© 2000 by Oxford University Press
Journal of the National Cancer Institute Monographs, No. 27, 157-159,
2000
© 2000 Oxford University Press
Chapter 10: Hope for Prevention—Perspective of the Cancer Advocate
Correspondence to: Elizabeth A. Hart, R.N., B.A., Hart International, 9051 Oak Path Lane, Dallas, TX 75243 (e-mail: hart.elizabeth{at}worldnet.att.net).
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ABSTRACT |
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 TopNotes Abstract Composition of PanelQuestions and ConcernsImmediate Benefits of Current...Intermediate Benefits of Current...Long-Term Benefits of ResearchRisk FactorsHormone ResistanceTranslationFunding of ResearchConclusionReferences |
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Breast and prostate cancer survivors and advocates participated as panelists with scientists in an interactive panel discussion following 2 days of scientific presentations on "Estrogens as Endogenous Carcinogens in the Breast and Prostate." Advocates raised several issues of concern and questions related to the research presented. Concerns included the following: 1) a global fear of developing either breast or prostate cancer and recurrence from these tumors, 2) a specific fear that estrogen replacement therapy could enhance the development of new breast cancers and stimulate recurrence in breast cancer survivors, and 3) a concern that researchers examining minority communities should have sensitivity to the specific culture under study and an understanding of specific research issues that are relevant in those communities. The questions raised included the following: 1) What are the implications of resistance to antiestrogen therapies and what is the appropriate sequencing of hormone therapy for longer-term benefit? 2) Can one identify women and men at risk for cancer who do not have the usual risk factors? 3) Where does the development of blood or urine tests to screen for cancer currently stand? 4) Can research findings be translated into effective therapies more rapidly? 5) Can the status of this translational process be communicated to the public in a meaningful way by breaking down language barriers? 6) What means are available to develop more creative ways to fund pilot studies that do not require preliminary data and to create new funding mechanisms to respond to the needs of scientists, particularly those that work collaboratively from multiple institutions and multidisciplines? 7) How can the need for increased emphasis on and visibility for prostate cancer be communicated? Following the interactive dialogue, scientists and advocates suggested more collaborative research with sustained funding avenues, continued dialogue and collaboration between scientists and advocates, and more collaborative research groups like the Cancer Cube.
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COMPOSITION OF PANEL |
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TopNotesAbstractComposition of PanelQuestions and ConcernsImmediate Benefits of Current...Intermediate Benefits of Current...Long-Term Benefits of ResearchRisk FactorsHormone ResistanceTranslationFunding of ResearchConclusionReferences |
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A multidisciplinary panel, chosen to create a dialogue between scientists and patient advocates, discussed concepts arising from 2 days of intense scientific discussion at a meeting held on March 16–17, 1998, entitled "Estrogens as Endogenous Carcinogens in the Breast and Prostate." This landmark meeting was convened by a collaborative group called "The Cancer Cube," which is interested in demonstrating the causes of breast and prostate cancer. Panelists included the following:
- a young breast cancer survivor diagnosed at age 38 years,
- a breast cancer survivor with metastatic disease,
- a prostate cancer survivor with a brother and father (deceased) diagnosed with the disease,
- a prostate cancer advocate charged with the development of prostate cancer support groups nationwide and advocacy on behalf of those with prostate cancer,
- a high-risk individual with multiple family members either deceased or surviving breast, prostate, kidney, uterine, throat, and lung cancer.
- a scientist expert in chemical carcinogenesis,
- a scientist expert in clinical/translational sciences, and
- a scientist expert in hematology, oncology, and endocrinology.
In addition, all scientists (both presenting and in the audience) and advocates participated in an interactive dialogue following brief presentations by panel members. Advocates on the panel listened to the research presented for 2 days and then articulated issues important to the advocacy community and to the public at large relating to the presentations.
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QUESTIONS AND CONCERNS |
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TopNotesAbstractComposition of PanelQuestions and ConcernsImmediate Benefits of Current...Intermediate Benefits of Current...Long-Term Benefits of ResearchRisk FactorsHormone ResistanceTranslationFunding of ResearchConclusionReferences |
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The issue of cancer prevention is the most critical concern to breast and prostate cancer survivors, their families, advocates, and the public at large. The rapid advances in cancer research in recent years raise expectations that an answer may well be forthcoming in the not-too-distant future. For some, the answer will come too late. Within the advocacy community and the public, there is a tremendous sense of urgency to advance research from the laboratory to the clinical setting as quickly as possible. Fear was an underlying theme throughout the discussion: fear of cancer in general and fear of recurrence. A specific fear related to the possibility that estrogen replacement therapy could increase the risk of developing new breast cancers and the rate of recurrence in breast cancer survivors (1).
