EGRP Hosts Workshop on Understudied Rare Cancers

(co-sponsored with the NIH Office of Rare Diseases)

magnifying glass Workshop title

Appendices:

Appendix A:

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Cancer Site Working Group Report: Brain and Eye Cancer

Chair: Melissa L. Bondy, Ph.D.;
Co-Chair: Daniela Seminara, Ph.D.

Discussion Questions:
a) What is the state of the science—what do we know?

Much descriptive epidemiology is available for brain and eye cancer, including information on sex, age, and race differences. Several important scientific advances have been made in brain cancer research since 2000, including evidence for a connection with immunologic factors, studies of angiogenesis, identification of molecular markers, and the role of 1p/19q deletions in oligodendromas. However, there is still a great deal of uncertainty about the factors causing brain tumors. Progress has not been as fast as hoped, partially because most studies thus far have included only small sample sizes.

b) What are the scientific gaps—what do we not know?

The working group came up with a long list of knowledge gaps, including:

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 group identified six major areas that impede brain cancer research:

  1. Biospecimens—lack of normal tissue and cerebrospinal fluid (CSF) banks and access to brain tumor samples. These problems might be solved by creating CSF repositories, brain tumor tissue banks, autopsy brain banks, or by using discarded Guthrie cards.

  2. Data quality—lack of early exposure data, which could be solved by familial studies and registries.

  3. Ascertainment—rapid mortality in some tumor types leads to bias in data collection. This could be avoided with ultra-rapid ascertainment and reporting and by utilizing the cancer registries.

  4. HIPAA and confidentiality—impedes sharing of biospecimens and data. Master biospecimen sharing agreements among multiple institutions could solve this problem.

  5. Collaboration—competition for funding and publications impede collaborative studies in the United States, while differences in ownership, privacy, and healthcare structures impede international collaborations. These problems could be eased by increasing funding for consortia and enhancing the international brain tumors epidemiology consortium.

  6. Communication—lack of communication could be eased by Web portals and a semi-private database for use by physicians and scientists.

d) What expertise, disciplines, and linkages do we need to "bring to the table" to enhance progress?

The working group listed:

e) What are the partnering opportunities with other DCCPS programs?

The working group mentioned a SEER project in which samples and data from discard repositories are made available to the general scientific community. Members also suggested collaborations among the different Institutes. Researchers could also take advantage of NCI cooperative groups such as the HMO Cancer Research Network (CRN) and the Mouse Model Consortium. (The Mouse Model Consortium is funded by NCI, but it is not a DCCPS program.)

The group highlighted technology integration as a priority for action because microarrays, proteomics, and methylation studies have been used successfully in other cancers.

Appendix B:

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Cancer Site Working Group Report: Endometrial Cancer

Chair: Pamela L. Horn-Ross, Ph.D.;
Co-Chair: Virginia W. Hartmuller, Ph.D., R.D.

Discussion Questions:
a) What is the state of the science—what do we know?

Endometrial cancer rates are highest in Caucasian women (26 per 100,000) and lower in other groups (17 per 100,000), and recent observations suggest increasing rates in African-American women. The 5-year relative survival is substantially higher in Caucasian women (87%) compared with African-American women (61%). Primary risk factors include obesity and hormone therapy (HT), particularly estrogen-only therapy. The "unopposed estrogen hypothesis" explains a portion of the relationship between obesity and endometrial cancer.

b) What are the scientific gaps—what do we not know?

The working group came up with a long list of knowledge gaps, including:

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 group identified scientific, infrastructure, and technical obstacles:

d) What expertise, disciplines, and linkages do we need to "bring to the table" to enhance progress?

The list included:

e) What are the partnering opportunities with other DCCPS programs?

The working group suggested that NCI's Cancer Information Service (CIS) could help with minority recruitment. Corporate partnerships might be sought to help fund consortium meetings. The DCCPS-funded HMO Cancer Research Network (CRN), DCCPS Applied Research Program (ARP), and other databases could also be pressed into service for endometrial cancer research.

