Mammographic density and breast cancer risk: current understanding and future prospects

Variations in percent mammographic density (PMD) reflect variations in the amounts of collagen and number of epithelial and non-epithelial cells in the breast. Extensive PMD is associated with a markedly increased risk of invasive breast cancer. The PMD phenotype is important in the context of breast cancer prevention because extensive PMD is common in the population, is strongly associated with risk of the disease, and, unlike most breast cancer risk factors, can be changed. Work now in progress makes it likely that measurement of PMD will be improved in the near future and that understanding of the genetics and biological basis of the association of PMD with breast cancer risk will also improve. Future prospects for the application of PMD include mammographic screening, risk prediction in individuals, breast cancer prevention research, and clinical decision making.     

Radiation therapy and breast preservation: past achievements, current results, and future prospects.

In this overview the historical development of breast-conserving therapy is sketched briefly from its origins in the second and third decades of this century, and current radiotherapeutic techniques are described. All randomized trials thus far conducted using modern radiotherapy indicate that total mastectomy provides no survival advantage compared with breast-conserving techniques. In patients suitable for such treatment, macroscopically complete local tumor excision followed by appropriate radiotherapy will lead to 90-96% local control in the breast at 5 years, and 81-93% at 10 years. It is likely that the strategy of reserving total mastectomy for treatment of intramammary failures will result in ultimate local control of disease on the chest wall which is superior to that provided by primary total mastectomy. Future prospects include the use of primary chemotherapeutic approaches for larger tumors, extending the possibilities of breast conservation to a majority of patients with tumors classically considered unsuitable for lumpectomy. In this context an increase in the use of radiotherapy in the primary treatment of breast cancer is anticipated.     

Breast cancer activism: past lessons, future directions

Breast cancer activism has become a fixture in the United States, where fundraising events are ubiquitous and government financing of research into the disease has skyrocketed. Activists in other countries are now reporting similar accomplishments. Here, predominantly using the United States as a case study, I analyse the recent successes of breast cancer activism. I also raise a series of questions about the future goals of activism.     

Statins and cancer: current and future prospects

Non-coding RNA (ncRNA), a class of RNAs that do not code protein but have regulatory functions, can regulate gene expression and replication of hepatitis B virus or hepatitis C virus and play an important role in the virus-host interaction and the development of hepatocellular carcinoma (HCC). Deregulated ncRNAs in surgically removed hepatic tissues and circulation can be prognostic and diagnostic markers, respectively. ncRNAs functioning as either tumor suppressors or oncogenes can be therapeutic options. Here, we summarize the deregulated ncRNAs associated with the infections and HCC and focus on their roles on early diagnosis, prognosis prediction and therapeutic option of HCC.     

Vasculogenic mimicry: current status and future prospects

In 1999, Maniotis reported that blood vessels of highly aggressive uveal melanomas are formed by tumor cells instead of endothelial cells. He termed this novel concept in tumor vascularization vasculogenic mimicry (VM). Since then, VM has been seen in several malignant tumor types such as breast cancer, liver cancer, glioma, ovarian cancer, melanoma, prostate cancer, and bidirectional differentiated malignant tumors. Laser scanning confocal angiography, electron microscopy, and three-dimensional cell culture have confirmed the existence of VM. The molecular mechanisms that underlie VM are not fully clear, but metalloproteinases via their cleavage of laminin, VE-cadherin by promoting adherence of the VM channel wall to tumor cells, tumor cell dedifferentiation, and tumor microenvironment have been shown to play a role in VM. Zhang and co-workers have proposed a three-stage phenomenon among VM channels, mosaic blood vessels, and endothelium-dependent blood vessels, wherein all three patterns participate in tumor blood supply. Therapeutic strategies that target endothelial cells have no effect on tumor cells that engage in VM. VM-targeting strategies include suppressing tyrosine kinase activity and using a knockout EphA2 gene, downregulating VE-cadherin, using antibodies against human MMPs and the laminin 5gamma2 chain, and using anti-PI3K therapy. We review here the current status of research on VM; discuss molecular mechanisms of VM, factors affecting VM formation, and its clinical significance; and explore the development of novel tumor-targeted treatments that are based on the biochemical and molecular events that regulate VM.     

