Special Report - Cancer Prevention Research · Remarkable progress in precision medicine and immune-oncology, driven by extraordinary recent advances in genome-wide sequencing,

Special Report

Transforming Cancer Prevention throughPrecision Medicine and Immune-oncologyThomasW.Kensler1,AvrumSpira2, JudyE.Garber3,EvaSzabo4,J. JackLee5,ZigangDong6,AndrewJ.Dannenberg7,William N. Hait8, Elizabeth Blackburn9, Nancy E. Davidson10, Margaret Foti11, and Scott M. Lippman12

ABSTRACT We have entered a transformative period in cancer prevention (including early detec-tion). Remarkable progress in precision medicine and immune-oncology, driven by

extraordinary recent advances in genome-wide sequencing, big-data analytics, blood-based technologies, anddeep understanding of the tumor immune microenvironment (TME), has provided unprecedented possibil-ities to study the biology of premalignancy. The pace of research and discovery in precision medicine andimmunoprevention has been astonishing and includes the following clinical firsts reported in 2015: drivermutations detected in circulating cell-free DNA in patients with premalignant lesions (lung); clonal hema-topoiesis shown to be a premalignant state; molecular selection in chemoprevention randomized controlledtrial (RCT; oral); striking efficacy in RCT of combination chemoprevention targeting signaling pathwayalterations mechanistically linked to germline mutation (duodenum); molecular markers for early detectionvalidated for lung cancer and showingpromise for pancreatic, liver, andovarian cancer. IdentificationofHPVasthe essential cause of a major global cancer burden, including HPV16 as the single driver of an epidemic oforopharyngeal cancer in men, provides unique opportunities for the dissemination and implementation ofpublic health interventions. Important to immunoprevention beyond viral vaccines, genetic drivers ofpremalignant progression were associated with increasing immunosuppressive TME; and Kras vaccine efficacyin pancreas genetically engineered mouse (GEM) model required an inhibitory adjuvant (Treg depletion). Inaddition to developing new (e.g., epigenetic) TME regulators, recent mechanistic studies of repurposed drugs(aspirin, metformin, and tamoxifen) have identified potent immune activity. Just as precision medicine andimmune-oncology are revolutionizing cancer therapy, these approaches are transforming cancer prevention.Here, we set out a brief agenda for the immediate future of cancer prevention research (including a "Pre-CancerGenome Atlas" or "PCGA"), which will involve the inter-related fields of precision medicine and immuno-prevention – pivotal elements of a broader domain of personalized public health. Cancer Prev Res; 9(1); 2–10.�2016 AACR.

A Time of TransformationImmense breakthroughs in understanding the progression of

genomic events and inflammatory microenvironment that drivepremalignancy provide unprecedented possibilities to transformcancer prevention. Although opinions about the current state ofcancer prevention science are still wide-ranging (1–5), as is charac-teristic of emerging fields, we stand on the cusp of opportunity. Justas precision therapy and immunotherapy are transforming cancertreatment, precision medicine and immunoprevention are now

moving to the clinic with great promise. Additional gains, such asidentification of tractable molecular targets, more sophisticated riskstratification strategies and algorithms, better preclinical models,earlier detection of premalignant lesions and early-stage cancers,new agents, rational development of combinatorial chemopreven-tive interventions, current availability of 14 FDA-approved drugsand vaccines for application to cancer prevention (5) and advancesin implementation science (defined as the application of what wealready know), all point to a strong possibility to reduce cancer

1Universityof Pittsburgh, Pittsburgh, Pennsylvania and JohnsHopkinsBloomberg School of Public Health, Baltimore, Maryland. 2BostonUniversity, Boston, Massachusetts. 3Dana-Farber Cancer Institute,Boston,Massachusetts. 4Division of Cancer Prevention, National Can-cer Institute, Rockville, Maryland. 5The University of Texas MDAnder-sonCancerCenter,Houston,Texas. 6TheHormel Institute,UniversityofMinnesota, Minneapolis, Minnesota. 7Weill Cornell Medical College,NewYork, NewYork. 8JanssenResearch &Development, LLC, Raritan,New Jersey. 9Salk Institute for Biological Studies, La Jolla, California.10University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania.

11American Association for Cancer Research, Philadelphia, Pennsyl-vania. 12Moores Cancer Center, University of California San Diego, LaJolla, California.

Corresponding Author: Scott M. Lippman, Director, UC San Diego MooresCancer Center, 3855 Health Sciences Drive MC 0658, La Jolla, CA 92093. Phone:858-822-1222; Fax; 858-822-0207; E-mail: [email protected]

doi: 10.1158/1940-6207.CAPR-15-0406

�2016 American Association for Cancer Research.

Special Report

Cancer Prev Res; 9(1) January 20162

Research. on October 17, 2020. © 2016 American Association for Cancercancerpreventionresearch.aacrjournals.org Downloaded from

http://cancerpreventionresearch.aacrjournals.org/

incidence, morbidity, and mortality in the near future. Given thattheglobalburdenof cancer is enormousand increasing (thenumberof diagnosed cases is expected to growworldwide from13.3millionin 2010 to 20million by 2030; ref. 6), cancer prevention (includingearly detection) is essential to our ability to lessen the burden ofcancer in our lifetime. The optimism surrounding progress in cancertherapeutics ispropelling investigation intoapplicationsof enablingtechnologies and extrapolation of effective interventions in estab-lished disease to the more difficult challenges of cancer preventionor interception (7).

Here, we set out a brief agenda for the near-term future ofthis exciting field through the inter-related disciplines of precisionmedicine and immunoprevention—elements of a broaderdomain of personalized public health.

Biology of PremalignancyThere has been increasing focus on themolecular origins of cancer

over the last several years (8). In contrast to studies in malignancy,however, genome-wide analyses of premalignancy have been rare.Remarkable technological advances in next-generation sequencing(NGS; requiring only nanograms of startingDNA/RNA fromminutebiopsies down to single cells), computational biology, and high-throughput functional screening have now provided us with very

real possibilities to deeply probe the biology of premalignancy.Recent studies in lung squamous premalignancy of single nucleotidepolymorphism arrays identified losses of tumor suppressors RNF20and SSBP2 and amplification of the RASGRP3 oncogene (9) andRNA-seq analyses identifying 3q26.33–3q29 (including SOX2)amplification/overexpression (10). Surprisingly, circulating DNAcontaining cancer driver mutations has been detected in circulatingcell-free DNA in patients with atypical adenomatous hyperplasia,preinvasive (premalignant) lesions of the lung, which could be usedfor early detection and to follow the effects of preventive interven-tions (11). Studies of the airway field of injury have detected EGFRmutations in adjacent histologically normal epithelium of EGFR-mutant lung adenocarcinoma (12), and whole-genome expressionprofilinghas identifiedother activatedoncogenic signaling pathways(e.g., PI3K/AKT) in the airway of smokers with premalignant lesionsand/or lung cancer (13) and in the cytologically normal bronchialairway of smokers with premalignant lesions, potentially enablinggenomic approaches to monitoring the preventive effects of PI3Kinhibitors (14). This precision genomics approach is currently beingtested in aphase IIbprevention trial ofmyo-inositol amonghigh-risksmokers with premalignant lesions.

Recent studies support the model that a specific sequence ofacquired genomic events over many years characterize the transi-tion from normal epithelium to invasive carcinoma and that

Figure 1.The molecular alterations associated with early pathological steps preceding the development of invasive carcinoma have not been well characterized. APre-Cancer Genome Atlas (PCGA) is needed both to support the collection and molecular profiling (circus plot) of premalignant lesions (purple cells)to identify the sequence of initial driver events that cause normal cells (orange cells) to acquire cancer hallmarks that enable lesions (purple cells) toprogress to fully invasive carcinoma, including the critical "additional genomic events" (e.g., checkpoint/tumor suppressor loss or other co-activatingevent) that transform premalignancy (purple cells in the fourth circle to the right) to cancer (far right). In addition to defining the sequence of genomicdriving events in specific neoplastic sites, characterizing the premalignant inflammatory microenvironment, including the contribution of the stromaand immune cell (blue) regulation, will provide a better understanding of the selective forces that determine which molecular drivers give an evolutionaryadvantage to drive premalignant lesions to become invasive cancer. This figure is modified in part from Campbell et al. (21).

