EGRP Hosts Workshop on Understudied Rare Cancers
Meeting Summary
 Session
Chair: Margaret R. Spitz, M.D., M.P.H.
Professor and Chair, Department of Epidemiology
The University of Texas M. D. Anderson Cancer Center
 Edward Trapido, Sc.D.
Associate Director, Epidemiology and Genetics Research Program (EGRP)
Division of Cancer Control and Population Science (DCCPS)
National Cancer Institute (NCI)
Dr. Trapido opened the meeting by describing how investigators were chosen
to attend the meeting. Attendees included EGRP-funded investigators working
on rare cancers, defined as cancers of organ sites with 40,000 or fewer cases
per year. The purpose of the meeting was to facilitate a broadening of EGRP’s
portfolio of research grants to include more understudied and rare cancers.
The following types of cancers are being addressed by this workshop, and
EGRP-funded investigators working on them were included:
- Brain and ocular cancer
- Oral cavity and pharynx cancer
- Head and neck cancer
- Endometrium, ovary, and testis cancer
- including cancers of the vulva,
vagina, and penis (no studies are currently funded on these cancers)
- excluding cervical cancer because the etiology is well understood
- Digestive and urinary systems cancer
- including esophagus, stomach, liver,
and kidney cancer
- also including small intestine, anus, gallbladder,
and ureter (no studies are currently funded on these cancers)
- Larynx,
bones, joints, soft tissues, thyroid, and other endocrine systems
- Non-Hodgkin’s lymphoma, which has more than 40,000 cases per year
but is understudied;
Hodgkin’s
disease; leukemia; myeloma; and Kaposi's sarcoma.
Pancreatic cancer was excluded for the purposes of this workshop because
a Program Announcement (PA) on the disease recently was issued, and another
funding opportunity is planned.
EGRP-funded investigators were asked to suggest the names of junior investigators,
who were also invited to the workshop to promote interest in the study of
rare cancers.
 Isis
S. Mikhail, M.D., M.P.H., Dr.P.H.
Program Director, Clinical and Genetic Epidemiology Research Branch (CGERB)
EGRP, DCCPS, NCI
Dr. Mikhail reported on a workshop, held at the 1st
NCI Epidemiology Leadership meeting, to gather input from NCI investigators on why and how best to study
rare cancers. The workshop focused on adult tumors. Rare adult cancers were
defined as those with an incidence of less than 15 per 100,000 or fewer than
40,000 cases per year.
Workshop participants indicated a number of reasons why the study of rare
cancers is worthwhile. As a group, rare cancers can have a large impact,
especially in certain populations. The total incidence from all rare tumors
is substantial, and rates of some have risen steadily over the last several
years (for example, esophageal cancer). Some rare cancers are highly lethal,
and those that occur at a young age result in significant years per life
lost. Some otherwise rare cancers occur disproportionately in specific ethnic
groups, such as male breast cancer in Zambians or nasopharyngeal cancer in
Asians.
In addition, the study of rare cancer etiology could improve our understanding
of all cancers. Some rare tumors tend to have a simpler etiology (for example,
retinoblastoma, angiosarcoma), which if understood might provide insight
into the etiology of common, more complex cancers. Family studies have shown
that some rare cancers tend to be heritable, thus perhaps shedding light
on genetic mechanisms. Also, the first study of a rare tumor is more likely
to give useful results than the 101st study of a more common and complex
tumor that has thus far proven intractable.
There are ethical reasons to study rare cancers as well. Rare tumors have
been given much less attention by the research community. Patients who have
rare cancers should not carry the burden of disease alone and should be allowed
some hope that a cure is in the future.
Workshop participants also addressed the question of how best to study rare
cancer etiology. Several methods were proposed, including the use of descriptive
data from the Surveillance, Epidemiology and End Results (SEER) Program,
the use of existing cohorts, and piggy-backing onto existing clinical trials.
Multiple existing cohorts, while modest in size individually, could be combined
to potentially identify moderate to strong risk factors. A potential caveat
would be whether or not questionnaire data and biospecimens had been collected
and, if they had, whether these materials would be obtainable. Existing clinical
trials have been used before to gather etiologic data on childhood cancers.
There is a potential for bias because clinical trial cases are likely to
have the worst prognosis. Workshop participants noted that we cannot afford
to be overly fastidious in studying rare cancers as strong apparent risk
factors should be robust to small biases. Dr. Mikhail urged researchers to
stay “open minded” about this approach.
The participants also highlighted the importance of new studies that could
be designed to address specific hypotheses, to generate fresh samples for
use in phenotypic assays, or to allow molecular characterization of subgroups
within a specific rare cancer type. These new studies could be integrated
with prognosis and treatment studies, and pool baseline data from multiple
rare tumor types. The studies could be simplified by creating a common rare
tumor protocol, including a single questionnaire and a common biospecimen
collection protocol. Participants recommended that such studies be hospital-based
since “that’s where the money is.”
Dr. Mikhail concluded by noting that both the use of existing cohorts and
clinical trials, and the design of new studies will depend on building partnerships
among researchers, along with a supportive infrastructure for collaboration.
Workshop participants proposed that NCI set aside supplemental funds to explore
the feasibility of using the NCI-designated Comprehensive
Cancer Centers to facilitate such partnerships.
 Benjamin
F. Hankey, Sc.D.
Chief, Cancer Statistics Branch (CSB)
Surveillance Research Program (SRP), DCCPS, NCI
The next two speakers described how tumor registries could be used to advance
study of rare cancers. Dr. Hankey provided a series of tables and graphs
showing statistics on rare cancers from the SEER database. The tables and
graphs, which showed incidence rates, mortality rates, trends, survival data,
and other statistics were intended for use in the working group sessions
if needed.
In addition to statistical data, Dr. Hankey described a number of services
that SEER provides. Researchers can access SEER’s public-use file through
the Internet, along with software tools that can facilitate their own statistical
analyses. For example, SEER software can be used to calculate different types
of survival rates, including crude, net, observed, and relative. It can be
used to calculate frequencies, incidence rates, and prevalence. Such tools
might be useful for generating etiologic hypotheses. Researchers who do not
have time to learn how to use the tools can also ask the SEER staff to perform
desired analyses.
Two main Web sites give researchers access to SEER cancer data and statistical
tools:
- The SEER Program at the Cancer
Statistics Branch: Contains the SEER public-use file, SEER statistics
tutorials, and cancer statistics.
- The Statistical Research and Applications
Branch: Contains software tools, such as CancerServ, for cancer survival
analysis; CompPrev, for prevalence analysis; and DevCam, for calculating
the probability of developing or dying of cancer.
SEER’s data and advanced statistical tools might be especially valuable
for the study of rare cancers, Dr. Hankey said.
 Holly L. Howe, Ph.D.
Executive Director
North American Association of Central Cancer Registries
In a presentation on population-based cancer registries, Dr. Howe described
the work of the North American Association of Central Cancer Registries (NAACCR),
an umbrella organization of all cancer registries and surveillance programs
in the United States and Canada. NAACCR defines standards for data collection
and incidence statistics, trains registration professionals on these standards,
certifies registries achieving high data quality, releases an annual statistical
monograph, conducts population-based cancer research and surveillance, and
promotes the use of population-based cancer incidence data in cancer research
conducted by others.
Dr. Howe revisited the question of rare cancer definition. She suggested
that no standard definition exists and many are used: cancers with rare organ/histology
combinations; rare subtypes of common cancers (for example, inflammatory
breast cancer); and rare, exposure-related cancers, such as mesothelioma.
She also noted that some cancers are only rare in specific age groups or
populations. She suggested that a rare cancer might also be defined as an
orphan cancer, one with no support, no advocates, and no population-based
information. Without a standard definition, studies on rare tumors will not
be compatible and surveillance statistics used for directing research of
rare tumors will also be inconsistent.
In addition to definition, registries face other challenges in registering
rare cancers. There are questions about the validity of diagnosis. If a cancer
appears to be very rare in a given data set, is it due to reporting or coding
errors or inconsistency in pathology interpretation? These errors will affect
statistics for rare cancers, and even the definition of a rare cancer itself.
