Cancer Prevention by Delay1 Commentary Re: J

Vol. 8, 305–313, February 2002 Clinical Cancer Research 305

The Biology Behind Cancer Prevention by Delay1 Commentary re: J. A. O’Shaughnessy et al., Treatment and Prevention of Intraepithelial Neoplasia: An Important Target for Accelerated New Agent Development. Clin. Cancer Res., 8: 314–346, 2002.

Scott M. Lippman and Waun Ki Hong2 elephant certainly encompasses the delay of cancer development Department of Clinical Cancer Prevention, Division of Cancer and all of the molecular biological complexity this implies. Prevention [S. M. L.], and Department of Thoracic/Head and Neck This commentary will present strong evidence for the bi- Medical Oncology, Division of Cancer Medicine [S. M. L., W. K. H.], ological basis and clinical benefit of delay. We hope it may The University of Texas M. D. Anderson Cancer Center, Houston, stimulate a new way of looking at cancer chemoprevention, Texas 77030 especially for readers who believe that prevention must be Introduction tantamount to a complete or permanent incidence reduction, which we heartily dispute. We also will outline the novel con- Chemoprevention only recently matured into a standard modality for controlling epithelial carcinogenesis. This maturity cept of delaying cancer by molecular detours. resulted from the landmark United States FDA3 approvals of tamoxifen for reducing breast cancer risk in three settings (1) Chemoprevention and Biological Considerations of and from FDA approvals of several agents for treating advanced Cancer Delay premalignancy, or IEN, most recently the NSAIDs diclofenac and celecoxib in the IEN settings of actinic keratosis and FAP Cancer chemoprevention can be defined in practical clini- (2, 3). We were privileged to serve on the AACR Task Force on cal terms as the reduction in the rate of cancer development, or IEN that prepared the Special Article “Treatment and Preven- incidence, by single or combined agents for the period of a tion of Intraepithelial Neoplasia: An Important Target for Ac- Phase III (cancer end point) trial (5), as seen in the BCPT (1). celerated New Agent Development,” which appears elsewhere Animal carcinogenesis studies suggest broadening this defini- in this issue (3). We now have the honor of writing “The tion by adding the concept of a rate reduction based on a fixed Biology Behind. . . ” commentary on this seminal report docu- number of cancers developing over a longer time (in treated menting the importance of IEN end points to the field of cancer versus control animals). Regarding the first definition, it is not chemoprevention. entirely clear whether the incidence reduction in the BCPT Although chemoprevention has come of age as a cancer- resulted from eradicating premalignant clones or delaying car- control modality (1–5), the biology behind cancer chemopre- cinogenic progression. It probably resulted from both. The sec- vention, including treating and/or preventing IEN, has been ond, animal-based definition, however, is the essence of cancer tinged with riddle. One researcher touches the tail and claims, delay. Evidence from both the clinic (discussed in a later sec- “It’s a snake of temporary inhibition.” Another touches the leg tion) and the laboratory (discussed below in this section) indi- and declares, “It’s a tree of permanent reversal.” A third re- cates that a substantial part of chemopreventive activity involves searcher touches the side and says, “It’s a wall of risk reduc- delay. tion.” As in the parable of the blind men and the elephant, most Implying that the preventive effect lasts for a finite period of us are blinded to one extent or another by our specialized (whether therapy is stopped or not), the concept of cancer or perspectives on cancer chemoprevention. Although possibly IEN delay is not new to chemoprevention (6–10), having been encompassing permanent or complete prevention, the whole addressed comprehensively in the laboratory with respect to the classic phases of chemical carcinogenesis. Delay terminology is used in describing the standard animal measures of chemopreventive efficacy, which include measures of decreases in the rate Received 12/21/01; revised 12/28/01; accepted 12/31/01. of tumor development, even if the incidence eventually returns 1 Supported in part by the Cancer Center Support Grant CA16672 from to that in the control group, and of overall decreases in the the National Cancer Institute, NIH. S. M. L. holds the Anderson Clinical incidence or number of tumors. The decreased rate of tumor Faculty Chair for Cancer Treatment and Research. W. K. H. is an development is measured by the increased time of tumor la- American Cancer Society Clinical Research Professor and Fellow Na- tional Foundation Cancer Research and holds the Charles A. LeMaistre tency, which is the time between carcinogen exposure and either Distinguished Chair in Thoracic Oncology, M. D. Anderson Cancer the first tumor or 50% of the overall tumor incidence. Active Center. chemopreventive agents can produce a several-month shift to 2 To whom requests for reprints should be addressed, at Department of the right in the curves of the time-to-tumor-development (laten- Thoracic/Head & Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 80, cy) and survival durations in rodents. Considering the large Houston, TX 77030. Email: [email protected]. ratios of human:rodent tumor latencies and life spans (e.g., 3 The abbreviations used are: FDA, Food and Drug Administration; ϳ50:1 for humans:mice), this shift could represent years or IEN, intraepithelial neoplasia; NSAID, nonsteroidal anti-inflammatory decades of increased time-to-cancer and survival in humans. drug; FAP, familial adenomatous polyposis; BCPT, Breast Cancer Pre- vention Trial (as reported in Ref. 13); APC, adenomatous polyposis coli; “Even a delay in [bladder] tumor development [by retinoids] of DCIS, ductal carcinoma in situ; SPT, second primary tumor. as little as 7 to 10 weeks in the rat,” stated Hicks (and echoed by Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2002 American Association for Cancer Research. 306 Cancer Prevention by Delay