3www.aacrjournals.org Cancer Prev Res; 9(1) January 2016

Transforming Cancer Prevention



specific "driver" events, acquired in a particular order, enable cellsto progress from benign growth to an invasive phenotype. A studysequenced 293 cancer-relevant genes in primary melanomas andtheir adjacent precursor lesions to study the succession of geneticalterations during melanoma progression (15). Whereas benignnevi harbored BRAF V600E mutations exclusively, this studyidentified an intermediate (premalignant) category ofmelanocyticneoplasia characterized by additional mutations, including TERTpromotermutationsandNRASmutations, and foundamutationalsignature implicating ultraviolet radiation as a major driver ofmelanocytic neoplasia progression. Ultra-deep sequencing of 74cancer genes in 234 biopsies of sun-exposed eyelid epidermisrevealed mutations similar to those seen in many malignancies,includingNOTCH1/2 and FAT1 genes (16).NOTCH1 drivermuta-tions have also been detected in oral premalignancy (17). Studiesin breast lobular carcinoma in situ, pancreatic mucinous cysts, andBarrett esophagus have identified genomic patterns of premalig-nant progression to cancer, which have important implications forrisk prevention and early detection (18–20). Some data suggestthat drivermutations in early neoplasia can differ from those in thecorresponding cancer. A critical next step for this field will bedeveloping systematic approaches for whole-genome profiling ofpremalignant lesions followed longitudinally as they progresstoward cancer–the proposed initiative "Pre-Cancer Genome Atlas"or "PCGA" (21). This initiativewill provide critical insights into themolecular events (and possible sequence) in premalignant cellsand their microenvironment that drive progression to invasivecancer (Fig. 1), enablingprecision approaches to cancer preventionand early detection.

As described above, the proposedPCGA focuses on solid tumorsof epithelial origin; however, it also applies to hematologicalneoplasia. The Cancer Genome Atlas (TCGA) did include oneblood cancer [acute myelogenous leukemia (AML)]. Recent geno-mic studies suggest that clonal hematopoiesis is a pre-malignantstate. Somatic mutations observed mostly in three genes(DNMT3A,TET2, and ASXL1), known drivers of hematologicmalignancies, have been identified in the blood of people withouta known hematologic disorder. The prevalence of thesemutations,termed clonal hematopoiesis of indeterminate potential, increaseswith age (22) and is associatedwith increased risk of progression toa blood cancer (23). Somatic mutations typical of myelodysplasticsyndrome (MDS) and AML have been found in up to 40% ofpatients with idiopathic cytopenias of undetermined significance(24) who may be at greatest cancer risk. Clonal hematopoiesisdetected by deep sequencing was identified in aplastic anemia (25)andassociatedwith risk ofdeveloping therapy-relatedMDSorAML(26). Several prospective studies of ICUS and CCUS have beeninitiated to identify patients with preclinical MDS (27) most likelytoprogress and therefore potential candidates for early treatment orprevention. Related hematologic neoplasia work is studying themonoclonal gammopathy of undetermined significance (MGUS)–multiple myeloma sequence, including smoldering myeloma,which has an overall risk of progression to malignancy (multiplemyeloma)of10%per year (comparedwith1%peryear forMGUS).Recent genomic and immune studies of MGUS progression areproviding novel targets for precision and immune prevention (28).

Precision MedicineChemoprevention

The status of this field, including RCTs, has been recently re-viewed (4, 5) and includes notable successes (e.g., with selective

estrogen receptor modulators and aromatase inhibitors in breastcancer) and failures (vitamin E and selenium in prostate cancer).Two important new RCTs (29, 30) include a positive trial of oralnicotinamide (which enhances DNA repair) in nonmelanomaskin cancer, typically caused by UV-induced DNA damage (29);this provocative result is consistentwith an earlier report of topicalDNA repair enzymes in xeroderma pigmentosum, a germlineDNA repair disorder (31). The first precision medicine RCT inchemoprevention (EPOC) was reported just two months ago(32), beginning a new era of molecular selection in this field(33). Perhaps the most promising current precision medicineapproach to change standard of care in cancer prevention involvesmolecular selection (based on prostaglandin pathway studies) forthe repurposed (and now established) chemopreventive drugaspirin in colorectal neoplasia. In September 2015, the US Pre-ventive Services Task Force (USPSTF) recommended low-doseaspirin for colorectal cancer (CRC) prevention based on age andrisk (34), amajormilestone for the field of cancer prevention. TheUSPSTF's recommendation for aspirin use in this setting acknowl-edges the substantial body of data that now exists supportingaspirin's efficacy for the prevention of CRC. Given aspirin'spotential adverse effects (e.g., bleeding), further tailoring aspirinuse is a high priority. A series of recent reports based on studies ofcolorectal neoplasia, prostaglandins, and aspirin mechanismsupport a precision medicine approach in this setting: (i) highurinary PGE-M levels were prognostic (associated with advancedadenomas risk) and predictive for aspirin and/or NSAID preven-tive activity (35); (ii) aspirin reduced colorectal cancer risk inpatients with high 15-hydroxyprostaglandin dehydrogenasemRNA expression in the normal mucosa adjacent to cancer(36); and (iii) aspirin, NSAIDs, or both were associated withreduced colorectal cancer risk and the association of these agentswith risk differed based on an SNP at chromosome 12 thatcould potentially affect prostaglandin synthesis (37). A relatedstudy reported that SLCO2A1 mutation carriers develop early-onset colon neoplasia and are NSAID resistant, suggesting forthe first time that disordered prostaglandin catabolism canmediate inherited susceptibility to colorectal neoplasia inhumans, mimicking the phenotype of the related HPGD-nullmouse (38). SLCO2A1 encodes the prostaglandin transporter,shown to play a critical role in colorectal neoplasia (39). RelatedNSAID/CRC clinical trial data include: PIK3CAmutation in CRC(genetic driver also detected in adenomas) may predict aspirinefficacy (40), 5-aminosalicylates (related to NSAIDs but poorlyabsorbed) were associated with reduced colorectal neoplasiarisk in the inflammatory bowel disease ulcerative colitis (41),and recent standard-of-care-changing RCTs in hereditary CRC(see Germline mutations below).

Early detectionDeveloping and validating precision medicine approaches for

early cancer detection remains a critical challenge in the preven-tion field. Standard, conventional screening includes mammog-raphy (and MRI for high-risk women, e.g., with BRCA mutationcarriers or Li-Fraumeni syndrome), colonoscopy and fecal occultblood tests, PAP and HPV tests, and low-dose computed tomog-raphy for breast, colon, cervical, and lung tumors, respectively.Newer screening approaches in clinical development to detectpremalignant disease include the following hepatic studies: MRIand magnetic resonance elastography (42), 3D molecular MRIcollagen imaging (43), and plasma eicosanoid lipidomic

Kensler et al.

Cancer Prev Res; 9(1) January 2016 Cancer Prevention Research4



profiling (44) detecting the fibrosis and inflammation charac-terizing non-alcoholic steatohepatitis or NASH, a precursor ofliver cancer, the fastest-rising epithelial cancer in the US. ThisNASH work has important implications for liver cancer surveil-lance and prevention (45).

