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Breast cancer: current practice and key advances

David M Vigushin
MB BCh MRCP PhD
Senior Lecturer in Cancer Medicine
Imperial College of Science, Technology and Medicine
Honorary Consultant in Medical Oncology
Hammersmith Hospitals NHS Trust
E:d.vigushin@ic.ac.uk

RC Coombes
MD PhD FRCP
Professor
Head of Department of Cancer Medicine
Imperial College of Science, Technology and Medicine
Hammersmith Hospital
Clinical Director of Cancer Services and Clinical Haematology
Hammersmith Hospitals NHS Trust
London

The overall five-year relative survival for women with breast cancer in England and Wales is 73.7%. However, for patients with recurrent or metastatic breast cancer, the prognosis remains poor, with a median survival of 18-24 months that has remained largely unaffected by current therapies.

Tamoxifen
Approximately 70% of human breast cancers express the oestrogen receptor (ER), and the majority of ER- positive cancers respond to direct inhibition of ER function or to reduction of circulating oestrogen levels. Tamoxifen, an oral nonsteroidal competitive ER antagonist, has been the hormonal agent of choice for over 20 years, both in the adjuvant setting and for metastatic disease, and is also active in the prevention of breast cancer. Adjuvant tamoxifen administered for five years following curative surgery for ER-expressing tumours reduces the 10-year mortality rate by up to 26%.(1)
 
Most women with advanced ER-positive breast cancer will respond to tamoxifen, and the response rate is highest in the postmenopausal group. However, most women with advanced disease initially sensitive to tamoxifen will ultimately develop resistance to the drug. In many such patients, the breast cancer continues to express functional ER and remains oestrogen-dependent, thereby retaining the potential to respond to endocrine therapies.

Aromatase inhibitors
Progestins, such as medroxyprogesterone acetate and megestrol acetate, were previously used as secondline therapy when tamoxifen failed. A major advance was the development of inhibitors of the aromatase enzyme. In premenopausal women, circulating oestrogens are predominantly synthesised in the ovaries, but after menopause, residual oestrogen levels derive from tissue conversion of adrenal androgens. This reaction is catalysed by aromatase, an enzyme found in many tissues such as breast and adipose, and overexpressed in some breast cancers. Initial aromatase inhibitors lacked specificity or potency or required parenteral administration. However, recent aromatase inhibitors - anastrazole, letrozole and exemestane - are potent and specific oral agents that reduce circulating oestrogen to almost undetectable levels and are highly active in postmenopausal women with hormone-responsive breast cancers.

Aromatase inhibitors are more effective than progestins following tamoxifen failure in advanced breast cancer.(2) In firstline endocrine treatment of advanced breast cancer, studies have shown equivalent response rate and response duration and improved time to disease progression for both anastrazole and letrozole compared with tamoxifen.(3) Initial indications are that the aromatase inhibitors are at least as effective as tamoxifen as primary (neoadjuvant) therapy for ER-positive breast cancer. Several studies to evaluate the potential benefits of aromatase inhibitors in early-stage disease are in progress, but it will be several years before the results are available.

Another novel approach to endocrine therapy is the development of a new class of antioestrogens that act as ER downregulators. Fulvestrant, the first ER downregulator to enter phase I/II clinical study, completely ablates the activity of endogenous oestrogens. Unlike tamoxifen, fulvestrant is devoid of oestrogenic activity and thus carries no risk of endometrial proliferation or carcinoma.(4) The place of fulvestrant in the therapeutic armamentarium for breast cancer is yet to be established.

Trastuzumab
Major new advances in the treatment of breast cancer are occurring as a direct consequence of our enhanced understanding of the molecular pathogenesis of the disease. It is now recognised that the human epidermal growth factor receptor HER-2 is amplified and overexpressed in 25-30% of breast cancers. HER-2 overexpression is associated with an aggressive form of breast cancer, and affected patients have substantially reduced disease-free and overall survival.

Trastuzumab is a recently developed recombinant monoclonal anti-HER-2 antibody for the treatment of patients with advanced breast cancer overexpressing HER-2. Firstline combination therapy with trastuzumab and cytotoxic chemotherapy is more effective than chemotherapy alone in reducing tumour size, and is the first treatment regimen to substantially prolong survival in metastatic breast cancer (by about five months).(5) The combination of trastuzumab plus anthracycline-based chemotherapy has the greatest efficacy, but is unfortunately also associated with a high risk of serious cardiotoxicity. Trastuzumab plus paclitaxel is more effective than paclitaxel alone, and the risk of cardiotoxicity is low.

