chemopreveniton

REVIEW

CURRENTOPINION Oral premalignant lesions: any progress with

systemic therapies?

Copyright © Lippincott W

1040-8746 � 2012 Wolters Kluwer

William N. William Jr

Purpose of review

To discuss the recent advances in oral cancer risk prediction, as well as agents that have been or arecurrently being tested in clinical trials, to treat oral premalignant lesions (OPLs) and prevent oral cancers.

Recent findings

Multiple predictive markers of OPL malignant transformation have been identified in retrospective orcorrelative studies involving patients enrolled in chemoprevention clinical trials, including chromosomalallelic imbalances, polysomy, p53, overexpression of podoplanin, p63 or epidermal growth factor receptor(EGFR), increased EGFR gene copy number, cyclin D1 polymorphisms, specific gene expression profiles,and specific DNA methylation profiles. Of these, loss of heterozygosity at specific chromosomal sites standsout as the most consistent and extensively characterized molecular marker of oral cancer risk described todate. This biomarker is now being prospectively integrated in chemoprevention clinical trials. Agents thathave been or are currently being tested in patients with OPLs include retinoids, epidermal growth factorreceptor inhibitors, cyclooxygenase-2 inhibitors, green tea extract, and peroxisome proliferator activatedreceptor-g agonists.

Summary

Despite extensive clinical investigations, a standard systemic therapy for patients with OPLs is yet to bedeveloped. Integration of biomarkers of cancer risk into clinical trials using novel agents will hopefullystreamline head and neck cancer chemoprevention research.

Keywords

chemoprevention, leukoplakia, oral premalignant lesions

Department of Thoracic/Head and Neck Medical Oncology, The Univer-sity of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Correspondence to William N. William Jr, MD, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Ander-son Cancer Center, 1515 Holcombe Boulevard, Unit 432, Houston, TX77030, USA. Tel: +1 713 792 6363; fax: +1 713 792 1220; e-mail:[email protected]

Curr Opin Oncol 2012, 24:205–210

DOI:10.1097/CCO.0b013e32835091bd

INTRODUCTION

The term chemoprevention was first introduced bySporn et al. [1] in 1976 and was defined as the use ofnatural, synthetic, or biologic compounds to halt,reverse, orprevent the initial phases of carcinogenesisor the progression of neoplastic cells to cancer. In2002, the American Association for Cancer Research(AACR) recommended the use of intra-epithelial neo-plasias as a model to develop chemoprevention strat-egies, as these conditions are near obligate precursorsto, and risk markers for invasive cancer, and often-times, in themselves, represent entities that requirefollow-up and/or treatment [2]. In 2006, the AACRupdated its recommendations to include ‘molecularintra-epithelial neoplasias’ as possible targets forchemoprevention in reference to molecular aberra-tions that emerge in microscopically normal appear-ing cells during the path of transformation fromnormal epithelium to cancer [3]. Within the contextof the AACR recommendations, oral premalignantlesions (OPLs) represent an excellent opportunity for

illiams & Wilkins. Unau

Health | Lippincott Williams & Wilk

chemoprevention translational research. OPLs havebeen clinically defined, are easily accessible for repeatexaminations and biopsies, and many of the histo-logical and molecular changes that develop duringthe early and late phases of malignant transform-ation have been well characterized [4]. Moreover,some studies demonstrate that surgical resectionof OPLs may not significantly reduce oral cancerincidence [5], illustrating the concept of field cancer-ization and multifocality of premalignant lesions,

thorized reproduction of this article is prohibited.

ins www.co-oncology.com

mailto:[email protected]

C

KEY POINTS

� Oral premalignant lesions (OPLs) represent an excellentplatform for chemoprevention translational research, asthey have been clinically defined, are easily accessiblefor repeat examinations and biopsies, and many of thehistological and molecular changes that develop duringthe early and late phases of malignant transformationhave been well characterized.

� Robust risk prediction models that include molecularbiomarkers are clearly needed to more accuratelyidentify OPLs at higher risk for malignanttransformation.

� To date, loss of heterozygosity at specific chromosomalsites is the best characterized molecular marker of oralcancer risk in patients with OPLs and is now beingused to prospectively select high risk individuals forparticipation in chemoprevention clinical trials.

� Several agents have been or are currently beingevaluated for cancer prevention in patients with OPLs,including retinoids, epidermal growth factor receptorinhibitors, cyclooxygenase-2 inhibitors, green teaextract, and peroxisome proliferator activator receptor-gagonists. However, despite these extensiveinvestigations, a standard systemic therapy for patientswith OPLs is yet to be developed.

