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© 2000 American Society for Clinical Oncology
Cancer Chemoprevention in the 21st Century: Genetics, Risk Modeling, and Molecular TargetsDepartments of Thoracic/Head & Neck Medical Oncology, Epidemiology, and Clinical Cancer Prevention, The University of Texas M.D. Anderson Cancer Center, Houston, TX. Address reprint requests to Waun Ki Hong, MD, Department of Thoracic/Head & Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 80, Houston, TX 77030; email whong{at}mdanderson.org
EPITHELIAL CANCERS ARE a major public health problem in the United States and throughout the world. Although there have been advances in combined-modality treatments, the last three decades have seen limited survival improvements in advanced epithelial disease. New approaches are desperately needed, and chemoprevention shows great promise in this regard. Sporn helped launch the modern era of cancer prevention research in 1976 when he coined the term chemoprevention.1 Sporn proposed that the concept of carcinogenesis should involve an evolutionary process that potentially could be interrupted, reversed, or modulated. He defined chemoprevention as the use of natural or synthetic agents to reverse or suppress this process. Proceeding from these precepts, modern chemoprevention has achieved enormous progress. The clinical benefit of chemoprevention was demonstrated spectacularly by the Food and Drug Administration’s (FDA) recent approvals of tamoxifen for breast cancer prevention2 and celecoxib for the control of familial adenomatous polyposis.3 These achievements crown over 20 years of progress in chemoprevention research encompassing hundreds of cancer chemoprevention studies, including over 70 randomized trials with more than 130,000 subjects.4,5 General chemoprevention is divided conceptually into the following three settings: (1) primary prevention, or preventing initial cancer in healthy individuals (eg, at high risk); (2) secondary prevention, or preventing cancer in patients with premalignant conditions; and (3) tertiary prevention, or preventing second primary cancer in patients cured of an initial cancer. The remarkably consistent results of tamoxifen in preventing breast cancer (reduced invasive breast cancer rates of from 43% to 49%) cover all three basic chemoprevention settings, which include primary prevention of breast cancer in healthy women at high risk for cancer development in the Breast Cancer Prevention Trial (BCPT), secondary prevention of breast cancer in patients with ductal carcinoma in situ (DCIS), and tertiary prevention of contralateral breast cancer in definitively treated breast cancer patients (Table 1).
Tamoxifen in breast cancer prevention also illustrates other important general principles of chemoprevention. Study sample sizes (and durations) decrease from primary to secondary/tertiary prevention trials. For example, primary (BCPT) versus secondary (DCIS) prevention involved 13,388 versus 1,804 women, respectively (see Table 1). Primary and secondary cancer prevention can be supported by tertiary prevention study. For example, the BCPT (primary) and DCIS study (secondary) were supported by results in contralateral breast cancer prevention (tertiary). Toxicity, adherence, and retention are greater concerns in primary prevention, which involves larger, longer studies and healthier populations than does secondary or tertiary prevention. The tamoxifen studies also illustrate an important new direction for cancer chemoprevention: the use of mechanistic/molecular-targeting studies (of selective estrogen-receptor modulators in this case) and compelling secondary findings (of contralateral breast cancer prevention in adjuvant trials) to provide strong rationales for definitive further trials (the BCPT and Study of Tamoxifen and Raloxifene [STAR] trial).5,6 Our program of clinical, basic, and translational head and neck cancer chemoprevention has played an important role in the efforts leading to the FDA approvals of tamoxifen and celecoxib. This program delivered the first definitive proof of principle for chemoprevention, demonstrating that premalignancy can be reversed and second primary cancers can be prevented through pharmacologic means.7 These results have spurred the development of numerous chemoprevention trials, and our ongoing pursuit of new strategies for preventing cancers of the head and neck, lung, esophagus, colon, bladder, prostate, skin, and breast is designed to bring further breakthroughs in cancer chemoprevention. The central theme of M.D. Anderson’s multidisciplinary chemoprevention program is translational research designed to increase our understanding of the biology (including the multistep process, field carcinogenesis, and the great cellular heterogeneity of epithelial lesions) (Fig 1) and reversal of carcinogenesis in preinvasive stages. Begun nearly 20 years ago, the following program of work is blazing novel paths into the new millennium, with indispensable grant support from the National Institutes of Health, the American Cancer Society, and the National Foundation for Cancer Research.
