Gemcitabine in metastatic breast cancer

Gemcitabine is a pyrimidine antimetabolite which has shown activity in metastatic breast cancer both as a single agent, but also in various combination regimens. It is characterized by a unique mechanism of action which includes cytotoxic self-potentiation, masked DNA chain termination and potent inhibition of DNA repair. The clinical application of gemcitabine is supported by a favorable toxicity profile. In metastatic breast cancer, several Phase II trials document the activity of gemcitabine in pretreated and unpretreated patients. In a single Phase III trial performed in elderly patients not pretreated, gemcitabine was inferior to epirubicin. High activity has, however, been obtained by the combination of gemcitabine with taxanes such as paclitaxel or docetaxel. In a randomized trial performed in anthracycline-pretreated patients, the combined use of gemcitabine and paclitaxel induced a significant improvement not only of response rate and time to disease progression, but also caused a significant increase in quality of life and survival when compared with paclitaxel alone. The combination of gemcitabine with vinorelbine and cisplatin has been validated in numerous Phase II trials and promises reliable activity in anthracycline- and/or taxane-pretreated patients. Triple-agent regimens such as gemcitabine/epirubicin/paclitaxel provided consistently high response rates in Phase II trials, but failed to show superiority over the 5-fluorouracil/epirubicin/cyclophosphamide regimen in a randomized Phase III trial. Based on high response rates and pathological complete remission rates achieved by preoperative induction therapy with gemcitabine/epirubicin/taxane regimens, ongoing trials focus on the incorporation of gemcitabine into neoadjuvant and adjuvant regimens.     

Gemcitabine in metastatic breast cancer

Gemcitabine is a pyrimidine antimetabolite which has shown activity in metastatic breast cancer both as a single agent, but also in various combination regimens. It is characterized by a unique mechanism of action which includes cytotoxic self-potentiation, masked DNA chain termination and potent inhibition of DNA repair. The clinical application of gemcitabine is supported by a favorable toxicity profile. In metastatic breast cancer, several Phase II trials document the activity of gemcitabine in pretreated and unpretreated patients. In a single Phase III trial performed in elderly patients not pretreated, gemcitabine was inferior to epirubicin. High activity has, however, been obtained by the combination of gemcitabine with taxanes such as paclitaxel or docetaxel. In a randomized trial performed in anthracycline-pretreated patients, the combined use of gemcitabine and paclitaxel induced a significant improvement not only of response rate and time to disease progression, but also caused a significant increase in quality of life and survival when compared with paclitaxel alone. The combination of gemcitabine with vinorelbine and cisplatin has been validated in numerous Phase II trials and promises reliable activity in anthracycline- and/or taxane-pretreated patients. Triple-agent regimens such as gemcitabine/epirubicin/paclitaxel provided consistently high response rates in Phase II trials, but failed to show superiority over the 5-fluorouracil/epirubicin/cyclophosphamide regimen in a randomized Phase III trial. Based on high response rates and pathological complete remission rates achieved by preoperative induction therapy with gemcitabine/epirubicin/taxane regimens, ongoing trials focus on the incorporation of gemcitabine into neoadjuvant and adjuvant regimens.     

Maintenance treatment in metastatic breast cancer

Metastatic breast cancer (MBC) occurs in 20–30% of women with breast cancer and is an incurable disease. Treatment is palliative and directed to prolong survival, decrease symptoms and improve patients’ quality of life. For patients with hormone receptor-negative disease or for hormone receptor-positive disease that has become resistant to endocrine therapy, or is progessing rapidly and life threatening, cytotoxic chemotherapy is indicated. However, the optimal duration of chemotherapy treatment for MBC is still a matter of debate. Studies using maintenance chemotherapy regimens standard in the 1990s showed a consistent benefit with a more prolonged time to progression, although an improvement in survival was only demonstrated in one study. Two recent trials with newer cytotoxic agents showed controversial results; whereas one study concluded that the policy of prolonging treatment in chemotherapy-sensitive patients, after aggressive, modern combination chemotherapy, cannot be recommended for women with MBC, the other study showed that maintenance therapy with pegylated liposomal doxorubicin significantly prolonged time to progression in MBC patients after first-line chemotherapy without significant clinical toxicity. Initial data regarding metronomic chemotherapy indicate that continuously low-dose cyclophosphamide and methotrexate is minimally toxic and effective in heavily pretreated breast cancer patients. In daily practice, maintenance chemotherapy is a reasonable strategy that prolongs time to progression in patients with MBC who did not show progression after first-line chemotherapy. However, this benefit should be considered together with toxicities of treatment and the patient’s preference.     

Chemotherapy in metastatic male breast cancer

14 male patients with metastatic breast cancer received a total of 20 chemotherapeutic trials with 2 basic combination regimens, namely, variants of the Cooper's regimen CMFVP and adriamycin-containing combinations. Overall, a 35% response rate was observed. Our data suggest that cancer of the breast in the male is responsive to the same combinations used in the female, with regimens including adriamycin being probably superior to regimens without it.     