This group also suggested the following major priorities for action:


Appendix C:

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Cancer Site Working Group Report: Esophageal, Liver, Stomach, and Renal Cancer

Chairs: Marilie D. Gammon, Ph.D., and Alexander S. Parker, Ph.D.;
Co-Chair: Mukesh Verma, Ph.D.

Discussion Questions:
a) What is the state of the science—what do we know?

The incidences of renal and liver cancers are increasing, while the incidence of gastric cancer is declining in the United States. However, gastric cancer remains high elsewhere in the world. Obesity is a risk factor in all of these cancers. Other risk factors include smoking and hypertension for renal cancer; hepatitis viruses B and C and alcohol for liver cancer; tobacco, alcohol, and low fruit and vegetable intake for esophageal cancer; and H. pylori infection, nitrosamines, and smoking for gastric cancers.

b) What are the scientific gaps—what do we not know?

The working group defined the following knowledge gaps:

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 group identified data collection as a special challenge in these rare cancers, resulting in high costs and an underappreciation of the difficulties by others in the scientific community. There are also problems translating study results from international populations to the United States and attracting good new investigators. The solutions suggested were to establish a rare tumor study section as well as specific RFAs. Members also suggested special considerations for new investigators in the review process.

d) What expertise, disciplines, and linkages do we need to "bring to the table" to enhance progress?

The working group suggested epidemiologists, geneticists, molecular biologists, biochemists, pathologists, clinicians, bioinformaticians, statisticians, behavioral biologists, health disparities researchers, and exposure assessment experts. Members also emphasized a need for cross-training at the junior level.

e) What are the partnering opportunities with other DCCPS programs?

Potential partners include the Epidemiology and Genetics Research Program (EGRP), SEER Program and Cancer Statistics Branch of the Surveillance Research Program (SRP), Applied Research Program (ARP); and Office of Cancer Survivorship (OCS), and collaborations with intramural NCI scientists.

This working group identified three main priorities for further action: find NCI scientists to act as partners, get the main players together face-to-face at a meeting to begin forming a consortium, and send a message to NCI indicating the need for special consideration for rare tumor proposals at review time.

Appendix D:

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Cancer Site Working Group Report: Head and Neck Cancer

Chair: Qingyi Wei, M.D., Ph.D.;
Co-Chair: Deborah M. Winn, Ph.D.

Discussion Questions:
a) What is the state of the science—what do we know?

The existing head and neck consortium has brought together more than 10,000 cases and 10,000 controls for pooled analysis. This analysis is considering risk factors such as occupation and the etiology of head and neck cancer among non-tobacco users and alcohol abstainers. The consortium will also look at mechanistic factors such as the influence of DNA repair genes, virus infections (such as human papillomavirus (HPV)), and associations with single nucleotide polymorphisms (SNPs). HPV infection has been linked to certain head and neck cancers, such as tonsillar cancer.

b) What are the scientific gaps—what do we not know?

The working group defined the following knowledge gaps:

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?

Like many of the working groups, this one identified both scientific and technical/infrastructure obstacles:

d) What expertise, disciplines, and linkages do we need to "bring to the table" to enhance progress?

DCCPS partnerships were not specifically addressed by this group.

e) What are the partnering opportunities with other DCCPS programs?

The working group singled out the Office of Cancer Survivorship (OCS) and SEER Program. It also suggested caBIG, SPORE-type programs, and collaborations with intramural NCI scientists.

This working group identified a number of priorities for further action:

Appendix E:

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Cancer Site Working Group Report: Hodgkin's Disease and Leukemia

Moderators: Sara S. Strom, Ph.D.;
Co-Chair: Isis S. Mikhail, M.D., M.P.H., Dr.P.H.

Discussion Questions:
a) What is the state of the science—what do we know?