Trastuzumab monotherapy is also effective in a small subset of patients with HER-2 overexpressing advanced breast cancer disease that is resistant or refractory to both taxane and anthracycline chemotherapy.(6)Clinical trials are now underway to delineate the potential utility of trastuzumab in the adjuvant treatment of early breast cancer and in combination with other cytotoxic drugs such as vinorelbine in advanced disease.

Cytotoxic chemotherapy
Cytotoxic chemotherapy is a valuable modality of treatment for all stages of breast cancer, regardless of the hormone receptor status. In the neoadjuvant setting, primary chemotherapy may allow an otherwise inoperable locally advanced breast cancer to be surgically excised, or breast conservation surgery to be used instead of mastectomy. A complete response to neoadjuvant chemotherapy may even avoid surgery altogether if radiotherapy is subsequently administered.

Neoadjuvant endocrine therapy can be used in patients with hormone receptor-positive breast cancers, but the response to chemotherapy is considerably more rapid. In the adjuvant setting, combination chemotherapy enhances overall 10-year survival by between 2% and 11%, with the greatest benefit in premenopausal women with axillary lymph node-positive disease.(1) Several large studies comparing CMF (cyclophosphamide, methotrexate and 5-fluorouracil) and anthracycline-containing regimens indicate a slight advantage for the anthracycline regimens in both pre- and postmenopausal women with early breast cancer.(1) The addition of sequential hormonal therapy following adjuvant chemotherapy to women with ER-positive breast cancer confers a significant, but small, survival advantage.(7) Studies to evaluate the role of taxanes in the adjuvant setting are in progress.

The treatment of advanced or metastatic breast cancer is palliative, and preservation of quality of life is still the primary aim of all systemic treatments. While endocrine therapies are the treatment of choice in cases of asymptomatic and nonlife-threatening metastatic disease in patients with hormone receptor-positive tumours, chemotherapy is necessary if metastases become symptomatic or if specific organ function is impaired. Many cytotoxic agents have shown activity in metastatic breast cancer, either as monotherapy or in combination. At present there are no data to support the superiority of any particular regimen. Factors such as previous chemotherapy for primary and/or metastatic disease, rate of disease progression, comorbid conditions, organ function, and oncologist/patient preference all influence the choice in individual patients. Recent advances include the development of new agents with reduced toxicity, such as vinorelbine, oral cytotoxics like capecitabine (a prodrug of 5-fluorouracil), and drugs that ameliorate chemotherapy-induced toxicity, such as cyclin-dependent kinase inhibitors to prevent alopecia, and desrazoxane to reduce anthracycline cardiotoxicity.

Conclusion
Over the past decade, enhanced understanding of the cellular and molecular biology of breast cancer, coupled with intensive translational research, has led to the development of new targeted therapies effective in all stages of breast cancer. For the first time, there is now the potential not only to enhance quality of life, but also to prolong survival of patients with metastatic disease. There is justifiable optimism that the coming years will see the introduction of many more highly effective and relatively nontoxic agents that will substantially improve the outlook for patients suffering from this common and often devastating malignancy.

Reference

  1. Early Breast Cancer Trialists' Collaborative Group. Tamoxifen for early breast cancer: an overview of the randomised trials. Lancet 1998;351:1451-67.
  2. 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):1142-52.
  3. Bonneterre J, Buzdar A, Nabholtz JM, et al. Anastrozole is superior to tamoxifen as first-line therapy in hormone receptor positive advanced breast carcinoma. Cancer 2001;92(9):2247-58.
  4. Robertson JF, Nicholson RI, Bundred NJ, et al. Comparison of the short-term biological effects of 7alpha-[9-(4,4,5,5,5-pentafluoropentylsulfinyl)-nonyl]estra-1,3,5, (10)-triene-3,17beta- diol (Faslodex) versus tamoxifen in postmenopausal women with primary breast cancer. Cancer Res 2001;61(18):6739-46.
  5. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344(11):783-92.
  6. Cobleigh MA, Vogel CL, Tripathy D, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease.J Clin Oncol 1999;17(9):2639-48.
  7. Fisher B, Dignam J, Wolmark N,et al. Tamoxifen and chemotherapy for lymph node-negative, estrogen receptor-positive breast cancer. J Natl Cancer Inst 1997;89(22):1673-82.

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