trials. Lancet 2000;355(9217):1757-1770.
- Priestman TJ, Baum M. Evaluation of quality of life in patients receiving treatment for advanced breast cancer. Lancet 1976;1:899-901.
- Hürny C, Bernhard J, Coates AS et al. Impact of adjuvant therapy on quality of life in women with node-positive operable breast cancer. Lancet 1996;347(9011):1279-1284.
- Juraskova I, Butow P, Lopez A et al. Improving informed consent: pilot of a decision aid for women invited to participate in a breast cancer prevention trial (IBIS-II DCIS). Health Expect 2008;11(3):252-262.
- Piccart M, Goldhirsch A, Wood W et al. Keeping faith with trial volunteers. Nature 2007;446(7132):137-138.