For Hodgkin's disease, risk factors include Epstein-Barr Virus (EBV) and socioeconomic status (SES). This disease also shows a bimodal age distribution, and gender and race differences.

Leukemias are a heterogeneous group for which there is scarce data. A few risk factors are known for certain types, for example, smoking, and chemical and occupational exposures. Leukemias also show gender differences.

b) What are the scientific gaps—what do we not know?

Hodgkin's disease:

Leukemias:

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?

These diseases share many of the same obstacles, according to the working group. Research on both suffers from a scarcity of patients, which could be remedied by inter-institutional and international collaborations. These collaborations should include clinical, epidemiological, and basic researchers. Such collaborations could be facilitated by funding mechanisms that promote multiple grant collaborations and that recognize multiple principal investigators on single grants.

Funding is also an issue for both diseases. This could be eased by increasing Federal funding, and enlisting the help of patient advocacy groups and foundations.

There is a lack of standardized methodologies—for example, control selection and data collection instruments. Collaborations would also be aided by the development of common methodologies. Certain leukemias also present an ascertainment obstacle due to their rapid mortality rates. This problem could be solved by rapid patient identification and enrollment at the time of diagnosis.

d) What expertise, disciplines, and linkages do we need to "bring to the table" to enhance progress?

For Hodgkin's disease, a multidisciplinary team should include virologists, molecular biologists, B-cell biologists, geneticists, immunologists, hematologists, and epidemiologists. For leukemias, the team should include hematologists, epidemiologists, molecular biologists, geneticists, and immunologists.

e) What are the partnering opportunities with other DCCPS programs?

The programs most relevant to these diseases include the Epidemiology and Genetics Research Program (EGRP) and its Analytic Epidemiology Research Branch (AERB), Applied Research Program (ARP), and the Surveillance Research Program (SRP).

This working group identified a number of priorities for further action:

For Hodgkin's disease:

For leukemias:

Appendix F:

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Cancer Site Working Group Report: Non-Hodgkin's Lymphoma, Myeloma, and Kaposi's Sarcoma

Moderators: James R. Cerhan, M.D., Ph.D., and Vaurice Starks, B.S.

Discussion Questions:
a) What is the state of the science—what do we know?

This working group defined a number of areas of knowledge:

  1. Pathobiology—In non-Hodgkin's lymphoma (NHL), malignancy originates mainly in B cells, sometimes in T cells, and rarely in other primary immune cells. Malignancy arises from molecular mistakes resulting from normal physiological responses. In multiple myeloma (MM), MGUS is a known precursor lesion, and cytokines and growth factors appear to be very important. Kaposi sarcoma (KS) is characterized by the presence of HHV-8/KSHV virus in all cases. KSHV has a latency period and codes for several gene products that play a role in cellular transformation.

  2. Classification—WHO classification system (developed to incorporate the revolution in our understanding of immunology) appears to be robust and reproducible. There is some evidence for specific risk factors in specific NHL subtypes. MM has a standard clinical definition. KS is well-classified and often clonal.

  3. Descriptive epidemiology—NHL rates are higher in men than women (a notable exception is follicular NHL) and in Caucasians relative to other racial/ethnic groups. Incidence and mortality rates have increased dramatically since the 1950s. NHL subtypes have different descriptive epidemiologies. For MM, incidence rates are higher in men and in African Americans and Hispanics. Classic KS shows male predominance while HIV-associated KS does not.

  4. Genetic risk factors—NHL shows modest familial influence; the others have limited data in this area.

  5. Environmental risk factors—For NHL, risk factors are EBV, immunosuppression, local inflammation/chronic antigenic stimulation, and HIV. MM is associated with high-dose ionizing radiation. KS is associated with HHV-8/KSHV and immunosuppression.

b) What are the scientific gaps—what do we not know?