Fig. 1 Leukoplakia-carcinoma progression models in the oral cavity. Top panels, the clinical progression of a patient’s white oral leukoplakia lesion (left) to an oral cancer (right) that developed 3 years after complete leukoplakia resection. Middle panels, histological progression from hyperplasia to invasive cancer. Bottom panels, a molecular progression model, in which the accumulation of genetic alterations is more important than the order.

The apparent loss of heterozygosity at 11q may represent allelic imbalance via cyclin D1 amplification at 11q13. Some molecular alterations, such as an autocrine growth loop involving transforming growth factor-␣ (TGF-␣) and epidermal growth factor receptor (EGFR) overexpression, can occur in carcinogen-exposed histologically normal epithelium. Molecular alterations will differ depending on carcinogenic exposure [e.g., to cigarette smoke, betel nuts, or human papillomavirus (especially for oropharyngeal cancer)], and on genetic susceptibility (e.g., affected by certain glutathione S-transferase genotypes and by helicase defects involved with DNA-repair genes). FHIT, fragile histidine triad. Modified with permission of the Massachusetts Medical Society from a figure originally published in The New England Journal of Medicine (20). Copyright © 2001 Massachusetts Medical Society. All rights reserved.

Moon et al.; Refs. 9, 10), “could equate to an extra 5 or 6 years for highly educated reflections on cancer delay in the clinical of symptom-free life for the human bladder-cancer patient.” setting. Sophisticated statistical models have been developed for The molecular basis of multistep carcinogenesis was first analyzing animal studies with respect to the carcinogenic phases illustrated by Vogelstein et al. (16) in studies of human adeno- and measures of drug efficacy (11, 12). The ability of these ma-carcinoma progression in the colon. The molecular biology models to assess delay is confounded by the usual termination of of multistep carcinogenesis subsequently has been worked out animal experiments before all of the possible latent tumors have in other epithelial sites, including the head and neck (Refs. developed in the treatment group and by forced carcinogenesis 17–21; Fig. 1), which exemplifies the molecular basis of cancer designed to produce a ϳ100% cancer incidence in control delay. Head and neck carcinogenesis involves accumulated mo- animals in a short time. lecular alterations that contribute to clonal expansion, intraepi- For decades, researchers studying animals have accepted thelial spread, lesion heterogeneity, and drug resistance. First the potential clinical impact of cancer delay. Within the clinical described 50 years ago as “field cancerization” in the setting of research and practice community, however, considerations of head and neck carcinogenesis (22), multifocal carcinogenesis is cancer delay gained prominence only recently and did so be- another fundamental concept of chemoprevention and involves cause of the dramatic trial results and FDA approvals of tamox- multiple genetically distinct clones and the lateral spread of ifen in breast cancer prevention (1, 5, 13–15). Needing many genetically related preinvasive clones (4, 20, 21). years or possibly decades of follow-up, it will be difficult, if not As indicated by advancing molecular studies, the lengthy impossible, to prove cancer delay in the human primary preven- process of carcinogenesis is multipath (23) as well as multistep tion setting, which involves healthy, frequently high-risk, sub- and multifocal. These studies have provided new perspectives jects (1). Nevertheless, recent advances in our understanding on chemoprevention and cancer delay. Depending on individual of the molecular and cellular biology of carcinogenesis allow differences in gene-environment interactions [Refs. 20, 24; e.g.,