The premier component of our program is head and neck cancer prevention. Beginning in the early 1980s with trials of high-dose 13-cis-retinoic acid (13cRA) in the oral premalignant lesion (OPL) and adjuvant settings, our program grew steadily to include a trial of 13cRA (v beta-carotene) in OPLs, long-term (ongoing) trials of low-dose 13cRA to prevent head and neck second primary tumors (SPTs) and to suppress OPLs, and trials of biochemoprevention (13cRA, interferon-alfa [IFN  ], and vitamin E) in the advanced premalignancy and adjuvant settings. Our translational approaches incorporate both the study of cellular and molecular multistep carcinogenesis (eg, in oral cancer prevention) and classical/molecular epidemiology (eg, in SPT prevention). Both approaches also are being applied within our programs of chemoprevention in the lung, colon, prostate, bladder, skin, breast, and other sites.
Oral Premalignant Lesions We also are studying mechanistically novel, less-toxic retinoids (eg, apoptosis inducers and receptor selective). Through parallel basic and translational investigations, we documented that the novel retinoid N-(-4-hydroxyphenyl)- retinamide (4-HPR) is a potent inducer of apoptosis independent of retinoic acid receptors (RARs) and is active in cell lines that are resistant to the nuclear retinoid receptor-selective retinoids (all-trans-retinoic acid, 13cRA, and 9-cis-retinoic acid). The precise mechanism of retinamide activity is unclear, but it seems to relate in part to the induction of reactive oxygen species, which occurs in approximately 20% of head and neck cancer cell lines.11 Based on these in vitro findings, we are conducting an ongoing trial of 4-HPR to test the hypothesis that this agent will be clinically active in patients with retinoid-resistant OPLs. In conjunction with this work, we recently identified novel retinamides (eg, 2-carboxyphenyl-retinamide) with more potent apoptosis-inducing effects than 4-HPR in head and neck cancer cell lines.12 Our translational studies also have shown that, alone among the retinoid receptors, RAR-beta mRNA expression is selectively lost in early stages of oral carcinogenesis (eg, expressed in only 40% of OPLs) and can be upregulated by 13cRA in humans.13 Another major reported molecular genetic finding of our OPL program involves the loss of heterozygosity (LOH) at chromosomes 3p and 9p in oral premalignancy patients.14 Our results suggest that losses of genetic material at chromosomes 9p21 and 3p14 are frequent and early events (eg, LOH in approximately 50% of OPLs) and might play important roles in regional clonal expansion of premalignant cells and subsequent cancer development. This work has recently been extended (to include LOH studies of other chromosomal sites) and confirmed independently by other groups.15,16 Other translational data from our group suggest that telomerase and p16 gene alterations can occur early in the pathogenesis of head and neck cancer.17,18 Another key area of program expertise involves the multidisciplinary study of surrogate end point biomarkers.19 Our translational work has led to the development of a statistical methodology/model for analyzing multiple biomarkers for the prediction of cancer development in patients with OPLs.20 In our multivariate Cox model, the panel of histology, chromosomal polysomy, p53, and LOH at chromosome 3p or 9p is the strongest predictor of head and neck cancer development (P = .0003). RAR-ß was not associated with cancer risk. We are working to further validate this statistical risk-modeling approach and extend it to other sites. This important work will help in developing molecular cancer risk models and early detection markers for advancing chemoprevention research and helping clinicians and patients to assess individual risk. The development of validated risk models is a major thrust of our ongoing research programs.
Our translational research findings have already led to new approaches in combination therapy. We found that resistance to retinoid treatment in advanced premalignant lesions is associated with higher levels of genetic instability and p53 expression,21 suggesting that the carcinogenic process is further advanced in these individuals. To overcome this resistance, we developed and conducted a series of studies using a combination of 13cRA, As continuing advances allow the development of risk models and more accurate identification of higher/highest-risk individuals, it should become possible to stratify chemopreventive therapy according to lesion biology. For example, patients with minimal nonspecific genetic changes could be treated with single-agent retinoids. Those with more advanced/clonal genetic changes, such as mutant p53, could be treated with combinations (eg, biochemoprevention), p53 gene therapy/targeting, or apoptosis inducers.5 Finally, the best approach for controlling lesions with increased expression of epidermal growth factor receptor (EGFR) or cyclooxygenase-2 (COX-2) might be to block these targets with specific inhibitors (Fig 2).