� Translational studies embedded in clinical trials willhopefully identify strategies involving novel markersand drugs that may be used to prevent head and neckmalignancies in the future.

Head and neck

thus requiring a systemic approach to address theepithelial surface at risk in its entirety.

We have previously reviewed clinical trialdesign strategies that would lead to the highestlikelihood of developing successful chemopreven-tion interventions [6

&

]. Among these are the need toidentify high cancer risk populations using clinicalmodels with accuracy improved by integration ofmolecular prognostic factors; the need to identifyactive and well tolerated drugs that have beenextensively tested in preclinical models specific toprevention, and that address pathways that aredysregulated in the process of carcinogenesis (and,preferably, that are also associated with high cancerrisk); the need to characterize predictive markers ofbenefit from chemopreventive drugs; and the needto identify intermediary endpoints that can providean early readout of the efficacy of a chemopreven-tive agent, thus streamlining the initial phases ofdrug development in this context. Some of theseaspects have been incorporated into clinical trialsfor oral cancer chemoprevention to a lesser orgreater extent. Herein, we will discuss the recentadvances in oral cancer risk prediction, as well as

opyright © Lippincott Williams & Wilkins. Unautho

206 www.co-oncology.com

agents that have been or are currently being testedin clinical trials to treat OPLs and/or prevent oralcancers.

ORAL CANCER RISK ASSESSMENT

One of the greatest challenges in the clinicalmanagement of patients with OPLs is to separatethe lesions that will have a benign course and willnot be the cause of significant morbidity from theones that are prone to malignant transformationand will require more intensive surveillance and,perhaps, clinical intervention. There are inconsis-tencies in the natural history of OPLs described inthe literature, and the reported risk of oral cancervaries from 0.06% per year (in community-based studies in developing countries, where theuse of smokeless tobacco is very common) [7,8]to 1–5% per year (in observational studies in theUSA involving patients followed at hospital-based,academic centers) [8,9]. Clinical factors that havebeen identified as markers of higher cancer risk inpatients with OPLs include older age, female sex,localization of the lesions to the floor of the mouthand/or ventral tongue (compared with the buccalmucosa and buccal commisures), nonhomogeneousclinical variant, larger size and extent, lack ofexposure to tobacco prior to the development ofthe lesion, and dysplasia on histological examin-ation [10]. Of these, dysplasia is, perhaps, thecriterion that has influenced clinical managementof OPLs the most [11]. However, the fact thatleukoplakias without dysplasia may still progressto cancer [12], the fact that there is a high inter-examiner and intra-examiner discordance rate asregards to the presence or absence, and grade ofdysplasia on histological examination [13–15],and the fact that not all studies found a correlationbetween the degree of dysplasia and cancer risk [16]highlight the importance of developing more accu-rate prognostic markers for OPLs besides clinical andhistological criteria. As such, several investigatorshave focused on studying the molecular abnormal-ities associated with malignant transformationof OPLs. In this setting, chromosomal allelicimbalances stand out as the most consistent andextensively characterized molecular marker of oralcancer risk described to date.

Chromosomal allelic imbalances occur early onin the process of oral carcinogenesis, oftentimes inlarge areas of the mucosa [17]. In 1996, Mao et al.[18] demonstrated that leukoplakia lesions harbor-ing loss of heterozygosity (LOH) in regions of thegenome containing tumor suppressor genes (3p14and/or 9p21) were associated with a risk of invasivecancer of 37%, compared with only 6% in lesions

rized reproduction of this article is prohibited.

Volume 24 � Number 3 � May 2012

Oral premalignant lesions William

without LOH at 3p14 and/or 9p21. These findingswere subsequently validated by larger retrospectivestudies from two independent groups [5,19,20].Likewise, in patients with a history of oral cancertreated with curative intent, the development ofleukoplakia harboring LOH at 3p and/or 9p wasalso associated with a substantially higher risk ofdevelopment of invasive cancer (72% at 5 years)compared with leukoplakias without LOH atthese chromosomal regions (6% at 5 years) [21].The presence of microsatellite alterations (i.e.,new alleles and/or LOH of 10 markers) at the histo-logically negative margins of resection in patientswith surgically treated head and neck squamouscell carcinomas was also a marker of a higher rateof recurrence compared with cancers with histologi-cally negative margins without such microsatellitealterations [22]. The fact that similar chromosomalabnormalities in premalignant lesions and/or histo-logically normal appearing mucosa are indicativeof an elevated risk of invasive cancer both inpatients with or without a prior history of oralcancer highlights the importance of identifyingmolecular intra-epithelial neoplasias as a possibletarget for chemoprevention. It also supports thedesign of clinical trials that include both patientswithout (i.e., secondary prevention) or with (i.e.,tertiary prevention) a prior history of oral cancer,as long as they carry similar molecular markersof cancer risk, utilizing a convergent approach ofadjuvant therapy and prevention [23]. This isfeatured in the erlotinib prevention of oral cancer(EPOC) trial [see section on epidermal growth factorreceptor (EGFR) targeted chemoprevention], thefirst clinical study to prospectively evaluate LOHas a biomarker of oral cancer risk and to use it asa tool to personalize chemoprevention [6