Mouse models of BRCA1 and their application to breast cancer research

Germline mutations of human breast cancer-associated gene 1 (BRCA1) predispose women to breast and ovarian cancers. In mice, over 20 distinct mutations, including null, hypomorphic, isoform, conditional, and point mutations, have been created to study functions of Brca1 in mammary development and tumorigenesis. Analyses using these mutant mice have yielded an enormous amount of information that greatly facilitates our understanding of the gender- and tissue-specific tumor suppressor functions of BRCA1, as well as enriches our insights into applying these preclinical models of disease to breast cancer research. Here, we review features of these mutant mice and their applications to cancer prevention and therapeutic treatment.     

Chemoprevention of breast cancer: current and future prospects

The groundwork for making the concept of breast cancer chemoprevention a clinical reality began over a century ago. Although tamoxifen's first clinical use was for the treatment of breast cancer, the earliest animal studies with the drug provided the scientific basis for chemoprevention. The extensive clinical experience, safety and laboratory data have made tamoxifen the current standard-of-care for the prevention of breast cancer in women at elevated risk. The STAR trial will address the value of raloxifene as a chemopreventative in postmenopausal women. Results will be available by 2005. Newer compounds are under development which hold the promise of expanded efficacy and narrower side-effect profile. These compounds will function as multifunctional medicines and will hold the promise of preventing breast and endometrial cancer, while providing the beneficial effects of preventing osteoporosis and coronary heart disease.     

PARP inhibitors for BRCA1/2-mutated and sporadic ovarian cancer: current practice and future directions

Poly(ADP-ribose) polymerase (PARP) inhibitors cause targeted tumour cell death in homologous recombination (HR)-deficient cancers, including BRCA-mutated tumours, by exploiting synthetic lethality. PARP inhibitors are being evaluated in late-stage clinical trials of ovarian cancer (OC). Recently, olaparib was the first PARP inhibitor approved in the European Union and United States for the treatment of advanced BRCA-mutated OC. This paper reviews the role of BRCA mutations for tumorigenesis and PARP inhibitor sensitivity, and summarises the clinical development of PARP inhibitors for the treatment of patients diagnosed with OC. Among the five key PARP inhibitors currently in clinical development, olaparib has undergone the most extensive clinical investigation. PARP inhibitors have demonstrated durable antitumour activity in BRCA-mutated advanced OC as a single agent in the treatment and maintenance setting, particularly in platinum-sensitive disease. PARP inhibitors are well tolerated; however, further careful assessment of moderate and late-onset toxicity is mandatory in the maintenance and adjuvant setting, respectively. PARP inhibitors are also being evaluated in combination with chemotherapeutic and novel targeted agents to potentiate antitumour activities. Current research is extending the use of PARP inhibitors beyond BRCA mutations to other sensitising molecular defects that result in HR-deficient cancer, and is defining an HR-deficiency signature. Trials are underway to determine whether such a signature will predict sensitivity to PARP inhibitors in women with sporadic OC.     

Race and cancer genetics: lessons from BRCA1

The effect of a patient's race or ethnicity on cancer incidence and mortality rates remains a neglected area of cancer research. However, with cancer statistics differing among various populations, research on racial and ethnic groups could provide clues to cancer trends. Definitions of ethnicity and/or race need to be established and standardizedfor use in study protocols. Accordingly, all research on ethnic groups must address two questions: (1) When is genetic research on a population appropriate? (2) How should researchers define a given population being studied?     

Renal cell carcinoma: current status and future prospects

The incidence of renal cell carcinoma (RCC) is increasing. Despite improvements in the management of localized RCC, most patients are diagnosed with advanced RCC, which is often refractory and associated with a poor prognosis. Although surgery is the only curative treatment for localized RCC, improved diagnostic methods facilitating early detection and characterization of renal tumors have enabled more effective use of less invasive treatments. Adrenal-sparing radical total nephrectomy, and laparoscopic radical and total nephrectomy are increasingly being performed in preference to radical nephrectomy. However, standard treatments for advanced RCC are largely unsuccessful. Radiotherapy is often used to control symptoms associated with RCC in patients unsuitable for surgery. Immunotherapy with cytokines is the standard systemic treatment for advanced RCC, and is associated with prolonged survival in a subset of patients, but is generally poorly tolerated. An increased knowledge of the underlying pathophysiology of RCC has resulted in the identification of molecular pathways involved in tumor growth. Promising new agents designed to target these pathways are in development.     

