AGING WOMEN AND BREAST CANCER Release Date: October 5, 1999 PA NUMBER: PA-00-001 National Institute on Aging National Cancer Institute National Institute of Nursing Research THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO THE STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA. PURPOSE This program announcement (PA) replaces PA-96-034, which was published in the NIH Guide, Vol. 25, No. 12, April 19, 1996. The National Institute on Aging (NIA), the National Cancer Institute (NCI), and the National Institute of Nursing Research (NINR) invite research applications to focus on the unique problems of older women with breast cancer. Breast cancer affecting elderly women is a major health problem. The purpose of this broad-based program announcement is to expand the knowledge base on breast cancer in older women through studies in the fields of biology, clinical medicine, epidemiology, and the behavioral and social sciences. HEALTHY PEOPLE 2000 Each NIH PA addresses one or more of 22 Health Promotion and Disease Prevention priority areas identified. These areas can be found via the WWW at http://odphp.osophs.dhhs.gov/pubs/hp2000 ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The mechanisms of support will be the individual research project grant (R01), exploratory/developmental grant (R21), and the Small grant (R03). Responsibility for planning, direction, and execution of the proposed project will be solely that of the applicant. For all competing individual research project grant (R01), small grant (R03) and exploratory developmental grant (R21) applications requesting up to $250,000 direct costs per year, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by NIH. Complete and detailed instructions and information on Modular Grant applications can be found at: https://grants.nih.gov/grants/funding/modular/modular.htm. Applications that request more than $250,000 in any year must use the standard PHS 398 (rev. 4/98) application instructions. RESEARCH OBJECTIVES Background Of the 175,000 new breast cancer cases estimated for 1999, over 82,000 will be in women 65 years or older (American Cancer Society, 1999). As national incidence and mortality data show, aging is an important risk factor for breast cancer. Age-adjusted rates reported by the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) Program reveal that women 65 years or older have an incidence rate of 440.6 per 100,000 population as compared to 74.5 per 100,000 for women under 65 years of age. The peak breast cancer incidence rate of 483.3 per 100,000 is in the age group 75-79 years. The breast cancer mortality rate for women under 65 years of age is 14.7 per 100,000 as compared to the rate for women 65 years and older which is 122.9 per 100,000. The peak mortality rate is 200.5 per 100,000 for women 85 years and older (SEER, 1999). This population-based epidemiologic evidence demonstrates the disproportionate number of older-aged women afflicted with breast cancer. Yet, there is insufficient information on biological mechanisms affecting the onset and progression of cancer in older women, recommended treatment, response of older women to cancer risks and symptoms, individual and family coping with breast cancer, and survival outcome (including quality of life). The dearth of data on these issues makes it difficult to provide answers to the many questions that arise about breast cancer in older women. The problems of breast cancer and its association with advanced age have not been adequately addressed. Breast cancer prevention, early detection, and management in older women may be complicated by the presence of other diseases, age-associated problems, and risk factors. No comprehensive guidelines for prevention, diagnosis, pretreatment evaluation, or treatment have been formulated which take into account the multiple health problems and recurrent medical, economic, and social needs of women age 65 and older who survive breast cancer or are newly diagnosed with the disease. Although older women are less likely to engage in cancer prevention practices such as mammography screening, little research has promoted the development of strategies to improve either patient or physician behavior to encourage communication about cancer prevention. Sufficient data on the treatment of elderly women with breast cancer are not available from clinical trials. With the changing age and ethnic profiles in the United States which project an expansion of the aged female population in coming decades, there is an even greater need to address the problems of breast cancer control for older women. The targeted areas of research relevant to this multidisciplinary solicitation are identified below. Biology --- Age-related factors in carcinogenesis. Applicants are encouraged to focus on biological factors that contribute to the increased incidence of breast cancer in older women and/or affect treatment outcome. The following examples are illustrative, but not exclusive: o The control of repair and cell death "programs," and how that relates to cell senescence, aging and cancer (e.g., research on BPH, caloric restriction, lymphocyte selection, cell loss), o Any age-related biological factors that affect the initiation, promotion, or treatment of cancer, including protein or gene therapy(e.g., research on control of telomerase expression, oxidative damage, mitochondrial function), o Age-related differences in invasion and metastases of breast cancer in older women, o Cell senescence in breast tissue, and age-related changes in gene expression affecting predisposition to cell immortalization, o Age-related differences in drug sensitivity and metabolism, o Age-related changes in sensitivity to systemic and local hormones, growth factors, and cytokines on breast cell proliferation and carcinogenesis, o Age-related changes in secretion of hormones, growth factors, and cytokines by breast tissue which act in a paracrine manner to alter the secretion of growth-promoting factors from nearby adipose andstromal tissues. o Age-related differences in stress, pain, and mood which contribute to the functional impairment of neuroendocrine, neuroimmunology, and neurotransmitter systems. Clinical Medicine --- The full range of prevention and treatment issues that involve screening, early detection, diagnosis, perioperative