&

].In addition to chromosomal allelic imbalances,

other strategies have been pursued to characterizemolecular changes that occur in the oral mucosaduring the process of carcinogenesis (especiallytobacco-induced). Bhutani et al. [24] have demon-strated that there is a high correlation of methyl-ation indexes in the promoter region of tumorsuppressor genes (a possible marker of cancer risk)in oral and bronchial tissues of smokers. Boyle et al.[25

&

] and Sridhar et al. [26] have also demonstratedconcordant tobacco-induced gene expression pro-file changes in oral and bronchial mucosa. Althoughthese molecular profiles are yet to be correlated withoral cancer risk, they represent promising strategiesthat may eventually be able to identify diffuseepithelial injury and assist in selecting high-riskcandidates for chemoprevention, as well as identi-fying molecular targets for chemoprevention drugdevelopment.

Copyright © Lippincott Williams & Wilkins. Unau

1040-8746 � 2012 Wolters Kluwer Health | Lippincott Williams & Wilk

CONTRIBUTIONS OF RETINOID-BASEDCHEMOPREVENTION TRIALS TOTRANSLATIONAL RESEARCHRetinoids are the most extensively studied class ofagents for head and neck cancer chemoprevention.In 1986, Hong et al. [27] reported the results ofa pivotal placebo-controlled randomized study of13-cis-retinoic acid at high doses (1–2 mg/kg perday) for 3 months in patients with oral leukoplakia.Patients assigned to the experimental arm experi-enced more toxicities, but had higher rates ofclinical response (67 versus 10%) and reversal ofdysplasia (54 versus 10%). However, 2–3 monthsafter treatment discontinuation, relapses occurredin 56% of the patients [27]. Vitamin A and/orb-carotene also induced oral leukoplakia clinicalresponses with a favorable toxicity profile inrandomized studies, but relapses were again frequent(50–66% of the patients) after treatment discontinu-ation [28–30].

Subsequent attempts at lowering the dose of13-cis-retinoic acid (to reduce toxicity) and prolong-ing treatment time to 1–3 years (to address the highrelapse rate after treatment discontinuation) werelargely unsuccessful, as the incidence of in-situ orinvasive cancer did not appear to be reduced onlong-term follow-up of the randomized trials usingthese strategies, despite a reduction in size of theleukoplakia lesions [31,32,33

&

]. Taken together, thestudies with retinoids in patients with leukoplakiafailed to develop a regimen that could be consideredstandard of care for management of this condition.Retinoids are effective in eliciting clinical, and evenhistological, responses but these effects are shortlived and do not correlate with reduced invasivecancer incidence long-term. Moreover, retinoidsdo not seem to be able to reverse the underlyingmolecular abnormalities in the oral mucosa, even ifthey produce a clinical or histological response [34].This illustrates the need to develop better strategiesthat can eliminate the premalignant clones andquestions the validity of using leukoplakia responseas a surrogate marker of efficacy in definitive trials.

Although the chemoprevention studies withretinoids have essentially been negative, they setthe stage for the collection of valuable biospecimensfor translational research that has contributed to abetter understanding of the biology of OPLs. Forexample, using specimens from patients enrolled insome of the aforementioned trials, investigatorsat M.D. Anderson Cancer Center have identifiedseveral predictive markers of OPL malignanttransformation, including chromosomal allelicimbalances [18,35], polysomy [35], p53 [35], over-expression of podoplanin [36], p63 [37] or EGFR [38

&

],increased EGFR gene copy number [38

&

], cyclin D1


ins www.co-oncology.com 207

C

Head and neck

polymorphisms [39,40], specific gene expressionprofiles [41

&

], and specific DNA methylation profiles[42

&

]. Although many of these markers still requirevalidation in independent datasets, they can be usedto inform preclinical experiments and future clinicalstudies to specifically address some of the molecularaberrations in OPLs that may confer a high cancerrisk.