Fig. 2 Detouring critical genetic events to delay multistep carcinogenesis. Top panel, the multistep process of head and neck carcinogenesis in terms of the phenotypic, histological changes and the associated chromosomal sites (in the boxes) that undergo alterations. Various combinations of 6–12 genes are thought to be involved in critical alterations leading to oral cancer. Detour 2 (top panel) can occur relatively early and is associated with a relatively long delay in cancer development (bottom panel). Cascade of arrows emanating from detour 2, the complex of sub- and micropathways potentially involved in detouring carcinogenesis at any point during the multistep process (although not depicted, similar pathways would apply to detours 1, 3, and 4, top panel). Coming earlier in the process, it is likely that detour 1 would produce a greater delay (bottom panel). Coming later, detours 2–4 would produce lesser delays in cancer development (bottom panel), because carcinogenesis would have accumulated a greater burden of mutations and larger sheer numbers of progressing premalignant cells. Whereas single agents may produce the initial detours, it may be possible to design combinations of agents that work in multiple detour pathways to even further prolong latency. Bottom panel, X-axis, the years beginning with carcinogenic initiation; Y-axis, the total incidence of a particular cancer. Black curve at the left, the control (c, untreated multistep carcinogenesis); dotted green curve at the right, the hypothetically greatest delay possible, or an intervention before hyperplasia.

involving DNA-repair capacity (25)], an estimated 6-to-12 critical Fig. 2 depicts a model of head and neck carcinogenesis genetic events must accumulate, usually over 20 or more years, for illustrating our refined concept that cancer can be delayed by clinically detectable cancer to develop after carcinogenic exposure. molecular detours, or by molecular-targeting approaches that Slowing the mutational burden should delay IEN and cancer. Loeb detour multistep carcinogenesis down alternative pathways. The suggested that the rate of accumulated mutations could be delayed alterations of several genes, including p16 (on 9p), p53 (on 17p), by suppressing genomic instability and the mutator phenotype (26). and cyclin D1 (on 11q), are associated with the development of Therefore, agents producing a 2-fold reduction in random mutation head and neck cancer (20, 21). Several agents may reverse the rates early in carcinogenesis could double the latency period of effects of these genetic alterations. Fig. 2 illustrates this concept cancer development (e.g., from 20 to 40 years). This concept is with a hypothetical detour at p53. p53 mutations are associated supported by DNA adduct studies of skin and liver carcinogenesis/ with decreased apoptosis (31) and carcinogenic progression chemoprevention (27, 28). Skin cancer delay in rodents was asso- (32), and chemopreventive efficacy has been associated with ciated with slowing the mutation rate (27). Molecular-targeting enhancing apoptosis (33–35). Gene therapy has shown promise treatment of a DNA-repair defect reduced the rate of skin cancer in in restoring wild-type p53, thereby increasing apoptosis in these xeroderma pigmentosum patients (29). The DNA helicases have cells (5, 36). Other potential molecular detours may involve been implicated in the mutator phenotype, genetic instability, and correcting p16 inactivation with demethylating agents or gene high cancer incidences, making them potentially important future therapy and suppressing cyclin D1 amplification or activity with molecular targets for chemoprevention by cancer delay (30). antisense therapy or cyclin-dependent kinase inhibitors (20).

