Biology of lung cancer

Biology of Lung Cancer Claire R. Works and Betty B. Gallucci

Objectives: To provide a review of the biology of lung tumor development and progression, and advances in gene and antimetastatic therapies. Data sources: Review articles, research studies, and book chapters pertaining to the biology of lung cancer. Conclusion: Advances in understanding the molecular basis of lung cancer initiation, promotion, and progression will provide more effective methods of early detection and treatment of this disease. Promising new treatment methods based on tumor biology include gene

therapies, antibodies against growth factors, and agents that prevent angiogenesis and tissue invasion. Implications for nursing practice: An understanding of the biology of cancer assists nurses with the development of protocols for the assessment and monitoring of patients receiving treatments based on cancer biology. Oncology nurses will assume important counseling roles with the development of genetic testing and prognostic markers. Copyright © 1996 by W.B. Saunders Company

UR ABILITY to effectively treat and prevent lung cancer depends on understanding the biology of the disease. Currently, treatment decisions are based on the pathologic classification of lung carcinomas as either small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC). The 5-year survival rate for either type is only 10%. 1 Recent progress in cancer biology indicates that details of the molecular structure and function of the cell may be more useful than histologic type in predicting the tumor's aggressiveness, sensitivity to therapy, and prognosis. 2 In the future, lung cancer pathology reports will contain specific genetic information that will help predict prognosis and guide therapeutic decisions. The diagnosis of lung cancer is actually a late step in a complex biologic process that evolves over many years. Multiple genetic alterations are necessary for the development of a lung carcinoma that is clinically detectable. Because future methods of diagnosis and treatment of lung cancer will be based on its biology, oncology nurses should understand the molecular and genetic basis of the disease. This article will discuss the biology of lung tumor development and progression, and advances

in gene and antimetastatic therapies (see Table 1 for a glossary of terms). A brief overview of normal cell division and multistage carcinogenesis follows.

O

From the University of Washington Medical Center, Seattle; and Biobehavioral Nursing and Health Systems, University of Washington, Seattle, WA. Claire R. Works, MN, ARNP: University of Washington Medical Centel, Seattle, WA; Betty B. Gallucci, PhD, RN: Professo~ Biobehavioral Nursing and Health Systems, University of Washington, Seattle, WA. Address reprint requests to Claire R. Works, MN, ARNP, 2610 NE 54th St, Seattle, WA 98105. Copyright © 1996 by W.B. Saunders Company 0749-2081/96/1204-000555. 00/0 276

THE NORMAL CELL CYCLE

Normal cells are subject to mechanisms that regulate cell division, and cause the eventual aging and death of the cell. 3,4 Cancer develops when cells grow and divide outside normal regulatory mechanisms. The cell cycle consists of the stage of cell division (mitosis) and the DNA synthesis stage separated by two "gap" or "growth" stages, G1 and G2. A fifth stage, Go, is a non-dividing stage in which the cell is at rest. Cells in Go or G1 may be stimulated to divide in response to signals from growth factors (GFs). Before division there is a "restriction point" or "checkpoint ''5 where the DNA is "proofread" for any abnormality. If damage is detected, cell replication stops and the damaged DNA is repaired. Under normal conditions, if repair is impossible, cell death is induced (apoptosis). Each cell in the cycle is like a car traveling a circular highway, with a complex system of signals, delays, exits, and barriers. 6 The proliferation of a normal cell is controlled by a chain of chemical signals. The links in the chain are GFs, their receptors, message-carrying proteins in the cytoplasm, and regulatory proteins in the cell nucleus. First, cells in the environment release growth factors, which travel to the target cell. At the target cell membrane, or in the cytoplasm, the growth factor (ligand) binds to its receptor. This binding activates proteins in the cytoplasm of the target cell (signal-transduction