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IMMEDIATE BENEFITS OF CURRENT RESEARCH |
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TopNotesAbstractComposition of PanelQuestions and ConcernsImmediate Benefits of Current...Intermediate Benefits of Current...Long-Term Benefits of ResearchRisk FactorsHormone ResistanceTranslationFunding of ResearchConclusionReferences |
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Recent development of "designer antiestrogens" and use of surrogate drugs to give the benefits of estrogen without using estrogen itself were considered to be important practical advances. These approaches could immediately benefit patients. Designer estrogens that act positively to reduce bone loss, subsequent osteoporosis, and bone fractures, and yet do not adversely affect the breast, are now available (1). The potential of these agents to prevent cardiovascular disease is currently under study.
Following in this same vein are compounds that are being developed and tested as new antiestrogens. The potential is for longer-term benefit to women with metastatic breast cancer whose hormone-dependent tumors have become resistant to the standard antiestrogens (1). Blocking estrogen production with aromatase inhibitors, such as anastrazole (Arimadex) and letrozol (Femara), continues to provide benefit to patients whose tumors are resistant to standard antiestrogens. "Pure" antiestrogens, which do not have the potential to exert estrogen-like effects on certain tissues, are under study. These agents appear to be promising for the treatment of women whose breast tumors are resistant to tamoxifen. It has been suggested that some combination of these therapies, tailored to the individual's particular parameters, can extend the benefits of hormonal therapy.
Quality of life is an important issue for women surviving breast cancer. A number of treatments are currently available to alleviate estrogen-deficiency symptoms experienced by these women and to serve as surrogates for estrogen. As examples, the bisphosphonates act to prevent osteoporosis, the statin drugs lower cholesterol and ultimately prevent heart disease, low-dose vaginal estrogens provide relief from urogenital atrophy, and antidepressants deal with depression exacerbated by estrogen deficiency in susceptible individuals (1).
For prostate cancer survivors who experience medical or surgical castration and have vasomotor instability, many have benefitted from the administration of Clonidine or Megace. Again, the bisphosphonates are useful in treating osteoporosis in settings where androgens and estrogens are deficient (2).
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INTERMEDIATE BENEFITS OF CURRENT RESEARCH |
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TopNotesAbstractComposition of PanelQuestions and ConcernsImmediate Benefits of Current...Intermediate Benefits of Current...Long-Term Benefits of ResearchRisk FactorsHormone ResistanceTranslationFunding of ResearchConclusionReferences |
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Research presented offering intermediate benefits (research in process and not yet available for immediate application) to breast and prostate cancer survivors involves the continuing development of new drugs acting as hormonal antagonists. Some of these work specifically on the
-estrogen receptor and might have beneficial estrogen effects without having detrimental effects on the breast. For the prostate, researchers are beginning to look at the use of aromatase inhibitors in men with advanced prostate cancer. This approach is based on the hypothesis that there are mutations of the androgen receptor in advanced prostate cancer that make the receptors promiscuous in the sense that they are stimulated to a greater extent with estrogen than with androgen (1). |
LONG-TERM BENEFITS OF RESEARCH |
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TopNotesAbstractComposition of PanelQuestions and ConcernsImmediate Benefits of Current...Intermediate Benefits of Current...Long-Term Benefits of ResearchRisk FactorsHormone ResistanceTranslationFunding of ResearchConclusionReferences |
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For the long term, the hope is to prevent breast and prostate cancers. Greater understanding of the metabolic activation of estrogens in the body may suggest potential new prevention strategies. Scientists at the meeting suggest that certain metabolites of estrogen, both exogenous and endogenous, can generate mutations that could lead to cancer (Chapters 3 and 4). The theory suggests that estrogen receptor-mediated processes would allow these mutations to be propagated. Estrogens acting through receptors could induce cellular proliferation and increase the replication of mutated genes. Together, the genotoxic and cell proliferative effects of estrogen would enhance the process of cellular transformation and, eventually, cause cancer (see Symposium Overview).
Metabolic activation of estrogens involves the formation of catechol estrogen metabolites (products of estrogen metabolism, Chapter 5), which, when oxidized in a specific pathway, bind to DNA. These DNA–estrogen complexes cause depurination of DNA (adenine and guanine bases that fall out of DNA) and other DNA damage that leads to tumor initiation (Chapter 4). There is mounting evidence that the pathway leading to the formation of 4-hydroxy estrogens (carcinogenic in animals) is the real culprit, particularly when the enzymes (catechol-O-methyltransferases) that normally neutralize these products of estrogen metabolism are not present or are present at very low levels and, therefore, are not effective protectors (3–6). Of interest, the 2-hydroxylated estrogens, the major products of estrogen oxidation in mammalian species, form stable DNA adducts and are not carcinogenic (3–5). If these concepts are borne out, both breast and prostate, as well as other cancers, would share the same initiation process. The implications for prevention are immediate: inhibit metabolic activation of estrogens (particularly to 4-hydroxy estrogens) and enhance their metabolic protection (3,4).