EPIDERMAL GROWTH FACTORRECEPTOR-TARGETEDCHEMOPREVENTION

The lack of significant progress on clinical outcomeswith retinoid-based therapies in chemopreventionstudies over the past two decades, coupled with theparallel development of well tolerated and effectivemolecular-targeted drugs to treat invasive cancersof the aerodigestive tract, has sparked the interestto use the latter agents for chemoprevention.EGFR inhibitors were obvious candidates to beevaluated for head and neck cancer prevention,given the positive results observed with cetuximab-based therapies in established head and neck tumors[43]. This strategy is further supported by the morerecent finding from a retrospective study thatEGFR overexpression, or increased EGFR gene copynumber in OPLs was associated with a higher riskof development of invasive cancers [38

&

]. Moreover,in a mouse animal model of chemoprevention,erlotinib significantly prevented progression frommild oral dysplasia to moderate/severe dysplasia andinvasive carcinoma [44

&

].In 2006, the first head and neck cancer chemo-

prevention EGFR inhibitor trial was launched:the erlotinib prevention of oral cancer (EPOC,NCT00402779). In the ongoing EPOC study,patients with OPLs (with or without a prior historyof invasive oral cancer) are evaluated for LOH at 3p,9p and other key chromosomal sites in theirpremalignant lesions. Patients considered at highrisk (based on LOH criteria derived from the retro-spective studies of Mao et al. [18] and Rosin et al.[5,21]) are then randomized to receive placebo orerlotinib 150 mg orally daily for 1 year. The primaryendpoint of the study is incidence of oral cancer.Because the trial focuses on a molecularly definedhigh-risk population (estimated 3-year oral cancerrisk of 35–65%), it allows for a design with a rela-tively small sample size (N¼150 total patients), butyet with sufficient power to detect a possible effectof erlotinib in reducing invasive cancer incidence[6

&

]. This unique design can potentially addresssome of the limitations of the previous chemo-prevention studies that used endpoints of OPLhistological and/or clinical response, which may



not necessarily correlate with the more clinicallyrelevant endpoint of long-term incidence of inva-sive oral cancer [33

&

]. It is also the first trial that willattempt to prospectively validate a molecular-basedrisk assessment tool and couple it with clinicalintervention. In addition to EPOC, other ongoingstudies with cetuximab (NCT00524017), and erloti-nib plus celecoxib (NCT00400374) may providefurther evidence for a possible role of EGFR inhi-bitors for oral cancer chemoprevention.

CHEMOPREVENTION STUDIES WITHOTHER AGENTS

Besides retinoids and EGFR inhibitors, several otheragents have been studied for head and neck cancerchemoprevention. Selected completed or ongoingclinical trials are briefly reviewed below.

Multiple preclinical experiments and studiesinvolving human tissue specimens have demon-strated a possible role for cyclooxygenase (COX)-2in head and neck squamous cell carcinoma carcino-genesis [45]. In a randomized, placebo-controlled,phase IIb study of an oral rinse with the nonselectiveCOX inhibitor ketorolac, Mulshine et al. [46]observed clinical response rates of 30% in theketorolac arm and 32% in the placebo arm, withno significant differences in histological changesbetween the two arms. An explanation for the nega-tive results is the possible inadequate penetrationof the drug into the epithelium using an oralrinse formulation [46]. Papadimitrakopoulou et al.[47] evaluated different doses of the COX-2inhibitor celecoxib in patients with OPLs in a pilot,placebo-controlled study. There was no increasedactivity of the drug (100–200 mg orally twice daily),as assessed by clinical and histological responserates, compared with placebo [47]. Taken together,the lack of efficacy of ketorolac and celecoxib inthe aforementioned studies and the known risksof cardiovascular toxicity associated with COX-2inhibitors have decreased the enthusiasm for devel-oping these drugs for oral cancer chemoprevention.