Seminars in Oncology Nursing, Vo112, No 4 (November), 1996: pp 276-284

BIOLOGY OF LUNG CANCER

Table 1. Glossary of Terms Amplification: A gene that is duplicated, sometimes hundreds of times. May result in overexpression (overproduction) of the gene product. Chromosome: Contains the genetic information, in the form of genes. The nucleus of every human cell contains 46 chromosomes (23 from the mother, 23 from the father). Clone: Line of cells derived from a single cell. Deletion: Loss of one gene, a chromosomal segment, or an entire chromosome. Often results in loss of tumor-suppressor genes. Differentiation: The process of cellular growth and development culminating in the mature functional stage of the cell. DNA (Deoxyribonucleic acid): The genetic material, located in the cell nucleus. Gene expression: The process in which the information in a gene is used to produce its protein product. Gene: The basic unit of genetic material, carried at a specific place on a chromosome, composed of a sequence of DNA. Genome: The complete genetic information of a species. Growth factor receptor: A molecule on the cell surface or inside the cell, which recognizes a specific growth factor. Mediates transfer of signals within the cell. Growth factor: A protein produced by cells that acts to stimulate or prohibit proliferation of either the same cell or other cells. Ligand: Substance which activates its receptor. Monoclonal antibody: An antibody produced by a single clone of B lymphocytes. Nuclear regulatory protein: Protein that regulates DNA replication and cell division. May be encoded by oncogenes. Oncogene: A gene capable of inducing one or more characteristics of cancer cells. Point mutation: Alteration in the sequence of DNA in a gene, leading to a change of a single amino acid in the gene product. Proto-oncogene: A gene in a normal cell that influences the control of cellular proliferation and differentiation. Mutations or amplifications of proto-oncogenes cause them to function as oncogenes. Signal-transducing protein: Protein that conducts proliferative signal across the cell's cytoplasm to the nucleus. Translocation: Transfer of a gene from its usual chromosome to a new position on another chromosome. May result in loss of regulatory genes and the overexpression (overproduction) of the gene product. Tumor-suppressor gene: A gene which normally inhibits cellular proliferation. When mutated or deleted, it promotes the development of cancer. Also called anti-oncogenes.

proteins), which carry the message to the nucleus. Proteins in the nucleus (nuclear regulatory proteins) oversee the process of DNA replication and cell division? Each link in the chain must be present for a normal cell to divide.

Proto-oncogenes and Oncogenes GFs, growth factor receptors (GFRs), signaltransducing proteins, and nuclear regulatory pro-

277

teins are all protein products of normal, growthstimulatory genes, called proto-oncogenes. When proto-oncogenes are damaged so that their products are overexpressed or altered to promote tumor growth, they are called oncogenes. The genetic damage (due to chemical carcinogens, radiation, or viruses) causing such changes occurs in the form of point mutations, chromosomal translocations, and gene amplification. 7 Point mutations alter a single amino acid in the gene's protein product, making it function abnormally. 7 For example, an oncogene might code for an abnormal growth factor receptor, which is "turned on" even in the absence of GF. Chromosomal translocation refers to the transfer of a gene from its usual chromosome to a new position on another chromosome. 7 In the new location, the gene behaves abnormally. 6 Amplification means that a gene has been duplicated, sometimes hundreds of times. 4 Both translocation and amplification often result in overexpression (overproduction) of the gene product. a For example, an excessive quantity of GF may be produced, causing constant activation of its receptor. Normally, the activation of GFRs is transitory? By increasing GF production, or activating GFRs, signal-transducing proteins, or nuclear regulatory proteins, oncogenes may circumvent the normal growth-regulatory system at any point in the chain. Figure 1 depicts potential mechanisms by which oncogenes stimulate aberrant cellular proliferation and contribute to tumorigenesis.

Tumor-Suppressor Genes Normal cell division is regulated not only by growth-stimulatory genes (proto-oncogenes), but also by growth-inhibitory genes (tumor-suppressor genes or anti-oncogenes). Despite their name, the primary purpose of tumor-suppressor genes is to regulate normal cell growth, not to prevent tumors. Tumor-suppressor gene products are believed to have mechanisms of action similar to, but opposing, that of oncogene products. Signals inhibiting cell proliferation originate outside the cell, and involve receptors, signal transducers, and nuclear transcription regulators. 4 When tumor-suppressor genes are inactivated (through point mutation or deletion), cells are either unable to receive or unable to process growth-inhibitory signals. 8 Deletion can occur to one gene, a chromosomal seg-

278

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•

O GF

O

GFR

),

)

N

A

©. Q • •

•

_~

•

B • •

\

Fig 1. (A) The chain of events in normal cell proliferation; (1) represents GF, 12) the GFR, 13) signal transduction to the nucleus (N). (B) Potential mechanisms of aberrant cell division caused by activation of oncogenes; (1) represents autocrine production of GF, (2) activation of the receptor in the absence of GF, {3) activation of signal-transduction proteins without GF or GFR activation, (4) activation of nuclear regulatory proteins in the absence of other signals.