Current screening tests detect lesions with a very wide spec-trum of natural behavior from those with lethal potential tocompletely benign lesions. There is an urgent need to developprecision molecular tests to: (i) identify individuals at highestrisk who should undergo these screening tests (i.e., screeningbiomarkers), (ii) distinguish benign versus malignant lesionsfound on imaging modalities in order to determine which ofthese lesions should undergo invasive biopsy (i.e., diagnosticbiomarkers), and (iii) distinguish biologically indolent versusaggressive tumors that should be treated (i.e., prognostic bio-markers). Advances in computational biology and NGS tech-nology are revolutionizing our ability to discover genomicbiomarkers in relatively accessible biosamples. Nucleic acids,both noncoding RNA and DNA mutations, can now be mea-sured in circulating blood due to rapid advances in liquidbiopsy technology. These approaches were initially focused onknownmutations in commonly altered genes but are now beingextended to de novo mutations through unbiased analyses viagenome-wide approaches (46). Early stage cancers and pre-cancers may shed some DNA into the circulation (11), butdetection of somatic genetic alterations in the circulation in thissetting has been challenging and still requires much optimiza-tion in terms of the sensitivity and specificity of the assays.RNA-seq bioinformatics algorithms and high-throughput, iso-form-level RT-qPCR recently identified ovarian cancer-specificmRNA isoforms, suggesting the amazing possibility of ovariancancer early detection by PAP test (47). Furthermore, severalmRNA isoforms encode proteins with unique primary struc-tures, which could be targeted by peptide or T cell-basedvaccines.

These rapid advances in biomarker discovery science havestruggled to translate into the clinic due, in large part, to thechallenge in designing and implementing prospective studies tovalidate the biomarkers in the clinical setting in which the testswould be used. Two recent genomic biomarkers for early cancerdetection have overcome this important hurdle and successfullytranslated to the clinic. A highly sensitive stool DNA test wasvalidated as a screening tool for CRC (48). Gene-expressionalterations identified in the cytologically normal epithelium fromthe mainstem bronchus of smokers with lung cancer (14), led toa bronchial airway genomic classifier validated as a highly sen-sitive tool for lung cancer detection in two prospective, multi-center trials (49). This next generation of molecular testingholds the promise to detect biologically aggressive lesions, whichwould be transformational.

Germline mutations in cancer predisposition genesPrecision prevention may also involve risk stratification, early

detection, and risk reduction in patients carrying cancer predis-position genes, including both rare high-penetrance mutationsand–more common lower-penetrance – genetic variants. Surgicalprevention by removal of at-risk tissues is effective but may comeat a high cost in quality of life, such as prophylactic premeno-pausal oophorectomies. Many hereditary syndromes feature pre-disposition to tumors of multiple sites or include prominentinvolvement of sites not amenable to surgical risk reduction(e.g., Li Fraumeni, Cowden's, VHL or RASopathies). Strategies

exploiting specific molecular defects in malignancies developingin the setting of predisposition genes can provide insights intocancer prevention and therapy (50, 51).

Tumor testing for mismatch repair (MMR) deficiency in CRC(e.g., microsatellite instability [MSI]) establishes a new model oftargeted screening based on a cancer predisposition gene. Lynchsyndrome (LS), caused by a germline MMR gene mutation,accounts for ~3% of CRC characterized by MSI. A growing bodyof data indicates that this tumor testing of all newly diagnosedCRC (universal tumor screening) could identify LS familiesand patients shown to benefit from intensive surveillance (e.g.,colonoscopy) and risk-reducing surgery to prevent primary andsecond primary CRC (52, 53). Aspirin has also been shown toreduce LS CRC risk in RCT (54). 2015 US estimates are thatuniversal tumor screening will identify ~ 21,000 people with LS,producing substantial public health benefits (cancers prevented,lives saved and cost effective). Of note, 12-15% of newly diag-nosed CRC tumors are MSI-positive, but only 3% have LS. TheMSI-positive patients (including LS-negative patients not recom-mended for increased surveillance)were recently shown tobenefitfrom anti-PD-1 therapy (55), providing even greater support forthis tumor tissue screening approach.

A clinical breakthrough for this field is the very recent RCTreporting striking efficacy of combination chemoprevention infamilial adenomatous polyposis (FAP). Targeting the conver-gence between Wnt and EGFR signaling pathways and COX-2activity (alterations mechanistically linked to the germline ade-nomatous polyposis coli [APC] mutation causing this disease)with sulindac and erlotinib produced a highly significant reduc-tion in duodenal adenoma burden (56), far more active thansingle agent sulindac or aspirin (57). This finding has majorimplications on standards of care for this devastating disease,which can be associated with thousands of colorectal adenomasand a near 100% cancer risk. After prophylactic colectomy (stan-dard of care), duodenal adenocarcinoma is the leading cause ofcancer death for these patients.

Seminal work showing that BRCA1/2mutations induce defectsin DNA repair, which confer sensitivity to PARP inhibitors acrossassociated tumor types, including breast, ovary, prostate, andpancreas, establishes a new paradigm of targeted therapeutics inthe cancer predisposition setting (58). The possibility of specifictherapies for BRCA mutation carriers has led to incorporation ofBRCA germline characterization for all ovarian and triple-negativebreast cancers into the National Comprehensive Cancer Network(NCCN) guidelines. Opportunities for medical risk reduction forBRCA mutation carriers may target DNA-repair defects and/orcapitalize on other site-specific data, such as tamoxifen in breastcancer prevention (59). The application of genome-wide associ-ation study data as modifiers of high-penetrance genes or morecomplex risk models of common less-penetrance genes offerspromise formore precise personalized risk estimates (60). Loss ofheterozygosity screening of oral brushings may help stratify headandneck cancer risk in Fanconi anemia, a rareDNA repair disorderassociated with an extremely high risk of oral cancer (61). Novelvaccine prevention strategies in Lynch syndrome and BRCA1/2carriers are discussed in the next section.

ImmunopreventionViral vaccines

A successful example of immunoprevention is the nation-wide hepatitis B virus (HBV) vaccination program in Taiwan


www.aacrjournals.org Cancer Prev Res; 9(1) January 2016 5



that began in 1984 and produced an 80% reduction in theincidence of hepatocellular carcinoma (62). Expanding world-wide access to HBV vaccination is a harbinger of benefitsto come. Global perspectives on the patterns of human pap-illomavirus (HPV)-related cancers (e.g., oropharyngeal) andpreventing virally related cancers with vaccines, includingefforts to make these vaccines available to countries experienc-ing financial hardships, highlight the burden and challenges ofthese viral diseases (63, 64). EBV vaccine development has beenchallenging due in part to complex viral antigen expressionpatterns.

The standard three-dose schedule of prophylactic HPV vaccinegiven before infection has 90–100% efficacy in preventing HPVinfection and associated anogenital neoplasia (vulva, vagina,cervix, anus and penis), and limited data from secondary analysisof RCT in women reported vaccine protection for oral HPVinfection implicated in oropharyngeal cancer. High antibodyconcentrations have been reported in HPV-vaccinated youngerpopulations receiving two doses, which is now the schedulerecommended by the WHO for girls under 15 years (65). RCTsin Costa Rica and India suggest that even a single HPV16/18vaccine dose could induce a sustained antibody response (66, 67).Of great public health significance, planning is now under way foran RCT specifically designed to evaluate the protection of oneversus two doses in Costa Rica and a US immunobridging study(including males) done in parallel. Another preventive vaccineapproach is to eradicate existing premalignant lesions where thepathway to transformation is known. The first vaccine testedclinically in premalignant HPV disease (vulvar intraepithelialneoplasia) was composed of long peptides derived from HPV16E6andE7oncoproteins andproducedmajor activity and strong T-cell responses (68). This therapeutic vaccine approach has pro-duced histopathologic regression and viral clearance in a phase IIRCT in cervical intraepithelial neoplasia (69).