Second Primary Tumors A unique characteristic of epithelial cancers in the upper aerodigestive tract is their high rate of SPT development (3% to 7% per year in patients treated for stage I or II disease). SPT development in these patients results from field carcinogenesis. Because the entire tissue field has been damaged by chronic carcinogen exposure, local anticancer approaches have not been effective in preventing the development of new cancers. SPTs are the leading cancer-related cause of death in patients cured of an initial head and neck cancer (eg, in patients with early stage disease).25,26 To assess the efficacy of adjuvant 13cRA in patients definitively treated for an earlier head and neck cancer, we conducted a randomized, double-blinded, placebo-controlled study of high-dose 13cRA for 12 months in 103 stage I to IV patients. Although the therapy had no effect on cancer recurrence rates, patients receiving 13cRA showed a marked decrease in the development of SPTs.27 This was the first proof of principle for chemoprevention in humans, but as in our OPL studies, there were significant drawbacks. Patients receiving the high-dose therapy experienced significant toxic effects. Further, follow-up after the end of the study showed that the retinoid effect diminished over time. Three years after treatment cessation, the annual rate of SPT development was the same in both groups.28 To address these issues, we are conducting a large-scale National Cancer Institute (NCI)–supported phase III trial to determine whether 3 years of treatment with lower doses of 13cRA will be effective in preventing SPTs in patients cured of an initial early-stage head and neck cancer. Enrollment has been completed with 1,218 participants randomized, and the results should be available in 2002. Based on the activity in advanced premalignancy (discussed above), we developed an NCI-funded study of biochemoprevention as adjuvant therapy in the head and neck. This study showed major activity in the adjuvant head and neck setting,29 and as a result, we are currently planning further trials of this promising regimen. We have hypothesized that patients who develop second tumors constitute a genetically susceptible subgroup. To test this hypothesis, we conducted an in vitro case-control analysis that demonstrated that sensitivity to the mutagen bleomycin (either as a continuous or dichotomous variable) was an independent risk factor for head and neck cancers. Even after adjustment for tobacco and alcohol use, mutagen sensitivity had an adjusted odds ratio of 2.5.30,31 We then performed mutagen sensitivity analyses on 278 head and neck cancer patients whom we followed from 1987 to 1993, and our data showed that the mutagen-sensitive phenotype was a significant predictor of SPT risk.32 SPTs developed in 16 of the mutagen-sensitive patients (13.1%) and in 12 of the nonsensitive patients (7.7%). Mutagen hypersensitivity conferred a relative risk of 2.67 for SPT development.33
Despite their common etiology, tobacco-induced cancers of the lung and head and neck are being shown by our group and others to have major differences in their respective biologies and responses to chemopreventive agents. We first expanded our approach to the lung based on our early successes in the head and neck, but our two short-term, NCI-funded, placebo-controlled, randomized, translational chemoprevention trials (one of 13cRA and the other of 4-HPR) were ineffective in reversing bronchial squamous metaplasia in chronic smokers.34,35 The positive outcome of these negative findings is that they led us to new directions in translational lung cancer chemoprevention. Based upon the negative findings from these first two studies, we began to consider the possibility that chemoprevention might not be sufficiently powerful to overcome chronic, ongoing exposure to tobacco carcinogens. We therefore designed our ongoing lung chemoprevention study to include only former smokers. There are 45 million former smokers in the United States, and half of all newly diagnosed lung cancers occur in this group.36 Former smokers generally no longer are exposed to high levels of carcinogens, but our group has found that a substantial subset of these individuals have persistent clonal genetic alterations of the bronchial epithelium, which has significant clinical implications for these high-risk individuals.37 Our group has found that genetic alterations at chromosomal sites containing putative tumor-suppressor genes (ie, the FHIT gene at 3p14, the p16 gene at 9p21, and the p53 gene at 17p13) occur frequently in the bronchial epithelium of chronic smokers, even when this tissue seems histologically normal or only minimally altered. We have extensively studied the nuclear RAR-ß in non–small-cell lung cancer (NSCLC). This marker is suppressed in a large percentage of NSCLC patients, suggesting that the loss of expression of