Progress in the treatment of Early and Advanced Breast Cancer

Breast cancer represents a major health problem with more than 1,000,000 new cases and 370,000 deaths yearly worldwide. In the last decade , in spite of increasing incidence, breast cancer mortality is declining in the majority of developed countries. This is the combined result of better education, widespread screening programmes and more efficacious adjuvant treatments. The better knowledge of breast cancer biology allows nowadays to spare the cosmetic, physical and psychological consequences of radical mastectomy to the majority of breast cancer patients. The sentinel node technique is rapidly expanding and will further reduce the extent and the consequences of surgery. Several clinical and pathologic factors are used to discriminate between patients at low (<10%), average (10-40%) and high risk of relapse and international guidelines have been established to help clinicians to choose the appropriate postoperative treatments. Nodal status, tumor size, tumor grade, age, HER2 expression are universally accepted as important factors to define risk categories. Newer factors such as uPA/PAI-1, cyclin-E and other proliferative indices and gene expression profile are promising and will allow a better discrimination between patients at different risk. Their generalized use is however not yet recommended because of lack of reproducibility, necessity of fresh tumor samples, limited data and follow up. Endocrine manipulation with tamoxifen, ovarian ablation or aromatase inhibitors is the preferred option in case of endocrine-responsive tumors. Tamoxifen administered for five years has been considered for may years the standard treatment for postmenopausal patients; tamoxifen plus ovarian ablation is more effective than tamoxifen alone for premenopausal women. Recent data demonstrate that, for postmenopausal patients, the aromatase inhibitors are superior to tamoxifen with a different safety profile. At present time aromatase inhibitors represents the preferred option for postmenopausal patients. Chemotherapy is the treatment of choice in case of steroid receptor negative tumors. Polychemotherapy is superior to single agents and anthracycline containing regimens are superior to CMF. Six courses of FEC or FAC or the sequential administration of four doses of anthracycline followed by four CMF are the recommended regimens. New regimens including the taxanes have produced a further improvement in risk reduction and are reasonable therapeutic options. These agents are currently approved for adjuvant therapy in US and European Countries. Chemotherapy followed by endocrine therapy represents the standard adjuvant treatment of high risk patients with endocrine responsive tumors. For Her2-neu overexpressing tumors, the addition of trastuzumab, a monoclonal antibody directed against the extra-membrane portion of the Her2 receptor, significantly reduced the risk of recurrence and death. Primary chemotherapy is increasingly used in the treatment of locally advanced and operable breast cancer. The upfront administration of chemotherapy significantly increases the rate of breast conserving surgery and allows an in vivo chemosensitivity testing. A proportion of patients achieve a pathologic complete response and these patients have significantly better long term outcomes. Twenty-five to forty% of breast cancer patients eventually develop distant metastases. At this stage the disease is incurable, however treatments can assure a significant prolongation of survival, symptomatic control and maintenance of quality of life. In case of hormone receptor positivity and in the absence of visceral, life threatening disease endocrine manipulation is the treatment of choice. Active treatments include tamoxifen, ovarian ablation, aromatase inhibitors, pure antiestrogens and progestins. Aromatase inhibitors are the most active agents, however the choice and the sequence of endocrine therapies is also dictated by prior adjuvant treatment. Chemotherapy has to be preferred in case of receptor negative tumors, acquired resistance to hormones and aggressive visceral disease. Combination regimens are usually associated with higher response rates and sometimes survival prolongation and this approach should be recommended in young patients with good PS and visceral disease. On the contrary single agents have a better tolerability profile and should be the treatment of choice when a careful balance between activity and tolerability is needed. In case of Her2-positive tumors the combination of trastuzumab and chemotherapy is significantly superior to chemotherapy alone both in terms of response rates and survival.