Dr. Howe presented rare cancer data from the NAACCR Cancer in North America
(CINA) aggregated data set, from seven Canadian provinces, 42 U.S. States,
and Washington, D.C. These data represent cancer cases from about 60 percent
of the U.S. population and one-third of the Canadian population. These data
tables can be used in the working group sessions, if needed, along with the
SEER data.
Her group is planning an overview paper of rare tumors in the NAACCR aggregated
data set that will first establish a rare tumor definition for inclusion
in the manuscript, a data quality assessment, and then provide some descriptive
statistics for all included sites. Rare tumors with sufficient numbers to
enable more detailed epidemiologic descriptions will be identified, and a
consortium will be convened to prepare a series of manuscripts that may be
compiled into a monograph on rare tumors.
Dr. Howe proposed that NAACCR could help rare tumor research by acting as
a coordinating center for a rapid case ascertainment network (RCAN), which
could include all registries in the U.S. and Canada. A NAACCR RCAN could
provide quality control for diagnoses, obtain patient consents, collect biospecimens,
and refer consented participants to investigators for interviews. This population-based
RCAN would promote consistency and efficiency among studies conducted in
various states and regions. The large number of cases and population-based
research capability that would be offered by an NAACCR RCA network should
be especially valuable for the study of rare tumors, she said.
 My
30-Year Love Affair with Hodgkin’s Lymphoma—Lessons Learned (slides
in pdf format)
 Nancy Mueller, Sc.D.
Professor, Department of Epidemiology
Harvard School of Public Health
In the keynote address, Dr. Mueller described her experiences studying the
rare cancer Hodgkin’s lymphoma (HL). Hodgkin’s is noted for a “perplexing” bimodal
U.S. age-incidence curve that peaks in young adulthood, around age 25, followed
by a drop in incidence and another peak after age 45. The young adult form
of HL is associated with higher socioeconomic status, a smaller number of
siblings, a more highly educated mother, and living in a single family home.
All of these factors can influence the age of first childhood infections,
which led to the hypothesis that young adult HL was associated with delayed
infection by a common oncogenic agent.
Epstein-Barr virus, or EBV, was the “prime candidate,” Dr. Mueller
said, because it is B-cell tropic, and HL is a malignancy of B cells. Moreover,
HL patients often showed an abnormal antibody profile against EBV at first
diagnosis, and multiple studies have shown that altered EBV antibody levels
can be present years before and after HL diagnosis.
But molecular evidence for an EBV-HL link was lacking. Such evidence was
difficult to obtain before the availability of molecular biology techniques
because very few cells in an involved HL lymph node are actually malignant.
The breakthrough came in 1989 with the demonstration of clonal EBV genomic
DNA in about 30 percent of HL cases. The presence of clonal DNA implied a
very early role in HL pathogenesis, but if EBV was central to HL pathogenesis, “Why
not 100 percent?” asked Dr. Mueller.
Epidemiologic data presented several other paradoxes. EBV-genome-positive
HL cases were primarily older adults, not the young adults the hypothesis
would have predicted. EBV-positive status was found to be associated with
poorer living conditions, greater age at diagnosis, and other factors that
lead to poorer immune response. These results led to the further hypothesis
that EBV starts the oncogenic process in all HL, but is “kicked out” in
patients with adequate immune function and thus no longer detectable.
In the 1990s Dr. Mueller obtained a program project grant to test this hypothesis.
The project included a population-based case-control study carried out by
her group, a cohort study on pre-diagnosis specimens, and functional immunologic
analyses on biosamples from EBV-positive and EBV-negative cases. This study
found no evidence that EBV was involved in EBV-negative HL cases. Moreover,
there appeared to be no difference in the susceptibility of younger EBV-negative
HL cases to late infections, including EBV. She has since concluded that
EBV-negative HL may be due to another, as yet unknown virus, with a similar
transmission pattern to EBV and a greater oncogenic potential in immune-competent
persons.
Dr. Mueller followed this summary of her HL research by describing what
she has learned about the rewards and pitfalls of studying a rare cancer.
While post-childhood HL is highly curable, she said, it remains a significant
health problem for survivors and an intriguing scientific problem. However,
because HL is so rare, she found few epidemiologists with whom to share data,
and few basic scientists interested in collaboration. Funding was also a
problem, as HL receives a low priority in peer review and attracts few advocates.
She also highlighted the need for academic scientists to diversify their
portfolio by doing parallel research on another disease, both to gain additional
perspective and to maintain a good publication record. She said that it took
a good 10 years for her case-control study to be completed, from the time
of application through data acquisition and analysis.
Dr. Mueller concluded her talk by saying that the reward of rare cancer
research lies in the opportunity to make a difference. “It’s
really a labor of love...you do it because you care,” she said.
At the conclusion of her talk, Dr. Mueller was honored with a certificate
of appreciation for her contributions to epidemiology. “Nancy has been
an important leader in the epidemiological community, both within NCI and
in the wider scientific community,” Dr. Trapido said.
Edward Trapido, Sc.D.
Associate Director, EGRP, DCCPS, NCI
Dr. Trapido closed this opening session by describing NCI’s mission
and how EGRP and the present meeting fit into that mission. He noted that
the NCI challenge goal to eliminate the suffering and death due to cancer
by 2015 is getting ever closer. “We have our work cut out for us,” he
said. One of NCI’s primary goals is a better understanding of gene/environment
interactions, part of the mandate of EGRP.
Within the context of NCI, Dr. Trapido emphasized that although there are
budget issues, NCI spends the bulk of its $6.17 billion budget on extramural
research projects led by individual investigators. Budget issues include
a lack of increases, institutional “taps” for new initiatives,
and out-year commitments for multiyear awards. These pressures have increased
appreciation for the value of resource sharing, leading to the current data
sharing policy. Despite these pressures, however, he noted that NCI still
receives “the lion’s share” of funding, and there is still
a lot money for extramural research.
EGRP’s research portfolio runs the gamut from understanding subcellular
mechanisms of cancer to health outcomes in cancer patients. EGRP also has
budgetary issues with respect to its approximately 500 grants. Pay lines
are tougher, grant proposals are more closely scrutinized, and consortia
are becoming increasingly attractive as a means of maximizing resources.
But even with these issues, Dr. Trapido emphasized that there are still many
opportunities for individual investigators, particularly in rare cancers.
The purpose of this meeting is to gather together research leaders to explore
the scientific issues, identify the common roadblocks, and update researchers
on the funding available for rare cancers. Junior scientists were invited
to give them a chance to learn from experienced NCI-funded scientists. In
turn, NCI leaders have been invited to gather suggestions about new approaches
to the study of rare cancers that might enable them to justify new programs
and funding opportunities.
Ultimately, said Dr. Trapido, these new approaches are likely to include
transdisciplinary research in areas like behavioral and survivorship studies.
He also suggested that increased use of the Specialized
Programs of Research Excellence (SPOREs) and the Comprehensive
Cancer Centers would be likely to play a role. “Reaching
out towards other people really is the name of the game” for more effective
research, he said.
NCI-Supported
Opportunities for Training and Career Development in Cancer Research
Lester S. Gorelic, Ph.D.
Program Director, Cancer Training Branch, Office of the Deputy Director for
Extramural Science (DES), NCI
In a special session for young investigators in the early stages of their
careers, Dr. Gorelic described the two major types of extramural funding
that are available from NCI: institutional grants (grants awarded to the
institution to which the applicant applies for funding) and individual grants
(applicant applies directly to the National Institutes of Health (NIH)/NCI,
and the award is made directly to the applicant).
STEPS IN THE GRANTS PROCESS: Dr. Gorelic stated that the first step in the
grant process is for a young investigator to assess what his/her career goals
are before initiating a search for extramural funding opportunities. For
example, individuals with a doctoral degree should determine what their research
focus in for the immediate future, where they currently are in their career
development, how much research experience they already have, and what their
strengths and deficiencies are. For clinicians, it is also necessary to determine
whether their research career will be patient- or laboratory-focused, or
whether they plan to pursue a career in translational research. It is also
important that they conduct an assessment of the proposed research environment
to determine the level of support for research career development including
sources of funding, availability of appropriate onsite mentors, opportunities
for collaboration and other resources including accessibility to patients.