Combinations of molecular-targeting small molecules could enhance cancer delay by producing detours at multiple critical molecular events within the initiation, promotion, and progression phases of cancer development (1, 5, 20). The preceding paragraph cites several molecular targets in the setting of head and neck cancer chemoprevention. Of course there are many other important molecular-targeting approaches with the potential to delay cancer in various settings, e.g., the induction of cell dormancy to undermine clonal outgrowth (such as with angiogenesis inhibitors) and apoptosis induction (such as with lipoxygenase modulators, cyclooxygenase inhibitors, and retinamides; Refs. 5, 37– 45). Recent molecular-targeting studies involving the APC pathway in colorectal carcinogenesis support the molecular detour concept. The effects of APC mutation, an early event in colorectal carcinogenesis, can be reversed by NSAID inhibition of the downstream (from APC)-target peroxisome pro- liferator-activated receptor ␦ (PPAR␦; Ref. 44), which suggests a role for this detouring event in the established chemopreventive effects of NSAIDs (2, 3, 5, 38). The only possibility of completely preventing cancer is to eliminate (e.g., by apoptosis) all of the initiated and more-advanced premalignant cells and the carcinogenic exposure (e.g., tobacco). Eliminating all premalignant cells without stopping carcinogenic exposure may reset the 20- Fig. 3 The three major aspects of cancer delay. Top graph (analogous year carcinogenic clock but will not completely prevent or to animal delay experiments), possible delay scenarios in human settings eliminate cancer risk. This concept is supported by the sur- of virtually 100% cancer risk, such as in FAP or xeroderma pigmento- gical elimination of colorectal, oral, or breast IEN, which sum patients. The three curves to the right, delayed cancer development decreases cancer rates (3, 20, 46). Definitive surgical resec- followed by an increasing rate of development that does not return to the baseline (D1), that returns to the baseline (D2), or that exceeds the tion, however, is not always possible or acceptable in pre- baseline rate (D3).D1, similar to data of DNA-repair-targeted delay in vention settings, e.g., in germ-line mutation carriers or in xeroderma pigmentosum patients; D3, similar to data of 13-cis-retinoic patients with multifocal diffuse premalignant lesions (20, acid delay in xeroderma pigmentosum patients. Although not a 100% 47– 49). The potential of integrating chemoprevention with cancer-risk setting, the retinoid delay in head and neck cancer-related SPTs resembled the D2 curve. C, the control/baseline curve. Bottom local therapy is indicated by the addition of tamoxifen to graph, more typical scenarios of potential delay in major epithelial lumpectomy/radiation in treating DCIS, which reduced breast cancers, such as breast and prostate cancers (the curves are labeled cancer and IEN events from 13.4% to 8.2% over a period of similarly to the those in the top graph; exception: Y axis, annual incidence). 5 years (versus lumpectomy/radiation alone; Ref. 50).

Aspects of Delay Clinical Models of Delay Fig. 3 depicts the three major aspects of cancer delay, This section presents three chemoprevention models as reduced cancer rate followed by an increasing rate that (a) does paradigms of clinical or molecular delay in cancer development. not return to the baseline rate; (b) returns to the baseline rate; or The use of retinoids in head and neck carcinogenesis is the best (c) exceeds the baseline rate. The first two aspects could poten- model of the molecular basis and provides the clinical proof- tially be expected to result in clinical benefits of delayed cancer- of-principle of cancer delay. The selective estrogen-receptor and treatment-related morbidity and mortality and in reduced modulator-breast model best shows the preclinical evidence and lifetime cancer incidence. The third aspect, with its potential to potential clinical benefits of cancer delay. NSAIDs in colorectal increase lifetime cancer incidence, would be an undesirable carcinogenesis are an excellent model to show the clinical outcome of chemopreventive delay. There also are two poten- benefits of delaying IENs. tially undesirable expressions of any of the three delay aspects: Retinoid-Head and Neck Model and Cancer Delay. (a) enhancing the development of drug resistance, and (b) ac- Several trials involving retinoids and interferon ␣ in head and celerating late (more aggressive) lesions while delaying early neck IEN suggest that, without a molecular complete response, (more benign) lesions (51). These negative effects are also cancer is being delayed rather than completely prevented (52– potential concerns of delaying IEN progression. The potentially 58). Single-agent 13-cis-retinoic acid produced phenotypic re- negative effects require careful long-term follow-up of positive sponses but did not eliminate clones with p53 mutations. Pro- chemoprevention trials, such as the landmark BCPT (1) and longed 13-cis-retinoic acid therapy delayed IEN progression, celecoxib/FAP trials (2, 3, 13). although lesions eventually became resistant to the retinoid; and

