Review Articles in 2010

Men with locally advanced or high-risk prostate cancer may benefit from combined modality strategies. This Review discusses the approaches and rational for preoperative and intraoperative radiotherapy and compares them with the utility of postoperative radiotherapy. The urgent need for novel biomarkers for selection purposes is highlighted.

Selectively targeting cancer stem cells with novel therapeutics is gaining importance because disease recurrence after treatment-induced remissions is a major cause of morbidity and mortality. This Review discusses the pathways that are active during development, specifically the Wnt, Notch, and Hedgehog pathways, and the clinical development of therapeutic agents that target these pathways.

A personalized treatment approach for lymphoma has potential to improve treatment responses. In this Review, Anas Younes summarizes the current development status of novel agents for lymphoma and discusses strategies to move the field forward.

The high attrition rate for cancer drugs is discussed in this Review of the preclinical models available to cancer researchers and clinicians. The classic methods of drug discovery and analysis are described along with new preclinical strategies, including the genetically engineered mouse models and small-interfering RNA that have identified promising targeted drugs. Better knowledge of oncogenic signaling pathways and the mechanism of action of their inhibitors is probably the most effective way to improve the development of successful anticancer drugs.

There has been a growing interest in focal treatment for prostate cancer, although this remains a controversial area. Criticism of focal prostate therapy has been based on the fact that prostate cancer is a multifocal disease. The authors of this Review discuss the clinical and biological implications of multifocal prostate cancer in the context of focal therapy patient selection and treatment planning.

BRCAmutation carriers have an increased risk of developing breast cancer. Modern technology has made it possible to move genetic screening into the mainstream setting, which is important asBRCA status can influence treatment decisions. The authors of this Review discuss the assessment of familial cancer risk and the criteria for targeting BRCAmutation testing in women with breast cancer. They also examine how this genetic knowledge impacts on optimal patient management.

MicroRNAs (MiRNAs) can act as oncogenes or tumor-suppressor genes and have differential expression in tumor progression and metastasis. MiRNAs are involved in a number of pathways that contribute to metastasis, including migration, invasion, cell proliferation, epithelial-to-mesenchymal transition, angiogenesis and apoptosis. This Review provides a summary of the existing data documenting these functions and describes the clinical utility of miRNAs as prognostic and predictive biomarkers and their potential therapeutic applications in advanced cancer.

Image-guided core biopsy (IGCB) of the peritoneum and omentum is a minimally invasive, safe and accurate diagnostic tool for patients with suspected malignancy. With the use of either ultrasound or CT guidance, this technique provides sufficient material to enable assessment of specific cancer subtypes, distinguish recurrence from a new disease process, and inform prognosis. In this Review, the authors discuss IGCB and its clinical applications, and critically examine available alternatives.

TheTP53gene is mutated in 50% of reported cancer cases and the p53 pathway is often partially inactivated in the remaining 50%. Clinical trials assessing agents that exploit the p53 system are ongoing. This Review discusses the mechanism of action of these treatments and the future of p53-based therapy.

Adjuvant assessment tools for prognosis and prediction of treatment benefit in breast cancer aid clinical decision making; however, all these tools have limitations. For an individual diagnosed with early-stage breast cancer, recommendation of systemic therapy and selecting the most appropriate agent remains a challenge. The authors highlight the issues in choosing the most appropriate adjuvant therapy and provide some suggestions for how current assessment tools can be used to tailor treatment.

Genetic testing for breast cancer susceptibility is widely available in North America and in Europe. The optimum treatment of women with breast (or ovarian) cancer and aBRCA1 or BRCA2 mutation may be different from that of non-carriers. Thus, identifying the BRCAmutation status in patients could assist appropriate decision making for individualized cancer prevention, screening and treatment.

