BREAST CANCER IN THE NORTHEASTERN AND MIDDLE ATLANTIC UNITED STATES

NIH GUIDE, Volume 22, Number 2, January 15, 1993



PA NUMBER:  PA-93-39



P.T. 34



Keywords:

  Cancer/Carcinogenesis 

  Biomedical Research, Multidiscipl 

  Genetics 

  Biology, Molecular 

  Immunology 

  Nutrition/Dietetics 



National Cancer Institute



PURPOSE



Despite significant strides in prevention, diagnosis, and treatment,

breast cancer continues to be a leading cause of death in the United

States.  It has been estimated that approximately 46,000 women will

die of breast cancer in the United States in 1993 and that about 18

percent of all female cancer deaths in the U.S. will be due to

malignancies of the breast.  The average annual U.S. mortality rate

for breast cancer is 27.5 per hundred thousand.  Of particular

concern are recent data that point to an unexplained increase in

breast cancer incidence, and to breast cancer mortality rates that

exceed the national average, among women residing in certain of the

northeastern and mid-Atlantic states.



In the Report of the Senate Committee on Appropriations, regarding

the bill (H.R. 5677) making Fiscal Year 1993 appropriations for the

Departments of Labor, Health and Human Services, Education and

Related Agencies, there was included the following language:  "The

Committee is concerned by the high breast cancer mortality rates in

the northeastern and mid-Atlantic regions of the country and directs

the National Cancer Institute to conduct a study with update for four

succeeding years for the purpose of determining the factors

contributing to the high breast cancer mortality rates in

Connecticut, Delaware, Maryland, Massachusetts, New Hampshire, New

Jersey, New York, Rhode Island, Vermont and the District of

Columbia."



The National Cancer Institute (NCI) has devoted, and will continue to

devote, significant resources to studies of breast cancers.  However,

not only does a great deal remain to be accomplished so that more

effective preventive, diagnostic, and therapeutic modalities can be

established, but more emphasis on pertinent basic research is also

necessary.  This Program Announcement (PA) is one of several

initiatives that serve to notify and reaffirm to the scientific

community the continuing commitment of the NCI to expanding research

support in basic and applied studies of the etiology, biology and

immunology, genetic regulation, diagnosis, treatment, assessment of

demographics, patterns of care, and strategies for control and

prevention of breast cancer, but specifically to identify, as a

matter of the highest Institute priority, the support of such studies

as they may apply to populations within the localities identified in

the Congressional language cited above.  Research under this program

announcement also may include data collection, statistical analysis

and mathematical modeling, health services research, and information

database linkage studies to monitor progress toward cancer control.



HEALTHY PEOPLE 2000



The Public Health Service (PHS) is committed to achieving the health

promotion and disease prevention objectives of "Healthy People 2000,"

a PHS-led national activity for setting priority areas.  This PA,

Breast Cancer in the Northeastern and Middle Atlantic U.S., is

related to the priority area of cancer.  Potential applicants may

obtain a copy of "Healthy People 2000" (Full Report:  Stock No.

017-001-00474-0) or "Healthy People 2000" (Summary Report:  Stock No.

017-001-00473-1) through the Superintendent of Documents, Government

Printing Office, Washington, DC 20402-0325 (telephone 202-783-3238).



ELIGIBILITY REQUIREMENTS



Research grant applications may be submitted by domestic and foreign,

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.

Applications are encouraged from, but not limited to, sites with

direct access to the affected populations in the Northeastern United

States.  Further, the NCI is especially interested in receiving

applications from women and from minority investigators.  Foreign

institutions are not eligible for the First Independent Research

Support and Transition (FIRST) (R29) award.



MECHANISMS OF SUPPORT



Support of this program will be through the research project grant

(R01) or the First Independent Research Support and Transition

(FIRST) award (R29) as well as through competing supplemental awards

to currently active research project grants (R01) or Method to Extend

Research in Time (MERIT) awards (R37).  While there is no limit or

cap on the amount of total cost of an individual award under this

program, it is anticipated that the average annualized direct cost of

awards made under this PA will be approximately $35,000 for competing

supplements, $75,000 for FIRST awards and $150,000 for new research

project grants.  Investigators holding active R01 or R37 grants to

study breast cancer or related subjects, with at least one year of

support remaining at the time of the anticipated award, or

individuals desiring to apply for support under the R01 or R29

mechanisms, are specifically encouraged to apply for grants citing

this program announcement.



RESEARCH OBJECTIVES



The purpose of this program is to provide support for investigators

to pursue promising avenues of research addressed to breast cancer

incidence and mortality occurring in the aforementioned geographical

areas.  Studies may directly involve populations within this

geographical area, e.g., in clinical investigations, or may be

concerned with the full range of biological, genetic, environmental,

occupational, behavioral or clinical factors that may be relevant to

the disease in these populations.