this receptor may be associated with lung cancer development. We have also found that RAR-ß expression is lost in the lung tissue of heavy smokers who do not have invasive cancer, but its expression can be upregulated by treatment with 13cRA.38 Following up on these findings, we recently conducted a retrospective study of 156 patients to test the hypothesis that loss of expression of RAR-ß in stage I NSCLC is a prognostic factor of a poor clinical outcome.39 Unexpectedly, we found the opposite, that strong expression of RAR-ß was statistically significantly associated with poor outcome, a finding that should be validated in a large prospective study. Our group also has led a phase III intergroup trial testing the ability of 13cRA to prevent SPTs associated with stage I NSCLC.40 This definitive trial, involving 1,166 randomized NSCLC patients, was completed in February 2000, and the results are currently being analyzed. The ability to identify smokers with the highest risks of developing tobacco-related cancers has substantial implications for the success of chemoprevention trials. The development of quantitative risk models for lung cancer is particularly challenging, though, because it must account for interindividual differences in susceptibility to tobacco carcinogens. Our approach to risk assessment is multi-tiered, beginning with a detailed epidemiologic assessment and followed by lymphocyte analysis (the least invasive approach) of an array of phenotypic and genotypic susceptibility markers. Higher-risk individuals receive the next tier of risk assessment in target tissue. A long-term goal of this effort is to correlate lymphocytic markers with changes in target tissue. Standard epidemiologic variables such as age, sex, and ethnicity provide some evidence of genetic susceptibility and are important for evaluating gene-environment interactions. We have also demonstrated that individuals with susceptible genotypes develop lung cancer at younger ages and with lower levels of tobacco exposure than those with nonsusceptible genotypes.41 On the other hand, the genetic component is less influential in individuals with extremely high levels of tobacco exposure, when the environmental influence may overpower genetic predisposition. Familial aggregation of lung cancer provides indirect evidence of the role of genetic predisposition. These studies suggest that a small proportion of lung cancer is due to lung cancer genes, but these are unlikely to be the cause of the vast majority of lung cancers. There are a number of genetic factors that are thought to abrogate the effects of environmental carcinogens, thus explaining differences in individual susceptibility. These factors include genetic polymorphisms in the enzymes responsible for activating and detoxifying tobacco carcinogens and in DNA repair genes (Fig 3). There is an extensive literature on the role of phase I activating enzymes (eg, CYP450 and myeloperoxidase) and phase II detoxifying enzymes (eg, glutathione-S-transferases and epoxide hydrolase) in lung cancer risk.42 The ability to monitor and repair carcinogen-induced DNA damage is another determinant of cancer susceptibility. An expanding body of evidence shows that suboptimal DNA repair capacity is a risk factor for cancer.43 An extreme example of this would be patients with xeroderma pigmentosum, who have a defect in nucleotide excision repair, and who exhibit more than 1,000-fold increased risks of skin cancer. An extensive effort is now underway to screen DNA repair genes for sequence variations.44
To measure DNA repair capacity in lung cancer patients and normal controls, we have performed phenotypic assays using the in vitro host cell reactivation assay and transfecting plasmids damaged with the tobacco mutagen, benzo[a]pyrene, in peripheral lymphocyte cultures. DNA repair capacity was significantly lower in lung cancer cases than in controls and also lower in younger lung cancer patients compared with older patients.45 There was a significant trend for increasing risk as DNA repair capacity decreased. The mutagen sensitivity assay, in which in vitro mutagen-induced breaks are quantitated, has identified sensitivity to challenge mutagens as a significant risk factor for lung cancer, with a risk estimate of 2.87 (M. Spitz and X. Wu, unpublished data). Current smokers and lighter smokers (< one pack per day) had highest risk estimates. When we used two challenge mutagen assays in parallel, bleomycin and benzo[a]pyrene, there was a five-fold increased cancer risk.46 We are also intensively studying phenotype/genotype and diet-gene interactions to determine their role in lung cancer development. For example, isothiocyanates (ITCs) are nonnutrient compounds found in cruciferous vegetables thought to have anticarcinogenic properties and to also serve as a substrate for GSTs. We evaluated dietary intake of ITCs and GSTM1 and GSTT1 genotype