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RISK FACTORS |
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TopNotesAbstractComposition of PanelQuestions and ConcernsImmediate Benefits of Current...Intermediate Benefits of Current...Long-Term Benefits of ResearchRisk FactorsHormone ResistanceTranslationFunding of ResearchConclusionReferences |
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Another issue of significance to advocates was the ability to identify women early on who do not have the usual risk factors. It was considered important as well to utilize blood or urine tests to screen for cancer. There are currently studies in process looking at biomarkers of DNA damage prior to the development of breast cancer, one of which is a blood assay indicating the presence of high anti-HmdU (5-hydroxymethyl-2'-deoxyuridine: an oxidized thymidine) autoantibody titers in healthy women with a family history of breast cancer (7). This would permit the screening of individuals prior to the clinical manifestation of cancer and provide the possibility of prevention.
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HORMONE RESISTANCE |
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TopNotesAbstractComposition of PanelQuestions and ConcernsImmediate Benefits of Current...Intermediate Benefits of Current...Long-Term Benefits of ResearchRisk FactorsHormone ResistanceTranslationFunding of ResearchConclusionReferences |
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Resistance to antiestrogen therapy and the appropriate sequencing of hormone therapy for longer-term benefit was discussed at length as a major issue. Clearly, there is benefit to complete blockage of estrogen in individuals relapsing on tamoxifen (Nalvodex) in some settings, yet, in other settings, it is inappropriate to begin with complete estrogen blockade and then expect an antiestrogen to work effectively. So, the most effective sequence for maximum benefit over time seems to be the treatment with adjuvant antiestrogens that are strong antagonists but weak agonists, followed later on by a pure antiestrogen (1).
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TRANSLATION |
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TopNotesAbstractComposition of PanelQuestions and ConcernsImmediate Benefits of Current...Intermediate Benefits of Current...Long-Term Benefits of ResearchRisk FactorsHormone ResistanceTranslationFunding of ResearchConclusionReferences |
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In addition to the specific research issues raised, advocates focused on translating research findings to the public in a meaningful way. How could one break down the language barrier between scientists, advocates, and the public at large? Advocates have become increasingly involved in the research process in the last 10 years, having successfully led the push for increased funding for cancer research, having participated in peer review of basic, clinical, and translational research proposals [(8); Andejeski Y, Sharp-Breslau E, Hart E, Lythcott N, Alexander L, Rich I, et al.: manuscript in preparation for publication], and are increasingly included on policy, review, and decision-making bodies. They read the scientific literature. Many have large constituencies in need of accurate research information that is readily available in layman's terms and can be easily disseminated to the public. Scientists were urged to begin to break through the language barrier with the idea of making research findings readily accessible to the lay individual in terms that they could understand. Advocates want to be involved and to help in moving research forward on the fastest track possible, including assistance with funding.
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FUNDING OF RESEARCH |
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TopNotesAbstractComposition of PanelQuestions and ConcernsImmediate Benefits of Current...Intermediate Benefits of Current...Long-Term Benefits of ResearchRisk FactorsHormone ResistanceTranslationFunding of ResearchConclusionReferences |
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Funding of research was a major point of discussion. Advocates felt that more creative ways of funding pilot studies should be forthcoming. Funding of those studies should not necessarily require preliminary data. At the moment, limited ways of funding exist for pilot studies that can subsequently lead to applications for more traditional funding. Collaborative efforts such as the Cancer Cube (see Introductory Remarks) have an equally difficult time finding appropriate funding mechanisms, although efforts are being made by the National Cancer Institute (Bethesda, MD) to address this issue. Members of the Cancer Cube, which include an advocate, work in multiple research centers. Collaboration among centers provides a unique way to enhance research because it allows wide sharing of specific expertise and cutting-edge technology. Highly technical resources are shared, and specific objectives are chosen by the group to advance research more efficiently and effectively.
Funding of research on prostate cancer remains definitively lower than that of breast cancer or acquired immunodeficiency syndrome (AIDS). In the 1997/1998 Labor HHS Appropriation, signed in November 1997, prostate cancer received approximately $89.5 million compared with $348.6 million in breast cancer, with AIDS at $226.4 million (9). Prostate cancer needs more visibility, as do a number of other cancers. However, the advocates and scientists both felt strongly that one disease should not be pitted against another. The need is to figure out how to raise sufficient monies to fund the necessary basic, clinical, and translational research which, in specific instances, has applicability in a number of diseases, not just breast or prostate cancer. It is important as well to have trained researchers from and in minority communities, who have sensitivity to the culture and understanding of specific research issues that are relevant in those communities. The U.S. Department of Defense is currently conducting a consensus conference strategy to develop a blueprint for including training of minority researchers at the predoctoral through postdoctoral level.
