Lung Cancer and Lymphoma - DNA Analysis and Molecular Genetics

DNA analysis (i.e., molecular genetics) can be used in evaluating lung cancer, and can reliably separate lung tumors into their morphologic categories of squamous, large cell, small cell, and adenocarcinoma. Gene expression profiling (GEP) may have even more utility in the assessment of patients with non-small cell lung cancers (NSCLCs) and similar histology.

Several investigators have attempted to subclassify these tumors by correlating GEP patterns with clinicopathologic variables.
A series that included 41 lung adenocarcinomas identified three prognostically separate subgroups. The genes involved in this classification included thyroid transcription factor, hepsin, cathepsin L, vascular endothelial growth factor C (VEGF-C), and the intercellular adhesion molecule-1 (ICAM-1).
In another report of 139 lung adenocarcinomas defined four distinct subclasses. Tumors expressing neuroendocrine-type genes had a significantly less favorable survival than those lacking such characteristics. The genes that defined the neuroendocrine cluster adenocarcinomas included dopa decarboxylase, achaete-scute homolog 1, and the serine protease kallikrein 11.
Others used GEP to predict outcome from surgery in 67 patients with resected stage I adenocarcinoma. A specific group of genes distinguished high-risk from lower risk groups, with significantly different survival. Among the 50 genes comprising the risk index were erbB2, VEGF, S100P, cytokeratin 7 and 18, and fas-associated death domain protein.
In another series of 125 patients from Taiwan with surgically resected NSCLC, 16 genes were identified that correlated with increased or decreased survival. Further RT-PCR validation assay confirmed the microarray findings and showed that survival was significantly associated with five of the 16 genes (DUSP6, MMD, STAT1, ERBB3, and LCK). The five-gene signature was further validated in microarray data from patients of Western population and was an independent predictor of recurrence and overall survival for patients with surgical resection of NSCLC without any adjuvant therapy. This GEP profile is being used to select high risk patients for adjuvant chemotherapy in prospective clinical trials.
Lymphoma - Gene expression profiling (GEP) by means of DNA microarrays is an evolving approach to classification, diagnosis, and prognostication of Non-Hodgkin's Lymphoma (NHL).
As an example, diffuse large B-cell lymphoma (DLBCL) is a clinically heterogeneous disease in which approximately 40 percent of patients with advanced stage disease respond well to combination chemotherapy and are long-term survivors. Using GEP, DLBCL has been subclassified into three distinct molecular subgroups, germinal center B-cell-like (GCB), activated B-cell-like (ABC), and other (type 3), that appear to be derived from different stages of B-cell differentiation, utilize different oncogenic mechanisms, and differ clinically in their ability to be cured by multiagent chemotherapy.
Patients whose tumors express genes characteristic of germinal center B cells (GCB) have a significantly better outcome from chemotherapy than those whose gene expression is more typical of activated B cells (ABC). In one series for example, a clustering algorithm applied to 58 patients with DLBCL receiving cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) chemotherapy separated patients into two groups with very different five-year overall survival rates (70 versus 12 percent).
Although most of the early studies used fresh frozen tissue sections, similar results have been reported with GEP performed on formalin-fixed, paraffin-embedded material. No formal head-to-head comparisons of GEP from fresh versus archived materials have yet been performed.
GEP has also been used to develop a more precise molecular diagnosis of primary mediastinal B-cell lymphoma, a clinically unfavorable entity that cannot be reliably distinguished from other types of diffuse large B-cell lymphoma. These tumors do poorly with CHOP chemotherapy alone and may need more aggressive therapy than used for standard DLBCL.

Finally, GEP has the potential to reveal new therapeutic molecular targets. As an example, the ABC subtype of DLBCL is characterized by constitutive activation of the nuclear factor kappaB (NF-kappaB) signaling pathway; interference with this pathway selectively kills these lymphoma cells. The ubiquitin-proteasomal pathway and the NF-kappaB axis are intimately involved in the control of apoptosis. Inhibitors of this pathway (eg, proteasome inhibitors) can induce apoptosis in human leukemia cells that ectopically express the antiapoptotic protein Bcl-2. One such agent, the synthetic dipeptide boronic acid bortezomib, is a potent promoter of apoptosis in several human tumor cell types.
Summary - The rapidly evolving field of DNA microarray analysis and gene expression profiling has wide-ranging implications for the molecular classification of tumors, refinement of prognostic estimates, and prediction of response to therapy. Despite its exciting potential and significant recent advances, this field remains relatively new, and it is premature to conclude that microarray data can be used as a sole means of classifying cancers or predicting outcomes of treatment.
Among the specific challenges that must be met are the need for larger studies with appropriate validation, standardization of methods and establishment of guidelines for the conduct and reporting of studies, and the formation of repositories and registries where research institutions may deposit data for comparison with independent works involving the same malignant disorder. Finally, DNA microarray-based tests must demonstrate utility in prospectively designed clinical trials before this technology is considered a routine part of clinical evaluation. These studies may eventually establish a new treatment paradigm in personalized cancer therapy in the future.