Symptom management in metastatic breast cancer

Approximately 40,000 women die as a result of breast cancer each year and many more live with advanced disease. When breast cancer recurs, the goals of treatment often shift from one of cure to controlling the disease for as long as possible while palliating symptoms interfering with the patient's functional status and quality of life. This requires ongoing discussions with the patient and family about the goals of care. Many symptoms depend on the site of metastasis, with bone being the most frequent, and commonly occur with fatigue, depression, insomnia, and pain. The purpose of this paper is to identify and provide an overview of the management of the most common symptoms in patients with breast cancer metastases.     

Therapeutic oophorectomy in metastatic breast cancer

One hundred five patients undergoing therapeutic oophorectomy for metastatic breast cancer (n = 105) from 1975 to 1985 were reviewed. There were 54 responders (51%) to oophorectomy, with a median duration of response of 16 months (range, 3 to 129 months). Thirty of 42 (71%) estrogen receptor (ER)-positive patients responded to oophorectomy versus five of 24 (21%) ER-negative patients (P less than 0.001). Of the 39 patients with unknown ER status, 19 (49%) responded to oophorectomy. Osseous, soft tissue, and pulmonary metastases responded at similar rates. Of the 16 patients who had received adjuvant chemotherapy, there were five responders (31%) to oophorectomy. Second-line endocrine therapy was effective in 29 of 53 (55%) patients. Fifteen of 28 (54%) ER-positive patients responded to second-line endocrine therapy while two of six (33%) ER-negative patients responded. Twenty-three of 37 (62%) oophorectomy responders responded to second-line endocrine therapy versus six of 16 (38) nonresponders. Oophorectomy appears to be a valuable palliative treatment for metastatic breast cancer. ER-positive patients have the best chance of responding to this therapy. However, ER-negative patients have a reduced but definite chance of responding with a good duration of response. Response to further endocrine treatments is predicted by response to oophorectomy and to a lesser degree by ER status.     

Targeting angiogenesis in metastatic breast cancer

Angiogenesis has become an important target in the treatment of several solid tumors, including breast cancer. As monotherapy, antiangiogenic agents have demonstrated limited activity in metastatic breast cancer (MBC); therefore, they have generally been developed for use in combination with chemotherapies. Thus far, the experience with antiangiogenic agents for MBC has been mixed. The results from one study assessing addition of the monoclonal antibody bevacizumab to paclitaxel led to approval of bevacizumab for MBC. However, the modest improvement of progression-free survival rates in subsequent MBC studies has led to reappraisal of bevacizumab. Phase III studies have not produced evidence supporting use of the multikinase inhibitor sunitinib alone or in combination with MBC chemotherapy. Experience with sorafenib in a phase IIb program indicates potential when used in select combinations, particularly with capecitabine; however, phase III confirmatory data are needed. Although antiangiogenic therapies combined with chemotherapy have increased progression-free survival rates for patients with MBC, increases in overall survival times have not been observed. Some studies have tried to combine antiangiogenic agents such as bevacizumab and sunitinib or sorafenib, but that approach has been limited because of toxicity concerns. Sequential use of antiangiogenic agents with differing mechanisms of action may be an effective approach. Despite setbacks, angiogenesis will likely remain an important target of treatment for selected patients with MBC.     

Docetaxel-anthracycline combinations in metastatic breast cancer

The taxanes and anthracyclines have emerged as the most active agents for treating women with advanced breast cancer. As such, investigation of the two drug classes in combination regimens has been eagerly pursued. The rationale for combining docetaxel with an anthracycline includes high clinical activity of each individual agent, lack of complete clinical cross resistance, and non-overlapping toxicity profiles. Phase II trials of the docetaxel combinations with either doxorubicin or epirubicin showed high activity, with acceptable tolerability in patients with metastatic breast cancer. Consequently, three randomized trials have compared docetaxel-anthracycline-based regimens with standard anthracycline-based polychemotherapies as first-line therapy for women with advanced breast cancer. Improved outcome was reported in favor of the docetaxel-anthracycline combinations, with manageable hematologic toxicity and favorable non-hematologic safety profiles. Therefore, docetaxel-anthracycline combinations represent a validated option in first-line treatment for women with advanced breast cancer, and are further evaluated as adjuvant treatment for early stage breast cancer, with already promising prospects and the potential to change the natural history of breast cancer.     

Sarcoidosis mimicking metastatic breast cancer

The clinical and radiographic aspects of sarcoidosis and malignancy might mimic one another, making the distinction between the two difficult in some cases. Although there have been many theories on the link between sarcoidosis and malignancy, the association remains unproven. An unfortunate consequence of the presence of both entities in the same patient is the risk of misdiagnosis and incorrect treatment. We describe 3 patients who presented with locally advanced breast cancer and who were found to have pulmonary findings for metastatic disease that were proven upon biopsy to be consistent with sarcoidosis.     