ment, or an entire chromosome. 7 Inactivated tumor-suppressor genes are found in most human tumors. 4 CARCINOGENESIS

Carcinogenesis (Fig 2) is a multistep process occurring over time. 9 The stages of carcinogenesis are initiation, promotion, and progression. Initiation refers to irreversible, nonlethal genetic damage to the cell caused by chemicals, radiation, or viruses. If DNA damaged by a carcinogen is not repaired and the cell divides, the daughter cells inherit the abnormal DNA and are called initiated cells3 ° Initiated cells do not have autonomy of growth.It Chemicals Radiation Viruses

Normal Cell

Promotors

Initiated

) Cell

LUNG CANCER INITIATION

Oncogenes and Lung Cancer Initiation Cigarette smoking causes up to 90% of all lung cancer. 14 Nitrosamines in tobacco probably represent the largest human exposure to alkylating agents. 15 In the initiation stage, carcinogens in

Genetic Abnormalities Passed O n

Initiated Cell ) Proliferates

Fig 2.

In tumor promotion, another compound causes excessive proliferation of the initiated cells. 1° There can be a long-latency period between initiation and promotion. 1° Cigarette smoke contains both initiators and promoters. 4 The final step, tumor progression, refers to invasion and metastasis. 9 Each stage of carcinogenesis may involve various oncogenes, tumor-suppressor genes, GFs, and GFRs. Lung cancer probably develops over at least a decade. H The exact genetic sequence of events in lung cancer carcinogenesis is not yet completely understood, and it may be that the progressive accumulation of genetic alterations is more important than their precise sequence. ~z13 The molecular changes occurring in each stage of lung cancer development are difficult to discern, because these tumors are rarely surgically excised and there is no routine procedure to monitor lung tissue. In contrast, the process of colon carcinogenesis is much better understood; surgical specimens are available and early tissue abnormalities are detected by colonoscopy. The following is a discussion of the major oncogenes and tumor-suppressor genes that may play a role in the initiation of lung cancer. Our intent is to provide a framework for understanding the mechanisms of oncogenes, tumor-suppressor genes, and their products in lung cancer. This explanation of oncogene involvement during the various steps of lung cancer carcinogenesis will evolve with advancing knowledge. Subsequent sections address the biology of lung tumor promotion and progression.

Tumor

Progression

Malignant ) Cell

Multistage carcinogenesis.

) Invasion

) Metastasis

BIOLOGY OF LUNG CANCER

tobacco smoke (polycyclic aromatic hydrocarbons, nitrosamines, some aromatic and heterocyclic amines) bind to cells' DNA, causing oncogene activation through point mutations, translocations, and amplifications? °,~5 Oncogenes that may be involved in the initiation of lung carcinoma include the ras family and one member of the erb family. 12,14,16 Some oncogenes are named after the viruses in which they were originally discovered. Ras is named for the rat sarcoma virus; erb for the avian erythroblastosis virus. In some cases, the name also distinguishes between strains of the virus; H-ras and K-ras are named for Harvey and Kirsten sarcoma virus. N-ras refers to a gene first discovered in neuroblastoma. 17 K-ras gene mutations are found in approximately 30% of NSCLC tumors and cell lines, but are not found in SCLC. 18-2° Ras genes encode signal-transduction proteins, which transmit proliferative signals from the cell membrane to the nucleus. 2~ These proteins would normally be activated only by a GFR that has bound with its GF. When the ras gene is altered through point mutation, its product behaves abnormally. It sends continuous proliferative signals to the cell's nucleus, even though the GFR is not activated. 4 The effect of ras point mutations are often compared to a switch that is turned on and is unable to be turned off. 22 Mutated ras drives the cell into proliferation (C Kemp, personal communication, November 1995). Apparently the carcinogens in cigarette smoke induce mutations in ras. 18,23Ras mutations are rare in non-smokers, 23 whereas they have been noted in 46% of lung tumors from smokers. 22 K-ras mutations in lung adenocarcinoma are associated with poor survival. 24,25 Mutated ras initiates skin carcinoma in an animal model, 26 and may play a role very early in lung cancer development.~4 Other evidence links ras mutations with lung cancer progression, not initiation. 27,28Any particular oncogene may be involved in more than one stage of carcinogenesis, and the stages may not be completely discrete. Her-2/neu (a member of the erb family of oncogenes) may also be involved early in lung cancer development.~,2~ Its product is a GFR, which is similar to the epidermal growth factor receptor (EGFR). When amplified, Her-2/neu codes for excessive numbers of abnormal GFRs, which send continuous proliferative messages to the nucleus. 4 Although not a significant factor in SCLC,