lesion progression, or drug resistance, was associated with per- the three distinct settings of: healthy high-risk women (primary sistent genotypic alterations and cancer development. These prevention); the IEN DCIS (secondary prevention); and early- data suggest that cancer delay could result from prolonging the stage breast cancer (tertiary prevention; Refs. 1, 24). The studies interval between critical genetic events in the multistep process. in the first two settings also found similar reductions in the Combined retinoic acid-interferon therapy eradicated some development of IEN [lobular carcinoma in situ (LCIS), DCIS]. clones; others persisted, despite complete phenotypic reversion, Estimates based on the BCPT (a definitive breast cancer pre- and probably retained the capacity to progress into phenotypi- vention trial in 13,388 women) suggest that tamoxifen could cally apparent lesions (20, 21, 57–59). The combination results prevent up to 500,000 primary breast cancers in the United suggest that eradicating premalignant clones also can achieve States over a 5-year period. Another important potential benefit cancer delay. of tamoxifen in delay of breast cancer, depending on the reli- The effects of 13-cis-retinoic acid on SPTs associated with ability and development of risk monitoring tools (e.g., ductal head and neck cancer (60) provided the proof-of-principle of lavage; 67), would be to delay prophylactic bilateral mastec- cancer-delay’s clinical benefit. One year of high-dose 13-cis- tomy in younger women at very high-risk because of inherited retinoic acid produced a significant annual reduction in the BRCA2 mutations (68, 69). incidence of SPTs, which disappeared 3 years after stopping The BCPT was largely responsible for raising the debate on treatment (61). Although lasting only 3 years, this delay in SPT the value of cancer delay in the clinical chemoprevention setting development was still clinically important, because SPTs are the (14, 15), a debate taken up during the September 1998 Onco- leading cause of cancer death in early-stage-head-and-neck- logic Drugs Advisory Committee (ODAC) meeting that consid- cancer patients (62). ered the approval of tamoxifen for the BCPT setting of healthy, The relatively short 3-year delay in the head and neck SPT high-risk women. For the most part, chemoprevention does not setting raises the issue of the timing of a preventive intervention. conform neatly to the widespread expectation that preventing or The three general settings of prevention are: primary (healthy, protecting against a disease entails taking a pill or shot to frequently high-risk); secondary (premalignancy); and tertiary achieve virtually 100% protection, as with many vaccines. (treated cancer patients with no present signs of disease; Ref. Phase III prevention trials generally target reductions in cancer 24). Because tertiary prevention confronts very advanced stages incidence or risk of from 25% to 50%. Although these reduc- of fieldwide premalignancy (63) and likely-remaining micro- tions are not complete prevention, they certainly produce clin- scopic cancer after definitive primary cancer therapy (64), it ical benefits by reducing the catastrophic effects of breast, should produce lesser delays than may occur with earlier inter- colon, and other major epithelial cancers (benefits that are ventions in the primary or secondary settings. countered to lesser or greater degrees by expected and unex- Selective Estrogen-Receptor Modulator-Breast Model pected