Clinical oncology update

Review of recent trials of chemotherapy for advanced breast cancer: the taxanes

Despite advances in breast cancer treatments and related 5-year survival outcomes, metastatic breast cancer cures remain elusive. The current standard of care includes a combination of surgery, radiation therapy and drug therapy. However, even the most advanced procedures and treatments do not prevent breast cancer recurrence and metastasis. Once metastasis occurs, patient prognosis is poor. Recent elucidation of the spatiotemporal transit of metastatic cancer cells from primary tumor sites to distant sites provide an opportunity to integrate knowledge of drug disposition in our effort to enhance drug localization and exposure in cancer laden tissues . Novel technologies have been developed, but could be further refined to facilitate the distribution of drugs to target cancer cells and tissues. The purpose of this review is to highlight the challenges in metastatic breast cancer treatment and focus on novel drug combination and nanotechnology approaches to overcome the challenges. With improved definition of metastatic tissue target, directed localization and retention of multiple, pharmacologically active drugs to tissues and cells of interest may overcome the limitations in breast cancer treatment that may lead to a cure for breast cancer.

Cytological features such as cell size and intracellular morphology provide fundamental information on cell status and hence may provide specific information on changes that arise within biological tissues. Such information is usually obtained by invasive biopsy in current clinical practice, which suffers several well-known disadvantages. Recently, novel MRI methods such as IMPULSED (imaging microstructural parameters using limited spectrally edited diffusion) have been developed for direct measurements of mean cell size non-invasively. The IMPULSED protocol is based on using temporal diffusion spectroscopy (TDS) to combine measurements of water diffusion over a wide range of diffusion times to probe cellular microstructure over varying length scales. IMPULSED has been shown to provide rapid, robust, and reliable mapping of mean cell size and is suitable for clinical imaging. More recently, cell size distributions have also been derived by appropriate analyses of data acquired with IMPULSED or similar sequences, which thus provides MRI-cytometry. This review summarizes the basic principles, practical implementations, validations, and example applications of MR cell size imaging based on TDS and demonstrates how cytometric information can be used in various applications. In addition, the limitations and potential future directions of MR cytometry are identified including the diagnosis of nonalcoholic steatohepatitis of the liver and the assessment of treatment response of cancers.

Research on specific drug responses of circulating tumor cells (CTCs) provides very important information for treatment of cancer patients at a patient-specific level. For this reason, platforms for high capture efficiency of CTCs are essential for clinical evaluation of patient-specific drug responses of CTCs. Recently, nanostructure based platforms have been developed with a high capture efficiency of more than 93% due to high-affinity binding and the 3D nanotopographic features of the nanostructure substrate. In this study, the breast carcinoma cell-line (BT20) cells with an ultra-low abundance range were captured by streptavidin (STR)-functionalized silicon nanowire (SiNW) platforms for evaluation of capture efficiency. A capture efficiency of more than 90% was achieved. Specific drug responses of BT20 cells captured on STR-SiNW platforms were analyzed using tamoxifen or docetaxel as a function of incubation time and dose, and compared with a 96-well plate platform. The drug responses of CTCs on STR-SiNW platforms were more sensitive than a 96-well plate platform. In addition, CTCs were successfully captured and evaluated their size distribution from the blood of breast cancer patients using fluorescence imaging. In conclusion, we suggest that the SiNW platform is adaptable for clinical use in evaluation of CTCs and drug response tests.

Paclitaxel (Taxol^®) has been successfully combined with the monoclonal antibody trastuzumab (Herceptin^®) in the treatment of ErbB2 overexpressing cancers. However, this combination therapy showed an unexpected synergistic increase in cardiac dysfunction. We have studied the mechanisms of paclitaxel/anti-ErbB2 cardiotoxicity in adult rat ventricular myocytes (ARVM). Myofibrillar organization was assessed by immunofluorescence microscopy and cell viability was tested by the TUNEL-, LDH- and MTT-assay. Oxidative stress was measured by DCF-fluorescence and myocyte contractile function by video edge-detection and fura-2 fluorescence. Treatment of ARVM with paclitaxel or antibodies to ErbB2 caused a significant increase in myofilament degradation, similarly as observed with an inhibitor of MAPK-signaling, but not apoptosis, necrosis or changes in mitochondrial activity. Paclitaxel-treatment and anti-ErbB2 reduced Erk1/2 phosphorylation. Paclitaxel increased diastolic calcium, shortened relaxation time and reduced fractional shortening in combination with anti-ErbB2. A minor increase in oxidative stress by paclitaxel or anti-ErbB2 was found. We conclude, that concomitant inhibition of ErbB2 receptors and paclitaxel treatment has an additive worsening effect on adult cardiomyocytes, mainly discernible in changes of myofibrillar structure and function, but in the absence of cell death. A potential mechanism is the modulation of the MAPK/Erk1/2 signaling by both drugs.

Anthracyclines and the taxanes are now used earlier in the course of therapy for metastatic breast cancer, and increasingly as part of adjuvant treatment. Accordingly, novel therapies are warranted, including alternatives to anthracyclines and combination strategies in the setting of disease resistance to or disease progression after anthracycline and taxane therapy. Gemcitabine is part of this strategy. The gemcitabine/paclitaxel combination has emerged as part of a new standard of combination therapy for advanced breast cancer, based on phase III data showing superiority of this combination over paclitaxel alone in the first-line therapy setting. Gemcitabine alone, or in combination with paclitaxel and other agents, is also undergoing evaluation in other settings including the refractory metastatic setting, as part of management of patients with HER2-positive disease, and also as part of adjuvant therapy for breast cancer.