Non-Hodgkin's lymphoma

Multiple myeloma

Kaposi's sarcoma

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 group identified a number of scientific obstacles and solutions for each cancer. For NHL and MM, the basic immunology and virology needs to be translated into valid, reliable, robust, and cost-effective measurements for use in epidemiological studies. Exposure assessments for both cancers need to be better developed and standardized. The molecular classification of NHL is incomplete. MM suffers from a lack of funding. KS needs more studies in populations with a high prevalence of KS, which are mostly in developing countries.

Technical and infrastructure needs were many and varied. For NHL, multicenter studies are needed to obtain sufficient sample sizes, particularly to address rarer subtypes. There is a need for prediagnostic specimens. Central pathology review and classification is difficult and expensive, and needs to be standardized. Money is needed to develop infrastructure such as control registries so that population-based controls can be obtained more easily. Access to minority populations is needed.

For MM, the use of prediagnostic specimens and cohort studies requires a very large study size or very long follow up to accrue sufficient cases. Case-control studies are made difficult by high case fatality. There is a need for centralized communication and resources, perhaps by Web portals. MM researchers need better access to minority and non-Western populations. The group suggested that the SPOREs could increase their emphasis on epidemiological projects to alleviate some of these problems.

For KS, there is a lack of research infrastructure in the developing countries where it is most prevalent. This could be alleviated by establishing functional research sites in those countries. These centers could also attract and train needed international collaborators. Another suggestion was to use AIDS cohort studies as a resource for KS research.

For all cancers, there are multiple obstacles to consortium participation (academic recognition; authorship; meaning of independence; indirect costs; review at study section). Funding mechanisms are also problematic (R03 too small; R01 size not flexible enough). Few (or almost no) studies result in slow follow up of promising leads (literature evolves slowly).

d) What expertise, disciplines, and linkages do we need to "bring to the table" to enhance progress?

For all cancers, immunology (better measures of immune function), virology/microbiology (pathogen identification; new models of how pathogens lead to cancer), pathology (classification), molecular biology (relevant pathways), genetics (host, viral, and tumor), epidemiology, bioinformatics, and biostatistics (analysis of complex pathways and interactions).

e) What are the partnering opportunities with other DCCPS programs?

The following suggestions were made:

The working group identified a large number of action items and priorities for each disease:

Non-Hodgkin's lymphoma

Multiple myeloma

Kaposi's sarcoma

General (all three types)

Appendix G:

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Cancer Site Working Group Report: Ovarian and Testicular Cancer Working Group

Moderators: Roberta Ness, M.D., M.P.H., and J. Fernando Arena, M.D., Ph.D.

Discussion Questions:
a) What is the state of the science—what do we know?

The working group concentrated primarily on ovarian cancer, which shows significant heterogeneity of tumors. There are three well-recognized protective effects: child bearing, breastfeeding, and oral contraceptive use. The incidence is approximately 15 per 100,000 and 1.5 percent of women will develop ovarian cancer sometime in their lifetime. There is virtually no cancer under the age 40, and it is less common in African Americans. The presence of BRCA1 and 2 increases the risk of ovarian cancers, and BRCA carriers generally have a lower age of incidence.

b) What are the scientific gaps—what do we not know?

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?

This working group concentrated primarily on the solutions, suggesting that an ovarian cancer consortium be formed. The consortium could perform case-control studies to identify genetic polymorphisms, and cohort studies to identify biomarkers and other prognostic factors, and could pool data and resources. The group suggested using the template of the brain consortium and taking advantage of international studies and active survivor groups. Inclusion of multidisciplinary investigators would promote understanding of the biology of infertility and ovarian cancer.

The group had several other proposed solutions to improve study of ovarian cancer. Members suggested leveraging ongoing clinical trials to gather epidemiological data and using cohorts from other diseases, such as cardiovascular disease. Case-control studies could be used for pooling to examine gene-gene and gene-environment interactions; whereas cohort pooling would be best used for the study of biomarkers. Common data elements and common histologic definitions would also be useful. This group also suggested special study sections for rare cancers.

d) What expertise, disciplines, and linkages do we need to "bring to the table" to enhance progress?