A number of prevention studies have focused on the growingpublic health epidemic of HPV-associated oropharyngeal can-cer (70), including two early-detection research studies: oro-pharyngeal "PAP" smears (71) and influence of childhoodtonsillectomy effect on subsequent oropharyngeal cancer(72). The dramatic cancer disparity of blacks versus whites inHPV-positive oropharyngeal cancer (73) is well established;updated data suggest that these patterns may be changing overtime (74). No premalignant lesions have been identified in thissetting, but current prevention work is focusing on oral HPV16infection, which tracks closely to oropharyngeal cancer, e.g.,both are 4-fold higher and increasing in men compared towomen (70). A recent report on the long-term persistence oforal HPV16 infection in men (75) adds important new data tothe scarce natural history information currently available.Genomic and imaging studies to identify high-risk groups andearly neoplasia in the setting of persistent oral HPV16 infectionare ongoing.

Non-viral vaccinesRecent clinical success of HPV (including therapeutic) vaccines

for prevention and checkpoint inhibition (proving that immunitycan inhibit cancer growth) for therapy has generated tremendousenthusiasm for non-viral vaccine immunoprevention. Theimmune-checkpoint inhibitors (e.g., targeting CTLA-4 or PD-1), which act on previously induced T cells, are producing durableremissions in some patients with metastatic, previously treated

cancers. Their utility in prevention, however, is limited bytheir serious autoimmune toxicities. Furthermore, it is notclear that these checkpoint signals are important in early TME.Vaccines are an immune approach that is broadly available,specific, cost-effective, and work best in immunocompetentindividuals. Vaccines targeting cancer-associated antigens havebeen studied extensively over the last 30 years in thousands ofpatients and have been shown to have a very favorable safetyprofile setting the stage for prevention vaccines, and limiteddosing should improve implementation and adherence.Tumor-specific antigens (TSAs), such as KRAS and p53mutationsexclusively on tumor/premalignant cells, have safety advantagesas vaccine targets compared with tumor-associated antigens(TAAs) present on tumor and normal cells because of potentialfor less autoimmune toxicity.

Although more complex and recent than the development ofvaccines against foreign pathogen-associated viral targets (e.g.,hepatitis B), vaccines against the less-immunogenic neoanti-gens (genetic drivers and other tumor antigens) are showingpromise in preclinical prevention models (e.g., Kras in pancreasmodels; activating EGFR mutations in lung adenocarcinoma;refs. 76–78) and have now entered early-phase clinical trials(e.g., HER2 and MUC1). This focus is very timely, as evidencedby a major new initiative by Cancer Research UK, which justissued a £20M Grand Challenge that includes a charge todevelop vaccines to prevent non-viral cancers (79). The firstclinical trial of a preventive vaccine based on a tumor anti-gen was in patients with advanced colorectal adenomas (80).The vaccine consisted of the 100-mer peptide derived from thetandem repeat region in the TAA MUC1 extracellular domainand adjuvant, toll-like receptor (TLR)-3-agonist Poly-LCIC. Itelicited a strong humoral and cellular MUC1-specific immunityand increased IgG levels after a booster injection at one year,demonstrating induction of immune memory. Patients whodid not respond (i.e., no increase in MUC1 IgG antibody)had high levels of circulating myeloid-derived suppressorcells (MDSCs) before vaccination, providing the first clinicalevidence suggesting that non-infectious/viral vaccines will re-quire adjuvants/immune modulators that decrease immuno-suppression (e.g., reduce suppressive immune cell populationslike MDSCs and Tregs at the time of vaccination). The vaccinewas well tolerated without any toxicity or evidence of auto-immunity. Currently, this vaccine is being tested for efficacy(prevention of adenoma recurrence) in a multicenter RCT(NCT02134925).

Classic adjuvants are stimulants such as non-specific bacterialextracts and newer subtype-specific TLR stimulants. More recent-ly, GEM model studies indicate that the first genetic alterationscan initiate a cascade of genetic, epigenetic, and inflammatorychanges that lead to an immunosuppressive TME (consistentwith the clinical data discussed above; ref. 80), suggesting needfor inhibitory adjuvants for vaccine preventive efficacy. Thishypothesis was supported when Kras vaccine efficacy (reduc-ed pancreatic intraepithelial neoplasia progression) in theKras-p53-Cre mouse model required Treg depletion. Recentstudies in pancreatic models found that metformin and aspirincan modulate inflammatory pathways within the early TMEthat promote tumorigenesis, suggesting their potential as adju-vants to enhance vaccine efficacy (81, 82). Current work in thiscontext is developing more specific adjuvants (e.g., miRNA orother epigenetic regulators) to reverse the functional (tumor

Kensler et al.




promoting/ immunosuppressive) immune cell polarity to in-hibit the immunosuppressive TME.

Genomic technologies and large data sets are helping identifyvaccine targets for cancer prevention, including early geneticdrivers in premalignancy. Preclinical studies demonstrate thatmulti-antigen vaccines are more effective than single-antigenvaccines by inducing immunity to more antigens, generatingmore activated T cells homing to the premalignant lesion (83).A multi-antigen vaccine for colon cancer, targeting several immu-nogenic proteins that are upregulated in adenomas and conservedthrough carcinoma (84), is moving toward the clinic. Preliminarystudies of single-antigen vaccines are encouraging in reducingpolyp formation in AOM-treated mice and APCmin mice. Impor-tant to CRC prevention is the finding that aspirin (recentlyrecommended for CRC prevention by the USPTF; see above) canincrease tumor-trafficking CD8 T cells to enhance immunosur-veillance and reverse immune escape (and modulate earlyTME inflammatory pathways) in premalignant lesions, suggestingthe significant potential of combining aspirin with CRC vaccines(81, 82, 85).

Gene amplification resulting in abnormal overexpression ofnon-mutated self-antigens is an early event in the malignanttransformation of many solid tumors. A three-antigen vaccine(targeting IGFBP2, IGF-1R, and HER2—all upregulated inhigh-risk breast lesions from DCIS to atypical hyperplasia)was shown to be safe and effective in transgenic mice (83) andwill start phase I clinical trials in the first quarter of 2016. Afive-antigen vaccine targeting breast cancer stem cells (immu-nizing against CD105/Yb-1/SOX2/CDH3/ and MDM2) calledSTEMVAC is currently in clinical trials (NCT02157051). Fur-ther clinical development of these vaccines will be based onimmunogenicity in the phase I trials. A prophylactic lungcancer vaccine, using the same approach in terms of genomicscreening and then functional screening to identify candidateproteins upregulated in dysplasia and conserved in stage I/IIdisease, is in development.

Immunoprevention may also involve patients carrying cancerpredisposition genes. A novel example of this approach involvesa vaccine targeting hTERT under development for BRCA carriers(86). This vaccine is being tested clinically now in the adjuvantsetting with plans tomove to BRCA1/2-healthy carriers initially ina window trial before prophylactic surgery. A vaccine targetingmutations that define Lynch syndrome to prevent the develop-ment of cancer is under development (87) and is extremelyexciting and promising given the striking efficacy of immuno-therapy approaches in the treatment of colorectal cancer in thiscontext (55).