Dr. Richard Graydon, http://www.medauthor.com, trained as an Oncologist, holding both M.D. and PhD degrees, andspecializes in molecular genetics and cancer research. His education and experience have provided him analytical and clinical skills for keen insight into diagnosis, treatment, and care of cancer patients. See http://www.medauthor.com for further information

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Chemoradiation In Cancer Therapy

Chemoradiation In Cancer Therapy

The medical uses of ionizing radiation have expanded dramatically since Wilhelm Roentgen first discovered it at the end of the last century. In particular, it has proven to be an effective agent in the ongoing battle against cancer. It is presumed that the essential target for radiation is cellular DNA where it acts through the formation of free radicals to directly or indirectly cause double-stranded breaks. It is these doublestranded breaks in the DNA that are felt to be the lethal lesion that malignant cells sustain from therapeutic radiation.

It was in the period of World War II that it was possible to induce lasting remissions

and potential cures of hematological malignancies with nitrogen mustard (1), which was

really the first chemotherapeutic agent put to widespread use in the treatment of malignant

disease. Since that time, a multitude of other drugs have come and gone in the search

for a cure. A few drugs appear to have found a more lasting place in the therapeutic

armamentarium, including doxorubicin, cisplatinum, cyclophosphamide, and 5-fluorouracil.

A new generation of drugs with varied mechanisms of action has appeared in

the last decade and also has the potential to remain as key in the treatment of cancers.

These agents include paclitaxel, docetaxel, gemcitabine, irinotecan, and vinorelbine.

Although oncologists and researchers have often tried to cure cancers with radiation

alone or with various chemotherapeutic strategies, in general these have been met with

limited success for any number of reasons, which will be outlined below. The strategy of

integrating different treatment modalities into a more comprehensive approach to both

local control and the treatment of micrometastatic disease, often referred to as combined

modality therapy, has been met with some success. Although the delivery of neoadjuvant

and adjuvant chemotherapy may contribute to improved local control, it is less clearly

demonstrable than with concurrent therapy. This chapter will focus on combined modality

therapy with an emphasis on concurrent chemoradiation. It will attempt to set the

background with an examination of the rationale and the difficulties that are inherent with

concurrent therapy from the point of view of both the delivery of radiation and of chemotherapy.

Beyond this it will illustrate some of the gains achieved in therapy using a

concurrent treatment approach. Finally it will focus on the potential for the future that lies

in an increased understanding of the molecular players in neoplastic processes as well as

the response of malignant cells to therapy with radiation and chemotherapy. The integration

of new agents that are aimed against more specific cellular targets than either

radiation or traditional cytotoxic chemotherapy may significantly influence the success

of combined modality therapy in the future.

TREATMENT PARADIGMS

Surgical therapy as a sole modality often fails because micrometastatic disease is

already present at the time of surgery or because malignant cells are present beyond the

surgical margins of the resection. Radiation therapy is sometimes added before or after

surgical resection to decrease the possibility of local recurrence when it is felt that there

is a high enough probability of residual malignant cells being present after surgery.

However, radiation therapy as both a sole modality of treatment or as an adjuvant or

adjunctive therapy may fail to sterilize tumors because of micrometastases or because the

dose of radiation that can be safely delivered is limited by the tolerance of the surrounding

normal tissues. Certainly the explosion of new technology in the current computer age

has improved our ability to deliver further radiation in a more conformal fashion. However,

in those malignancies that have a high propensity for distant spread of disease,

delivery of higher doses of conformal radiation may not prove to be a satisfactory approach

to the problem. Unfortunately chemotherapy rarely proves to have a curative role on its

own in the treatment of solid tumors.

BIOLOGY COMPLICATES THE DELIVERY OF RADIATION
The delivery of therapeutic radiation is limited by the tolerance of the surrounding
normal tissues. Data have been compiled over many years that suggest which structures
are able to tolerate certain doses with acceptable amounts of toxicity (2). This model for
thinking about how to plan the delivery of radiation has changed considerably with the
advent of new computer- and automation-driven technologies that allow for the more
conformal delivery of dose to the gross tumor and to the clinical target volume. New
analytical tools called dose volume histograms, which allow for a definition of the dose
delivered to a percentage of an organ, have begun to replace more traditional concepts of
normal tissue tolerance. Although these technology-related advances allowfor the delivery of higher doses of radiation, this may only be an effective strategy in those
tumors whose biology makes them amenable to a local therapy as the sole modality of
treatment. Those tumors that have a predilection for the early dissemination of
micrometastases cannot be effectively treated by a local therapy alone. However, those
tumors that tend to remain localized for longer periods of time may have several biologic
reasons that underlie their resistance to radiation.