Personalized Medicine: Challenge and Promise

Judith Salmon Kaur & Daniel G. Petereit

Published online: 9 March 2012# Springer Science+Business Media, LLC 2012

Abstract The new health care buzz words include “person-alized or individualizedmedicine.” Populations such as Amer-ican Indians and Alaska Natives potentially have much to gainfrom this new science to overcome the known health dispar-ities in these populations. This will require participation andacceptance of diverse populations. This article reviews thepromise and challenges of individualizing cancer care usingprinciples of community-based participatory research.

Keywords American Indian . CBPR . Genotype .

Cancer health disparities

Introduction

The new health care buzz words are “personalized medi-cine” or “individualized medicine.” Ever since the completehuman genome sequence was published 10 years ago, therehas been great hope that genomic sciences will provideways to optimize medical care [1]. Populations such as

American Indians and Alaska Natives (AIAN) could havemuch to gain from this new science to overcome the knownhealth disparities present in these populations. Cancer iscertainly a ripe area for this type of research, but so far,there has been little education or inclusion of AIAN patients,clinicians caring for them, nor policy makers within the Indianhealth system in this effort.

In the past decade, the National Cancer Institute (NCI) hascommissioned a specific branch, the Center to Reduce CancerHealth Disparities (CRCHD), dedicated to community-basedparticipatory research and evidence-based medicine to over-come these disparities. The CRCHD coordinates and strength-ens the NCI cancer research portfolio in basic, clinical,translational, and population-based research to address cancerhealth disparities. One program within CRCHD is the Com-munity Networks Program (CNP) which supports outreach tominority and other underserved communities across the coun-try. Many of these CNPs are partnering with NCI on programssuch as GMaP and BMaP described below.

GMaP and BMaP

State of the art medicine today acknowledges that “one sizedoesn’t fit all” and that approximately 30% of all medica-tions either do not work or are too toxic for certain individ-uals [2]. Potentially, minority populations would have themost to gain from understanding these issues because theyare more likely to have individuals with genetic variantsmodifying drug metabolism or function. NCI has fundedAdministrative Supplements for Minority Biospecimens/Biobanking—Geographic Management Programs dedicatedto ensuring the adequate and continuous supply of high-quality human biospecimens from multi-ethnic communities

J. S. Kaur (*)Mayo Clinic Comprehensive Cancer Center,200 First Street SW,Rochester, MN 55905, USAe-mail: Kaur.judith@mayo.edu

D. G. PetereitDepartment of Radiation Oncology, John T. Vucurevich CancerCare Institute, Rapid City Regional Hospital,Rapid City, SD 57701, USAe-mail: dpetereit@regionalhealth.com

D. G. PetereitDepartment of Human Oncology,University of Wisconsin School of Medicine and Public Health,Madison, WI, USA

J Canc Educ (2012) 27 (Suppl 1):S12–S17DOI 10.1007/s13187-012-0322-7

for cancer research. The plan is to create regional networksfocused on cancer health disparities research and care.

However, so far minority communities have not beendirectly involved with these regional hubs, which are inthe early stages of development. Finding the targets fordetection, therapy, and prevention involves the nascentfields of genomics, proteomics, and metabolomics, all ofwhich depend on high-quality biospecimens. Even underideal circumstances, it will likely take years of research toidentify the genetic contribution for most common diseases.Genomic technology has dramatically outpaced understand-ing of human genetics and our ability to conduct the publiceducation necessary to enlighten consumers of this newtechnology. There are significant difficulties inherent to mean-ingful clinical application of such information [3]. The generalpublic has maintained hope while expressing frustration thatdespite very substantial investment and effort over the past30 years, the overall survival rate of cancer patients haschanged little [4]. Certainly, most ethnic and racially diversecancer patients, who suffer excessmorbidity andmortality froma variety of cancers, have doubts as to the relevance of cancerresearch and clinical trials to improving their well-being.

As stated by McGuire et al. in Science, “relating genotypeto phenotype is the challenge for genetic medicine over thenext century” [4]. Scientists argue that without a truly robust

mechanism for selecting the right treatment for the rightpatient at the right time—the central concepts of personalizedmedicine—we will continue to see only incremental improve-ments and have little hope for substantial survival gains.Future clinical trials are now being designed with a plan toincorporate biomarker development [5]. Figure 1 shows thecurrent GMaP program and components. Table 1 shows thepotential benefits of the GMaP project to researchers andfederal partners in the research enterprise.