Mammary ductoscopy: current status and future prospects.

BACKGROUND: Mammary ductoscopy (MD) allows direct visualisation of the mammary ducts using sub-millimetre fiberoptic microendoscopes inserted through the ductal opening onto the nipple surface. The sharp clear magnified images are viewed on a video monitor. Such scopes have working channels that allow irrigation and ductal lavage for cytological analysis. MD can be performed under local anaesthesia in the office setting. This article reviews the evolving role of MD in the diagnosis and treatment of intraductal breast disease. METHODS: A literature search was carried out from Pubmed for indexed articles published over the last 30 years using the keywords 'mammary ductoscopy' and 'breast ductoscopy'. RESULTS: The search yielded 27 indexed published articles and reports. Important major reports and studies were reviewed, screened and tracked for other relevant publications. The most important articles were analysed and discussed. The review also includes our published and unpublished original work in the field of MD. CONCLUSIONS: MD is a useful diagnostic adjunct in patients with pathological nipple discharge (PND). Furthermore, it can reduce the number and extent of duct excision operations for PND. However, its potential use in the early detection of breast cancer, guiding breast conserving surgery (BCS) for cancer, therapeutic ablation of intraductal disease, and guiding risk-reducing strategies among high risk women requires further research and evaluation. Future developments include the development of a biopsy kit, combining MD with molecular diagnostic markers and real-time optical biopsy system for the diagnosis of pre-malignant and early malignant disease and radiofrequency for curative ablation of intraductal lesions.     

Prostate brachytherapy: current states and future prospects]

The paper presents the characteristics, the place and the limits of brachytherapy in prostate radiotherapy. While sparing the rectal wall, erectile function as well as urinary continence, I(125) and Pd(103) permanent implants represent interesting approaches for good prognosis tumours in comparison to surgery or conformal external beam radiotherapy with similar cure rates. Overcoming easily the problems of organ motion and patient positioning while allowing doses per fraction as high as 10 Gy, brachytherapy is an excellent boosting method in the treatment of intermediate or unfavourable prognosis tumours of which alpha/beta is 1,5 Gy. Encouraging biological control rates of 80-90% have been published in phase II trials. Compared to external beam radiotherapy, the heterogeneity of irradiation inside the clinical target volume should increase the probability of cure as for a specific dose, a significant part will be overdosed. So far, 120-130% of the prescribed doses are delivered to the peripheral zone at the origin of 70% of tumours. On the opposite, this heterogeneity is inducing an overdosage of the urethral bed at the price of higher toxicity levels in situations of previous obstructive syndrome and urethral stenosis. A better integration of the therapeutic modalities available, brachytherapy included, should increase our curative possibilities in the radiation treatment of prostatic cancer.     

Mouse models of neurofibromatosis 1 and 2

The neurofibromatoses represent two of the most common inherited tumor predisposition syndromes affecting the nervous system. Individuals with neurofibromatosis 1 (NF1) are prone to the development of astrocytomas and peripheral nerve sheath tumors whereas those affected with neurofibromatosis 2 (NF2) develop schwannomas and meningiomas. The development of traditional homozygous knockout mice has provided insights into the roles of the NF1 and NF2 genes during development and in differentiation, but has been less instructive regarding the contribution of NF1 and NF2 dysfunction to the pathogenesis of specific benign and malignant tumors. Recent progress employing novel mouse targeting strategies has begun to illuminate the roles of the NF1 and NF2 gene products in the molecular pathogenesis of NF-associated tumors.     