and/or postoperative management, adverse physical influences on surgical outcome, and influence of age on physician/surgeon treatment decisions for operative risk. Research questions centering on these processes may be addressed individually or combined. While related issues designated by the applicant will be considered, the following topics are of major interest to the NIA, NCI, and NINR: o Testing new interventions or treatment strategies, in older women especially, in the presence of patients" comorbid conditions to reduce age- associated complications or lessen age-associated reduction in treatment efficacy (as measured by treatment outcomes such as quality of life, functional status, and/or survival experience), o Age-associated and ethnicity-associated differences in breast cancer treatment efficacy and effectiveness for such outcomes as survival rates, treatment complications, side effects of treatment, and functional status, o Factors responsible for differences in treatment received (e.g., stage at diagnosis, presence of comorbid conditions, age selection bias by physicians) and the effects of interactions among such factors, o Special features of aging and/or symptoms of illness in old age that influence the treatment and care of older-aged breast cancer patients and relate to treatment differences or modifications made because of old age, o Assessment of the effectiveness of different treatments relative to the stage of disease and characteristics of old age (e.g., poor repair mechanisms, functional loss, greater susceptibility to toxicity of treatment), o Evaluation of tolerance and response to standard or experimental adjuvant chemotherapy regimens or multimodality breast cancer treatment interventions, controlling for physiologic parameters and other factors, o Effects of age-associated, cultural, and life-style changes on sensitivity, specificity, prognostic value, and predictive value for treatment responsiveness, of breast cancer screening and diagnostic techniques (e.g., mammography, MRI, gross and histopathologic breast and lymph node biopsy measures, receptor assays). Testing new methods and technologies to reduce age-associated problems in diagnosis and prognosis, o Barriers to recruitment of older women to breast cancer clinical trials (e.g., comorbid conditions, physical frailty, lack of transportation). o Studies designed to examine the impact of mental health interventions on the treatment outcomes and treatment costs for comorbid breast cancer in older women, with a focus on special populations (e.g., oldest-old, nursing home populations, minorities, older women diagnosed with genetic markers), o Exploration of the interaction of aging, the pharmacodynamics and pharmacokinetics of medications (e.g., anti-estrogen therapeutics and other types of chemotherapy) used to treat breast cancer, on mood and other measures of mental status in older women. Epidemiology --- Studies in the context of aging and/or old age that (1) investigate risk factors in cancer etiology, (2) evaluate methods of prevention, (3) elucidate the pattern of breast cancer as an illness for patients, and (4) improve clinical effectiveness of the diagnostic and management processes for older-aged women breast cancer patients. Studies may focus on the etiology of breast cancer in combination with data from other disciplines such as genetics and molecular epidemiology, or on issues in epidemiology and clinical practice that represent pressing clinical problems. o Relationships and interactions of aging and age to breast cancer risk (e.g., relative prominence of various physiologic and etiologic risk factors at different ages, factors affecting risk and age of onset of breast cancer in high-risk individuals), o Improved methods to identify high risk older women through development of new techniques to distinguish premalignant changes from nonmalignant age- associated changes in breast tissue, o Development of epidemiologic approaches addressing the possible role of related changes such as hormonal status, both endogenous and exogenous (exercise, education, nutrition, and immune function) as risk factors for breast cancer in women, o Prospective studies on the early detection, diagnosis, and treatment of aged breast cancer patients, o Analyses of existing databases applicable and relevant to addressing treatment of older women breast cancer patients. Emphasis on older ethnic populations is encouraged, o Effects of previous and/or concurrent illnesses on breast cancer treatment recommendations, o Occurrence of second breast cancer primaries: synchronous (two or more cancers present at the same time) and/or metachronous (first cancer followed by a second tumor at a later date), o Validation of new methodologies to identify high-risk older women, o Molecular epidemiology and epidemiologic studies of age- related biological factors that affect the onset, progression, metastatic behavior, and mortality outcome of breast cancer in older women, Behavioral and Social Sciences --- Special concerns include health behaviors and beliefs about aging and breast cancer, interactions between health professionals and older people, effects of breast cancer on psychosocial and physical functioning, sociodemographic factors related to breast cancer prevention in older women, long-term care for older women with breast cancer, and the complex interactions among aging, breast cancer and psychosocial disease, and gender influences. Research is also needed on older people"s attitudes toward breast cancer and aging, age differences in current cancer- related behaviors (e.g., willingness to obtain or prescribe a mammogram), strategies for encouraging doctor-patient interactions and treatment decisions, and the effects of living with cancer in later life. Researchers are invited to make age comparisons and to look at aging processes across the life course. Specific behavioral and social research issues of interest are listed. Related issues will be considered. o How age (e.g., aging processes or age-related attitudes or behaviors) affects the diagnosis, treatment and care of persons with breast cancer, o How age interacts with race, ethnicity, and socioeconomic status(SES) to affect attitudes and behavior and consequent diagnosis, treatment, and care, o Strategies for promoting behavioral change