Green tea polyphenols have been shown tobe able to modulate multiple molecular targets atvarious cellular levels that ultimately lead to apop-tosis, inhibition of cell proliferation, inhibitionof angiogenesis, and suppression of metastaticpotential (reviewed in detail by Kim et al. [48]).As such, these compounds have been postulatedto be able to prevent head and neck malignancies.Li et al. [49] conducted the first randomized,placebo-controlled trial of green tea (760 mg ofmixed tea capsules orally four times daily plus10% mixed tea ointment topically) in 59 patientswith OPLs. The response rate of 37.9% in the green



Oral premalignant lesions William

tea arm compared favorably to the 10% responserate in the placebo group [49]. Tsao et al. [50] inves-tigated three different doses of green tea extract(500, 750, or 1000 mg/m2 orally three times dailyfor 12 weeks) compared with placebo in a random-ized, phase II study of 41 patients with OPLs. Thedrug was well tolerated, and the authors observeda dose–response effect, with a 58.8% rate of lesionshrinkage in the two higher dose arms, comparedwith 18.2% in the placebo arm. There were nodifferences in oral cancer-free survival betweenthe groups [50]. Different formulations of green treeextracts [51] and combinations with other agents(such as EGFR inhibitors [52]) are currently beinginvestigated at the preclinical and clinical levels.

Retrospective epidemiologic studies havedemonstrated that diabetic patients treated withthiazolidinediones [peroxisome proliferator activa-tor (PPAR)-g agonists] had a lower incidence oflung cancers [53] and head and neck cancers [54]compared with diabetic patients who did not usethis specific class of oral hypoglycemic drugs. Inanimal models of oral carcinogenesis, the PPAR-gagonists pioglitazone [55] and troglitazone [56]decreased tongue carcinoma multiplicity and inci-dence, respectively, compared with placebo-treatedrats. On the basis of these observations, Rhodus et al.[57

&

] conducted a randomized, placebo-controlled,phase II study of pioglitazone 45 mg orally daily for3 months in 44 patients with oral leukoplakia.Clinical and/or histological responses were seen in68% of the 22 individuals treated with pioglitazone,compared with no significant changes detectedin the placebo group. A larger, randomized, multi-institutional, phase II study is currently underway comparing pioglitazone versus placebo inthe same setting to validate the previous findings(NCT00951379).

ONYX-015 is an attenuated adenovirus cyto-toxic to cells with dysfunctional p53-dependentsignaling pathways. A mouthwash with this virusled to histologic resolution of dysplasia in 37% of19 patients in a pilot clinical trial, but the majorityof the responses were transient [58]. In anotherclinical study using recombinant human adenovirus-p53 delivered through intra-epithelial injections, fiveof 22 patients (22.7%) experienced a completeregression of the leukoplakia lesion after 24 monthsof follow-up [59]. Arguably, despite the clinicalactivity seen in these two studies, mouthwashes orintra-epithelial injections may not be the optimalmode of delivery of adenoviruses to address thefield cancerization effect present in many patientswith oral leukoplakia. Thus, the question is raisedwhether this strategy will be effective in preventingcancers in the aerodigestive tract at large long-term.

Copyright © Lippincott Williams & Wilkins. Unau

1040-8746 � 2012 Wolters Kluwer Health | Lippincott Williams & Wilk

CONCLUSION

Unfortunately, despite extensive investigations,a standard systemic therapy for patients with OPLsis yet to be developed. Nonetheless, there havebeen many advances in head and neck cancerchemoprevention research, supported by improvedunderstanding of the molecular biology of OPLs.Molecular markers of malignant transformationhave been identified in retrospective studies andearly clinical trials with retinoids. This knowledgeprovides the opportunity to develop chemopreven-tive interventions focused on high-risk groups.Translational research embedded in ongoingchemoprevention studies will hopefully identifystrategies involving novel markers and drugs thatmay be used to prevent head and neck malignanciesin the future.

Acknowledgements

None.

Conflicts of interest

This work was supported by the National Institutes ofHealth grants P01 CA106451–06, P30 CA016672–36,and P50 CA097007-09.W.N.W. has received research grants from Eli-Lilly andAstellas Pharma Inc.

REFERENCES AND RECOMMENDEDREADINGPapers of particular interest, published within the annual period of review, havebeen highlighted as:
& of special interest&& of outstanding interest Additional references related to this topic can also be found in the CurrentWorld Literature section in this issue (p. 345).
1. Sporn MB, Dunlop NM, Newton DL, Smith JM. Prevention of chemicalcarcinogenesis by vitamin A and its synthetic analogs (retinoids). Fed Proc1976; 35:1332–1338.

2. O’Shaughnessy JA, Kelloff GJ, Gordon GB, et al. Treatment and prevention ofintraepithelial neoplasia: an important target for accelerated new agentdevelopment. Clin Cancer Res 2002; 8:314–346.

