ONCOLOGY Vol 24 No 1 | Oncology

Development of PARP Inhibitors: An Unfinished Story

January 15, 2010

In this issue of ONCOLOGY, Comen and Robson provide a timely overview of poly(ADP-ribose) polymerase (PARP) inhibitors and their potential for the treatment of breast cancer. The authors highlight the recent demonstration of synthetic lethality between PARP inhibition and loss of either of the breast cancer susceptibility genes, BRCA1 and BRCA2, as well as the development of PARP inhibitors that are suitable for clinical therapy. However, many questions pertaining to both the basic biology of PARP inhibition and the potential clinical implications of PARP inhibitors still need to be addressed. In the following commentary, we highlight some of these remaining challenges.

Lung Cancer in ‘Never-Smokers’: Molecular Factors Trump Risk Factors

January 15, 2010

While they represent a minority of patients with lung cancer, more than 20,000 people in the United States who never smoked cigarettes are diagnosed with lung cancer each year.[1] This makes lung cancer in “never-smokers” one of the 10 most common cancers-more common than ovarian cancer. In this issue of ONCOLOGY, Subramanian and Govindan give an overview of emerging data about lung cancer in never-smokers.[2] The data outlined in this review provide support for the hypothesis that we can define this collection of diseases affecting never-smokers not by the absence of a common risk factor (smoking) but by each tumor’s molecular features.

Lung Cancer in ‘Never-Smokers’: A Unique Entity

January 16, 2010

Lung cancer in “never-smokers” constitutes only a small proportion of patients with lung cancer. Nevertheless, the topic has recently attracted a good deal of attention. Initially this was due to the fact that never-smokers with lung cancer had better outcomes with epidermal growth factor receptor–tyrosine kinase (EGFR-TK) inhibitors, compared to tobacco smokers with lung cancer. More recently the identification of molecular changes unique to lung cancer in never-smokers has generated further interest in this disease. These findings have the potential to enhance our knowledge of lung cancer biology and lead to the development of new, more effective treatments for lung cancer. In this review, we summarize the existing body of knowledge on lung cancer in never-smokers.

Fire Without Smoke: Lung Cancer in ‘Never-Smokers’

January 15, 2010

Lung cancer remains the leading cause of cancer mortality, accounting for over 160,000 deaths in the United States and 1.18 million deaths worldwide each year.[1,2] Though tobacco smoking remains the most strongly associated risk factor for the development of lung cancer, 10% to 15% of lung cancer patients in the United States lack any history of tobacco use.

Lung Cancer in ‘Never-Smokers’: Beyond EGFR Mutations and EGFR-TK Inhibitors

January 15, 2010

Lung cancer is the leading cause of cancer death worldwide, responsible for over a million deaths annually. In the United States in 2009, it is estimated that 219,440 cases will be diagnosed and 159,390 deaths will be attributable to lung cancer.[1] The vast majority of these deaths are cigarette-smoking associated. However, an estimated 10% to 15% of these deaths will occur in “never-smokers.”

Cancer Chemotherapy in the Elderly Patient

January 15, 2010

The management of older patients with cancer is historically challenging because of a lack of prospective data regarding the appropriate management of this population. In this review, we address some of the issues and challenges surrounding the treatment of older cancer patients, including the withholding of medically appropriate treatment based on chronologic age, the historical omission of elderly from clinical trials, and the impact of geriatric assessment, and age-related changes in pharmacokinetics and pharmacodynamics. Finally, we conclude by discussing the existing evidence related to cancer treatment in the elderly, focusing primarily on the malignancies most commonly seen in older patients, and making general treatment recommendations where applicable.

Chemotherapy in the Elderly: Further Considerations

January 15, 2010

The review article by Drs. Gillison and Chatta represents a very nice overview of cancer chemotherapy in the older individual across a number of different tumor types. The authors correctly point out that it is very important to distinguish chronologic from physiologic age, and that older individuals have been historically underrepresented in cancer clinical trials. Many of the larger phase III clinical trials in this population are either not designed or not powered to look at individuals over the age of 70. Moreover, trials that do include older individuals often select for the most functional individuals with minimal competing comorbid conditions and often do not include or report secondary analysis that examines outcomes by age, health status, or a combination of both. As a result, health-care providers face challenges when communicating and selecting treatment options with patients and their companions.

Larger Questions About Chemotherapy in Older Patients

January 15, 2010

Drs. Gillison and Chatta present an up-to-date review of the systemic treatments available to elderly patients with the most common types of cancer. The only point I might add in the context of their review is about recently reported, promising data on targeted therapies in acute leukemia patients. A large proportion of older patients have acute lymphocytic leukemia positive for a t(9;22) translocation (Philadelphia chromosome–positive ALL).