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Her-2/neu is overexpressed in at least 30% of

adenocarcinoma and squamous cell carcinoma of the lung. 29,3° Amplified Her-2/neu oncogene appears to function during initiation of mammary carcinoma in an animal model. 16 Her-2/neu amplification in adenocarcinoma of the lung is associated with poor prognosis. 29 Tumor-Suppressor Genes and Lung Cancer Initiation

Deletion of the short arm of chromosome 3 (3p deletion) is common in all types of lung cancer, and may be an initiation event. 2~,3~,32The specific genes lost in this deletion are not yet known. It is postulated that chromosome 3p contains a tumorsuppressor gene, the loss of which allows malignant transformation to occur.a7.32 The deletion may be caused by smoking. 33 Deletion of the short arm of chromosome 3p occurs in virtually 100% of SCLC and up to 80% of lung adenocarcinoma. 34,35 Other tumor-suppressor genes involved in lung cancer include p53 and the retinoblastoma (Rb) gene. Both are associated with inherited cancers, suggesting a role early in tumor development. 36-38 The precise timing of Rb mutation in lung cancer carcinogenesis remains to be discovered? ,38 The retinoblastoma gene encodes a nuclear regulatory protein, which acts as a "brake" on cell proliferation. Point mutations or deletions of this gene lead to uncontrolled cell division. 4 For tumor initiation, both the maternal and paternal copies of the retinoblastoma gene in a cell must be mutated. One "good" copy will enable the cell to function normally. 4 The Rb product is inactivated in over 90% of small cell lung cancers and approximately 20% of non-small cell lung t u m o r s . 22,38-4° Point mutations of p53 are also common in both tumor types, and are discussed in the following section. LUNG CANCER PROMOTION Promotion, the second stage of carcinogenesis, involves alterations in the initiated cells that give them the ability to grow autonomously. ~° Eventually, these cells will expand to form a clinically evident tumor. ~° Promoting agents present in cigarette smoke are catechols, phenols, and terpenes. 4~ GFs, oncogenes, and tumor-suppressor genes all may contribute to tumor promotion. GFs in Lung Cancer Promotion

GFs are important chemical mediators in controlling cell growth. Their functions include initiating

280

cell division, stimulating DNA synthesis, and influencing cell migration, differentiation, and tissue remodeling. 4 When GFs released by one cell influence the proliferative activity of another, it is referred to as paracrine stimulation. This may occur between cells of the same or different tissue type. 4 Autocrine stimulation (the cell produces its own GFs) occurs frequently in lung cancer. 42 Excessive GF production may be the mechanism by which promoters stimulate proliferation of initiated cells, and several GFs are thought to be involved in lung cancer promotion. Gastrin-releasing peptide (GRP). GRP (or bombesin) is a GF for normal bronchial epithelial cells. Prolonged exposure to cigarette smoke induces chronic proliferation of the bronchial epithelium. 21 Hyperplastic pulmonary neuroendocrine cells produce excessive GRP, 43 and smokers without cancer have increased levels of GRP-like substances in their bronchoalveolar lavage fluid compared to non-smokers. 44 GRP is synthesized and secreted by SCLC cells, and stimulates their proliferation .45,46 Ligandsfor the EGFR. The EGFR is activated by epidermal growth factor (EGF), transforming growth factor-a (TGF-a), and amphiregulin (AR). 47 The receptor and its ligands may function in an autocrine fashion in NSCLC. 28,48EGFR expression on tumor cells can be increased by EGF or TGF-a produced by squamous cell lung cancer and human epidermoid carcinoma. 49,5° Non-small cell lung tumors have increased EGFR expression compared with normal lung. 51 High levels of TGF-a are associated with a poor prognosis in lung adenocarcinoma. 52 Amphiregulin may inhibit NSCLC growth, as it is underexpressed in more than 50% of these tumors compared to normal lung tissue. 47 Other GFs. Both small cell and non-small cell lung tumors respond to insulin-like growth factorI. 53,54 Arginine vasopressin and transferrin stimulate proliferation of SCLC cells. 55,56