The working group suggested multidisciplinary teams including pathologists, cellular and molecular biologists, epidemiologists, geneticists, immunologists, gynecologists, and oncologists.

e) What are the partnering opportunities with other DCCPS programs?

DCCPS partnerships were not specifically addressed by this group.

The working group identified priorities for both ovarian and testicular cancer:

Ovarian cancer

Testicular cancer

Appendix H:

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Working Group Participants List

Brain and Eye Cancer Working Group

Melissa Bondy, University of Texas M.D. Anderson Cancer Center– Chair
Daniela Seminara, National Cancer Institute – Co-Chair
Emily Dowling, National Cancer Institute – Recorder
Julie Buring, Harvard Medical School
Dominique Michaud, Harvard School of Public Health
John Neuberger, University of Kansas School of Medicine
Judith Schwartzbaum, Ohio State University
Maria Schymura, New York State Cancer Registry
Margaret Wrensch, University of California, San Francisco
David Lee, Sylvester Comprehensive Cancer Center/University of Miami
Manuela Orjuela, Columbia University
James Fisher, Ohio State University
Dora Il'yasova, Duke University Medical Center
Colleen McLaughlin, New York State Department of Health
Peter Inskip, National Cancer Institute
Ania Pollack, University of Kansas School of Medicine
Michael Scheurer, University of Texas M.D. Anderson Cancer Center
Ben Hankey, National Cancer Institute

Endometrial Cancer Working Group

Pamela Horn-Ross, Northern California Cancer Center – Chair
Virginia Hartmuller, National Cancer Institute – Co-Chair
Nancy Emenaker, National Cancer Institute – Recorder
Chu Chen, Fred Hutchinson Cancer Research Center
Immaculata Devivo, Brigham and Women's Hospital/Harvard Medical School
Anne Zeleniuch-Jacquotte, New York University School of Medicine
Jiali Han, Brigham and Women's Hospital/Harvard Medical School
Holly Howe, North American Association of Central Cancer Registries
Susan Reed, Fred Hutchinson Cancer Research Center/University of Washington
Herbert Yu, Yale University School of Medicine
Dana Christo, Johns Hopkins Bloomberg School of Public Health
Jennifer Doherty, Fred Hutchinson Cancer Research Center
Monica McGrath, Brigham and Women's Hospital/Harvard Medical School

Head and Neck Cancer Working Group

Qingyi Wei, University of Texas M.D. Anderson Cancer Center – Chair
Deborah Winn, National Cancer Institute – Co-Chair
Shannon Lynch, National Cancer Institute – Recorder
Gerry Funk, University of Iowa Hospitals and Clinics
Anna Giuliano, H. Lee Moffitt Cancer Center & Research Institute
Karl Kelsey, Harvard School of Public Health
Miriam Rosin, British Columbia Agency Cancer Research Centre
Elaine Smith, University of Iowa College of Public Health
Margaret Spitz, University of Texas M.D. Anderson Cancer Center
Yin Yao, Johns Hopkins University
John Lee, University of Iowa Hospitals and Clinics
Guojun Li, University of Texas M.D. Anderson Cancer Center
Sheila Zahm, National Cancer Institute
Heather Nelson, Harvard School of Public Health

Hodgkin's Disease and Leukemia Working Group

Sara Strom, University of Texas M.D. Anderson Cancer Center – Chair
Isis Mikhail, National Cancer Institute – Co-Chair
Megan Stephan (contractor) – Recorder
Jonine Bernstein, Memorial Sloan-Kettering Cancer Center
Hoda Anton-Culver, University of California, Irvine
Elizabeth Corder, Duke University
Randa El-Zein, University of Texas M.D. Anderson Cancer Center
William Field, University of Iowa
Sally Glaser, Northern California Cancer Center
Thomas Mack, Norris Comprehensive Cancer Center, University of Southern California
Theresa Keegan, Northern California Cancer Center
Xiaomei Ma, Yale School of Medicine
Nancy Mueller, Harvard School of Public Health