3. Kelloff GJ, Lippman SM, Dannenberg AJ, et al. Progress in chemopreventiondrug development: the promise of molecular biomarkers for prevention ofintraepithelial neoplasia and cancer: a plan to move forward. Clin Cancer Res2006; 12:3661–3697.

4. Lippman SM, Hong WK. Molecular markers of the risk of oral cancer. N Engl JMed 2001; 344:1323–1326.

5. Rosin MP, Cheng X, Poh C, et al. Use of allelic loss to predict malignant risk forlow-grade oral epithelial dysplasia. Clin Cancer Res 2000; 6:357–362.

6.&

William WN Jr, Heymach JV, Kim ES, Lippman SM. Molecular targets forcancer chemoprevention. Nat Rev Drug Discov 2009; 8:213–225.

This review discusses novel trial designs that could streamline chemopreventionresearch.7. Gupta PC, Mehta FS, Daftary DK, et al. Incidence rates of oral cancer and

natural history of oral precancerous lesions in a 10-year follow-up study ofIndian villagers. Community Dent Oral Epidemiol 1980; 8:283–333.

8. Petti S. Pooled estimate of world leukoplakia prevalence: a systematic review.Oral Oncol 2003; 39:770–780.

9. Silverman S Jr, Gorsky M, Lozada F. Oral leukoplakia and malignanttransformation. A follow-up study of 257 patients. Cancer 1984; 53:563–568.

10. William WN Jr, Liu C, Lippman SM. Chemoprevention of head and neckcancers. In: Olshan AF, editor. Epidemiology, pathogenesis and preventionof head and neck cancers. 1 ed. New York, New York: Springer; 2010.pp. 107–202.


ins www.co-oncology.com 209

C

Head and neck

11. van der Waal I, Axell T. Oral leukoplakia: a proposal for uniform reporting. OralOncol 2002; 38:521–526.

12. Pindborg JJ, Daftary DK, Mehta FS. A follow-up study of sixty-one oraldysplastic precancerous lesions in Indian villagers. Oral Surg Oral Med OralPathol 1977; 43:383–390.

13. Pindborg JJ, Reibel J, Holmstrup P. Subjectivity in evaluating oral epithelialdysplasia, carcinoma in situ and initial carcinoma. J Oral Pathol 1985;14:698–708.

14. Abbey LM, Kaugars GE, Gunsolley JC, et al. Intraexaminer and interexaminerreliability in the diagnosis of oral epithelial dysplasia. Oral Surg Oral Med OralPathol Oral Radiol Endod 1995; 80:188–191.

15. Karabulut A, Reibel J, Therkildsen MH, et al. Observer variability in thehistologic assessment of oral premalignant lesions. J Oral Pathol Med1995; 24:198–200.

16. Cruz IB, Snijders PJ, Meijer CJ, et al. p53 expression above the basal cell layerin oral mucosa is an early event of malignant transformation and has predictivevalue for developing oral squamous cell carcinoma. J Pathol 1998; 184:360–368.

17. Califano J, van der Riet P, Westra W, et al. Genetic progression model forhead and neck cancer: implications for field cancerization. Cancer Res 1996;56:2488–2492.

18. Mao L, Lee JS, Fan YH, et al. Frequent microsatellite alterations at chromo-somes 9p21 and 3p14 in oral premalignant lesions and their value in cancerrisk assessment. Nat Med 1996; 2:682–685.

19. Partridge M, Emilion G, Pateromichelakis S, et al. Allelic imbalance at chromo-somal loci implicated in the pathogenesis of oral precancer, cumulative loss andits relationship with progression to cancer. Oral Oncol 1998; 34:77–83.

20. Partridge M, Pateromichelakis S, Phillips E, et al. A case-control studyconfirms that microsatellite assay can identify patients at risk of developingoral squamous cell carcinoma within a field of cancerization. Cancer Res2000; 60:3893–3898.

21. Rosin MP, Lam WL, Poh C, et al. 3p14 and 9p21 loss is a simple tool forpredicting second oral malignancy at previously treated oral cancer sites.Cancer Res 2002; 62:6447–6450.

22. Sardi I, Franchi A, Ferriero G, et al. Prediction of recurrence by microsatelliteanalysis in head and neck cancer. Genes Chromosomes Cancer 2000;29:201–206.

23. Abbruzzese JL, Lippman SM. The convergence of cancer prevention andtherapy in early-phase clinical drug development. Cancer Cell 2004; 6:321–326.

24. Bhutani M, Pathak AK, Fan YH, et al. Oral epithelium as a surrogate tissue forassessing smoking-induced molecular alterations in the lungs. Cancer PrevRes (Phila) 2008; 1:39–44.