Chronic lymphocytic leukemia (CLL) can present as an acute leukemia that is aggressive and life threatening or in an indolent form that will not require treatment over decades. A number of methods are available to clinicians for the prediction of disease progression and survival on an individual basis, including clinical staging systems and a plethora of novel molecular and biological factors that correlate with the outcome of CLL. This Review provides a concise discussion of the most important discoveries and gives guidance on how to implement novel prognostic tools in the clinical management of CLL by applying the criteria of evidence, relevance, and simplicity to the selection of prognostic markers.

Circulating tumor cells (CTCs) have a crucial role in the metastatic cascade, tumor dissemination and progression. Furthermore, CTCs are involved in treatment failure, therapy resistance and disease progression. New therapeutic possibilities are offered by the established clinical prognostic and predictive value of CTCs with the additional possibility of using them for the real-time monitoring of systemic-therapy efficacy. This Review discusses the future clinical applications of CTCs in breast cancer including the incorporation of CTCs as end points in clinical trials and the blockade of tumor dissemination and self seeding via the therapeutic targeting of CTCs.

Synthetic lethality has emerged as a novel approach to treat cancer. Inhibitors of poly (ADP-ribose) polymerase, a target that has synthetic lethality withBRCAmutations, have already shown promise in clinical trials. The authors of this Review describe the clinical application of synthetic lethality for patients with breast cancer, and discuss biomarkers that can be used to select patients who will respond to this therapy. Other potential genes that could be involved in synthetic lethality, and are thus new targets, are also explored.

Triple-negative breast cancer tumors relapse more frequently in spite of good initial response to chemotherapy, and have a worse prognosis than hormone receptor-positive, luminal subtypes. New systemic therapies are urgently needed because hormonal therapies and HER2-targeted agents are ineffective in this group of tumors. Poly (ADP-ribose) polymerase inhibitors, angiogenesis inhibitors, EGFR-targeted agents, and src kinase and mTOR inhibitors are among the therapeutic agents being actively investigated in clinical trials in these patients.

This article reviews resistance to chemotherapy in metastatic castration-resistant prostate cancer (CRPC), which is a result of mechanisms of resistance specific to prostate cancer and to general mechanisms common to different cancer types. New therapies targeting these mechanisms are outlined and their potential impact in future and ongoing clinical trials is discussed. Knowledge of the mechanisms of drug resistance offers great hope for future effective therapy; however, drug resistance in metastatic CRPC is multifactorial and complex and the development of new medical therapies remains challenging.

Nanotechnology offers great promise for the detection, prevention and treatment of cancer. Current limitations of this technology include the heterogeneous distribution of nanoparticles to tumors, caused in part by the physiological barriers presented by the abnormal tumor vasculature and interstitial matrix. This Review discusses these barriers and summarizes strategies that have been developed to overcome them. It additionally examines design considerations for the optimization of delivery of nanoparticles to tumors.

Radiotherapy has an important role in the treatment of metastatic epidural spinal cord compression; when used alone, it is important to select the most suitable radiotherapy regimen. In this Review, Rades and Abrahm report that longer-course radiotherapy is associated with better local control than short-course radiotherapy. However, short-course radiotherapy is more suitable than longer-course treatment in patients with a poor prognosis.

Adjuvant treatment with anthracycline–taxane combination therapy in high-risk early-stage breast cancer has raised the important question of how to manage patients who relapse. In the metastatic setting, one option is rechallenging with the same agent, or class of agent, that has been used in the adjuvant setting. This Review comprehensively examines the evidence from clinical trials for rechallenging with both anthracyclines and taxanes, and highlights issues to be examined in the context of future clinical trials.

Bone is the most common site of breast cancer metastasis, resulting in substantial morbidity and mortality. A number of therapies are being developed, including bisphosphonates, which target factors that promote tumor growth in bone. The authors of this Review outline the underlying mechanisms that drive this pathological process, and highlight potential molecular targets that will improve therapeutic interventions for metastatic breast cancer. Tools that assess response in individual patients and guide appropriate treatment are also discussed.