For clinicians, it is also important to assess the institutional culture
as it relates to the support of clinical research versus clinical practice.
After formulating a career development plan, young investigators should
search for extramural funding from Federal sources, professional societies,
and foundations, and can do so by accessing their Web sites. Published compendia
and professional colleagues are also good sources of information. After selecting
potential funding sources, it is very important for individuals to identify
the appropriate contact person at the funding agency who can help determine
which program is the most appropriate for the applicant’s needs.
NIH/NCI FUNDING TRAINING OPPORTUNITIES: Dr. Gorelic then described 14 NIH
and NCI grant mechanisms that are appropriate for various stages in the career
track of young investigators and span the continuum from the earliest stages
of mentored career development awards to those awarded to established investigators.
- Institutional awards made directly to an institution include the
National Research Service Award (NRSA) T32 program, which provides research
training for those with very limited research experience as well as for
postdoctorals; the K12 award that provides funding for clinicians who wish
to conduct patient-oriented research; and the NCI R25T program, one of
the fastest growing segments in NCI’s grant portfolio, which supports
a research career development experience that is directly relevant to epidemiologists.
- Individual
awards include the F32 postdoctoral fellowships or career (K) awards
which can be mentored for individuals early in their research career development,
unmentored for individuals who are transitioning to their first independent
position or are within the first 2 years of a first independent research
position, or for established principal investigators who need protected
time to expand their own research programs and to mentor those of young
investigators.
Individuals who are early in their epidemiologic research careers should
consider the NIH F32, K08, or K23 awards, or the NCI K07, which is an award
specifically for individuals pursuing a career in cancer prevention, control,
behavioral, or population sciences research. The NCI K22 should be considered
by mentored individuals (Ph.D., health professional degree) who are pursuing
a research career in cancer prevention, control, behavioral, or population
sciences, or who have health professional degrees and are pursuing careers
in basic or patient-oriented cancer research and are ready to transition
to their first independent position, or who are within the first 2 years
of their first independent research position. Federally employed Ph.D.-basic
scientists are also eligible to apply for the NCI K22. A unique feature of
the NCI K22 is that applicants do not need a sponsoring institution to apply
for an award and have up to 12 months to identify an appropriate sponsoring
institution to “activate” an award should it be made. Finally,
mid-career investigators in patient-oriented research or established investigators
in cancer prevention, control, behavioral, or population sciences, are eligible
for the NCI K05 award, which provides protected time to expand their research
program and to mentor young investigators.
Individuals from groups underrepresented in biomedical research should refer
to the NCI Comprehensive Minority Biomedical Branch (CMBB) for additional
opportunities for support of research training and career development.
Web sites: Training
Opportunities Supported by NCI,
and CMBB.
GUIDELINES FOR PREPARING A GRANT APPLICATION: Dr. Gorelic presented general
guidelines that young investigators should follow when they are considering
submitting an application for extramural funding. First and foremost, they
should work with their mentor(s) and with the NIH/NCI grant program contact
person to identify the funding mechanism(s) that are appropriate considering
the stage in their career and their desired research career plans.
The “K” Awards: Dr. Gorelic also focused on the elements that
are critical to preparing a successful application for mentored individual
NIH/NCI career (K) awards. Major elements for the “K” awards
are the career development plan (that includes a description of the research
plan), the didactic plan, and the expertise of the selected mentors/co-mentors/collaborators.
The proposed sponsors (mentors) must have expertise and current research
support in the proposed area of training, as well as a proven track record
in training researchers.
Dr. Gorelic advised that the research plan should be focused and should
include a small number of well-defined, hypothesis-driven specific aims.
Preliminary data should be introduced to show that the applicant has some
experience in the methodology to be used to achieve the objectives of the
research plan, and must be introduced in a situation where there is a question
of feasibility of the proposed studies. The research plan must parallel the
objectives of the proposed career development plan. The application should
identify potential pitfalls and explain how the pitfalls will be circumvented
and should cite, in the Background section, the critical research by others
in the field. Everything in the career development and research plans should
be developed through careful consultation with the sponsor (for a mentored
award).
If one is applying for a career transition award (K22), it is important
to demonstrate that the applicant is ready to begin an independent research
program and that he/she will be able to submit a research-type (“R”)
application before the third year of the grant. If additional expertise is
needed, individuals should be brought on as collaborators, but not as mentors.
Process for Submitting an Application: Dr. Gorelic advised that applicants
should submit their NIH application using the most current electronic PHS
Form 398 and should pay attention to the required criteria and format, including
the required font size. The application should include the applicant’s
biosketch (and for mentored awards those of their mentor(s) including information
on the mentor(s)’ current research support) and documentation pertaining
to human subjects and inclusion of women, minorities, and children in research. [Note: NIH
is transitioning to mandatory use of the new SF 424 Research and Related
(R&R) application and electronic submission. Access the following
Web site for the timeline and other information: era.nih.gov/ElectronicReceipt.]
If an application submitted to the NIH includes research that falls within
the mission of more than one NIH Institute (for example, National Institute
of Child Health and Human Development (NICHD), National Institute on Aging
(NIA)), the applicant should include a cover letter with the application
and in that letter request that the primary assignment should be made to
the Institute that represents the major focus of the application, and a secondary
assignment to the other Institutes providing a scientific justification for
this request. This alerts the NIH staff that this application is being considered
by more than one Institute, and they can collaborate with one another on
its review and possible award.
At the end of his talk, Dr. Gorelic described the process that a grant application
follows through the NIH system. Applications are sent to the NIH Center for
Scientific Review (CSR), where they are assigned through the referral process
either to an Institute study section or to a CSR special emphasis panel (for
example, F32 awards). (At the NCI, K award and T32 applications are assigned
to different study sections, with care taken not to review basic and clinical
research applications in the same Institute review group.) In the event that
an application is not funded, Dr. Gorelic encouraged the investigators “not
to give up,” but that once they receive the Summary Statement, they
should contact the Program Director who is assigned to their application.
The Program Director will assist an applicant in interpreting the critiques,
and provide additional input on the review that will be useful in assembling
the revision of their original application. For mentored career development
awards, the applicant should discuss the critiques with their mentor(s) prior
to contacting their Program Director.
Creating
Consortia: Rationale, Roadblocks, and Successes
 Session Chair: Leslie Bernstein, Ph.D.
Professor, Norris Comprehensive Cancer Center
University of Southern California
 Daniela Seminara, Ph.D., M.P.H.
Program Director, CGERB, EGRP, DCCPS, NCI
Dr. Seminara presented her work on the characteristics and formation of
consortia and other large-scale collaborative scientific projects. She described
consortia as an “emerging new research paradigm” in which large
interdisciplinary teams of scientists work together collaboratively, using
common protocols and methods and performing coordinated parallel or pooled
analyses. This approach to research creates synergy by exposing scientists
from different disciplines to new concepts and approaches, she said. For
epidemiologists, consortia can provide the resources necessary to study the
effects of environmental exposures, identify genetic factors, evaluate GXE
interactions, unravel the etiologic heterogeneity of tumor subgroups, and
determine prognostic factors. Consortia can facilitate the rapid replication
of findings, the pooling of data to increase sample size, and the initiation
of new large-scale studies.
EGRP supports epidemiology consortia with several different types of designs,
including cohort studies designed to track multiple outcomes and identify
converging mechanisms; more specialized case-control studies, generally focusing
on less common tumors; and family-based studies that might identify high
or intermediate penetrance genes and show effects of environmental modifiers.
Another large segment of the EGRP-supported consortia concentrates on research
infrastructures with hybrid design, such as the Breast and
Colon Cancer Family Registries (BC-CFR). Dr. Seminara
emphasized the growing importance of this approach to the conduct of research
by listing established or emerging consortia focusing on 15 different cancers.
The EGRP works to foster consortia development by identifying research priorities,
assessing needs and providing resources, facilitating communication, and
aiding in study implementation. A program task is also to evaluate consortia’s
performance, develop milestones, and incorporate best practices for high
research standards. The recently established EGRP Consortia Working Group
reviews the status of EGRP-supported consortia, identifying issues and obstacles,
and proposing solutions. Through the soon-to-be-established consortia Web
site, EGRP plans to disseminate information about how to plan, develop, and
evaluate consortia to give the general research community the benefit of
its expertise in this area.