Inhibition of Poly(ADP)-Ribose Polymerase as a Therapeutic Strategy for Breast Cancer

January 15, 2010

As knowledge increases about the processes underlying cancer, it is becoming feasible to design “targeted therapies” directed toward specific pathways that are critical to the genesis or maintenance of the malignant phenotype. Poly(ADP-ribose) polymerase (PARP) inhibitors are an example of this new framework. DNA damage repair is a complex and multifaceted process that is critical to cell survival. Members of the PARP family are central to specific DNA damage repair pathways, particularly the base excision repair (BER) pathway. PARP inhibition, with subsequent impairment of the BER mechanism, may enhance the cytotoxicity of agents that generate single-strand breaks in DNA, such as radiation and certain chemotherapy drugs. In addition, PARP inhibitors may induce death through “synthetic lethality” if the DNA repair mechanisms that rescue BER-deficient cells are themselves impaired. This mechanism is thought to underlie the impressive results of PARP inhibition in BRCA-associated breast and ovarian cancer, and may also account for the reported benefit of this approach in “triple-negative” breast cancer. This review will examine the current understanding of PARP inhibition as a treatment for breast cancer, ongoing clinical trials, and future directions for this new approach.

PARP Inhibitors: What We Know and What We Have Yet to Know

January 16, 2010

Pharmacologic strategies targeting the DNA of tumor cells have been in use for much of the past century for many different cancer types. Radiation has also been a long-employed strategy to cause DNA damage and subsequent tumor cell death. However, the class of agents designed to inhibit the enzyme poly-(ADP-ribose) polymerase (PARP) have taken this a step further-these agents do not damage DNA themselves, but rather, inhibit the repair of DNA via inhibition of the base excision single-strand repair pathway. PARP inhibitors have been shown preclinically and clinically to enhance the affects of chemotherapies known to damage DNA or interefere with DNA replication. However, the most exciting use of PARP inhibitors may be in exploiting the concept of synthetic lethality. In this setting, the concept is based on two factors: (1) BRCA1/2-positive malignancies cannot use one of the major pathways to repair double-strand DNA breaks (ie, homologous recombination), and (2) making the base excision repair pathway nonfunctional via inhibition of PARP leads to tumor cell death, as unrepaired single-strand breaks are converted into double-strand breaks.

Biology and Management of Rare Primary Extranodal T-cell Lymphomas

January 15, 2010

Peripheral T-cell lymphomas (PTCLs) are uncommonly encountered malignancies in the United States, and hepatosplenic T-cell lymphoma (HSTCL), subcutaneous panniculitis-like T-cell lymphoma (SPTCL), and enteropathy-type T-cell lymphoma (ETTCL) are rare subtypes of PTCLs that often present with primarily extranodal disease. Despite the fact that these tumors have distinct clinical and pathologic features, they are often diagnosed after significant delay. The combination of delay in diagnosis with ineffective therapies has resulted in a poor prognosis in most cases. Techniques that identify T-cell receptor gene rearrangements and flow cytometry that can identify characteristic immunophenotypes have guided our understanding of the underlying cell of origin of these rare PTCLs. As knowledge regarding the biology of these lymphomas increases alongside the development of newer therapeutics with novel mechanisms, clinicians must accordingly improve their familiarity with the clinical settings in which these rare malignancies arise as well as the pathologic features that make them unique

Rare PTCLs: Treatment Lagging Behind Pathobiologic Advances

January 16, 2010

Peripheral T-cell lymphomas, or PTCLs, represent an uncommon and biologically heterogeneous group of hematologic malignancies, accounting for less than 10% of all non-Hodgkin lymphomas worldwide, with marked geographic differences. Due to their low prevalence, variable clinical presentation and phenotypic heterogeneity, these lymphomas have historically been difficult to diagnose and categorize. Since the introduction of immunophenotyping and molecular genetic methods, as well as the development of comprehensive classification systems, there have been significant advances in diagnostic accuracy, classification, and our understanding of the biologic behavior of different PTCL subtypes. However, the molecular pathogenesis of most subtypes of PTCL remains incompletely understood, and treatment outcomes with conventional anthracycline-based chemotherapy regimens are generally significantly inferior to those in aggressive B-cell lymphomas.

Omega-3

January 15, 2010

Omega-3 fatty acids have gained popularity over the past decade as growing scientific evidence supports their use in preventing cardiovascular disease, depression, rheumatoid arthritis, and asthma, and in slowing cognitive decline. Because they are essential and cannot be synthesized in the human body, omega-3 fatty acids should be obtained through diet by consuming fish and nuts, or in supplemental form.