Breast cancers treatment response

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. 

It has been suggested that tamoxifen, one of the most effective therapeutic and chemopreventive agent for breast cancer, modulates protein kinase C through oxidative stress in breast cancer cells [194], Unfortunately, most breast cancers initially responsive to tamoxifen treatment later become resistant. Schiff et al. [195] suggested that the conversion of breast tumors to a tamoxifen-resistant phenotype is associated with oxidative stress and depends on significantly enhanced SOD activity in tumors. 

Furthermore, it is critical for physicians to determine which combination of treatment is most suitable for each individual patient. However, it still remains challenging to make an accurate predictive assessment of a patient s risk or response to certain treatment regimens. Advances in microarray technology promise breakthroughs in personalized medicine for breast cancer treatment. To date, the prediction models based on microarray technology for breast cancer have focused mainly on either transcriptional profiles or proteomic profiles, instead of the integrated transcriptional and proteomic profiles. 

Tumors that are steroid hormone-sensitive may be either (1) hormone-responsive, where the tumor regresses following treatment with a specific hormone (2) hormone-dependent, where removal of a hormonal stimulus causes tumor regression or (3) both. Hormone treatment of responsive tumors is usually only palliative, except in the case of the cytotoxic effect of glucocorticoids (for example, prednisone) on lymphomas. Removal of hormonal stimuli from hormone-dependent tumors can be accomplished by surgery, for example, in the case of orchiectomy for patients with advanced prostate cancer, or by drugs, for example in the case of breast cancer, treatment with the antiestrogen... 

Idoxifene has been evaluated as a breast cancer treatment for postmenopausal patients [296, 297]. In one study, 321 postmenopausal patients with unknown receptor status or hormone receptor-positive metastatic breast cancer were randomized to receive either tamoxifen or idoxifene as first-line endocrine therapy for their advanced disease. Complete plus partial response rates were 9 and 13% for tamoxifen and idoxifene, respectively. The median time to progression was slightly higher for idoxifene (140 versus 166 days), but these differences were not statistically significant. Morbidity was similar for both groups. The authors concluded that in postmenopausal women with metastatic breast cancer idoxifene had similar efficacy and toxicity to tamoxifen [298]. However, idoxifene has not been developed further because of concerns about uterine prolapse [299]. This side-effect is not seen with tamoxifen. 

Wiechec E, Hansen LL (2009) The effect of genetic variability on drug response in conventional breast cancer treatment. Eur J Pharmacol 625 122-130... 

The measurement of ER has become a standard assay in the clinical management of breast cancer. The presence of ERa identifies those breast cancer patients with a lower risk of relapse and better clinical outcome. Receptor status also provides a guideline for those tumors that may be responsive to hormonal intervention. But only about half of ER-positive patients respond to hormonal therapies. Of those who respond initially, most will eventually develop an estrogen unresponsive disease following a period of treatment even though ERa is often still present. Mutant receptors and constitutively active r eceptors as well as hormone-independent activation of the ERa are discussed. The involvement of ER 3 isoforms is under investigation. 

In breast cancer patients, total PR status is measured for hormonal treatment. The presence of PR is associated with increased survival rates and hormonal responsiveness of mammary tumors. PR agonists are widely used in contraception, HRT, breast cancer, and endometrial hyperplasia. Antiprogestins such as RU486 are used for blocking ovulation and preventing implantation, and in addition they are in clinical testing for the induction of labor and to control various neoplastic transformations. 

The test system was considerably less sensitive to endosulfan when mouse ER, rather than human ER, was used to mediate (3-gal activity (Ramamoorthy et al. 1997). In similar assays, endosulfan at 10 jM had no effect on (3-gal activity in yeast Saccharomyces) transfected with either the human or rainbow trout ER (Andersen et al. 1999). In addition, no effect was observed on transcriptional activation of HeLa cells transfected with plasmids containing an estrogen receptor as a responsive element (Shelby et al. 1996). Endosulfan also did not induce transient reporter gene expression in MCF-7 human breast cancer cells at an incubation concentration of 2.5 pM (Andersen et al. 1999). Maximum endosulfan-induced ER-mediated luciferase reporter gene expression occurred in vitro in a T47D human breast adenocarcinoma cell line at approximately 10 pM, while 50% expression of luciferase occurred at about 5.9 pM the maximum expression was approximately 59% of the effect from exposure to 0.03 nM estradiol (0.00003 pM) (Legler et al. 1999). Luciferase expression from combined treatment with endosulfan and dieldrin was additive over concentrations ranging from 3 to 8 pM. 

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... 

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. 

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