adverse effects). Chemoprevention in this regard paral- and Cancer Delay. Selective estrogen-receptor modulators lels cancer therapy, in which the word “treatment” (implying the can prolong the latency of breast tumors in animals by weeks or ability to reduce cancer burden) generally replaces “cure” with months. The animal evidence suggests that tamoxifen’s protec- respect to major epithelial cancers. It may be possible, however, tive effects wear off after stopping treatment and that prolonged to use vaccines or antimicrobial agents to block the initiation of, tamoxifen treatment can prolong the cancer delay. Jordan or completely prevent, certain cancers caused by infectious showed that tamoxifen treatment for 1 month beginning 1 month diseases, such as cervical cancer associated with human papil- after 7,12-dimethylbenz[a]anthracene (DMBA)-induced carci- lomavirus, gastric cancer associated with Helicobacter pylori, nogenesis in rats produced a dose-related delay in palpable and hepatocellular carcinoma associated with hepatitis B and C mammary tumor development (65). However, tumors appeared viruses (5, 70, 71). in all of the treated animals after tamoxifen was stopped, al- A BCPT-related criticism of cancer delay is that it may not though overall tumor burden was reduced. Prolonged tamoxifen decrease cancer mortality because only early lesions may be treatment (e.g., for 6 months) prevented tumors in over 90% of delayed (14, 15). Even a delay in less aggressive lesions, how- the animals during treatment. How long the preventive delay ever, could have a major impact on morbidity and quality of life. lasts in humans is undefined, however. Five or 10 years of Another BCPT criticism is that it delayed clinical cancer via tamoxifen appear to reduce SPT incidence (to an equivalent treating subclinical, microscopic invasive cancer (1, 5, 14). degree) for at least 10 years (66). Recent data in patients with Extensive statistical modeling on the BCPT data suggests that DCIS [National Surgical Adjuvant Breast and Bowel Project some of the BCPT reduction in breast cancer incidence resulted (NSABP) B24 trial] indicate that, after 5 years of tamoxifen from the effects of tamoxifen on microscopic invasive cancer treatment, the reduction in breast-cancer-incidence reduction is (72). Nevertheless, delaying the expression of clinical disease persisting for 7 years. The preventive value of longer-term or by treating microscopic invasive cancer (or microscopic DCIS) continuous tamoxifen likely never will be tested in humans, at would be a positive effect of delay (73). Other modeling on least not in the primary prevention setting (healthy, frequently BCPT data suggests that tamoxifen may prolong overall and high-risk; Ref. 24), because of this agent’s serious potential side quality-adjusted survival in the highest-risk subjects (74). effects (1). NSAID-Colorectal Model and Cancer Delay. The The use of tamoxifen in patients at high risk of developing NSAID-colorectal carcinogenesis model illustrates the potential breast-cancer is a paradigm of the clinical benefits of cancer clinical benefits of IEN (adenoma) delay. As defined in the delay. Tested in Ͼ50,000 women, tamoxifen has produced AACR IEN Task Force article in this issue of Clinical Cancer remarkably consistent invasive-cancer prevention/risk reduction Research (3), IEN is a noninvasive lesion that has genetic results in the narrow range of 43–49% and is FDA-approved in abnormalities, loss of cellular control functions, and some phe-