Dr. Seminara said that the Consortium Working Group has developed a set
of criteria with which to evaluate proposed consortia. First they look at
the scientific rationale: are there scientific questions that only this consortium
can address? Clearly defined leadership roles and an appropriate organizational
structure are also very important. The proposal should address issues such
as data and specimen sharing, and publication policies. It should also address
potential difficulties due to differences in design, data variables, and
specimen acquisition and storage among the different research groups involved.
She addressed some of the funding issues faced by consortia. Consortia require
larger financial commitments over longer periods of time, which are difficult
to obtain given current infrastructure and funding mechanisms, especially
with tighter pay lines. She illustrated potential new funding mechanisms
for consortial grants and satellite grants that are currently under development
at NIH. For consortial grants, RFAs could be issued to solicit additional
applications to become an integral part of a specific consortium. These applications
would be reviewed within the context of that consortium. Satellite grants,
for proposals that are affiliated with the consortium only by scientific
serendipity, would not become an integral part of the consortium. In both
cases, continued funding would depend on the success of both the individual
project and the overall consortium.
She described a number of other challenges faced by consortia. These include
effective communication and coordination among the research groups belonging
to the consortium, sufficient informatics and analytical support to handle
very large data sets, and overcoming institutional boundaries that separate
scientists working in different disciplines. Consortia must also find ways
to rapidly integrate cutting-edge technologies, including genomic methods,
and to form biorepositories that can facilitate the storage and use of critical
biosamples. She mentioned the sharing of intellectual property rights and
authorship as additional challenges. The Consortium Working Group can provide
suggestions and support to help emerging consortia for deal with these and
other difficulties.
Lastly, Dr. Seminara gave some examples of consortia that have recently
published results or commentaries. These included the Human Genome Epidemiology
Consortium (HuGE), the International Consortium for Prostate Cancer Genetics
(ICPGG), and the Genetic Epidemiology of Lung Cancer Consortium (GELC). She
said that she expects such very large consortia to provide additional challenges
in the future, as consortia “superstructures” will be needed
to support their activities.
 Melissa L. Bondy, Ph.D.
Professor of Epidemiology
The University of Texas M. D. Anderson Cancer Center
Dr. Bondy described her work with the Brain Tumor Epidemiology Consortium
(BTEC). It is estimated that there will be 17,000 new brain tumor cases and
13,100 deaths from brain tumors in the United States in 2005. Brain tumor
rates are increasing, especially for adults over age 65, although the apparent
increase might be attributable to advances in detection technology. However,
brain tumors are still quite rare, and research consortia are needed to provide
adequate numbers for epidemiologic study, she said.
The BTEC, which was initiated at a meeting organized by NCI in 2003, was
formed to promote multicenter, interdisciplinary collaborations leading to
the understanding of etiologies, outcomes, and prevention of brain tumors.
Pooled or parallel analyses from different labs could provide sufficient
data to study statistically difficult questions, such as the roles of gene-gene
and gene-environment interactions. The consortium also aims to help its members
keep up with the latest molecular and genomic advances, so that brain tumor
epidemiology can be understood at the molecular level.
The consortium consists of an international, multidisciplinary group of
investigators including epidemiologists, statistical geneticists, neurosurgeons,
oncologists, neuropathologists, and basic scientists. It also includes brain
tumor advocates and fundraising organizations. The consortium is overseen
by a coordinating committee, with U.S. and European chairs, and includes
four research focus groups concentrating on adult glioma etiology, family
studies, meningiomas, and pediatric brain tumors.
The BTEC’s first funded initiative will undertake the first large
epidemiological study of meningiomas. This multicenter study will examine
environmental, genetic, pathological, and clinical variables associated with
meningioma risk. Dr. Bondy described some of the difficulties the consortium
encountered in applying for funding. She said there was initially some uncertainty
as to how to submit the proposal to NCI, but that they succeeded by submitting
a group of linked R01s. At review time, the study section had difficulty
finding outside reviewers since almost everyone in the field was involved
in one of the linked proposals.
The National Brain Tumor Foundation (NBTF) has also funded two multicenter
pilot studies initiated by the BTEC. One study will look at single nucleotide
polymorphisms in the DNA repair gene pathway to gather clues about the etiology
of glioblastomas. A second study will focus on the descriptive epidemiology
of oligodendroglioma, seeking to classify and identify risk factors for this
very rare tumor.
The BTEC is now seeking funding for a large consortium to be called GLIOGENE,
which would target the genetic epidemiology of familial and sporadic gliomas.
This consortium would build on a number of previously established relationships
among centers in the United States and Europe, including several SPORE programs.
It will include a steering committee, made up of principal investigators
from each site, and an advisory committee, made up of experts in genetics,
molecular biology, and brain tumors. Dr. Bondy stressed the importance of
having such outside advisors to maintain high scientific standards.
Dr. Bondy closed by describing some of the reasons for BTEC’s success.
In terms of logistics, the Central Brain Tumor Registry provides administrative
support for handling meeting planning and finances, a difficult task to accomplish
through individual institutions. The BTEC has attracted long-term support
for meetings and pilot projects through foundations such as NBTF and from
NCI. Scientifically, the BTEC consists of a highly collaborative and committed
group of investigators, who are gathering retrospective data for merged analyses,
initiating prospective studies, and creating opportunities for young investigators.
They are also developing criteria for publications so that all participants
can receive proper credit for their work. These activities should greatly
increase our knowledge about the little understood etiology of brain cancers.
Opportunities
for Partnerships Along the DCCPS Cancer Control Continuum
 Session Chair: Robert T. Croyle, Ph.D.
Director, DCCPS, NCI
Dr. Croyle opened the session on partnership opportunities in cancer control
research by describing the organizational structure of the Division
of Cancer Control and Population Sciences (DCCPS). DCCPS
includes the Office of Cancer Survivorship (OCS) and four programs: Epidemiology
and Genetics Research Program (EGRP), Behavioral Research Program (BRP),
Applied Research Program (ARP), and Surveillance Research Program (SRP).
He highlighted a variety of DCCPS resources of potential
interest: SRP's biostatistics group and funded investigators, and the BRP-funded
Centers of Excellence in Cancer Communications Research, Transdisciplinary
Tobacco Research Centers (TTURC), and Transdisciplinary Research on Energetics
and Cancer (TREC) Centers which are soon to be awarded
Oct. 2005.
DCCPS also conducts research on how to assess health disparities and collaborates
with NCI's Center to Reduce Cancer Health Disparities. These programs may
be potential sources of data, resources, and collaborators for EGRP-funded
investigators.
He said that when DCCPS considers funding by exception grant applications
that are outside the payline, it looks at whether the investigator is taking
advantage of existing resources and the most effective strategies for achieving
the research aims. He encouraged investigators to piggyback on existing
resources, for example, the SEER/Medicare-linked database, HMO Cancer Research
Network (CRN), and NCI's Cancer Information Service (CIS).
Roberta, this would read more easily if it was organized as a list or in
columns:
Web sites for the above mentioned resources:
Benjamin F. Hankey, Sc.D.
Chief, Cancer Statistics Branch (CSB), SRP, DCCPS, NCI
Dr. Hankey described the Surveillance Research Program (SRP) which includes
two branches: the Cancer Statistics Branch and the Statistical Research and
Applications Branch.
The Cancer Statistics Branch collects and analyzes data to answer questions
about cancer incidence, mortality, and the cancer-related health status of
various regions and populations in the United States. This branch provides
a number of resources for the study of rare cancers, including the SEER Program.
The 2006 release of the SEER public-use file will include ecologic data from
the Census Bureau and other sources at the county level. SEER data are also
linked to cohort data from the National Longitudinal Mortality Study, which
includes 26,000 linked cases from 11 registries. The SEER registries themselves
provide high-quality data and mechanisms for rapid case ascertainment and
rapid-response surveillance studies.
The Cancer Statistics Branch is also interested in promoting geographic
information systems (GIS) studies and held a workshop in June to address
the development of future GIS methods. SEER also holds an annual meeting
to explore topics for study using the rapid response surveillance mechanism,
one of a number of meetings that might be useful to research consortia.