25.&

Boyle JO, Gumus ZH, Kacker A, et al. Effects of cigarette smoke on the humanoral mucosal transcriptome. Cancer Prev Res (Phila) 2010; 3:266–278.

Together with the studies cited in [24,26], this work identifies signaturesthat characterize tobacco-induced diffuse epithelial injury and could potentiallyrepresent markers of cancer risk.26. Sridhar S, Schembri F, Zeskind J, et al. Smoking-induced gene expression

changes in the bronchial airway are reflected in nasal and buccal epithelium.BMC Genomics 2008; 9:259.

27. Hong WK, Endicott J, Itri LM, et al. 13-cis-retinoic acid in the treatment of oralleukoplakia. N Engl J Med 1986; 315:1501–1505.

28. Stich HF, Hornby AP, Mathew B, et al. Response of oral leukoplakias to theadministration of vitamin A. Cancer Lett 1988; 40:93–101.

29. Stich HF, Rosin MP, Hornby AP, et al. Remission of oral leukoplakias andmicronuclei in tobacco/betel quid chewers treated with beta-carotene andwith beta-carotene plus vitamin A. Int J Cancer 1988; 42:195–199.

30. Sankaranarayanan R, Mathew B, Varghese C, et al. Chemoprevention of oralleukoplakia with vitamin A and beta carotene: an assessment. Oral Oncol1997; 33:231–236.

31. Lippman SM, Batsakis JG, Toth BB, et al. Comparison of low-dose isotretinoinwith beta carotene to prevent oral carcinogenesis. N Engl J Med 1993;328:15–20.

32. Papadimitrakopoulou VA, Hong WK, Lee JS, et al. Low-dose isotretinoinversus beta-carotene to prevent oral carcinogenesis: long-term follow-up.J Natl Cancer Inst 1997; 89:257–258.

33.&

Papadimitrakopoulou VA, Lee JJ, William WN Jr, et al. Randomized trial of13-cis retinoic acid compared with retinyl palmitate with or without beta-carotene in oral premalignancy. J Clin Oncol 2009; 27:599–604.

This is one of the largest and longest term chemoprevention trials in patients withOPLs. This trial highlights the poor correlation between leukoplakia response ratesand long-term oral cancer incidence.34. Mao L, El-Naggar AK, Papadimitrakopoulou V, et al. Phenotype and genotype

of advanced premalignant head and neck lesions after chemopreventivetherapy. J Natl Cancer Inst 1998; 90:1545–1551.

35. Lee JJ, Hong WK, Hittelman WN, et al. Predicting cancer development in oralleukoplakia: ten years of translational research. Clin Cancer Res 2000;6:1702–1710.

36. Kawaguchi H, El-Naggar AK, Papadimitrakopoulou V, et al. Podoplanin:a novel marker for oral cancer risk in patients with oral premalignancy. J ClinOncol 2008; 26:354–360.



37. Saintigny P, El-Naggar AK, Papadimitrakopoulou V, et al. DeltaNp63overexpression, alone and in combination with other biomarkers, predictsthe development of oral cancer in patients with leukoplakia. Clin Cancer Res2009; 15:6284–6291.

38.&

Taoudi Benchekroun M, Saintigny P, Thomas SM, et al. Epidermal growthfactor receptor expression and gene copy number in the risk of oral cancer.Cancer Prev Res (Phila) 2010; 3:800–809.

This study provides evidence for a role for EGFR in OPL malignant transformationand supports the investigation of EGFR inhibitors for oral cancer chemoprevention.39. Papadimitrakopoulou VA, Izzo J, Mao L, et al. Cyclin D1 and p16 alterations

in advanced premalignant lesions of the upper aerodigestive tract: role inresponse to chemoprevention and cancer development. Clin Cancer Res2001; 7:3127–3134.

40. Izzo JG, Papadimitrakopoulou VA, Liu DD, et al. Cyclin D1 genotype, responseto biochemoprevention, and progression rate to upper aerodigestive tractcancer. J Natl Cancer Inst 2003; 95:198–205.

41.&

Saintigny P, Zhang L, Fan YH, et al. Gene expression profiling predicts thedevelopment of oral cancer. Cancer Prev Res (Phila) 2011; 4:218–229.

This is one of the only studies to correlate high throughput gene expressionsignatures with oral cancer risk in patients with OPLs.42.&

Saintigny P, Jelinek J, Pickering CR, et al. DNA methyltransferase-3B(DNMT3B) in oral cancer (OC) development. J Clin Oncol 2011; 29:1506.