Cancer treatment trials--past failures, current progress and future prospects

Randomized trials are usually too small to provide decisive evidence on the effectiveness of cancer therapy, and most therapeutic developments have been based on studies of tumour response. This approach, together with survival comparisons using historical controls, has led to the development of effective chemotherapy for a few very responsive tumours, but not for most common cancers, where the impact of treatment on survival is quite small. It is difficult to distinguish effective and ineffective innovations in the treatment of such cancers, and consistent progress, in which the more effective treatments are developed and the less effective ones discarded, cannot be achieved without comparisons based on large numbers of randomized patients. The combined evidence on adjuvant therapy for breast cancer and colorectal cancer is reviewed, and a new meta-analysis of published chemotherapy trials in advanced ovarian cancer is presented. The evidence that certain adjuvant regimens can prolong survival is conclusive for breast cancer and quite strong for colorectal cancer, and there is suggestive evidence that cis-platinum prolongs survival in advanced ovarian cancer. Such results illustrate the importance of large randomized trials in evaluating and improving the treatment of common cancers. The major difficulty in achieving large patient entry to randomized studies is the reluctance of many oncologists to participate in collaborative clinical research. The reasons underlying this reluctance, and the way in which such collaboration should be organized to meet these objections, are also discussed.     

Chemoprevention of lung cancer: current status and future prospects

The statistics on lung cancer form a powerful argument to develop new methods to control this most deadly form of cancer. Chemoprevention is one of these new approaches. Carcinogens from cigarette smoke form the link between nicotine addiction and lung cancer. At the same time it has become increasingly clear that dietary and genetically determined factors play an important role in modulating the individual susceptibility and are linked to the chemoprevention approach. In spite of many positive pre-clinical observations, most of the experiences with potential chemopreventive agents such as retinoids and antioxidants in individuals at risk for lung cancer have been negative so far. Moreover, beta-carotene was associated with an increased lung cancer incidence in two large randomized studies, most likely due to negative interaction with cigarette smoke. The recent progress in diagnostic techniques and molecular biology has led to a new paradigm for chemoprevention and there is considerable optimism regarding the potential of new molecules and antibodies that target specific cellular receptors or mutations. This article reviews the lung cancer chemoprevention efforts of the last two decades and also gives prospects for the next coming years.     

Chemoprevention of colon cancer: current status and future prospects

Colorectal cancer is an important public health problem in the western world. Although some progress has been made in the prevention and management of this disease, colon cancer still remains one of the most common types of epithelial malignancies in both genders and is essentially incurable when it reaches the most advanced stages. Given the substantial morbidity and mortality associated with colorectal malignancies and their treatment, cancer prevention in its many forms emerges as a very attractive approach. Colorectal cancer chemoprevention refers to the administration of natural or synthetic compounds to block, reverse, delay or prevent the development of invasive large bowel neoplasms. The ultimate goal of implementing a chemopreventive intervention in the general, or alternatively, in an at-risk population is to decrease the incidence rate of the specific cancer being targeted. This article reviews the present status of colorectal cancer chemoprevention. Current insights into the molecular and genetic models of human colorectal carcinogenesis, preclinical models for efficacy testing as well as into promising biomarkers for colorectal chemoprevention are provided. The developmental status of many promising agents is also discussed emphasizing the epidemiological evidence, preclinical information substantiating an anticarcinogenic effect, their postulated mechanism of action and the status of human clinical development. Our perspective of the future prospects in this scientific area is also provided and has been predicated primarily on the firm belief that the proper integration of advances in the biology of colon carcinogenesis, experimental therapeutics and clinical trial methodology will be critical for the success of this promising field.     

Chemoprevention of lung cancer: current status and future prospects

Lung cancer is the leading cause of cancer death in the United States. The current mainstays of lung cancer therapy are surgery, radiation and chemotherapy. These interventions have produced slight declines in mortality rates in the last 5 years however, it appears unlikely that marked improvements will occur in the near future. This grim overview argues strongly for new, emerging approaches for controlling this disease. Chemoprevention is the use of specific natural or synthetic substances with the objective of reversing, suppressing or preventing carcinogenic progression to invasive cancer. Whether primary, secondary or tertiary settings, prevention has the highest potential to improve the dismal statistics associated with this cancer. Several randomized clinical or translational chemoprevention trials have been conducted. All have so far produced either neutral or harmful primary endpoint results showing that lung cancer was not prevented by alpha-tocopheral, beta-carotene, retinal, retinyl palmitate, N-acetylcysteine or isotretinoin in smokers. Secondary results supporting treatment with isotretinoin in 'never' and former smokers and data from prevention trials involving selenium and vitamin E however, are encouraging and offer a promising direction for future clinical study. Other areas of promise for future lung cancer chemoprevention study include the study of molecular markers of risk and drug activity, molecular targeting study, improved imaging techniques and new drug delivery systems.