Breast cancer metastatic, treatment

Tan AR et al (2004) Evaluation of biologic end points and pharmacokinetics in patients with metastatic breast cancer after treatment with erlotinib, an epidermal growth factor receptor tyrosine kinase inhibitor. J Clin Oncol 22 3080-3090... 

A 51-year-old woman with metastatic breast cancer started treatment with capeeitabine 2500 mg/m daily for 14 days every 21 days. Treatment was stopped after 8 days because she developed diarrhoea, vomiting and hand-foot syndrome. She improved with parenteral hydration and symptomatic treatment, but 3 weeks later still had diarrhoea, leg oedema and hand-foot syndrome. She was found to have been taking folic acid 15 mg daily for several weeks before starting capecitabine and had continued to take it during and after capecitabine treatment. The patient s condition improved when the folie acid was stopped, but she then developed diarrhoea and fever followed by necrotic colitis and she died from septic shock and vascular collapse. It is possible that the concurrent use of folic acid enhanced the toxicity of capecitabine. ... 

MTX is part of curative therapeutic schedules for acute lymphoblastic leukemias (ALL), Burkitt s lymphoma, and choriocarcinoma. It was also used in adjuvant therapy of breast cancer. High dose MTX with leucovorin rescue can induce about 30% remissions in patients with metastatic osteogenic sarcoma. MTX is one of the few antineoplastic drugs that can be safely administered intrathecally for the treatment of meningeal metastases and leukemic infiltrations (routine prophylaxis in ALL). In addition, MTX can be used as an immunosuppressive agent for the treatment of severe rheumatoid arthritis and psoriasis. 

Toremifene is an estrogen receptor antagonist. The pharmacokinetics of toremifene are best described by a two-compartment model, with an a half-life of 4 hours and an elimination half-life of 5 days. Peak plasma concentrations are achieved approximately 3 hours after an oral dose. Toremifene is metabolized extensively, with metabolites found primarily in the feces. Toremifene is used for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor-positive or unknown tumors. Toremifene causes hot flashes, vaginal bleeding, thromboembolism, and visual acuity changes. 

Determine the treatment goals for early-stage, locally advanced, and metastatic breast cancer. 

The goal of therapy with early and locally advanced breast cancer is to cure the disease. Breast cancer is currently incurable after it has advanced beyond local-regional disease. The goal of treatment of metastatic breast cancer is to improve symptoms, maintain quality of life, and extend survival. Thus it is important to choose therapy with good activity while minimizing toxicities. Treatment of metastatic breast cancer with either cytotoxic or endocrine therapy often results in regression of disease and improvements in quality of life. 

Toremifene is another commercially available SERM for the treatment of breast cancer. It exhibits similar efficacy and tolerability to tamoxifen in the metastatic setting. Cross-resistance to toremifene has been demonstrated in patients with tamoxifen-refractory disease.51 Therefore, toremifene appears to be an alternative to tamoxifen in postmenopausal patients with positive or unknown hormone-receptor status with metastatic breast cancer. 

Fulvestrant is a new agent approved for the second-line therapy of postmenopausal metastatic breast cancer patients who have tumors that are hormone-receptor-positive. Studies examining the role of fulvestrant in the treatment of metastatic breast cancer have compared this agent with anastrozole. Given anas-trozole s mechanism of action, only postmenopausal women were eligible for these trials. There is no biologic reason why fulvestrant should not produce similar outcomes in premenopausal... 

Cytotoxic chemotherapy is eventually required in most patients with metastatic breast cancer. Patients with hormone-receptor-negative tumors require chemotherapy as initial therapy of symptomatic metastases. Patients who respond initially to hormonal manipulations eventually cease to respond and go on to require chemotherapy. The median duration of response is 5 to 12 months, but some patients will have an excellent response to an initial course of chemotherapy and may live 5 to 10 years or longer without evidence of disease. In general, median survival of patients after treatment with commonly used drug combinations for metastatic breast cancer is 14 to 33 months. The median time to response has ranged from 2 to 3 months in most studies, but this period depends in large part on the site of measurable disease. The median time to appearance of response is between 3 and 6 weeks in patients whose disease is primarily in the skin and lymph nodes, 6 to 9 weeks in patients with metastatic lung involvement, 15 weeks in patients with hepatic involvement, and nearly 18 weeks in patients with bone involvement. Thus it is often the case that an immediate response to therapy is not... 

Vinorelbine, a microtubule interactive agent, also has shown impressive response rates in metastatic breast cancer.60 Vinorelbine was approved by the FDA in 1994 for the treatment of non-small cell lung cancer. It is not approved for breast cancer, but response rates to vinorelbine range from 30% to 50%, with an overall 5% complete response rate in phase I and phase II studies in patients with advanced breast cancer. Importantly, paclitaxel, docetaxel, and vinorelbine do not appear to be cross-resistant with anthracyclines, which are arguably considered first-line treatment of metastatic breast cancer. 

Tamamura H, Hori A, Kanzaki N, et al. T140 analogs as CXCR4 antagonists identified as anti-metastatic agents in the treatment of breast cancer. FEBS Lett 2003 550 79-83. 