This study identifies a potential novel way of assessing cancer risk in patients withOPLs, by focusing on DNA methylation signatures.43. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for

squamous-cell carcinoma of the head and neck. N Engl J Med 2006;354:567–578.

44.&

Leeman-Neill RJ, Seethala RR, Singh SV, et al. Inhibition of EGFR-STAT3signaling with erlotinib prevents carcinogenesis in a chemically-inducedmouse model of oral squamous cell carcinoma. Cancer Prev Res (Phila)2011; 4:230–237.

This preclinical study provides support for the evaluation of EGFR inhibitors for oralcancer chemoprevention in clinical trials.45. Lin DT, Subbaramaiah K, Shah JP, et al. Cyclooxygenase-2: a novel molecular

target for the prevention and treatment of head and neck cancer. Head Neck2002; 24:792–799.

46. Mulshine JL, Atkinson JC, Greer RO, et al. Randomized, double-blind,placebo-controlled phase IIb trial of the cyclooxygenase inhibitor ketorolacas an oral rinse in oropharyngeal leukoplakia. Clin Cancer Res 2004;10:1565–1573.

47. Papadimitrakopoulou VA, William WN Jr, Dannenberg AJ, et al. Pilot rando-mized phase II study of celecoxib in oral premalignant lesions. Clin CancerRes 2008; 14:2095–2101.

48. Kim JW, Amin AR, Shin DM. Chemoprevention of head and neck cancer withgreen tea polyphenols. Cancer Prev Res (Phila) 2010; 3:900–909.

49. Li N, Sun Z, Han C, Chen J. The chemopreventive effects of tea on human oralprecancerous mucosa lesions. Proc Soc Exp Biol Med 1999; 220:218–224.

50. Tsao AS, Liu D, Martin J, et al. Phase II randomized, placebo-controlled trial ofgreen tea extract in patients with high-risk oral premalignant lesions. CancerPrev Res (Phila) 2009; 2:931–941.

51. Siddiqui IA, Adhami VM, Bharali DJ, et al. Introducing nanochemopreventionas a novel approach for cancer control: proof of principle with green teapolyphenol epigallocatechin-3-gallate. Cancer Res 2009; 69:1712–1716.

52. Zhang X, Zhang H, Tighiouart M, et al. Synergistic inhibition of head and necktumor growth by green tea (-)-epigallocatechin-3-gallate and EGFR tyrosinekinase inhibitor. Int J Cancer 2008; 123:1005–1014.

53. Govindarajan R, Ratnasinghe L, Simmons DL, et al. Thiazolidinediones andthe risk of lung, prostate, and colon cancer in patients with diabetes. J ClinOncol 2007; 25:1476–1481.

54. Govindarajan R, Siegel ER, Simmons DL, Lang NP. Thiazolidinedione (TZD)exposure and risk of squamous cell carcinoma of head and neck (SCCHN).2007 ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007; 25:1511.

55. Suzuki R, Kohno H, Suzui M, et al. An animal model for the rapid inductionof tongue neoplasms in human c-Ha-ras proto-oncogene transgenic rats by4-nitroquinoline 1-oxide: its potential use for preclinical chemopreventionstudies. Carcinogenesis 2006; 27:619–630.

56. Yoshida K, Hirose Y, Tanaka T, et al. Inhibitory effects of troglitazone,a peroxisome proliferator-activated receptor gamma ligand, in rat tonguecarcinogenesis initiated with 4-nitroquinoline 1-oxide. Cancer Sci 2003;94:365–371.

57.&

Rhodus N, Rohrer M, Pambuccian S, et al. Phase IIa chemoprevention clinicaltrial of pioglitazone for oral leukoplakia. J Dent Res 2011; 90(A): 945.

This study demonstrates promising activity of PPAR-g agonists in OPLs andprovides support for a larger, randomized, ongoing study of pioglitazone in thissetting.58. Rudin CM, Cohen EE, Papadimitrakopoulou VA, et al. An attenuated

adenovirus, ONYX-015, as mouthwash therapy for premalignant oraldysplasia. J Clin Oncol 2003; 21:4546–4552.

59. Li Y, Li LJ, Zhang ST, et al. In vitro and clinical studies of gene therapy withrecombinant human adenovirus-p53 injection for oral leukoplakia. Clin CancerRes 2009; 15:6724–6731.



chemopreveniton

Documents