The missing essential component is to identify commu-nity priorities, develop trust, and implement culturally accept-able interventions. Potentially, the community and communitymembers will benefit from identifying the most effective treat-ments with the fewest side effects for each patient. If minoritycommunity members are not involved in this endeavor, how-ever, health disparities will only increase, not decrease.

Community-Based Participatory Research Examples

The Walking Forward Program (WFP) is a community-based participatory research study designed to enhanceAmerican Indian (AI) enrollment on cancer treatment trials.The WFP was initiated in September 2002 as an NCI-funded study under the Cancer Disparities and Research

Fig. 1 Current GMaP program and components

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Partnership program awarded to Rapid City RegionalHospital (RCRH)–PI D Petereit [6]. The WFP has beenimplemented on three AI reservations home to the CheyenneRiver Sioux Tribe, Rosebud Sioux Tribe, and the Oglala SiouxTribe, as well as the urban AI community in Rapid City, SouthDakota. These reservations also include three of the five poorestcounties (Todd, Shannon, and Ziebach counties) in the USA.AIs are about 8.5% of the South Dakota’s population (USCensus 2000), of which about 70,000 reside in the areas servedby the WFP. This project involves a genetic study to elucidatethe underlying genetic basis for the higher incidence ofradiation-induced toxicities anecdotally reported in some AIcancer patients undergoing radiation treatment—analysis of theataxia telangectasia mutated (ATM) gene (ATM−) [7]. Initialplanning included community and patient surveys identifiedbarriers to cancer care in this underserved population.

The high rates of cancer mortality in the AI communitiesappear, in part, to arise from the lack of cancer screening,knowledge regarding screening, consequences of presen-tation at a late disease stage and treatment options, aswell as socioeconomic factors. The WFP developed aregional research infrastructure, established trust withthe AI communities, [8], and implemented a patient naviga-tion program (Klewien B, Hamann S 2008; [8–12]). Theseactivities, in the near term, resulted in identification ofcommunity-specific barriers to cancer care and greater patientaccruals to clinical trials [13–15].

Since geographic remoteness from treatment centers andduration of a conventional course of radiation treatmentpresent significant challenges to AI patients [16], it washypothesized that these barriers might be lowered throughvarious programs tailored to this population. These included:patient navigation; treatment options and clinical trials offer-ing a shorter course of radiation via brachytherapy and/orintensity-modulated radiotherapy [17, 18]; and a comprehen-sive educational program encouraging screening and earlydetection. Treatment options that offer a shorter course ofradiation would be more attractive to AIs and potentially lead

to higher rates of completion of treatment and thus higher curerates. It was also postulated that cancer education in these AIcommunities would eventually lead to AI cancer patientsseeking treatments at early stages of the disease (stage migra-tion). The project initiated a study of the ATM gene to deter-mine if there is a correlation between radiation toxicities andATM heterozygosity, which over the long termwill help guidetherapy and symptom management strategies.

The WFP approach to enhancing accrual of AI patients toclinical trials is summarized in Fig. 2. The increased enroll-ment to clinical trials is the result of the comprehensivepatient navigation program that enhanced trust, increasedcancer screening and education, leading to detection andimmediate referral for treatment.

Table 1 Potential benefits of the GMaP project to researchers and federal partners

Researcher Federal partner

Better integrated and stronger research, training, and core programsacross regions

Increased leveraging of research dollars

Joint regional workshops to facilitate communication and disseminations More efficient program management:

• Joint site visits

• Standardized site visit reports

• Regional coordinating committees

Integration of GMaP/BMaP members into regional and community planningand decision-making processes for sustainability of CHD andbiospecimen/biobanking efforts

Joint concept development for new funding opportunities

Common metrics and evaluation of CHD and biospecimen science

CHD Cancer Health Disparities

Fig. 2 Walking Forward Program approach to enhance participation ofAI patients to clinical trials