CMF regimen is a combination of cyclophosphamide, MTX, and 5-FU, and represents one of the treatments of choice for women with non-metastatic breast cancer, significantly increasing disease-free and overall survival. A recent report in a... 

In phase I clinical trials 47 patients, all of whom had previously failed standard treatments for solid tumors, received the drug in the UK, Italy, and Switzerland on three different schedules.123,124 Dose-limiting toxicities have been defined as bone marrow depression and diarrhea. The latter is treatable with loperamide. Signs of biological activity were seen. Notably one patient with metastatic pancreatic cancer showed a partial response (for 4 months) and two further patients, one with metastatic melanoma and one with bronchoalveolar carcinoma, also showed partial responses. In a phase I trial in combination with 5-FU, a partial response in breast cancer was observed.125 Furthermore, a reduction in tumor marker levels was observed in two patients, one with ovarian cancer, and one with colon cancer. Phase II studies have shown partial responses in cisplatin-resistant ovarian and nonsmall-cell lung cancer.126,127 The indications are that the profile of clinical activity is different and complementary to the mononuclear platinum agents. 

Treatment of metastatic breast cancer if tumour overexpresses HER2 protein... 

Umemura, S., Sekido, Y., Itoh, H., and Osamura, RY. 2002. Pathological evaluation of HER2 overexpression for the treatment of metastatic breast cancers by humanized anti-HER2 monoclonal antibody (trastuzumab). Acta Histochemica et Cytochemica, Kyoto 35(2), 77-81. 

Goldenberg, M.M., "Trastuzumab, a Recombinant DNA Derived Monoclonal Antibody, a Novel Agent for the Treatment of Metastatic Breast Cancer," Clin. Ther., 21, 309-318 (1999). 

Metastatic bone disease (MBD) is characterized by very high levels of bone turnover in regions proximal to the tumour [33]. Bone resorption inhibitors such as bisphosphonates represent the current standard of care for the treatment of bone metastases primarily due to breast or prostate cancer and multiple myeloma. It has been proposed that other strong anti-resorptives such as a Cat K inhibitor could be useful in the treatment of bone metastases. Evidence for this has been presented in the form of a preclinical MBD model in which human breast cancer cells are implanted into nude mice. Treatment with a Cat K inhibitor gave a significantly lower area of breast cancer-mediated osteolytic lesions in the tibia [34]. In a separate study, the efficacy of a Cat K inhibitor in the reduction in tumour-induced osteolysis was found to be enhanced in the presence of the bisphosphonate zolendronic acid [35,36]. When prostate cancer cells were injected into the tibia of SCID mice, treatment with a Cat K inhibitor both prevented and diminished the progression of cancer growth in bone [37]. 

Capecitabine was clinically first approved for the co-treatment of refractory metastatic breast cancer. Its therapeutic spectrum has been expanded to include metastatic colorectal cancer, and there are hopes that it might broaden further as positive results of new clinical trials become available. Capecitabine, thus, affords an impressive gain in therapeutic benefit compared to 5-FU due to improved oral bioavailability and relatively selective activation in and delivery to tumors. 

Finally, one of fhe most recent and most interesting approvals of a new formulation of paclifaxel was fhe approval of the agent ABl-007 (Abraxane ) (Abraxis Oncology, Schaumburg, IL, U.S.A.) (paclifaxel protein-bound particles for injectable suspension [albumin-bmmd]). It is indicated for treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. The endpoint for that pivotal trial of Abraxane vs. paclitaxel was a... 

O Shaughnessy, J.A. et al.. Weekly nanoparticle albumin paclitaxel (Abraxane) results in longterm disease control in patients with taxane-refractory metastatic breast cancer. Breast Cancer Research and Treatment, In Lippman, M.E., Editor-in-Chief, Special Issue 27th Annual San Antonio Breast Cancer Symposium, Kluwer Academic Publishers, Dordrecht, Vol. 88, Suppl. 1, 2004, Abstr. 1070. 

The phase-three results were unblinded in March 2003 and overall, for all types of metastatic brain cancer, were reported as nonpositive, showing the drug to have efficacy but not at the statistical level set at the beginning of the trial by Alios Therapeutics Inc. for a successful phase-three trial. The subset analysis for the different types of metastatic cancer to brain, however, showed that breast cancer patients had a 100% increase in survival. The 500 plus patient trial also demonstrated RSR 13 to be extremely safe, confirming our early design feature of using a known antilipidemic drug, clofibrate, as a substructure. An NDA for RSR 13 with trade name efaproxaril was reviewed by the PDA on a fast track review for use in treatment of metastases of breast cancer to brain. 

Tamoxifen is on oestrogen-receptor antagonist. It is used in post-menopousol women with oestrogen-receptor-positive metastatic breast cancer at a dose of 20 mg doily. It con also be used in combination with chemotherapy. Severe side-effects ore infrequent however, it is associated with a small risk of endometrial cancer. Patients should be informed and reassured that the benefits of the treatment at this dose outweigh the risk. 

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