information in 503 lung cancer cases and 465 controls.47 Cases reported significantly lower ITC intake. Current smokers who were homozygous null for the GST null genotype and who consumed less ITC were at two-fold higher lung cancer risk. Serum markers such as insulin growth factors may also have potential in risk characterization. We have recently reported that elevated serum insulin-like growth factor-1 levels were coupled with increased lung cancer risk, whereas elevated levels of the binding protein, insulin-like growth factor-binding protein-3, were associated with reduced lung cancer risk.48 We also have demonstrated that there may be joint effects from elevated insulin-like growth factor-1 levels and mutagen sensitivity.49 Results from recent family, twin, and molecular genetic studies provide supportive evidence of a role for genetic factors in smoking behavior. Several polymorphisms in the human D2 dopamine receptor gene, located on chromosome 11q, have been identified. The presence of rare variant alleles is associated with a reduced number of dopamine binding sites in the brain, resulting in a deficit in the dopamine reward system and an enhanced reward when exposed to dopaminergic agents. Such individuals would likely be more vulnerable to nicotine dependence. Results from our previous study lend support to this hypothesis, in that persons who exhibited A1 or B1 genotypes were more likely to have smoked 100 or more cigarettes in their lifetime, started smoking at an earlier age, and reported fewer quit attempts.50 More recently, we demonstrated differences in the frequency of the A1 and B1 risk alleles by ethnicity, a relationship between smoking status and genotype status among Mexican-Americans, and evidence that the presence of the A1 allele was significantly associated with familial aggregation of smoking-related cancers among lung cancer probands.51 It is most likely that multiple susceptibility factors must be accounted for to represent the true dimensions of gene-environment interactions. For the future, we must capitalize on technologic advances in high throughput approaches for rapid, large-scale genotyping, using automated workstations capable of extracting DNA from blood samples and performing DNA amplification, hybridization, and detection. Although the equipment is expensive, its ability to acquire hundreds more genotypes and protein targets a thousand times faster and with less sample will ultimately result in dramatic reductions in the cost of our existing assays while conserving precious resources. To support this new technology, the need for state-of-the-art archival laboratories is emerging. These laboratories will be used for long-term storage and tracking of human samples using individualized bar coding and tracking systems, a cryogenic repository of blood components, and a room temperature-based, automated storage system for acquiring large DNA libraries.
Nonsteroidal anti-inflammatory drugs (NSAIDs) are a major focus of colorectal cancer prevention study.52 The preventive activity of these agents against colorectal cancer development is supported by epidemiologic studies, various experimental models, and clinical trials.53-55 Most recently, the FDA has approved the NSAID celecoxib, which is a selective COX-2 inhibitor, to reduce the polyp burden of patients with familial adenomatous polyposis (FAP), who have an inherited germ-line APC mutation conferring virtually a 100% risk of colon cancer. The FDA approval was based in large part on the results of a definitive trial led by M.D. Anderson investigators using celecoxib in 77 FAP patients. This study achieved a statistically significant 28% reduction in mean polyp number (v 4.5% in the placebo group; P = .003) and 30.7% reduction in polyp burden (v 4.9% in the placebo group, P = .001) using 400 mg of celecoxib twice daily for 6 months.3 Many studies have shown that the induction of apoptosis (the loss of which seems to play a major role in carcinogenesis56) seems to be the primary mediator of NSAID activity in vitro and in vivo in colorectal cancer. There also is a tremendous body of data regarding the role of COX-2 expression and prostaglandin synthesis in colorectal carcinogenesis.52,57 COX-2 is expressed in all stages of human colon carcinogenesis, and mechanism-based drug targeting studies have suggested that colon carcinogenesis can be suppressed by COX-2 inhibition.57 The inhibition of COX-2 and prostaglandin synthesis has been proposed as the major mechanism of NSAID chemopreventive effects, suggesting a link between apoptosis induction and COX-2 inhibition. Some studies, however, have indicated that NSAID-induced apoptosis can occur independently of COX-2 inhibition, suggesting that NSAIDs have other possible mechanisms and molecular targets.58,59 Following up on these data, our gastrointestinal prevention program is conducting extensive molecular