The Statistical Research and Applications Branch, develops statistical methods
for analyzing trends in cancer rates, evaluating the impact of cancer control
interventions, and for evaluating the impact of geographical, social, behavioral,
genetic, and health care delivery factors on the cancer burden. This branch
develops software tools for generating epidemiologic statistics using the
SEER public-use file. It also is investigating the use of GIS methods.
Dr. Hankey provided a list of Web sites that can be used to obtain more
information about SRP activities and resources:
 Martin L. Brown, Ph.D.
Chief, Health Services and Economics Branch (HSEB), Applied Research Program
(ARP), DCCPS, NCI
Dr. Brown described the mission of the Applied
Research Program (ARP) and
how its work might be of interest to those studying rare cancers. ARP supports
the evaluation of patterns and trends in cancer-associated health behaviors,
practices, genetic susceptibilities, health services, economics, and outcomes.
Its staff also monitors and evaluates cancer control activities in the United
States and determines the influences of these factors on cancer incidence,
morbidity, mortality, survival, cost, and health-related quality of life.
It can provide technical assistance with databases and surveys, and advise
on grant issues.
ARP has a number of resources applicable to rare cancers. One is the Breast
Cancer Surveillance Consortium, which includes study of prognostic factors
for the rare cancer ductal carcinoma in situ (DCIS). Another important resource
is the HMO Cancer Research Network, or CRN. This is a network of cancer research
centers associated with large nonprofit HMOs. The network, which covers a
population of 10 million, provides a large scope of data including pharmacy
information, and large diverse populations. These populations include large
numbers of cases of rare cancers such as multiple myeloma, esophageal cancer,
and glioblastoma. The CRN is carrying out several multicenter studies, including
one on pancreatic cancer etiology and one on multiple myeloma. Outside investigators
can access the CRN by submitting a proposal to collaborate with CRN investigators.
Initial estimates of cancer cases and related health care and pharmaceutical
use can be obtained through the CRN Virtual Data Warehouse.
Dr. Brown described another resource known as SEER-Medicare, which is a
linkage of SEER data with Medicare data. This resource provides detailed
information about elderly persons with cancer and represents a retrospective,
longitudinal data set that can be used for a number of types of epidemiologic
and health services studies. It includes huge numbers of Medicare recipients
and will continue to grow as the population ages. More than 150 studies have
already taken advantage of this resource. The database is not for public
use but access can be gained by a straightforward process.
Dr. Brown listed several Web sites for further information on access to
data and collaboration with these resources:
 Julia H. Rowland, Ph.D.
Director, Office of Cancer Survivorship (OCS), DCCPS, NCI
According to Dr. Rowland, cancer
survivorship research seeks to identify
and control adverse cancer- and treatment-related outcomes to provide a knowledge
base that will allow optimal follow-up care and surveillance of cancer survivors,
and to optimize health after cancer treatment. She said that epidemiologic
studies should focus not only on survival but on all the things that make
survival possible, including long-term effects and predisposing factors that
might make for a poor trajectory. Survivorship studies can use classic epidemiological
research designs such as cohort and case-control studies, and trial/intervention
designs.
She provided some examples of epidemiologic research germane to survivorship,
including studies on the incidence and risk factors of physiological late
effects, such as cardiotoxicity; examination of lifestyle and health behaviors,
such as exercise and smoking, on morbidity; and identification of protective
factors, especially in “extraordinary” survivors. She also identified
a number of gap areas that epidemiologic research could address, such as
the influence of predisposing factors on survivorship outcomes, health outcomes
in long-term survivors, the role of co-morbidity, and the roles of socio-cultural
and behavioral factors, family, and post-treatment care on outcomes.
Dr. Rowland suggested that existing studies and databases supported by NCI
could be leveraged to collect data about survivorship and provide answers
for some of these gap questions. New multidisciplinary studies could also
be used to link epidemiologic data such as risk factors to survivorship outcomes.
Susan E. Rivers, Ph.D.
Senior Research Coordinator, New England Cancer Information Service
Yale Cancer Center
Dr. Rivers explained that the Cancer Information
Service, or CIS, is an
NCI program that operates through contracts with academic institutions, hospitals,
and Comprehensive Cancer Centers. The CIS operates three component services,
including an Information Service, a Partnership Program, and a Research Program.
The CIS provides answers to individuals seeking information
on cancer through toll-free phone numbers, instant messaging, and by e-mail
through NCI’s Web site (cancer.gov). Comprehensive information is provided
on cancer risks and prevention, symptoms and diagnosis, and treatments and
clinical trials.
The Partnership Program collaborates with trusted community organizations
to reach minority and medically underserved populations with cancer information.
The outreach effort helps to enroll these populations into cancer detection
and prevention programs as well as into clinical trials. It also provides
training to those organizations on cancer-related topics and the use of NCI
resources, links organizations with similar goals, and helps plan and evaluate
programs.
The Research Program seeks to understand, apply, and disseminate effective
communication approaches to educate the public about cancer and contribute
to cancer control efforts. Research themes include testing novel health communication
and education interventions, increasing access and use of cancer-related
information, discovering effective models for disseminating cancer information,
and understanding general information seeking behaviors.
Dr. Rivers said that the CIS provides an opportunity for investigators to
collaborate with highly skilled researchers who have access to large numbers
of cancer information seekers, many eager to participate in research. The
CIS provides multiple venues for dissemination of information, often in partnership
with organizations that can reach minority and underserved populations. Its
staff is highly trained and can provide cancer content expertise, design
research methodology, obtain informed consent, and design and administer
eligibility assessments and baseline questionnaires.
Health
Informatics, caBIG, and Population Sciences and Cancer Control (slides
in pdf format)
 Deborah M. Winn, Ph.D.
Chief, Clinical and Genetic Epidemiology Research Branch (CGERB), EGRP, DCCPS,
NCI
Dr. Winn presented the work of the Health Informatics Steering Committee,
whose mission is to apply health informatics tools to DCCPS research activities
in order to optimize new data collection as well as the use of existing data.
The committee also promotes the application and sharing of data and research
advances with individuals and communities. Key focus areas include cancer
care and surveillance, data collection and analysis strategies in population
science, behavioral and cancer survivorship research, and the application
of GIS methods to cancer data and bioimaging.
She described an NCI initiative known as caBIG, for cancer Biomedical
Informatics Grid. The grid represents a network of individuals
and institutions, designed to facilitate the sharing of cancer-related data,
tools, and infrastructure. The network includes about 50 NCI-designated Cancer
Centers, including participants from the cancer and biomedical research communities,
private industry, and patient advocacy groups.
Working groups within caBIG are taking open-source, open-data approaches
to such tasks as clinical trials management, integrative cancer research,
and tissue banks and pathology tools. Other groups are planning systems architecture,
vocabularies, and common data elements. Strategic-level groups are involved
in strategic planning, addressing data sharing and intellectual capital issues,
and training efforts. Tools are under development to handle data from cutting
edge technologies such as microarrays, proteomics and computational genomics.
The Health Informatics Steering Committee joined with the extramural community
and the NCI Center for Bioinformatics, which developed caBIG, to create the
Population Sciences Special Interest Group within the Integrated Cancer Research
Working Group. This interest group is focusing its efforts on developing
tools and resources to facilitate epidemiologic and cancer control research.
DCEG and DCCPS also have created a joint project to develop common data
elements (CDEs) for population sciences and cancer control. These CDEs, which
are being developed for subject areas like demographics, tobacco history,
and body mass index, will be placed in the Cancer Data Standards Repository,
or caDSR, along with common vocabularies. Thus, the caDSR will provide unambiguous
semantics for the data collected in all cancer studies and trials. The caDSR
will also provide a Form Builder tool that can build standardized questionnaires
and forms using the CDEs and vocabularies. These standardized forms will
be stored in the repository for use by others in the research community.
They should allow for more consistent data collection and analysis, reduction
of errors, and vastly enhanced data sharing and data pooling capabilities.
Transdisciplinary
Science: Partnering Population, Basic and the Clinical Sciences
 Session Chair: Graham A. Colditz, M.D., Dr.P.H.
Professor of Medicine, Brigham and Women’s Hospital
Harvard University
 Jonine L. Bernstein, Ph.D.