Implementation ScienceExpanded efforts to refocus on implementation science will be

essential to further progress in cancer prevention. More than 50%of cancers are preventable through lifestylemodifications, includ-ing increased physical activity, reduced obesity, and eliminationof cigarette smoking (88). Standard screening tests (mammogra-phy and CRC screening) are unevenly distributed from state tostate and also county to county (89). Greater use of effectivemedical interventions across all sectors of society adds to thepotential to prevent the majority of cancer and reduce disparities.A renewed focus on and funding of implementation science incancer (of note, >90% of NCI funding in this field is focused onprevention; ref. 90) is due to the growing recognition of the

difficulty translating evidence into practice. Recent advancesinclude new models, methods, metrics, and measurement toolsto study the complex, multi-level factors (e.g., organizational)that influence effective adoption and maintenance and accep-tance of study designs beyond RCTs. The importance of imple-mentation science also applies to precision medicine and immu-noprevention as briefly discussed below. For example, uptake ofCRC universal tumor screening for Lynch syndrome is limiteddespite data showing clear public health benefits (discussed indetail above inGermline mutations section) and recommendationsof several professional organizations, including NCCN. Tamox-ifen (and related FDA-approved agents) produces durable reduc-tion of breast cancer risk by 75% (91) in atypical hyperplasia(10% of patients with a biopsy for benign breast disease; invasivecancer risk of 30% at 25 years [92], similar to BRCA mutationcarriers). Appalling under-use in this high-risk subset suggests thatproviders and patients are not fully aware of the clinical risks andbenefit in this setting.

Identification of HPV as the cause of a major global cancerburden, including as a necessary driver of cervical cancer (theleading cause of cancer deaths in women in many developingcountries) and a dramatically increasing subset of oropharyngealcancer among men in the US and other developed countries,provides exceptional prospects for implementation of publichealth interventions (70). Three HPV vaccines – bivalent (HPV16 and 18), quadrivalent and 9-valent – have been FDA-approved(first in 2006), but the uptake remains slow in parts of the US andworld. In 2013, only 38%of girls and 14%of boys in the USwerefully vaccinated despite recommendations from the CDC, Amer-ican Academy of Pediatrics, and other groups. HPV vaccination inthe US is lower in areas of high cervical cancer incidence andmortality and among non-Hispanic Blacks, helping direct publichealth implementation efforts (93). Major global efforts are nowfocusing on implementing HPV vaccination programs in coun-tries where the burden of disease is highest, including throughschool-based programs in low-income countries (65, 94). RecentRCTs suggest that a single vaccine dose can provide durableprotection against HPV infection (66, 67), which if confirmedby the planned definitive RCT, would dramatically improvevaccine implementation and uptake globally.

ConclusionRemarkable advances inNGS (including single cell sequencing),

liquid biopsy technology, computational biology methods andalgorithms, and high-throughput functional screening are trans-forming cancer prevention through the inter-related fields of pre-cision medicine and immune oncology. These extraordinary toolsprovide unprecedented opportunities to interrogate the biology ofpremalignancy, including site-specific genomic events that initiateacascade of genetic and epigenetic changes and an inflammatory(increasingly immunosuppressive) TME, driving premalignantprogression to cancer. These studies are identifying driver muta-tions in the blood of patients with epithelial premalignant lesions(11) and premalignant states for blood cancer (23, 24) and areproviding molecular targets for prevention (including vaccines)and early detection, including a bronchial airway genomic classifiervalidated for lung cancer (49) and promising leads for pancreatic,liver, and ovarian cancer (43, 44, 46, 47). Prostaglandin pathwaystudies may help personalize standard aspirin CRC prevention(34–38) and possibly other agents targeting this pathway such asiloprost, the most promising lung cancer chemopreventive agent





based onpositive phase II RCT (95). Study of the biology of tumorsthat develop in individuals carrying predisposition mutations hasled to recent paradigm-changing therapy (e.g., PARP and immunecheckpoint inhibitors in BRCA carriers and LS; refs. 55, 58, 96) andprevention (e.g., chemoprevention, screening, and vaccines in LSand FAP; refs. 53, 54, 56, 86, 87). Clinical success of HPV vaccinesfor cancer prevention (including encouraging RCT data supportingsingle-dose prophylactic vaccine [66, 67] and therapeutic vaccinefor cervical premalignancy [69]) and checkpoint inhibitors forcancer therapy has generated tremendous enthusiasm for immu-noprevention, including developing vaccines targeting premalig-nant genetic drivers (EGFR, Kras, andHrasmutations; refs. 76–78).Targeting the TME has shown promise in GEM models, includingarresting progression of intraepithelial neoplasia (97) and as adju-vants for non-viral vaccines (98). Potential vaccine adjuvantsinclude repurposed drugs (aspirin and metformin; refs. 81, 82,85, 98) and new agents under development (e.g., epigeneticregulators). Even tamoxifen (FDA-approved for breast cancer pre-vention) was just shown to have striking off-target immune effects(99). Finally, studies of microbiome effects on inflammatory andimmune mechanisms influencing cancer development are also

providing novel insights into and directions for cancer prevention(100, 101). Just as precision therapy and immunotherapy aretransforming cancer treatment, precision medicine and immuno-prevention approaches are being translated to the clinic and show-ing great promise. We stand at the edge of a new frontier that willinclude comprehensively characterizing the molecular and cellularevents that drive premalignant progression (e.g., the PCGA). Thetechnology and science are evolving rapidly and herald a new era ofprecision medicine and immunoprevention in cancer preventionthat will require new paradigms for implementation into clinicalpractice.

AcknowledgmentsThe authors express their appreciation to Drs. Graham Colditz, Nora Disis,

Karen Emmons, Olivera Finn, Heather Hampel, Elizabeth Jaffee, Ki Hong, andBarry Kramer for helpful discussions.

Grant SupportThis work was supported in part by grant NIH/NCI P30 CA023100 28.

Published online January 7, 2016.

References1. Tomasetti C, Vogelstein B. Cancer risk: role of environment. Science

2015;6223:729–31.2. Wu S, Powers S, ZhuW, Hannun YA. Substantial contribution of extrinsic

risk factors to cancer development. Nature 2015; Dec 16. doi: 10.1038/nature16166. [Epub ahead of print].

3. Potter JD. The failure of cancer chemoprevention. Carcinogenesis2014;5:974–82.

4. Meyskens FL Jr, Mukhtar H, Rock CL, Cuzick J, Kensler TW, Yang CS, et al.Cancer prevention: obstacles, challenges and the road ahead. JNatl CancerInst 2015;108:djv309.

5. Maresso KC, Tsai KY, Brown PH, Szabo E, Lippman S,Hawk ET.Molecularcancer prevention: Current status and future directions. CA Cancer J Clin2015;5:345–83.

6. Bloom DE, Cafiero ET, Jan�e-Llopis E, Abrahams-Gessel S, BloomLR, Fathima S, et al. The global economic burden of non-com-municable diseases. Geneva (Switzerland): World EconomicForum; 2011.

7. Blackburn EM. Cancer Interception. Cancer Prev Res 2011;6:787–92.8. Herbst RS, Heymach JV, Lippman SM. Lung Cancer. N Engl J Med 2008;

13:1367–80.9. Nakachi I, Rice JL, Coldren CD, Edwards MG, Stearman RS, Glidewell SC,

et al. Application of SNP microarrays to the genome-wide analysis ofchromosomal instability in premalignant airway lesions. Cancer Prev Res2014;2:255–65.

10. Ooi AT, Gower AC, Zhang KX, Vick JL, Hong L, Nagao B, et al. Molecularprofiling of premalignant lesions in lung squamous cell carcinomasidentifies mechanisms involved in stepwise carcinogenesis. Cancer PrevRes 2014;5:487–95.

11. Izumchenko E, Chang X, Brait M, Fertig E, Kagohara LT, Bedi A, et al.Targeted sequencing reveals clonal genetic changes in the progression ofearly lung neoplasms and paired circulating DNA. Nat Commun2015;6:8258.

12. Tang X, Shigematsu H, Bekele BN, Roth JA, Minna JD, Hong WK, et al.EGFR tyrosine kinase domain mutations are detected in histologicallynormal respiratory epithelium in lung cancer patients. Cancer Res2005;17:7568–72.