targeting studies of the roles of COXs and lipoxygenases (LOXs) within NSAID effects on colorectal carcinogenesis. Our recent novel findings indicate that 15-LOX-1 (the main enzyme for metabolizing linoleic acid into 13-S-hydroxyoctadecadienoic acid, which induces apoptosis) is decreased and, further, that NSAID-induced 15-LOX-1 is critical to NSAID-induced apoptosis in colorectal cancer.60 Continuing study of the roles of the COXs and LOXs promises to produce important new insights into the mechanisms underlying NSAID effects in colorectal carcinogenesis. In addition to this avenue of research, we also have an active translational program studying retinoids and NSAIDs for esophageal cancer prevention. This program has resulted in several important mechanistic findings, including the identification of RAR-ß loss in carcinogenic progression and retinoid response61,62; a lack of correlation between RAR-ß loss and 3p LOH63; and that COX-2 is overexpressed and NSAIDs induce apoptosis in vitro.64
Our investigators also are deeply involved in a recently funded phase III trial to prevent prostate cancer, the Selenium and Vitamin E Cancer Prevention Trial (SELECT), which is a follow-on to the ongoing Prostate Cancer Prevention Trial (testing the 5- -reductase inhibitor, finasteride), both of which are NCI Intergroup trials coordinated by the Southwest Oncology Group (SWOG).65 SELECT will be the largest cancer chemoprevention trial ever conducted, using a 2x2 factorial design to test selenium and vitamin E in 32,400 men. The impressive team of SELECT investigators was assembled from major national trials groups (SWOG, Eastern Cooperative Oncology Group, Cancer and Leukemia Group B, North Central Cancer Treatment Group, and Radiation Therapy Oncology Group), the National Cancer Institute, the Veterans Affairs system, and the Canadian NCI/Urology Oncology Group. The trial will take 12 years to complete (5 years for accrual and 7 to 12 years for treatment and follow-up). The rationale for the study of these agents was provided by striking secondary findings of prostate cancer prevention in two prior large-scale NCI phase III trials, the Alpha-Tocopherol, Beta Carotene (ATBC) Cancer Prevention Study and a trial of selenium in preventing nonmelanomatous skin cancer.65 A profoundly important aspect of SELECT is its planned biorepository of invaluable blood and tissue specimens for translational study of molecular epidemiologic risk and other cellular/molecular biomarkers. Our program also has a major role in two other SWOG-coordinated translational studies of selenium that complement SELECT, including a randomized pharmacodynamic study in presurgical (prostatectomy) patients (initiated by M.D. Anderson investigators) and a phase III trial in patients with high-grade prostatic intraepithelial neoplasia. The in vivo models for prostate cancer chemoprevention study are limited. We recently documented selective in vitro selenium-induced growth inhibition and apoptosis in malignant versus normal human prostate cells. Our program of bladder cancer prevention includes two NCI-sponsored translational phase III trials in superficial bladder cancer, one involving 4-HPR and the other involving the selective COX-2 inhibitor celecoxib. These complementary studies are designed to test the chemopreventive efficacy of 4-HPR primarily in earlier-stage patients or celecoxib’s ability to enhance bacillus Calmette-Guerin adjuvant efficacy in later-stage patients. Both studies are supported by animal model results showing that 4-HPR accumulates in the bladder and is active in bladder carcinogenesis and also that COX-2 plays an important role in bladder carcinogenesis, which responds to COX-2 inhibitors.67
Based on our initial study of the novel combination of 13cRA plus IFN in the treatment of advanced squamous skin cancer,68 we expanded our work with this combination into an ongoing translational program of head and neck (discussed above) and skin cancer prevention. M.D. Anderson investigators recently found that profound defects occur in retinoid and IFN signaling in skin squamous cell carcinoma. These defects include the suppression of IFN levels, the IFN-stimulated-gene-factor-3 proteins, nuclear retinoid receptors (especially RAR- and RXR-, which are predominantly expressed in the skin), and tazarotene-induced-gene-3 (a retinoid-regulated tumor suppressor gene).69-72 These data suggested the hypothesis that epidermal cells can lose the ability to use physiologic levels of retinoids and IFN for controlling growth, differentiation, and apoptosis, contributing to the development of skin cancer, and that pharmacologic levels of retinoids and IFN can restore responsiveness in neoplastic epidermal cells by saturating the remaining retinoid and IFN signaling proteins. We are testing this hypothesis in a phase III chemopreventive and adjuvant trial in skin squamous cell carcinoma.