Associate Attending Epidemiologist, Memorial Sloan-Kettering Cancer Center
Dr. Bernstein discussed her work with the Women’s Environment, Cancer
and Radiation Epidemiology Study, also known as the WECARE Study. This interdisciplinary,
multicenter study was designed to investigate the joint roles of radiation
exposure and genetic susceptibility in second primary cancers in women with
breast cancer.
Only 5 to 10 percent of women with breast cancer develop a second primary
cancer in the contralateral breast, making this a rare cancer. Breast cancer
patients are two to five times more likely to develop a second breast cancer
than are women in the general population without breast cancer to develop
a first cancer. The risk of developing a second primary persists for at least
30 years. Although epidemiologic data are scarce, the only other consistently
identified risk factors for second primary breast cancer are: early age at
diagnosis of the first primary breast cancer, lobular histology of the first
primary, a family history of breast cancer, and carrying mutations in the
cancer genes BRCA1 and 2.
Radiation treatment for the first primary also elevates the risk of developing
a second primary, while tamoxifen and chemotherapy do not, which led to the
idea that risk might be associated with DNA damage and damage repair pathways.
ATM (for ataxia-telengectasia gene mutation) is activated by DNA damage,
such as that from radiation exposure. ATM lies upstream and controls a number
of damage control proteins, including the Chk2 protein, which interacts with
the P53 tumor suppressor. Homozygous mutations in the ATM gene cause the
disorder ataxia telengectasia (A-T), an autosomal recessive disease characterized
by progressive neuronal degeneration, immunologic deficiency, and premature
aging and death.
A-T is also characterized by increased radiosensitivity and susceptibility
to cancer. This led to the hypothesis tested by the WECARE Study that women
who carry a single ATM gene mutation may be more susceptible to radiation-induced
breast cancers than those with no mutations. To improve the chances of detecting
the effects of these relatively rare mutations, in the WECARE Study, women
with asynchronous bilateral breast cancer serve as cases and women with unilateral
breast cancer serve controls. Preliminary results show that women who carry
a deleterious ATM mutation and who received radiation treatment for their
first primary have a much higher risk of developing a second breast cancer
than do women who do not. Ongoing studies are looking at genes in the entire
ATM-Chk2 DNA repair pathway, as well as the roles of BRCA1 and 2.
Dr. Bernstein also described the organization of this large successful collaborative
study. Since the cancer is rare, and a large sample size was required to
achieve adequate statistical power, the study involves multiple data collection
centers. Multiple genotyping laboratories are also needed to analyze the
very large, complex ATM gene, as well as laboratories with experience in
the technical challenges of measuring radiation exposure. The study includes
more than 70 investigators from 25 institutions, 5 countries, and 7 time
zones.
The WECARE field organization includes working groups that direct different
aspects of data collection and analysis, such as Radiation Dosimetry, Genotyping,
and Biostatistics. These groups are coordinated by a Steering Committee and
an Internal and External Advisory Committee, which Dr. Bernstein credits
with helping to keep the study moving. There are also subcommittees formed
to deal with practical issues such as biorepository use, budgets, and publications,
and to deal with the data analysis.
Dr. Bernstein ended her presentation
by describing some of the “lessons
learned” from the WECARE Study about interdisciplinary partnerships.
The study team worked well, she said, because it included deep expertise
in every scientific aspect of the study, along with a prior track record
of collaboration among many of the investigators. For the follow-up study,
they are planning to include more junior investigators. Communication within
the Working Groups was constant and effective, but she found that annual
meetings and e-mails were only barely adequate as a means of overall communication
with the team as a whole. Support from NCI was helpful but funding is an
issue now that the initial WECARE:ATM funding is finished. Additional funding
is needed to maintain the group’s infrastructure so that this work
can be built upon and future studies completed.
 Kenneth C. Anderson, M.D.
Director, Jerome Lipper Multiple Myeloma Center
Dana-Farber Cancer Institute
Dr. Anderson presented his work using both genomic and epidemiologic data
to guide clinical research on potential chemotherapeutic agents for the treatment
of myeloma. “Teamwork is the only way to go,” he said, making
the case for multidisciplinary approaches to rare cancer research. Dr. Anderson
leads a SPORE in myeloma.
Multiple myeloma is a disease resulting from excess plasma cells in the
bone marrow. The disease is incurable, although the median survival of 3
to 4 years with conventional therapy can be improved slightly with high-dose
therapy and bone marrow transplant. Myeloma accounts for 2 percent of cancer
deaths in the United States, and there are 14,400 new cases each year. Incidence
is especially high in African Americans and Pacific Islanders. Predisposing
factors include environmental exposures such as radiation or petroleum products,
and occupations such as farmer, paper producer, furniture manufacturer, or
wood worker.
Another predisposing factor for myeloma is the presence of a clinical syndrome
known as Monoclonal Gammopathy of Unclear Significance, or MGUS. MGUS occurs
in about 2 percent of individuals older than 50 years and is characterized
by less than 3.5 grams/liter monoclonal immunoglobulin and less than 5 percent
monoclonal bone marrow plasma cells. Individuals with MGUS have a 25-fold
higher risk of developing multiple myeloma within 20 years, as well as greatly
increased risks for other blood disorders such as macroglobulinemia, plasmacytoma,
and primary amyloidosis.
Dr. Anderson’s group is investigating how gene expression profiles
change in the progression from normal to MGUS to myeloma. They have identified
a large number of genes whose expression is either up-regulated or down-regulated
at different stages in the progression. These genes and their protein products
represent potential targets for therapy against myeloma. Dr. Anderson refers
to this research strategy as “oncogenomics.”
A total of 258 expressed oncogenes were identified. In order to target myeloma-specific
genes, genes that were over-expressed in more than one cancer were eliminated.
Some of the remaining genes were only over-expressed in certain patients.
For example, only 20 percent of patients over-expressed fibroblast growth
factor receptor 3 (FGFR30), a tyrosine kinase. A kinase inhibitor is in clinical
trials, but only those patients will be expected to show a response.
By these and other methods, Dr. Anderson’s group has identified seven
potential targets for anti-myeloma therapy. They have developed compounds
against six of these. In addition to the anti-FGFR3 agent, they are testing
inhibitors of angiogenesis, telomerases, the proteasome, and the stress response.
They are also working on an Mcl-1 antisense RNA as an anti-apoptotic agent.
Most of these studies involve cells in culture. But Dr. Anderson said that
it is important to remember that cells live in a particular microenvironment,
and this can change gene expression patterns. His group has identified many
of the genes that control the interactions of multiple myeloma cells with
cells in the bone marrow microenvironment. These studies have led to the
use of thalidomides to manipulate these interactions. One thalidomide compound,
revlimid, has been very successful in Phase III clinical trials.
Another drug that blocks tumor/microenvironment interactions is Velcade
(bortezomib). This drug gained FDA approval in less than 3 years from bench
to bedside, which Dr. Anderson attributes to the power of collaborative research.
Further demonstrating the value of teamwork, he said that two companies have
joined together to test bortezomib and revlimid together, a combination that
is successful in some patients who have failed treatment with one or the
other alone.
Dr. Anderson’s group is also using gene expression microarrays to
help predict clinical responses to drugs. He said that population studies
are needed to identify gene targets associated with drug sensitivity or resistance.
His group found that heat shock protein 27 (Hsp27) was over-expressed in
people who were resistant to his new proteasome inhibitor. He is now directing
a clinical trial to determine whether inhibiting Hsp27 indirectly, by inhibiting
p38 MAP kinase, will affect proteasome inhibitor resistance in these patients.
Dr. Anderson’s latest project, on IGF gene variation and multiple
myeloma risk, is funded by a SPORE career development award, which he called
a “wonderful model” for team-related integrated research. This
study will investigate the role of IGF-1 mediated signaling cascades in myeloma,
combining molecular biology and biochemistry, animal models, and epidemiological
research. The results could be useful in other cancers where this pathway
has been implicated, including breast cancer. Another new collaborative project
will investigate genetic risk factors for myeloma using single nucleotide
polymorphisms and epidemiologic studies.