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AIs appear to be hypersensitive to the effects of ionizingradiation. In a retrospective analysis of 61 AIs undergoingdefinitive radiotherapy at RCRH CCI, 50% of patientsexperienced grade 2 toxicities (G2) and 17% experiencedgrade 3 toxicities (G3). The majority of these toxicities wereskin reactions in patients with breast and colorectal cancer[13, 14]. This is manifested as a more severe skin reactionranging from a mild skin erythema to a patchy moistdesquamation with moderate edema eventually progressingto a confluent moist desquamation. Fear of this treatment-related side effect could potentially contribute to observedsignificant treatment delays in this patient population. In ananalysis from RCRH, 28% had delays >6 or more days, and15% had delays >11 days which could lead to compromisedtumor control [14, 19]. Homozygosity of mutations in ATMleads to extreme hypersensitivity to radiation [15, 16], whileheterozygosity may be associated with an increased risk fordeveloping cancer and radiation-induced toxicities [17]. Itwas postulated that studying the ATM gene in AIs wouldprovide a better understanding of the underlying molecularmechanism for the observed higher incidence of toxicities inthis population. Establishing a predictive molecular markercould help facilitate:

1. Accurate counseling of radiation side effects and treat-ment options.

2. Possible modification of the radiation treatment plan tominimize likely adverse effects.

3. If the presence of ATM does predispose AI to a higherincidence of cancer, then issues of education, screening,and lifestyle changes would be critical.

4. If a higher rate of ATM heterozygosity was observedamong the AI, genetic counseling would be a criticalpart of this study.

To date, 100 AIs (Rapid City) and 100 non-AIs (52 fromRapid City and 48 from UW–Madison) have participated inthe ATM study. A total of 25 single nucleotide polymor-phisms (SNPs) have been identified in 21 of 62 sequencedexons from 200 samples. Four of the variants have not beenreported in any of the current ATM databases, and are thuspotentially new variants. There was no statistically signifi-cant difference for total prevalence of SNPs among AI(40%) and non-AI (48%) patients (p00.32). Five SNPshad a prevalence of >2%, of which four occurred at a rateof >5% in one or both groups. The prevalence of these couldmeaningfully be compared statistically in the two groups.The only statistically significant difference among thegroups was the c.4138 C>T SNP seen in 8% of AI versus0% of non-AI patients (p00.007). However, this SNP ispredicted using the Polyphen software tool not to affectprotein function. The prevalence of those SNPs predictedto result in potentially deleterious missense mutations was

28% among non-AI and 18% among AI (p00.13). Of par-ticular interest is SNP c.5557 G>A, which had a prevalenceof 25% in non-AIs versus 14% in AIs (p00.07). Threehomozygous patients were identified for this SNP, all inthe non-AI group.

Analysis of toxicity data for the 200 patients enrolled in thistrial reveals that 53% have developed G2 acute toxicities, and18% G3. While the follow-up is relatively short, 16% havedeveloped G2 late toxicities, and 2% G3. Correlating the SNPdata with available patient toxicity data is underway andwill reveal any important SNPs that can be predictive ofradiosensitivity [20].

This program has two clear messages: (1) it is possible todo quality genetic research in an AIAN population as part ofan ongoing clinical trial and (2) the success of theprogram revolved around building trust and providingservices such as the Patient Navigator program so thatthe community could see direct benefit from the researchbeing offered.

The Havasupai Case

Biospecimen collection, annotation, and interpretationfor different diseases including cancer are increasing inthe hopes of gaining scientific understanding and im-provement in treatments available for patients. However,the use of biospecimens is fraught with many ethicalchallenges.

The general American public may have limited recogni-tion of a major suit by the Havasupai tribe against theArizona State University Board of Regents for alleged mis-use of research blood samples [21]. However, this issue isthe subject of continued discussions among tribes that havecollaborated in research or consider doing so in the future.

