Medical Oncology Unit
Institute for Cancer Research and Treatment (IRCC)
Breast cancer is a significant health problem in the industrialised Western world; it is the most common form of cancer among women in North America and most of Europe.(1,2) It is estimated that each year the disease is diagnosed in over one million women worldwide and causes the death of over 400,000 women. Recent evidence of a slight but steady decline in breast cancer mortality in Western countries since the early 1990s is reassuring news.(3) However, while early diagnosis and widespread use of adjuvant treatments for operable breast cancer are the likely explanations for this improvement, metastatic breast cancer is still considered an incurable disease.
The goals of treatment include symptom palliation and delay of disease progression, which can result in small improvements in survival. The therapeutic armamentarium for the treatment of metastatic breast cancer has expanded considerably over the last 15 years, with new chemotherapeutic agents, hormonal treatments and biologically targeted therapies. According to recent retrospective studies, as a result of the new anticancer treatments that have become available, survival rates for patients with metastatic breast cancer have increased.(4,5) This article summarises some of the most recent achievements in this field.
Several new chemotherapeutic agents are available for the treatment of metastatic breast cancer.(6–12) Paclitaxel and docetaxel, which belong to the taxane family, are at least as active as anthracyclines in metastatic breast cancer, and their use as first-line chemotherapy is now well established. Several other drugs, such as vinorelbine, gemcitabine and capecitabine, have demonstrated relevant antitumour activity and good tolerability.(7,8,13)
Pharmacological research aimed at improving the therapeutic ratio of anthracyclines and taxanes, the most active drugs in breast cancer, has led to new formulations of these agents.(9–12)
Capecitabine and vinorelbine are two new active agents, and the fact that they can be administered orally is associated with better patient compliance, a relevant issue in the palliative setting.
Chemotherapy is usually considered as the first therapeutic option for women with hormone receptor-negative disease or when rapidly growing metastatic disease represents a threat to the patient. In the latter case, multiple-agent chemotherapy is usually preferred because of a faster induction of tumour regression.
The most active and recent combinations include taxanes and anthracyclines, taxanes and capecitabine or gemcitabine, or combinations of taxanes, anthracyclines and capecitabine.(13–16)
Single-agent chemotherapy using different agents in sequence when tumour progression occurs represents a valuable and better-tolerated option for patients with less aggressive disease.
Endocrine therapy was one of the first forms of targeted therapy in the history of the treatment of cancer.
Almost two-thirds of breast cancers express the oestrogen and/or progesterone receptor, which can be targeted in several ways:
- Antagonising the oestrogen receptor using antioestrogens such as tamoxifen or toremifene.
- Stopping the endogenous production of oestradiol by using luteinising hormone-releasing hormone (LHRH) inhibitors in premenopausal women or aromatase inhibitors in postmenopausal women.(17–19)
- Destroying the oestrogen receptor by using drugs such as fulvestrant.(20)
Recently, in first-line studies in postmenopausal breast cancer patients, the newer aromatase inhibitors anastrozole, letrozole and examestane have shown excellent rates of tumour control in all patients, including those with visceral metastatic involvement.
Based on these results and not taking into account patients with life-threatening metastatic disease, it is now reasonable to consider first-line endocrine therapy as an alternative to chemotherapy for postmenopausal women with hormone receptor-positive disease, even in the presence of visceral metastatic involvement.
Patients once considered candidates for chemotherapy can now experience prolonged chemotherapy-free periods by using various sequences of endocrine treatments.
Biologically targeted therapies
Trastuzumab is the first monoclonal antibody registered for the treatment of metastatic breast cancer. This antibody recognises the product of the oncogene HER2, a member of the epidermal growth factor (EGFR) family, which is amplified in 20–30% of breast cancers.
As a single agent in appropriately selected patients, trastuzumab has an activity rate of approximately 34%, which is similar to results obtained with single-agent chemotherapy.(21) As predicted by preclinical models, trastuzumab combined with chemotherapy results in increased response rate and a survival advantage, compared with chemotherapy alone.(22) Trastuzumab can be combined with various cytostatic agents, resulting in high response rates. Thus, trastuzumab-based combinations are widely utilised in patients with HER2-positive metastatic breast cancer.(23)
Several other biologically targeted therapies are the topic of intense investigation in phase I, II and III clinical trials. The epidermal growth factor receptor (EGFR or HER1), another member of the EGF family, is a suitable target for anticancer therapies. The two most studied EGFR inhibitors in breast cancer are gefitinib and erlotinib. Both compounds, which are oral tyrosine kinase inhibitors, were studied as single agents in heavily pretreated groups of women with metastatic breast cancer. However, the results were discouraging, producing response rates of 1.6–7.4%.(24)
Recently, combined HER1 and HER2 blockage has been shown to be active in breast cancer with both HER1 and HER2 expression or overexpression.(25) Interestingly, tumour response was observed in patients with trastuzumab- refractory metastatic breast cancer.(25)
Other targeted therapies include the farnesyl transferase inhibitor tipifarnib, the mTOR (mammalian target of rapamycin) inhibitor rapamycin and the antivascular endothelial growth factor monoclonal antibody bevacizumab.(24) The latter agent is active as single agent and is associated with improved response rates when combined with chemotherapy, compared with chemotherapy alone.
Treatment options for metastatic breast cancer, which remains a fatal disease, have expanded over the last 15 years.
As the clinical course of metastatic breast cancer may vary considerably, with some patients experiencing dramatic progression and others presenting with more indolent disease, the availability of a large number of active anticancer drugs allows treatment tailoring according to the clinical and biological characteristics of each individual patient.
A shift in the paradigm of treatment for this disease is becoming evident: in the 1980s and up to the mid-1990s, it was believed that a high response rate was a prerequisite for the cure of metastatic breast cancer, and combination chemotherapy including the most active drugs (such as anthracyclines and taxanes) was the pursued strategy. After failure of first-line treatments, patients had few options left.
With several active and well-tolerated agents available, it is now possible to conceive strategies aimed at transforming metastatic breast cancer into a chronic disease. The patterns of cure will consequently change, with prolonged use of well-tolerated agents, preferably oral, as the most likely scenario.
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