Chemotherapy for metastatic breast cancer

The treatment of metastatic breast cancer aims to relieve symptoms by controlling disease and prolonging survival with better QOL. The meta-analysis demonstrated the significant advantage for overall survival by chemotherapy with a longer period. It means that chemotherapy can prolong survival. The major chemotherapies contain anthracyclines or taxanes. For HER 2-overexpressing breast cancer, a standard treatment utilizes trastuzumab-containing chemotherapy. The other active agents include vinorelbine, capecitabine, S-1, mitomycin and gemcitabine. Bisphosphonates combined with chemotherapy or hormone therapy are able to alleviate pain or complications of osteolytic bone metastasis. Experimental agents, such as monoclonal antibody or small molecular kinase inhibitor, are investigated for clinical use. The treatments, either chemotherapy or hormone therapy, could be performed in sequence in order to minimize toxicities and maximize efficacy. In selecting the most appropriate treatment for metastatic breast cancer, it is recommended to consider patients' preference by providing the correct information on the status of disease, efficacy and toxicities of chemotherapy.     

Chemotherapy for metastatic breast cancer

Cytotoxic chemotherapy is a mainstay of treatment for advanced breast cancer. Treatment of metastatic (also called stage IV, advanced, or recurrent) breast cancer is not considered curative. Rather, the goals of treatment with chemotherapy are to prolong survival, alleviate or prevent tumor-related symptoms or complications, and improve quality of life. While the purpose of chemotherapy is to prevent or alleviate symptoms, chemotherapy paradoxically carries considerable toxicities that cause substantial symptoms in patients, notoriously including fatigue, nausea, vomiting, diarrhea, hair loss, mucositis, neutropenia, and neuropathy. Balancing the benefits and the side effects of chemotherapy is further complicated by the natural history of advanced breast cancer, which can be quite prolonged and typically involves multiple lines of chemotherapy, especially in patients whose tumors respond to treatment.     

Update on metastatic breast cancer

Conclusions Although the great majority (80%) of patients diagnosed with breast cancer have disease that is limited to a locoregional area (breast and/or axillary lymph nodes), almost half of them eventually develop metastatic disease. An extensive array of basic and clinical research has been performed throughout the last decade in an attempt to improve the outcome for these patients. In spite of significant recent advances, cure after a diagnosis of metastatic breast cancer is a rather elusive goal utilizing current therapeutic options. At this time there are many therapeutic options and not a single “only” way to treat all patients. Participation in clinical trials remains a major priority. The role of taxanes has been expanded, and new data have started to demonstrate their improved efficacy, compared to older agents, as first-line or second-line therapy for patients with metastatic breast cancer who are eligible for systemic therapy. Paclitaxel with trastuzumab is emerging as the treatment of choice for patients with HER2 overexpressing breast cancer who are eligible for first-line chemotherapy. Given the novel mechanisms of action of new antitumor compounds coupled with their favorable toxicity profiles, however, continued improvements in survival and quality of life may be achieved in patients with advanced disease. The responsibility of the treating physician will continue to include providing patients with clear information on the crucial role of clinical trial participation for proper determination of whether these new alternative therapies should eventually be incorporated as standard of care. The social and economic importance of metastatic breast cancer in our society makes this a priority.     

Cytopathology of metastatic breast cancer

A 52-year-old woman developed an infiltrating ductal carcinoma of the breast 16 years after being treated for comedocarcinoma of the left breast. Although the tumor was high grade with lymphatic space invasion and incompletely excised, the patient declined adjunctive therapy. Within 2 years, she developed metastasis to supraclavicular lymph nodes, which was diagnosed by fine-needle aspiration cytology.     

Chemotherapy of metastatic breast cancer

The most powerful prognostic factor in the treatment of metastatic breast cancer continues to be the response to induction chemotherapy. The range of drugs which are widely used in the treatment of advanced disease, the anthracyclines, the taxanes and vinorelbine, have all shown interesting activity in terms of their ability to obtain both high response rates and long duration of response. The anthracyclines, doxorubicin (DX) and epiadriamycin (EPI) constitute the established reference agents in the treatment of metastatic disease, and combinations of these drugs with vinorelbine (VRB) and the taxanes, paclitaxel (PTX) and docetaxel (DCT), have produced major increases in objective response rates: PTX-DX (58%), DCT-EPI (69.4%), PTX-EPI (71.1%), VRB-DX (75%), VRB-EPI (77.1%). Suggestions for other combinations of chemotherapeutic agents which do not include anthracyclines available with well tolerated and effective drugs. The way forward after a response has been obtained remains an open question in which the limited efficacy of the available drugs and their cumulative toxicity needs to be balanced against the quality of life of patients during their disease. Defining the optimal strategy for the management of disease after induction treatment is a problem which needs to draw on the results of research, analysis of experience and insight into the needs of patients.