notypic characteristics of invasive cancer and that is associated The duration of the delay could depend on how early the with a substantial cancer risk. These and other IEN character- intervention begins within the multistep premalignancy proc- istics, including intraepithelial spread, heterogeneity, and drug ess and on risk responses determined by individual carcino- resistance (3, 20), make IEN difficult to eradicate with chemo- genic exposures and genetic susceptibilities. Treating prema- prevention. Just delaying IEN, however, could be clinically lignancy in its earliest stages could extend the latency period beneficial, even without complete and permanent cure or cancer by prolonging the intervals between more of the genetic delay, by reducing or delaying IEN and its screening-and- events along the cancer development pathway. Although therapy-related morbidity. It also is possible that IEN delay tamoxifen did not decrease the development of estrogen- would improve cancer-related morbidity and mortality. Obser- receptor-negative cancer in the high-risk subjects of the vational studies have found decreased incidence of adenoma in BCPT (13), animal studies have suggested that selective conjunction with decreased incidence or mortality of colorectal estrogen-receptor modulators may delay estrogen-receptor- cancer associated with NSAIDs (3). The incidence of sporadic negative breast tumor formation if given early enough in the adenomas has been reduced in recent randomized clinical trials carcinogenic process (73, 80). As suggested by the use of of NSAIDs. Whether delaying cancer or just the premalignancy, retinoids in head and neck SPT prevention, treating prema- IEN delay could extend the years of healthy, high-quality life. lignancy during later stages may produce smaller gains in As described earlier in the context of the retinoid-head and neck delay, because later stages involve an advanced number of IEN model (20, 56–58), it is important to evaluate IENs in molecular alterations, and fewer genetic events and intervals clinical chemoprevention trials, when possible or feasible, for remain to be prolonged. Retinoids achieved even smaller SPT genetic and molecular progression. The clinical benefit of partial delays in skin cancer patients with xeroderma pigmentosum IEN response to treatment may depend on the molecular profile (81), which has DNA helicase defects and other factors that of the residual IEN (compared with that of IEN in placebo- worsen gene-environment interactions and genomic instabil- treated subjects). A potential drawback of IEN delay was illus- ity and increase the mutational burden. Intervening in earlier trated by studies of the NSAID, sulindac, in FAP (75, 76). preinvasive stages may also limit multifocal spread. Remov- Adenomatous polyps reappearing after sulindac suppression, or ing the carcinogenic exposure (e.g., by smoking cessation) delay, were more difficult to screen because of a flattened should enhance chemopreventive delay, whether earlier or appearance (in contrast to the situation with tamoxifen, which later in the process. may enhance mammographic screening by its antiestrogenic The list of more common terms describing or defining effect of decreasing breast density). chemopreventive activity includes “suppression,”“arrest,”“re- Celecoxib (a selective inhibitor of cyclooxygenase-2) versal,”“block,” or “inhibition” of premalignancy, and more has been FDA approved for reducing the IEN burden of recently, “cancer risk or incidence reduction.”“Delay” should adenomatous polyps in FAP patients (2), who have an inher- be added to this list and removed from any list of pejorative ited germ-line APC mutation causing hundreds of polyps by terms used to discount chemoprevention. A pejorative and, we the teen years and conferring virtually a 100% risk of colon believe, mistaken view of delay came to the fore when critics cancer by age 50. The sulindac-FAP studies suggested that discounted the BCPT’s clinical benefit because they thought, in NSAIDs delay, rather than permanently arrest, polyp development (77). NSAID delay of adenomatous polyps could part, that tamoxifen may have merely delayed cancer develop- delay prophylactic proctocolectomy in children until they can ment (15). Perhaps Sporn’s classic definition of chemopreven- complete high school and cope better with the morbidity of tion, “to arrest or reverse premalignant cells” [Sporn et al. (7) this procedure. High-dose celecoxib significantly reduced the and Sporn and Newton (82)] connotes permanent or absolute number of adenomatous polyps in patients by 28% (compared prevention to many people, which helps to overshadow the with placebo). Combinations of NSAIDs and other drugs chemopreventive value of delay. based on molecular interactions (43, 78) may improve this On the basis of the strong evidence from animal studies and effect in FAP, and agent combinations may be required suggestive evidence from clinical/translational studies, it is generally for delay in the settings of late-stage IEN or SPT likely that clinical cancer chemoprevention is virtually synony- risk (79), which involve the accumulation of an advanced mous with cancer delay (with a few exceptions, such as vacci- number of molecular abnormalities. nation against diseases that cause cancer). Because the median age of cancer diagnosis in the United States is 70 years and average life expectancies are 74 years for men and 79 years for Conclusions women, cancer delay can be tantamount to permanent preven- The ideal, and possibly general perception of the role, of tion for many people. This clinical interpretation of the field was cancer chemoprevention is to develop vaccine-like regimens presaged by Wattenberg in 1966 (6), when he wrote, “Even capable of eradicating cancer risk. After decades of extremely partial additional protection. . . which results in a prolongation hard-won incremental advances in reducing epithelial cancer of the latent period, might have the effect of preventing or incidence and risk, researchers now realize that chemopreven- minimizing significant manifestations of a malignant process tive agents rarely, if ever, will completely or permanently pre- during a normal life span,” and by Sporn and Newton in 1979 vent the enormously complex progression of premalignancy to (82), who wrote “Phenotypic suppression is not the ultimately malignancy in many sites. A major component of chemopre- desirable way to prevent cancer....[but is] a practical approach ventive success will be measured by periods of delayed cancer to prevention by extending the latency period.” Cancer delay development, morbidity, and mortality. and the resulting clinical benefits will stand in the front lines of

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