Tumor-Suppressor Genes in Lung Cancer Promotion The p53 gene, sometimes called the "guardian of the genome," normally prevents genetically damaged cells from replicating. 57 Normal p53 compels genetically damaged cells to pause in the G1 phase of division, allowing time for the damage to be repaired. 57 If repair is unsuccessful, the p53 gene triggers apoptosis (cell death). 4 Cells with inacti-

WORKS AND GALLUCCI

vated p53 (through deletion or point mutation) contribute to cancer promotion by replicating damaged DNA, and passing the abnormality on to many m o r e cells. 37,57 These cells are predisposed to additional mutations and may possess a growth advantage over normal cells. 4,57,58 Mutation or deletion of p53 is the most common genetic abnormality in human cancer, and occurs at different stages in various types of neoplasms. 59-61 Fifty percent of lung cancers have p53 gene deletion, and mutations have been found in 80% of SCLC and 45% of N S C L C . 4'61'62 Cigarette smoke probably contributes to these mutations in both major types of lung cancerY ,63 LUNG CANCER PROGRESSION

Progression refers to the third and final stage in carcinogenesis, tumor invasion of adjacent tissue and eventual distant metastases. The majority of cancer deaths are caused by the effects of metastatic tumor, not the primary tumor. Two-thirds of patients with SCLC have distant metastases at the time of diagnosis, as do one-third of those with NSCLC.64, 65

Oncogenes in Lung Cancer Progression The myc family of oncogenes (C-myc, L-myc, and N-myc) may be involved in lung cancer progression. The letter designation of each family member refers to the site of its discovery. C-myc is found in virtually all nucleated cells, L-myc was first found in small cell lung cancer, and N-myc in neuroblastoma. 4 Myc gene amplification occurs in 20% of SCLC, and 8% of N S C L C . 42'66 Amplified myc genes overexpress nuclear regulatory proteins that stimulate the transcription of other growthregulatory genes. 4 The cell divides continually, becoming immortal. 67 Myc amplification probably occurs fairly late in lung cancer development. 42 In SCLC, amplified myc genes are associated with rapid tumor growth and poor prognosis, suggesting a role in tumor progression. 28,6s,69 Table 2 summarizes the characteristics and clinical application of oncogenes and tumor-suppressor genes in lung cancer. TREATMENT ADVANCES BASED ON MOLECULAR BIOLOGY

Knowledge of lung cancer biology may lead to more effective treatment strategies. Several new approaches to treatment are currently under investigation. These include gene therapy, interference

BIOLOGY OF LUNG CANCER

281

Table 2. Oncogenes and Tumor-Suppressor Genes in Lung Cancer Mutation

Oncogenes Her-2/neu

Frequency (%)

TumorType

Stageof Carcinogenesis

Clinical Applications

Amplification

30

Adeno SCC

Initiation

K-ras

Pt mutation

30

NSCLC

Initiation

Mycfamily

Amplification Amplification

20 8

SCLC NSCLC

Progression

Early detection marker Prognostic indicator Gene therapy target Early detection marker Prognostic indicator Gene therapy target Prognostic indicator

100 80 50 80 45 90 20

SCLC Adeno All types SCLC NSCLC SCLC NSCLC

Initiation

Early detection marker

Promotion or initiation

Gene therapy

Initiation or promotion

Early detection marker

Tumor-suppressor genes 3p p53

Rb

Deletion Deletion Deletion Pt mutation Pt mutation Deletion or Pt mutation Deletion or Pt mutation

Abbreviations: Adeno, adenocarcinoma; SCC, squamous cell carcinoma; Pt, point.

with GFs, induction of cellular differentiation, and various strategies to block tumor progression.