13. Kadara H, Shen L, Fujimoto J, Saintigny P, Chow CW, Lang W, et al.Characterizing the molecular spatial and temporal field of injury in early-stage smoker non–small cell lung cancer patients after definitive surgeryby expression profiling. Cancer Prev Res 2013;6:8–17.

14. Gustafson AM, Soldi R, Anderlind C, ScholandMB, Qian J, Zhang X, et al.Airway PI3K pathway activation is an early and reversible event in lungcancer development. Sci Transl Med 2010;26:26ra25.

15. Shain AH, Yeh I, Kovalyshyn I, Sriharan A, Talevich E, Gagnon A, et al. TheGenetic evolution of melanoma from precursor lesions. N Engl J Med2015;20:1926–36.

16. Krauthammer M, Kong Y, Bacchiocchi A, Evans P, Pornputtapong N,Wu C, et al. Exome sequencing identifies recurrent mutations in NF1and RASopathy genes in sun-exposed melanomas. Nat Genet 2015;9:996–1002.

17. Rettig EM, Chung CH, Bishop JA, Howard JD, Sharma R, Li RJ, et al.Cleaved NOTCH1 expression pattern in head and neck squamous cellcarcinoma is associated with NOTCH1 mutation, HPV status, and high-risk features. Cancer Prev Res 2015;4:287–95.

18. Sakr RA, Schizas M, Carniello JV, Ng CK, Piscuoglio S, Giri D, et al.Targeted capture massively parallel sequencing analysis of LCISand invasive lobular cancer: repertoire of somatic genetic alterations andclonal relationships. Mol Oncol 2015; Nov 14. pii:S1574-7891(15)00200-8. doi: 10.1016/j.molonc.2015.11.001. [Epub ahead of print].

19. Permuth-Wey J, ChenDT, FulpWJ, Yoder SJ, Zhang Y, Georgeades C, et al.Plasma MicroRNAs as Novel Biomarkers for Patients with IntraductalPapillary Mucinous Neoplasms of the Pancreas. Cancer Prev Res 2015;9:826–34.

20. StachlerMD, Taylor-Weiner A, Peng S,McKenna A, Agoston AT,Odze RD,et al. Paired exome analysis of Barrett's esophagus and adenocarcinoma.Nat Genet 2015;9:1047–55.

21. Campbell J, Mazzilli S, Reid M, Platero S, Beane J, Spira A. The case for aPreCancer Genome Atlas (PCGA). Cancer Prev Res 2016;2 (in press).

22. Jaiswal S, Fontanillas P, Flannick J, Manning A, Grauman PV, Mar BG,et al. Age-related clonal hematopoiesis associated with adverse outcomes.N Engl J Med 2014;26:2488–98.

23. Steensma DP, Bejar R, Jaiswal S, Lindsley RC, Sekeres MA, Hasserjian RP,et al. Clonal hematopoiesis of indeterminate potential and its distinctionfrom myelodysplastic syndromes. Blood 2015;1:9–16.

24. Kwok B, Hall JM, Witte JS, Xu Y, Reddy P, Lin K, et al. MDS-associatedsomatic mutations and clonal hematopoiesis are common in idiopathiccytopenias of undetermined significance. Blood 2015;21:2355–61.

25. Yoshizato T, Dumitriu B, Hosokawa K, Makishima H, Yoshida K, Towns-ley D, et al. Somatic mutations and clonal hematopoiesis in aplasticanemia. N Engl J Med 2015;1:35–47.

26. Wong TN, Ramsingh G, Young AL. Role of TP53 mutations in the originand evolution of therapy-related acute myeloid leukaemia. Nature2015;7540:552–5.

27. Cargo CA, Rowbotham N, Evans PA, Barrans SL, Bowen DT, Crouch S,et al. Targeted sequencing identifies patients with preclinical MDS at highrisk of disease progression. Blood 2015;21:2362–5.


Kensler et al.



28. Dhodapkar MV, Sexton R Prospective analysis of antigen-specific immu-nity, stem-cell antigens, and immune checkpoints in monoclonal gam-mopathy. Blood 2015;22:2475–8.

29. Chen AC, Martin AJ, Choy B, Fern�andez-Pe~nas P, Dalziell RA, McKenzieCA, et al. A Phase 3 Randomized Trial of Nicotinamide for Skin-CancerChemoprevention. N Engl J Med 2015;17:1618–26.

30. Baron JA, Barry EL, Mott LA, Rees JR, Sandler RS, Snover DC, et al. A trialof calcium and vitamin D for the prevention of colorectal adenomas.N Engl J Med 2015;16:1519–30.

31. Yarosh D, Klein J, O’Connor A, Hawk J, Rafal E, Wolf P. Effect of topicallyapplied T4 endonuclease V in liposomes on skin cancer in xerodermapigmentosum: a randomised study. Xeroderma Pigmentosum StudyGroup. Lancet 2001;9260:925–9.

32. William WN Jr,Papadimitrakopoulou V, Lee JJ, Mao L, Cohen EE, LinHY, et al. Erlotinib and the risk of oral cancer: the erlotinib preventionof oral cancer (EPOC) randomized clinical trial. JAMA Oncol 2015;5:1–8.

33. Bauman JE,Grandis J.Oral cancer chemoprevention-the endof EPOC, thebeginning of an epoch of molecular selection. JAMA Oncol. 2015;10.1001/ jamaoncol. 2015.4637:1–2.

34. Chubak J, Kamineni A, BuistDSM,AndersonML,Whitlock EP. Aspirin usefor the prevention of colorectal cancer: an updated systematic evidencereview for the U.S. Preventive Services Task Force. Rockville (MD): Agencyfor Healthcare Research and Quality; 2015

35. Bezawada N, Song M, Wu K, Mehta RS, Milne GL, Ogino S, et al. UrinaryPGE-M levels are associated with risk of colorectal adenomas and che-mopreventive response to anti-inflammatory drugs. Cancer Prev Res2014;7:758–65.

36. Fink SP, Yamauchi M, Nishihara R, Jung S, Kuchiba A, Wu K, et al. Aspirinand the risk of colorectal cancer in relation to the expression of 15-hydroxyprostaglandin dehydrogenase (HPGD). Sci Transl Med 2014;6:233re2.

37. NanH, Hutter CM, Lin Y, Jacobs EJ, Ulrich CM,White E, et al. Associationof aspirin and NSAID use with risk of colorectal cancer according togenetic variants. JAMA 2015;313:1133–42.

38. Guda K, Fink SP, Milne GL, Molyneaux N, Ravi L, Lewis SM, et al.Inactivating mutation in the prostaglandin transporter gene, SLCO2A1,associated with familial digital clubbing, colon neoplasia, and NSAIDresistance. Cancer Prev Res 2014;8:805–12.

39. Holla VR, Backlund MG, Yang P, Newman RA, DuBois RN. Regulation ofprostaglandin transporters in colorectal neoplasia. Cancer Prev Res2008;2:93–9.

40. Liao X, Lochhead P, Nishihara R,Morikawa T, Kuchiba A, Yamauchi M,et al. Aspirin use, tumor PIK3CAmutation, and colorectal-cancer survival.N Engl J Med 2012;17:1596–606.

41. Zhao LN, Li JY, Yu T, Chen GC, Yuan YH, Chen QK. 5-Aminosalicylatesreduce the risk of colorectal neoplasia in patientswith ulcerative colitis: anupdated meta-analysis. PLoS One 2014;4:e94208.

42. Doycheva I, Cui J, Nguyen P, Costa EA, Hooker J, Hofflich H, et al.Non-invasive screening of diabetics in primary care for NAFLD andadvanced fibrosis by MRI and MRE. Aliment Pharmacol Ther 2016;1:83–95.