The Havasupai Tribe is made up of about 650 peoplewho mostly live in Supai Village, about 10 miles down ascenic side canyon of the Grand Canyon. The impoverishedcommunity is accessible only by helicopter or by a trail intothe Grand Canyon. Like many AIAN populations, theHavasupai tribal members had noted an increase indiabetes. The tribe earnestly requested help with thishealth disparity in 1989 and agreed to work with specificresearchers to provide blood and DNA. They understood thesamples would be used for collaborative research on diabetesonly. Samples drawn from Havasupai tribal members during1991–1994, however, were provided to other researcherswithout specific consent of individuals or the tribe. Specimenswere used to study other issues—some of which violatedtribal beliefs. When the tribe inadvertently learned that otherstudies had been done without their consent, they sued [22].The original suit in Arizona state court was thrown out on atechnicality, but the Arizona Court of Appeals reinstated the

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case. That Court of Appeals made a legal determination thatthe plaintiffs may have a privacy interest in their blood speci-mens. This was a new legal finding, that tribes mayhave privacy interests and can suffer “dignity harm.” Anegotiated out-of-court settlement was announced publicly onApril 21, 2010. The blood samples that had been the subject ofthe bitter lawsuit were restored to the tribe for proper burial onthe floor of the Grand Canyon (http://www.azcentral.com/arizonarepublic/local/articles/2010/04/22/20100422arizona-havasupai-tribe-regents-lawsuit.html).

Traditional Institutional Review Board standards revolvearound protecting individuals from harm, so this precedentmay have implications for future genetic research andbiospecimen collections involving tribal members [18, 23].Truly informed consent recognizes that different peoplehave different values and concerns. To enable eachindividual—and tribe—to make an informed decision, theresearcher must present information that is “understandable”(45 CFR§46.116, General Requirements for InformedConsent). Researchers engaged with AIAN tribes should beaware of this case because tribes will be sensitized to researchutilizing stored biospecimens. On a positive note, theHavasupai still believe that research can be valuable totheir people and acknowledged ASU’s efforts to im-prove oversight and conduct of research. The settlement,after 6 years of acrimony, now allows the beginning ofa partnership between the universities in Arizona andthe tribe.

There are many implications of this court case. Havasupaitribe and members, and other AIAN tribes and members, arenot unique in believing they have a privacy interest in theproper future use of their specimens given for researchpurposes. A recent nested research project involved membersof Group Health of Seattle who had consented to store theirspecimens and data in NIH’s national database of Genotypeand Phenotype as part of their participation in a larger study. Asubgroup of 1,159 (86%) who had already signed informedconsent documents to send their specimens and data wereinterviewed about the importance and acceptability ofdifferent methods the parent study could have used to sendtheir specimens to a central repository. Of the 365 participantsinterviewed, 90% said it was important to have been asked toconsent first (69% “very important,” 21% “somewhat impor-tant”); 70% said it was unacceptable to have sent their speci-mens to a central repository without telling them or asking forpermission (54% “completely unacceptable,” 16% “some-what unacceptable”); 67% said it was unacceptable to haveonly informed them by letter that their specimens and data hadbeen sent—without consent or an “opt-out procedure” (47%“completely,” 20% “somewhat”) thus using specimens anddata without at least on “opt-out” procedure is unacceptablenot just tomost AIAN people but also probably tomost peoplein the USA.

Conclusions

Cancer research priorities are currently focused on morespecific biomarkers that can individualize patient treatmentsin the hopes of improving survival from cancer. The devel-opment of a national program which focuses on developingregional infrastructure to collect annotated biospecimens(GMaP) is going forward as a priority of the NationalCancer Institute. This will require acceptance and participa-tion from a diverse population to draw conclusions aboutresponse rates, toxicities, and outcomes for new cancertherapies. The Spirit of E.A.G.L.E.S. is a national Commu-nity Networks Program working with all AIAN populationson education, training, and research across the cancer carecontinuum. This and other CNPs, which advocate for acommunity-based participatory research model, must nowengage their respective communities if these regional net-works are to be successful in accessing an adequate andcontinuous supply of high-quality human biospecimens fromracially and ethnically diverse (and presumably geneticallydiverse) underserved communities. Dialogue has now begunon how to achieve positive results that will help overcomecancer health disparities.

Acknowledgment This study was supported in part by U54–CA153605 (Kaur) and RFA 1U56CA99010-01 (Petereit), and U01114609. This was also presented in part at the 8th Triennial ChangingCancer Patterns in Native Communities in Seattle, WA on September11–14, 2010. Changing Cancer Patterns in Native Communities Na-tional Conference.

Conflict of Interest The authors declare that they have no conflict ofinterest.

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