In addition to contributing substantially to the National Surgical Adjuvant Breast and Bowel Project’s BCPT and STAR trials, we also have an active program studying DCIS. We recently completed a comprehensive DCIS study of predictive image analysis features, RAR-ß, HER-2, LOH, and other cellular/molecular markers.73,74 Another important component of our breast program involves the development of novel translational models to test the pharmacodynamic effects of new agents.75
Future directions in cancer chemoprevention undoubtedly will rely heavily on the development of molecular risk models and translational/mechanistic studies to develop novel chemopreventive agents (Table 2). 76-81 If certain molecular alterations (or panels of alterations) can be linked to cancer development, their reversal could be used as a surrogate end point for cancer prevention,19 just as the reversal of high cholesterol levels is accepted as a surrogate for heart disease prevention.81
New molecular technologies will be profoundly useful in (1) identifying promising new targets of drug activity and for the further study of existing candidate surrogate–end point markers, such as RAR-ß, LOH, COX-2, 15-LOX-1, signal transducers and activators of transcription, and estrogen receptors; (2) developing molecular risk models for identifying high-risk cohorts; and (3) developing preclinical drug-testing models, such as gene targeting/knockout models.5,72,78-82 The potential of chemoprevention to benefit individuals with extremely high molecular genetic risk is illustrated by the FDA’s approval of celecoxib in FAP, which provides a colon-cancer risk model involving an inherited germ-line APC mutation.3 This approach may apply to other scenarios involving extremely high genetic risk, eg, BRCA1/2 mutations and breast cancer.6 Not only does the translational study of cellular/molecular markers advance our understanding of carcinogenesis and related drug effects, but validated biomarkers also have the potential to replace the costly end point of cancer incidence in definitive phase III chemoprevention trials, which now require many years and thousands of participants to complete.19 With advances in molecular genetics, imaging, and novel screening tools, we are optimistic that it will be possible to detect premalignant disease and early-stage cancer in more and more people. We believe that patients diagnosed with premalignancy will become a growing subset of medical oncology practice, and chemopreventive approaches will be an effective therapeutic option for these individuals. Through molecular imaging techniques, it will be possible to identify abnormal clones and target specific agents to suppress or eradicate clones to make a significant impact on cancer prevention. Equally important, genetic polymorphism/phenotypic marker studies will allow individual risk to be pinpointed in patients who have not yet developed cancer. Through advances in these areas, it may be possible to manage high-risk patients even if their risk cannot be permanently lowered. As our studies have shown, underlying genetic damage can persist after chemopreventive treatment, and genotypically altered clones can manifest and re-grow as phenotypic changes. Unless chemopreventive therapies are found that are strong enough to eradicate these underlying clonal abnormalities, it may be that we are actually delaying cancer rather than preventing it. Nonetheless, this is a very worthy goal with important implications for public health. The use of long-term chemopreventive therapy to delay cancer onset in high-risk patients could offer these individuals many more years of healthy, high-quality life. We hope that this type of management will eventually allow cancer risk to be treated and monitored as a chronic disease, as is hypercholesteremia in the setting of heart disease. Our ongoing translational, multidisciplinary research programs offer a paradigm of cutting-edge chemoprevention research. Through this ongoing work, we hope to continue contributing to the worldwide effort to bring agents to the clinic that can effectively prevent or delay the development of life-threatening epithelial cancers.
Supported by the following grants from the National Institutes of Health: head and neck cancer prevention (grant nos. CA52051, CA79437, and CA75603); lung cancer prevention (grant nos. CA68437, CA55769, CA86390, CA45809, and CN25433); gastrointestinal cancer prevention (grant nos. CA74835 and CN65118); genitourinary cancer prevention (grant nos. CA77150, CA37429, CA77178, and CN85186); skin cancer prevention (grant nos. CA68233 and CA78560); and breast cancer prevention (grant no. CN25433 and NSABP). Our overall program of cancer prevention is supported in part by grant nos. CA16672, CN07-10 and CN08-17. I thank all of the numerous colleagues who contribute to my research programs, including Drs Adel El-Naggar, Walter N. Hittelman, Fadlo Khuri, Jonathan M. Kurie, J. Jack Lee, Jin Soo Lee, Reuben Lotan, Li Mao, Vassiliki A. Papadimitrakopoulou, Jae Y. Ro, Dong M. Shin, and Rodger J. Winn and Arianne Morgan for editorial assistance. I would also like to thank my invaluable mentors, especially Drs Irwin Krakoff, Charles LeMaistre, John Mendelsohn, and Robert Wittes. In addition, I deeply appreciate my family’s encouragement and, in particular, the life-long support and influence of my late brother, Suk Ki Hong, MD, PhD.
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INTRODUCTION
HEAD AND NECK CANCER...