Gene Therapy Antisense therapy. Gene therapy of lung cancer takes two basic approaches, either blocking expression of oncogene products or reinserting tumor-suppressor genes. The protein products of oncogenes maintain malignant behavior in cancer cells. Protein synthesis is controlled by ribonucleic acid (RNA), which is formed when deoxyribonucleic acid (DNA) transfers its genetic code to RNA in a process called transcription. Insertion of "antisense" DNA or RNA (DNA or RNA that is complimentary to the oncogene's own nucleic acids) into the cell nucleus prevents transcription of RNA and thus prevents the oncogene from producing its protein product, v° Clinical trials using antisense molecules against the oncogenes ras and Her-2/neu, and the tumor-suppressor gene p53 have been approved. 7°,w The efficacy of this therapy will probably be limited by the diversity of genetic mutations in lung cancer. Antisense directed against a specific oncogene will not correct other mutations that arise during the tumor's lifespan. 7~ Another drawback is that cellular nucleases quickly degrade the antisense nucleic acids. 72 Reinsertion of tumor suppressors. A second approach to gene therapy involves insertion of normal ("wild-type") p53 gene into cancer cells. This would restore normal p53 function, as the wild-type gene is dominant over its mutant form. 73

In theory, introduction of wild-type p53 would be effective only if every tumor cell successfully integrated and expressed the new gene. 71,74 Under optimal conditions in vitro (in a test tube), only 30% to 50% of the cells would be expected to take up the gene. TM These hypothetical drawbacks notwithstanding, introduction of wild-type p53 gene has shown promise in the laboratory. Introduction of wild-type p53 inhibited growth of human lung cancer cells that had been inoculated into mice. 73 Clinical trials of this therapy are in progress. 71

Therapy Directed Against GFs Interfering in GF function may yield effective therapies. In squamous cell lung cancer, monoclonal antibodies directed against EGFR block ligand binding without significant toxicities. 75 Monoclonal antibodies against gastrin-releasing peptide are being developed for use in patients with SCLC. 76 Other potential strategies include: agents to block production of growth factors or receptors, antireceptor antibodies coupled with toxins, or agents that inhibit the transmission of signals from the growth factor and receptor to the cell nucleus. 77

Cellular Differentiation Well-differentiated normal cells are subject to normal growth controls. They divide a given number of times, and ultimately die. A welldifferentiated tumor is one whose cells closely resemble those of the tissue of origin. In general,

282

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well-differentiated tumors are less aggressive. Inducing cell differentiation inhibits tumor growth in some cases. 78 Retinoids are substances related to vitamin A that stimulate cells to differentiate. A form of retinoid, all-trans-retinoic-acid, alters expression of myc genes, retards growth, and inhibits progression o f SCLC. 79

(TIMPs) oppose this action. 88 Synthetic or genetically engineered TIMPs are promising as future anti-metastatic therapy. 89 A new class of synthetic compounds, carboxyamide aminoimidazoles, interferes with signals that stimulate metastasis. These compounds block the growth of established metastases in animals, and are in clinical trials. 9°

Anti-Tumor Progression Therapy

SUMMARY

Several approaches to preventing tumor metastasis are being investigated. These include agents to inhibit tumor angiogenesis (growth of new blood vessels) or prevent tissue invasion. A solid tumor requires its own blood supply (angiogenesis) to grow larger than 1 or 2 cubic mm. 8° Tumor vascularization is an accurate predictor of future metastasis and disease relapse in non-small cell cancer of the lung. 81,82 Antiangiogenic agents theoretically would provide an effective means o f limiting tumor growth. Antibodies to the endogenous angiogenic factors angiogenin, basic fibroblast GF, and vascular endothelial growth factor, are being studied for their antitumor potential. 83-85AGM-1470 (TNP-470), an antiangiogenic factor which inhibits the proliferation of endothelial cells, is being evaluated alone and in combination with alpha/beta interferon in animal models of lung cancer. 8°,86,87 Tumors use enzymes called metalloproteinases to invade blood vessels and adjacent tissues. Endogenous tissue inhibitors of metalloproteinases

Knowledge o f cancer is progressing from the cellular to the molecular level, presenting challenges and opportunities for oncology nursing. We need to understand the biology o f cancer to develop protocols for the assessment and monitoring of patients receiving treatments based on cancer biology. Activities and side effects of new therapies may be anticipated through understanding mechanisms of action. Development of genetic testing and prognostic markers will provide opportunities for oncology nurses to assume important counseling roles. Patients will need assistance in examining the ramifications both of seeking testing and of test results. Understanding cancer biology is essential as oncology nursing practice expands to include the technology of the future. ACKNOWLEDGMENT

The authors thank Linda Bavisotto, MD, Linda Cuaron, MN, OCN®,Robert Livingston, MD, and Diana Wilkie, RN, PhD, for review of the manuscript; and Richard Clement for assistance with preparation of the manuscript.

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