43. Farrar CT, DePeralta DK, Day H, Rietz TA, Wei L, Lauwers GY,et al. 3D molecular MR imaging of liver fibrosis and response torapamycin therapy in a bile duct ligation rat model. J Hepatol 2015;3:689–96.

44. Gorden DL, Myers DS, Ivanova PT, Fahy E, Maurya MR, Gupta S, et al.Biomarkers ofNAFLDprogression: a lipidomics approach to an epidemic.J Lipid Res 2015;3:722–36.

45. Neuschwander-Tetri BA, Loomba R, Sanyal AJ, Lavine JE, Van NattaML, Abdelmalek MF, et al. Farnesoid X nuclear receptor ligand obeti-cholic acid for non-cirrhotic, non-alcoholic steatohepatitis (FLINT): amulticentre, randomised, placebo-controlled trial. Lancet 2015;9972:956–65.

46. Sausen M, Phallen J, Adleff V, Jones S, Leary RJ, Barrett MT, et al. Clinicalimplications of genomic alterations in the tumour and circulation ofpancreatic cancer patients. Nat Commun 2015;6:7686.

47. Barrett CL, DeBoever C, Jepsen K, Saenz CC, Carson DA, Frazer KA.Systematic transcriptome analysis reveals tumor-specific isoforms forovarian cancer diagnosis and therapy. Proc Natl Acad Sci U S A2015;23:E3050–7.

48. Imperiale TF, Ransohoff DF, Itzkowitz SH.Multitarget stool DNA testingfor colorectal-cancer screening. N Engl J Med 2014;2:187–8.

49. Silvestri GA, Vachani A,Whitney D, Elashoff M, Porta Smith K, FergusonJS, et al. A bronchial genomic classifier for the diagnostic evaluation oflung cancer. N Engl J Med 2015;3:243–51.

50. Rahman N. Realizing the promise of cancer predisposition genes. Nature2014;7483:302–8.

51. Zhang J, Walsh MF, Wu G, Edmonson MN, Gruber TA, Easton J, et al.Germline mutations in predisposition genes in pediatric cancer. N Engl JMed 2015;24:2336–46.

52. Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al.Screening for the Lynch syndrome (hereditary nonpolyposis colorectalcancer). N Eng J Med 2005;18:1851–60.

53. Syngal S, Brand RE, Church JM,Giardiello FM,Hampel HL, Burt RW, et al.ACG clinical guideline: genetic testing and management of hereditarygastrointestinal cancer syndromes. Am J Gastroenterol 2015;2:223–62.

54. Burn J, Gerdes AM, Macrae F, Mecklin JP, Moeslein G, Olschwang S, et al.Long-term effect of aspirin on cancer risk in carriers of hereditary colo-rectal cancer: an analysis from the CAPP2 randomised controlled trial.Lancet 2011;9809:2081–7.

55. Le DT, Uram JN, Wang H, Bartlett BR, Kemberling H, Eyring AD, et al.PD-1 blockade in tumors with mismatch-repair deficiency. N Engl J Med2015;26:2509–20.

56. Samadder NJ, Neklason D, Kanth P, Byrne KR, Samowitz W, Jasperson K,et al. Effect of COX and EGFR inhibition on duodenal neoplasia infamilial adenomatous polyposis: a randomized placebo-controlled trial.Gastroenterology 2015;4:S93–4.

57. Burn J, BishopDT, Chapman PD, Elliott F, Bertario L, DunlopMG, et al. Arandomized placebo-controlled prevention trial of aspirin and/orresistant starch in young people with familial adenomatous polyposis.Cancer Prev Res 2011;5:655–65.

58. Kaufman B, Shapira-Frommer R, Schmutzler RK, Audeh MW,Friedlander M, Balmaña J, et al. Olaparib monotherapy in patientswith advanced cancer and a germline BRCA1/2 mutation. J Clin Oncol2015;3:244–50.

59. Phillips KA, Milne RL, Rookus MA, Daly MB, Antoniou AC, Peock S, et al.Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2mutation carriers. J Clin Oncol 2013;25:3091–9.

60. Couch FJ, Wang X, McGuffog L, Lee A, Olswold C, Kuchenbaecker KB,et al. Genome-wide association study in BRCA1 mutation carriers iden-tifies novel loci associated with breast and ovarian cancer risk. PLoSGenet2013;9:e1003212.

61. Smetsers SE, Velleuer E, Dietrich R, Wu T, Brink A, Buijze M, et al.Noninvasive molecular screening for oral precancer in Fanconi anemiapatients. Cancer Prev Res 2015;11:1102–11.

62. Chiang CJ, Yang YW, You SL, Lai MS, Chen CJ. Thirty-year outcomes ofthe national hepatitis B immunization program in Taiwan. JAMA 2013;9:974–6.

63. KaneM. Preventing cancer with vaccines: progress in the global control ofcancer. Cancer Prev Res 2012;1:24–9.

64. Lowy DR, Schiller JT. Reducing HPV-associated cancer globally. CancerPrev Res 2012;1:18–23.

65. Herrero R, Gonz�alez P, Markowitz LE. Present status of human papillo-mavirus vaccine development and implementation. Lancet Oncol2015;5:e206–16.

66. Safaeian M, Porras C, Pan Y, Kreimer A, Schiller JT, Gonzalez P, et al.Durable antibody responses following one dose of the bivalent humanpapillomavirus L1 virus-like particle vaccine in the Costa Rica vaccinetrial. Cancer Prev Res 2013;11:1242–50.

67. Sankaranarayanan R, Prabhu PR, Pawlita M, Gheit T, Bhatla N, MuwongeR, et al. Immunogenicity and HPV infection after one, two, and threedoses of quadrivalent HPV vaccine in girls in India: a multicentre pro-spective cohort study. Lancet Oncol 2015, doi.org/10.1016/ S1470-2045(15)00414-3.

68. Kenter GG1, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der MeerDM, Vloon AP, et al. Vaccination against HPV-16 oncoproteins for vulvarintraepithelial neoplasia. N Engl J Med 2009;19:1838–47.

69. Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J, et al.Safety, efficacy, and immunogenicity of VGX-3100, a therapeutic syn-thetic DNA vaccine targeting human papillomavirus 16 and 18 E6 and E7proteins for cervical intraepithelial neoplasia 2/3: a randomised, double-





blind, placebo-controlledphase 2b trial. Lancet. 2015 Sep16 [Epub aheadof print].

70. Gillison ML, Chaturvedi AK, Anderson WF, Fakhry C. Epidemiology ofHuman Papillomavirus-Positive Head and Neck Squamous Cell Carci-noma. J Clin Oncol 2015;29:3235–42.

71. Fakhry C, Rosenthal BT, ClarkDP, GillisonML. Associations between oralHPV16 infection and cytopathology: evaluation of an oropharyngeal"pap-test equivalent" in high-risk populations. Cancer Prev Res 2011;9:1378–84.

72. Fahkry C, Andersen KK, Christensen J, Agrawal N, Eisele DW. Theimpact of tonsillectomy upon the risk of oropharyngeal carcinomadiagnosis and prognosis in the Danish cancer registry. Cancer Prev Res2015;7:583–9.

73. Settle K, Posner MR, Schumaker LM, Tan M, Suntharalingam MM,Goloubeva O, et al. Racial survival disparity in head and neck cancerresults from low prevalence of human papillomavirus infection in blackoropharyngeal cancer patients. Cancer Prev Res 2009;2:776–81.

74. Zandberg DP, Liu S, Goloubeva OG, Schumaker LM, Cullen KJ. Emer-gence of HPV16-positive oropharyngeal cancer in Black patients overtime: University of Maryland 1992–2007. Cancer Prev Res 2015;1:12–9.

75. Pierce Campbell CM, Kreimer AR, Lin HY, FulpW, O'KeefeMT, Ingles DJ,et al. Long-term persistence of oral human papillomavirus type 16: theHPV Infection in Men (HIM) study. Cancer Prev Res 2015;3:190–6.