Dr. Anderson concluded with two lessons learned from his studies of rare
cancers. First, he has developed a new treatment paradigm that targets both
the cancer cell and its microenvironment. This paradigm may prove useful
for other cancers. Second, the SPORE collaborative oncogenomic and population
studies have proven very useful for identifying new therapeutic targets and
for informing the design of clinical protocols.
 Jorge Gomez, M.D., Ph.D.
Chief, Organ Systems Program
National Cancer Institute
Dr. Gomez followed Dr. Anderson’s talk with a discussion of some of
the general issues involved in multidisciplinary research, and how NCI can
facilitate this research. He defined multidisciplinary research as studies
performed by a team of experts, based on common scientific goals. There are
many projects now that cannot be accomplished using single investigator research,
although the R01 is still the basis of most biomedical research.
He said that the NCI staff can facilitate such research in a number of ways.
They can help initiate and promote interactions among scientists. They can
provide administrative advice, including pre-application consultation and
advice on funding opportunities and program requirements. They can also help
coordinate with other NCI programs and help to establish partnerships with
private industry. He emphasized that their role should be facilitative rather
than regulatory.
Dr. Gomez described a number of trends occurring in translational research.
This research is incorporating new technologies into patient research and
supporting the development of new drugs and novel clinical interventions.
It is also opening up new, more creative ways of interacting with private
industry and involving patient advocacy groups.
Translational research requires flexible management of the interactions
between grantees, NCI, and NIH programs, and other government agencies. A
high level of leadership is needed to coordinate and support these interactions,
in the context of an appropriate organizational structure. It also requires
the resources to respond quickly and efficiently to newly identified gaps. “Rare
diseases are outside the line,” Dr. Gomez concluded, and will require
new models for management and funding that can support translational, multidisciplinary
approaches.
 Shelia Hoar Zahm, Sc.D.
Deputy Director, Division of Cancer Epidemiology and Genetics (DCEG), NCI
Dr. Zahm brought forward another perspective on the challenges facing transdisciplinary,
integrative, and translational research. First, she noted that such research
requires sufficient funding and resources to enable adequate communication,
including in-person meetings, to plan and ensure successful conduct of complex
projects. Adequate and continued funding is also a necessity to fully exploit
the resources developed by the study.
A major challenge is the increasing complexity of projects as disciplines
are added to a study. With each discipline often needing unique data, biospecimens,
or environmental specimens, there is the risk that the protocol may become
a crushing burden for staff and subjects. Lengthy questionnaires, complicated
environmental and biospecimen collection, shipping, and storage procedures,
and other requirements can be logistically challenging, expensive, decrease
response rates, and lead to staff burnout. In the face of decreasing response
rates, transdisciplinary studies, in particular, may need to increase incentives
paid to subjects and may need to grapple with the best method to inform subjects
of the possible study components without jeopardizing participation. Researchers
launching transdisciplinary projects need to seek the best scientific collaborators,
but it helps to also seek collaborators who are reasonable, communicate well,
and are willing to compromise appropriately, if necessary. This is especially
important because as the science becomes more complex, it becomes harder
to judge the value of proposals for study components that are outside one’s
own discipline.
Transdisciplinary research is challenging but well worth it, she said, providing
a “veritable goldmine” of data. Factors that promote success
include good communication, mutual respect, real-time monitoring of each
component, and sufficient resources.
Panel
Discussion: Rare Cancer Advocates and Survivors: The Few and Far Between
 Session Chair: Julia H. Rowland, Ph.D.
Director, Office of Cancer Survivorship, DCCPS, NCI
Panelists:
- Douglas Bank
President and Editor
Testicular Cancer Resource Center
- Richard N. Boyajian, R.N., M.S.
Lance Armstrong Foundation Adult Survivorship Clinic
Perini Family Survivors Center
Dana-Farber Cancer Institute
- Cary Zahrbock
National Coalition for Cancer Survivorship
In this discussion, the moderator, Dr. Rowland, asked the panelists to respond
to a series of questions about the role of epidemiology in the life of cancer
survivors and members of the public who have never had cancer.
1) How accessible is epidemiology to consumers?
Panelists responded that many people do not understand what epidemiology
is and have difficulty understanding how risk factors apply to them (for
example, the difference between relative, absolute, and individual risk).
They felt that many people get their information from television in a form
that may not be accurate or readily understandable. People need to know how
they can apply epidemiologic data to themselves and their families in practical
ways. They would benefit from information that emphasizes the key, most important
messages. People are also especially attuned to messages that give them hope.
2) How effective are consumer advocacy programs in research and
related activities, such as the Director’s Consumer Liaison Group
(la.cancer.gov/dclg.html)?
Panelists noted that there are a number of consumer advocates who have been
trained to provide input in research-related activities. However, they also
felt that many of these individuals are underutilized. They advocated for
a more open process that includes consumer advocates and cancer survivors
on review panels for many types of grants and on Request for Applications
(RFA) review panels as well. They see this involvement as an important avenue
for communication between the public and scientists. They noted that the
training of advocates varies greatly and suggested that it may be useful
to have a way to review the training and or standardize the approach to orienting
advocates who wish to serve in this capacity, such as done in NCI’s
CARRA (Consumer Advocates in Research
and Related Activities) Program.
3) What are the biggest barriers preventing collaboration between scientists
and consumer advocates?
Scientists need to incorporate advocates into the process before the research
is created, they said. The advocates may bring about changes in protocols
by introducing a “human factor” that addresses whether a given
protocol is reasonable for the subjects participating. They did note that
some advocates who are survivors are unable to separate their emotions from
the science. Careful screening should be used to make sure advocates are
emotionally ready to participate in the research review and planning process.
Accessing survivors through groups, such as the CARRA Program, or established
advocacy groups can help scientists identify and enlist the input of trained,
articulate advocates.
4) What are the questions that consumers want to know about?
Panelists described a number of concerns and questions:
- What are the long-term and late effects of treatment?
- Should the chronic
and late effects of cancer be studied by treatment exposure and not based
solely on disease? This would provide a larger population and stop the
discussions about relevance by disease and perhaps also reveal differences
in patterns of effects experienced. It was acknowledged that this would
require a large effort in monetary levels and manpower.
- How can scientists
best study/validate late effects and side effects of treatment?
- What should
cancer survivors expect and what screening tools should they be using after
treatment ends?
- What should they be doing to promote a longer life and
prevent late effects?
- How can they promote their overall quality of life
after cancer?
- What is a cancer cluster? How do you know if a number of
cancers experienced by members of a group is significant and who would
you report it to?
- How does lack of insurance coverage affect cancer outcomes?
- Better morbidity
and mortality data could help cancer survivors who face discrimination
from life insurance companies and potential employers.
5) What are the lifestyle and family effects of cancer?
People with a cancer diagnosis want to know how to lessen the impact of
disease both on themselves and their families. Often they want to make their
lifestyles healthier, and they need information about how to do this, the
panelists said. They also need tools to help them make such changes, like
smoking cessation programs. Further, they need to know what they should tell
their families about risks both to themselves and to other family members.
If a cancer is hereditary, what steps should they take to protect their
family? What is the level of evidence regarding lifestyle modification and
reduction of cancer risk? Could this information help families reduce their
cancer burden? To what extent are factors that may be associated with risk
of cancer also be predictors of survival or morbidity after a cancer diagnosis?
This, they felt, is where we need more answers. Finally, genetic links or
risks need to be looked at in larger study populations instead of smaller
cohorts.
Many also have psychosocial needs that are going unmet the panelists pointed
out. Their quality of life may be poor because of psychological rather than
physical effects of cancer. Psychologists need more training to deliver this
care and more programs need to be developed to help survivors and their loved
ones deal with these problems.
6) How can advocates help with epidemiologic research?
Panelists said that cancer survivors are often eager to share information
about their lifestyles and participate in research, but are not asked to
do so. They suggested several ways that advocates/survivors could help researchers.
For example, scientists wishing to find survivors of rare cancers could go
to cancer survivor groups. These groups might also be able to help set up
community-based research and be trained to carry it out. They felt that outreach
and study enrollment carried out by survivors might be more effective because
they are peers or fellow patients. The panel also suggested that giving tax
credits to participants might be an effective way to enroll more survivors
and more cases and controls for studies. Scientists could also team up with
advocates when going to policymakers to seek funding because the survivors,
by bringing their personal experience, would allow the scientists to tell
a more compelling story. In summary, the panel felt consumers and cancer
advocacy groups are eager to be part of the research process and can contribute
valuable perspectives and practical assistance to epidemiologists.