by older women and their health care providers to increase preventive health behaviors, and how to implement such changes on community-wide basis over long periods of time (e.g., institutional and financial incentives as in coverage for mammograms), o Social and behavioral processes and interventions in symptom recognition of breast cancer, as well as interpretation and action for cancer-related symptoms in older women, o Doctor/older patient interactions and their influence on breast cancer- related behaviors. Strategies for improving cancer related communications, adherence to medical and life-style recommendations, and encouraging appropriate health utilization and functional outcomes, o Behavioral and social factors affecting cancer treatment decisions (e.g., joint influence of age, SES, and race/ethnicity as well as patient preferences, payer source, coverage), o Self-management interventions for coping with breast cancer, such as increasing self- efficacy regarding cancer treatment and employing pain management strategies, o Relationship of community and area level factors (e.g. location and availability of preventive diagnosis and treatment services)independent of, or in interaction with, sociodemographic and psychosocial characteristics of older women that affect diagnosis, treatment, self-care, and family caregiving, o Consequences of cancer in older women for household arrangements and the provision of resources by family and social network members, o Strategies to reduce caregiver burden and how caregiving is influenced by age, family and household structure and composition, and the economic and social burdens caregiving imposes. o Strategies that combine information sharing with psychosocial support to aid patients/caregivers facing complex health related decisions. o Clarification of the relationships and interactions of aging, biologic and psychosocial factors which contribute to the comorbidity of breast cancer and mental disorders in older women (e.g., late onset depression, early onset depression with recurrent episodes, schizophrenia, etc.) and how these factors contribute to the course, diagnosis and treatment of both illnesses. Although not a formal sponsor of this PA, the National Institute on Mental Health (NIMH) is interested in receiving applications if comorbid cancer and mental disorders in women such as depression or anxiety are the focus of study. Of particular interest are studies of risk, course, and outcome that inform the development of new interventions aimed at mental disorders, symptoms, or related disability. The interventions may be prevention, treatment, or rehabilitation. For more information, see the NIMH program announcement, PA-99-071, "Research on Co-Morbidity: Etiology and Prevention" at http://www.nimh.nih.gov/grants/pamenu.htm. Please contact Peter Muehrer, Ph.D., Health and Behavioral Sciences Research Branch, NIMH, at 301/443-4708, Email: [email protected]. DEFINITION OF "OLD AGE" OR "ELDERLY" FOR THIS PROGRAM ANNOUNCEMENT This PA focuses in particular on women aged 65 years and older because the highest cancer incidence and mortality rates are found in this age group. Also, women in their mid- seventies and older are generally those most severely affected by breast cancer and are already quite likely to have preexisting chronic conditions. However, the definition of "old age" or "elderly" is flexible and dependent on investigator- defined parameters. Applicants are expected to identify what is meant by "old" in the context of their research. Age comparisons with younger women are appropriate and maybe included. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994, https://grants.nih.gov/grants/guide/notice-files/not94-100.html APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98). Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, Phone (301) 710-0267, Email: [email protected]. Applications are also available on the internet at https://grants.nih.gov/grants/funding/phs398/phs398.html Submit a signed, typewritten, original of the application, including the checklist and five signed photocopies in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: https://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years, - List selected peer-reviewed publications, with full citations. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. o Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? o Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? o Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? o Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? o Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program priority INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Rosemary Yancik, Ph.D. Cancer Section, Geriatrics Program National Institute on Aging Gateway Building, Suite 3E327 7201 Wisconsin Avenue Bethesda, MD 20892-9205 Telephone: (301) 496-5278 FAX: (301) 402-1784 Email: [email protected] Claudette G. Varricchio, DSN, RN, OCN, FAAN Division of Cancer Prevention and Control National Cancer Institute Executive Plaza North, Suite 300 Bethesda, MD 20892 Telephone: (301) 496-8541 FAX: (301) 496-8667 Email: [email protected] Janice Phillips, Ph.D., R.N. Program Director National Institute of Nursing Research Building 45, Room 3AN12 Bethesda, MD 20892-6300 Telephone: (301) 594-6152 FAX: (301) 480-8260 Email: Janice_Phillips@ nih.gov Direct inquiries regarding fiscal matters to: Mr. Joseph Ellis Grants and Contracts Management Office National Institute on Aging Gateway Building, Suite 2N212 7201 Wisconsin Avenue, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: [email protected] Mr. Robert E. Hawkins, Jr. Grants Administration Branch National Cancer Institute Executive Plaza South, Room 243 Bethesda, MD 20892 Telephone: (301) 496-7800 Ext. 213 FAX: (301) 496-8601 Email: [email protected] Mr. Jeff Carow Grants Management Office National Institute of Nursing Research Building 45, Room 3AN-32 Bethesda, MD 20892-6301 Telephone: (301) 594-5974 FAX: (301) 480-8256 Email: [email protected] AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.866. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410), as amended by Public Law 99-158, 42 USC 241 and 285) and administered under PHS grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.

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