76. Nasti TH, Rudemiller KJ, Cochran JB, Kim HK, Tsuruta Y, Fineberg NS,et al. Immunoprevention of chemical carcinogenesis through earlyrecognition of oncogene mutations. J Immunol 2015;6:2683–95.

77. Keenan BP, Saenger Y, Kafrouni MI, Leubner A, Lauer P, Maitra A, et al. AListeria vaccine and depletion of T-regulatory cells activate immunityagainst early stage pancreatic intraepithelial neoplasms and prolongsurvival of mice. Gastroenterology 2014;7:1784–94.

78. Ebben JD, Lubet RA, Gad E, Disis ML, You M. Epidermal growth factorreceptor derived peptide vaccination to prevent lung adenocarcinomaformation: an in vivo study in a murine model of EGFR mutant lungcancer. Mol Carcinog 2015 Sep 7. doi: 10.1002/mc.22405. [Epubahead of print].

79. Cancer Research UK. Challenge 1: prevention vaccines; 2015 [cited 2015Dec 2] Available from: https://www.cancerresearchuk.org/funding-for-researchers/how-we-deliver-research/grand-challenge-award/chal-lenge1?wssl¼1

80. Kimura T, McKolanis JR, Dzubinski LA, Islam K, Potter DM, Salazar AM,et al. MUC1 vaccine for individuals with advanced adenoma of the colon:a cancer immunoprevention feasibility study. Cancer Prev Res 2013;1:18–25.

81. Zelenay S, van der Veen AG, Bottcher JP, Snelgrove KJ, Rogers N, Acton SE,et al. Cyclooxygenase-dependent tumor growth through evasion ofimmunity. Cell 2015;162:1257–70.

82. Yue W, Yang CS, DiPaola RS, Tan XL. Repurposing of metformin andaspirin by targeting AMPK-mTORand inflammation for pancreatic cancerprevention and treatment. Cancer Prev Res 2014;7:388–97.

83. Disis ML, Gad E, Herendeen DR, Lai VP, Park KH, Cecil DL, et al. Amultiantigen vaccine targeting neu, IGFBP-2, and IGF-IR prevents tumorprogression in mice with preinvasive breast disease. Cancer Prev Res2013;12:1273–82.

84. Broussard EK, Kim R, Wiley JC, Marquez JP, Annis JE, Pritchard D, et al.Identification of putative immunologic targets for colon cancer preven-

tionbased on conserved gene upregulation frompreinvasive tomalignantlesions. Cancer Prev Res 2013;7:666–74.

85. Marzbani E, Inatsuka C, Lu H, Disis ML. The invisible arm of immunityin common cancer chemoprevention agents. Cancer Prev Res 2013;8:764–73.

86. Rech AJ, Mick R, Martin S, Recio A, Aqui NA, Powell DJ Jr, et al. CD25blockade depletes and selectively reprograms regulatory T cells in concertwith immunotherapy in cancer patients. Sci Transl Med 2012;134:134ra62.

87. von Knebel Doeberitz M, KloorM. Towards a vaccine to prevent cancer inLynch syndrome patients. Familial Cancer 2013;2:307–12.

88. Colditz GA, Wolin KY, Gehlert S. Applying what we know to acceleratecancer prevention. Sci Transl Med 2012;127:127rv4.

89. DeSantis CE, Fedewa SA, Goding Sauer A, Kramer JL, Smith RA, Jemal A.Breast cancer statistics, 2015: Convergence of incidence rates betweenblack and white women. CA Cancer J Clin 2015; Oct 29. doi: 10.3322/caac.21320. [Epub ahead of print].

90. Neta G, Sanchez MA, Chambers DA, Phillips SM, Leyva B, Cynkin L, et al.Implementation science in cancer prevention and control: a decade ofgrant funding by the National Cancer Institute and future directions.Implement Sci 2015;10:4.

91. Vogel VG,Costantino JP,WickerhamDL,CroninWM,Cecchini RS, AtkinsJN, et al. Update of the national surgical adjuvant breast and bowel projectstudy of tamoxifen and raloxifene (STAR) P-2 trial: preventing breastcancer. Cancer Prev Res 2010;6:696–706.

92. Hartmann LC, Degnim AC, Dupont WD. Atypical hyperplasia of thebreast. N Engl J Med 2015;13:1271–2.

93. Moss JL, Reiter PL, Brewer NT. Correlates of human papillomavirusvaccine coverage: a state-level analysis. Sex Transm Dis 2015;42:71–75.

94. Sivaram S, Sanchez MA, Rimer BK, Samet JM, Glasgow RE. Implemen-tation science in cancer prevention and control: a framework for researchand programs in low- and middle-income countries. Cancer EpidemiolBiomarkers Prev 2014;11:2273–84.

95. Keith RL, Blatchford PJ, Kittelson J, Minna JD, Kelly K, Massion PP, et al.Oral iloprost improves endobronchial dysplasia in former smokers.Cancer Prev Res 2011;6:793–802.

96. Higuchi T, Flies DB, Marjon NA, Mantia-Smaldone G, Ronner L, GimottyPA, et al. CTLA-4 Blockade Synergizes Therapeutically with PARP Inhi-bition in BRCA1-Deficient Ovarian Cancer. Cancer Immunol Res 2015;11:1257–68.

97. Wang G, Lu X, Dey P, Deng P, Wu CC, Jiang S, et al. Targeting YAP-DependentMDSC Infiltration Impairs Tumor Progression. Cancer Discov2016;1:1–16.

98. Chu NJ, Armstrong TD, Jaffee EM. Nonviral oncogenic antigens and theinflammatory signals driving early cancer development as targets forcancer immunoprevention. Clin Cancer Res 2015;7:1549–57.

99. Corriden R, Hollands A, Olson J, Derieux J, Lopez J, Chang JT, et al.Tamoxifen augments the innate immune function of neutrophilsthrough modulation of intracellular ceramide. Nat Commun 2015;6:8369.

100. Lévy J, Cacheux W, Bara MA, L'Hermitte A, Lepage P, Fraudeau M, et al.Intestinal inhibition of Atg7 prevents tumour initiation through a micro-biome-influenced immune response and suppresses tumour growth. NatCell Biol 2015;8:1062–73.

101. Garrett WS. Cancer and the microbiota. Science 2015;6230:80–6.


Kensler et al.



2016;9:2-10. Cancer Prev Res Thomas W. Kensler, Avrum Spira, Judy E. Garber, et al. Immune-oncologyTransforming Cancer Prevention through Precision Medicine and

Updated version

http://cancerpreventionresearch.aacrjournals.org/content/9/1/2

Access the most recent version of this article at:

Cited articles

http://cancerpreventionresearch.aacrjournals.org/content/9/1/2.full#ref-list-1

This article cites 88 articles, 5 of which you can access for free at:

Citing articles

http://cancerpreventionresearch.aacrjournals.org/content/9/1/2.full#related-urls

This article has been cited by 18 HighWire-hosted articles. Access the articles at:

E-mail alerts related to this article or journal.Sign up to receive free email-alerts

Subscriptions

Reprints and

[email protected]

To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at

Permissions

Rightslink site. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC)

.http://cancerpreventionresearch.aacrjournals.org/content/9/1/2To request permission to re-use all or part of this article, use this link



http://cancerpreventionresearch.aacrjournals.org/content/9/1/2.full#ref-list-1

http://cancerpreventionresearch.aacrjournals.org/content/9/1/2.full#related-urls

http://cancerpreventionresearch.aacrjournals.org/cgi/alerts

mailto:[email protected]



Documents

Special Report - Cancer Prevention Research · Remarkable progress in precision medicine and immune-oncology, driven by extraordinary recent advances in genome-wide sequencing,