 Session Chair: Hoda Anton-Culver, Ph.D.
Professor and Chief, Epidemiology Division
University of California, Irvine
In the last session of the meeting, Dr. Anton-Culver presented a comprehensive
summary of information and action items generated by the working groups in
response to the following questions:
Discussion Questions:
- What is the state of the science—what do we
know?
- What are the scientific gaps—what do we not know?
- What obstacles
(scientific, infrastructure, technical) impede progress, and what needs
to be done to remove the obstacles? Are there solutions to some of these
problems that work?
- What expertise, disciplines, and linkages do we need
to “bring
to the table” to enhance progress?
- What are the partnering opportunities
with other DCCPS programs?
(Answers to questions “d” and “e” were not explicitly
discussed but are included in the individual working groups’ summaries.)
Question a) What is the state of the science—what do we know?
The working groups concluded that while at least some descriptive data are
available for all but the rarest subtypes, the amount of data available varies
widely by cancer type. Some cancers are well studied with respect to age,
gender, and ethnicity, but others are not. For some types, most research
data come from international studies, which may or may not be applicable
to American populations.
Action items:
- Find ways to translate international data to American populations
- Include
international investigators in new studies
- Initiate new research into differences
among racial groups with respect to etiology, response to treatment,
and expression of different rare cancer subtypes.
Question b) What are the scientific gaps—what do we not know?
Dr. Anton-Culver reported that the biological mechanisms underlying most
rare cancers are unknown. There is also a need for molecular markers that
could distinguish between subclasses within rare cancer types, especially
in complicated types such as head and neck, leukemia, and brain. Lack of
knowledge about the latency period between exposure and effect also hampers
understanding of etiology.
Action items:
- Identification and study of prediagnostic lesions could lead
to understanding of biological mechanisms
- Study of people with predisposing
conditions could also provide information about mechanisms and latency
period
- Study of susceptibility could lead to identification of molecular
markers for classification and early detection
- General research on major
physiological processes, such as energy balance, the blood-brain barrier,
viral load, immune mechanisms, and assessment of environmental exposures,
could shed light on mechanisms common to all cancers.
Question c) What obstacles (scientific, infrastructure, technical) impede
progress, and what needs to be done to remove the obstacles? Are there solutions
to some of these problems that work?
The working groups identified two major types of obstacles: those affecting
data collection and those affecting the ability of researchers to collaborate.
Data collection is plagued by a number of problems. There are standardization
issues, such as the lack of histological definitions for some cancers, lack
of standard core questionnaires, and lack of standard bioinformatics methods
and analyses. Practical issues may also impede data collection, including
difficulties in getting appropriate biospecimens (for example, skin biopsies
and other specialized samples); a need for ultra-rapid case ascertainment
in cancers with rapid mortality; Health Insurance Portability and Accountability
Act (HIPAA) and Institutional Review Board (IRB) issues; and the high costs
of data collection. Data analysis is impeded by the small sample sizes available
for most rare cancers. This is particularly a problem for junior investigators
because of their limited funding.
Problems preventing effective collaboration included limited contact between
scientists in different disciplines and a lack of appropriate funding mechanisms
for consortia and interdisciplinary research.
The groups proposed a number of solutions to these problems:
Action items:
- Increased funding for rare cancer research
- Cross-training for new investigators
to encourage interdisciplinary research
- Training for international fellows
to facilitate study in other countries
- Coordination of resources by a
central agency such as NCI
- Increased involvement of advocacy groups and
private organizations
- Encouraging universities to be flexible in giving
academic credit to investigators involved in multiple principal investigator
projects
- Formation of new consortia and expansion of existing consortia
by adding new investigators.
At this point in the presentation, Dr. Anton-Culver opened the floor to
the session chairs and any other participants who wished to discuss these
or other potential solutions to the challenges facing investigators of rare
cancers.
Four major themes emerged from the discussion:
- Need for improvements to the
review process for rare cancer research proposals
- Need for targeted funding
for rare cancers research
- Suggestions for promoting consortia formation
- Potential usefulness of
greater involvement of the cancer registries in research.
Improvements to the review process
Because rare cancers
require the study of large populations to achieve adequate sample size, the
price tag for such research is generally expensive. This is particularly
true if extra funds are needed for consortium building. Grant reviewers,
who often are not epidemiologists but instead are clinicians, generally do
not appreciate the reasons for these extra expenses. These reviewers can
be very critical, especially when the cancer involved is very rare and the
research might be considered to benefit only a small number of people.
One suggestion was to ask the CSR to form a special study section that could
take into account these special challenges. Because it is very difficult
to get CSR to form a new standing committee, it was suggested that ad hoc
study sections might be formed instead. However, even if this could be done,
there might be difficulty in getting enough researchers who could act as
outside reviewers because almost all of them would likely be involved in
the consortium covering their field. Another suggestion was to hold workshops
to educate reviewers from outside epidemiology on the specific challenges
of rare cancer research. It was also pointed out that, as multidisciplinary
consortia were formed, more basic scientists would be needed on study sections
to ensure adequate scientific review.
Epidemiologists attending this meeting were encouraged to take ownership
of the problem by acting as advocates for rare cancer research while serving
on study sections and when interacting with colleagues in other settings.
Another suggestion was that reviewers be asked to use the NIH CRISP database
(crisp.cit.nih.gov) to ensure that the proposals that they are reviewing
are really novel. This would cut down on duplication of existing research
and perhaps free up funding for more rare cancer research proposals.
Funding targeted specifically to rare cancers
Several workshop participants suggested that difficulties in competing against
other grants could be at least somewhat alleviated if more money were targeted
specifically to rare cancers—for example, through a RFA. A RFA would
also emphasize to reviewers NCI’s commitment to rare cancer study.
However, other participants felt that reviewers do not really pay attention
to whether a grant proposal targets a specific RFA.
Another suggestion was the creation of a funding level slightly above the
R03 so that junior investigators could obtain enough funding to get started
on rare cancer research.
Formation of consortia
Several participants discussed how to develop an infrastructure that would
support emerging consortia. Consortia planning grants could be used to
defray the costs of getting people face-to-face in order to start a new
consortium. Such funding would need to include an ongoing mechanism, so
that groups could have multiple meetings as needed without continually
applying for more funds. It was suggested that consortium grants include
a required mentoring component to help junior investigators get involved.
Participants noted that consortia should be investigator-driven and should
include new investigators as well as those from other disciplines. Consortia
could include both extra- and intramural NCI investigators if careful attention
were paid to keeping funds separate. Selection of consortium members could
use the criteria developed by Dr. Seminara (described earlier in the meeting).
Involvement of cancer registries
Representatives from several cancer registries said that the registries would
like to help with rare cancer research. They suggested including the state
registries in research plans, in addition to the SEER Program. NCI could
set aside some funds to help registries develop their ability to actively
participate in research, above and beyond funding for building the actual
research resources.
Better communication between NCI and outside organizations could also help
support the registries. The Centers for Disease Control and Prevention (CDC)
and the American Cancer Society (ACS) provide some support for registries.
This support could be coordinated with that of NCI through NAACCR as an umbrella
organization.
Other suggestions were to use the Comprehensive Cancer Centers for ultra-rapid
case registry and to form specific national registries for some rare cancers,
if needed.
Edward Trapido, Sc.D.
Associate Director, EGRP, DCCPS, NCI
Dr. Trapido wrapped up the session by stating that NCI would use the working
groups’ comments and suggestions to help prioritize funding mechanisms
and write new initiatives, and when discussing review issues with the CSR.
He addressed researchers’ frequently expressed concerns about funding
mechanisms for consortia by stating that NIH is already working on a mechanism
for funding multiple principal investigator grants. He said that NCI will
also ask the American College of Epidemiology and other professional organizations
to help set standards that will guide academic departments in evaluating
the work of junior investigators on multiple principal investigator, multidisciplinary
projects.
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