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CONCLUSION |
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TopNotesAbstractComposition of PanelQuestions and ConcernsImmediate Benefits of Current...Intermediate Benefits of Current...Long-Term Benefits of ResearchRisk FactorsHormone ResistanceTranslationFunding of ResearchConclusionReferences |
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The interactive dialogue between scientists and advocates was bold and enlightening, with articulation from both groups as to needs, cooperative efforts, and future directions. Advocates suggested more collaborative "Cubes" and creative funding mechanisms, while scientists suggested more collaborative research with sustained funding avenues and continued dialogue and collaboration with advocates. It was expressed and abundantly clear that both advocates and scientists share an equal passion for finding a cure and, even more important, preventing the initiation of breast and prostate cancers, as well as other cancers.
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NOTES |
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The Panel Members include the following: chair— Elizabeth A. Hart, President & CEO, Hart International, Dallas, TX; moderator—David G. Longfellow, Ph.D., Chief, Chemical & Physical Carcinogenesis Branch, Division of Cancer Biology, National Cancer Institute (NCI), Bethesda, MD; panel members—Winston Dyer, Community Coordinator of Minority Clinical Trials, CaP CURE, New York, NY; Carol Hochberg, Board Member and Committee Chairman of the Advocacy and Public Policy Committee of SHARE, New York, NY; Edison Liu, M.D., Ph.D., Director of Clinical Sciences, NCI; M. Brooke Moran, Director of Patient Advocacy and Government Affairs for the American Foundation for Urologic Disease, Baltimore, MD; Diana Rowden, Chairman of the Board of the Susan G. Komen Breast Cancer Foundation, Dallas; and Richard Santen, M.D., Professor, Division of Hematology, Oncology and Endocrinology, University of Virginia Health Science Center, Charlottesville.
I gratefully acknowledge all members of the Cancer Cube for their warm inclusion of an advocate in the formation and continuing work of the group and specifically Joachim Liehr, Ercole Cavalieri, Eleanor Rogan, David Longfellow, and Richard Santen for their counsel in preparation of this manuscript.
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REFERENCES |
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TopNotesAbstractComposition of PanelQuestions and ConcernsImmediate Benefits of Current...Intermediate Benefits of Current...Long-Term Benefits of ResearchRisk FactorsHormone ResistanceTranslationFunding of ResearchConclusionReferences |
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1
The Hormone Foundation, The Susan G. Komen Breast Cancer Foundation, Canadian Breast Cancer Research Initiative, National Cancer Institute of Canada, Endocrine Society, and the University of Virginia Cancer Center, Woman's Place. Consensus statement. Treatment of estrogen deficiency symptoms in women surviving breast cancer. J Clin Endocrinol Metab 1998;83:1993–2000.
2 Santen RJ, Borwhat M, Gleason S, Gore MJ, editors. Menopause-treatment options for women surviving breast cancer or concerned about estrogen replacement therapy. The Hormone Foundation, June 1998.
3 Liehr JG. Dual role of estrogens as hormones and pro-carcinogens: tumor initiation by metabolic activation of estrogens. Eur J Cancer Prev 1997;6:3–10.[CrossRef][Web of Science][Medline]
4
Cavalieri EL, Stack DE, Devanesan PD, Todorovic R, Dwivedy I, Higginbotham S, et al. Molecular origin of cancer: catechol estrogens-3,4-quinones as endogenous tumor initiators. Proc Natl Acad Sci U S A 1997;94:10937–42.
5 Stack DE, Byun J, Gross ML, Rogan EG, Cavalieri EL. Molecular characteristics of catechol estrogen quinones in reactions with desoxyribonuncleosides. Chem Res Toxicol 1996;9:851–9.[CrossRef][Web of Science][Medline]
6
Service RF. New role for estrogen in cancer? Science 1998;279:1631–3.
7 Frenkel K, Karkoszka J, Glassman T, Dubin N, Toniolo P, Taioli E, et al. Serum autoantibodies recognizing 5-hydroxymethyl-2'-deoxyuridine, an oxidized DNA base, as biomarkers of cancer risk in women. Cancer Epidemiol Biomarkers Prev 1998;7:49–57.[Abstract]
8 Waller M, Batt S. Advocacy groups for breast cancer patients. CMAJ 1995;152:829–33.[Abstract]
9 Labor, Health and Human Services Appropriation 105-78, November 1997.
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