Liver, Renal, Esophageal, and Stomach Cancer Working Group

Marilie Gammon, University of North Carolina, Chapel Hill – Chair
Alexander Parker, Mayo Clinic College of Medicine – Chair
Mukesh Verma, National Cancer Institute – Co-Chair
Sheri Schully, National Cancer Institute – Recorder
Joe Patel, National Cancer Institute
Cheryl Marks, National Cancer Institute
Jay Choudhry, National Cancer Institute
Alison Evans, Fox Chase Cancer Center
Sherri Stuver, Boston University School of Public Health
Manuela Gago-Dominguez, Norris Comprehensive Cancer Center/University of Southern California
Marsha Frazier, University of Texas M.D. Anderson Cancer Center
Jinyun Chen, University of Texas M.D. Anderson Cancer Center
Radoslav Goldman, Georgetown University
Karen Pawlish, New Jersey Department of Health and Senior Services
Kathryn McGlynn, National Cancer Institute
Leslie Bernstein, Norris Comprehensive Cancer Center/University of Southern California
Catherine Hoyo, Duke University Medical Center
Jie Lin, University of Texas M.D. Anderson Cancer Center
Christian Abnet, National Cancer Institute

Non-Hodgkin's Lymphoma, Myeloma, and Kaposi's Sarcoma Working Group

James R. Cerhan, Mayo Clinic College of Medicine – Chair
Vaurice Starks, National Cancer Institute – Co-Chair
Carmina Valle, National Cancer Institute – Recorder
Wendy Cozen, Keck School of Medicine, University of Southern California
Elizabeth Holly, University of Southern California, San Francisco
Francine Laden, Harvard School of Public Health
Otoniel Martinez-Maza, David Geffen School of Medicine, University of California
Kenneth Anderson, Dana-Farber Cancer Institute
Graham Colditz, Brigham and Women's Hospital/Harvard Medical School
Charles Wood, Nebraska Center for Virology
Brenda Birmann, Harvard School of Public Health
Paige Bracci, University of California, San Francisco
Christine Skibola, University of California, Berkeley
Shumin Zhang, Brigham and Women's Hospital/Harvard Medical School/Harvard School of Public Health
Mulugeta Gebregziabher, University of Southern California
Dalsu Baris, National Cancer Institute
Jill MacKinnon, Sylvester Comprehensive Cancer Center/University of Miami

Ovarian and Testicular Cancer Working Group

Roberta Ness, University of Pittsburgh – Chair
Fernando Arena, National Cancer Institute – Co-Chair
Scott Rogers, National Cancer Institute – Recorder
Julia Rowland, National Cancer Institute
Daniel Cramer, Brigham and Women's Hospital
Joanne Dorgan, Fox Chase Cancer Center
Susan Hankinson, Brigham and Women's Hospital/Harvard School
Betsy Kohler, New Jersey Department of Health and Senior Services
Leigh Pearce, Norris Comprehensive Cancer Center/University of Southern California
Harvey Risch, Yale University School of Medicine
Joellen Schildkraut, Duke University Medical Center
Victoria Cortessis, University of California, Los Angeles
Stephen Schwartz, Fred Hutchinson Cancer Research Center
Julia Greer, University of Pittsburgh
Kathryn Terry, Brigham and Women's Hospital
Russ Hauser, Harvard School of Public Health
Lynn Rosenberg, Boston University Medical Campus
Yawei Zhang, Yale University
Michael Thun, American Cancer Society
Anita Ambs, National Cancer Institute
Katherine McGlynn, National Cancer Institute