Topics of interest include:



o  studies of whether or not excess mortality can be identified as a

direct consequence of excess incidence in these jurisdictions or is

due entirely or in part to other factors, such as late stage at

diagnosis or problems with access or availability of good quality

care;



o  delineation of demographic characteristics, including prevalence

of personal, family, or socioenvironmental risk factors that could be

expected to result in higher than average incidence rates, such as

age at menarche, age at first birth, use of exogenous hormones,

and/or dietary patterns;



o  assessment, through environmental measurements and biochemical

analyses, of differences in exposure among appropriate samples of

women in areas of low and high breast cancer incidence (e.g., to

dietary and nutritional factors, to electromagnetic fields, to toxic

substances, especially pesticides, herbicides or contaminants from

sewage in drinking water and food); and



o  approaches to elucidate racial/ethnic/socioeconomic differences

with respect to breast cancer incidence and mortality and the

potential role(s) of suspected risk factors, for regions in these

jurisdictions having heterogeneous populations.



Interdisciplinary collaborations between geneticists, molecular

biologists, epidemiologists, environmental health scientists, public

health officials and others are encouraged.  While applications will

be accepted within any of NCI's relevant extramural program areas as

outlined below, the Institute would strongly urge the submission of

competing supplemental applications proposing novel projects that

represent laboratory-to-clinic transitions in breast cancer or that

offer the opportunity for participation of women or underrepresented

minority individuals.



The NCI is composed of four program Divisions that support extramural

research relevant to this program announcement.  The spectrum of

research supported by these Divisions is as follows:



The NCIs Division of Cancer Etiology plans and directs a national

program of basic research including laboratory, field, and

epidemiologic and biometric research on the cause and natural history

of cancer and means for  preventing cancer, and evaluates mechanisms

of cancer induction and promotion by chemicals, viruses, and

environmental agents.  Representative types of research activities

appropriate to this program announcement include, but are not limited

to, assessment of the relative contributions and interactions of

lifestyle, environment, occupation, genetic factors, viruses, and/or

metabolism on the risk of cancers of the breast.  In addition,

integrated multidisciplinary studies in chemical carcinogenesis are

encouraged to identify epithelial cell markers for various stages of

transformation, to identify inhibitors of carcinogenesis including

natural inhibitors in the human environment, and to determine the

specific molecular changes that occur as epithelial cells are

transformed.



The Division of Cancer Biology, Diagnosis, and Centers supports

research on the cellular and molecular biology of malignant cells,

the role of the immune system in tumor growth (including vaccine

research) and progression and on the transfer of basic research

findings to clinical application for the improved diagnosis/prognosis

of cancer.  In the area of cancer biology, areas of emphasis include,

but are not limited to:  soluble factors (e.g., hormones, growth

factors), and matrix and membrane macromolecules that modulate the

growth of tumor cells; the regulation of the expression of these

effectors and the mechanism of action; and the genetic events

responsible for progression of tumors to a highly  malignant and

metastatic state.  In the area of cancer immunology, specific

interests include, but are not limited to: cellular and humoral

immune recognition of tumor antigens, methods of improving immune

killing of tumor cells, immune control of tumor metastasis, other

regulatory effects of the immune system on tumor growth, and tumor

modulation of host immune function.  Studies are specifically

solicited for further research in these areas of immunology aimed at

the eventual development of vaccines for the primary or secondary

prevention of these cancers.  In the area of cancer diagnosis, areas

of emphasis include, but are not limited to: more precise staging of

tumors for prognostic and therapeutic decision making, more effective

monitoring of response to therapy, earlier detection of both initial

and recurrent tumors, and identification of populations at risk for

developing particular cancers.



The Division of Cancer Prevention and Control plans, develops,

directs, and coordinates research on prevention, control, and

community oncology.  Representative studies involve the

identification and evaluation of agents that may inhibit

carcinogenesis (initiation, promotion, transformation, and/or

progression).  These studies could include identification of

appropriate agents through literature searches or laboratory methods,

efficacy and toxicology studies in animals to aid in selection of

materials for human studies, and phase I and II clinical trials of

potential preventive agents.  Other research could focus on reduction

of cancer morbidity and mortality through early detection including

identification of biological markers of risk, exposure, and

pre-malignant events of progression.  Research on the roles of

nutrients, food groups, and other dietary components in cancer

incidence is appropriate including the influence of dietary  factors

on the modulation of cancer risk markers or intermediate endpoints.

Cancer control includes research on the development and testing of

intervention strategies to modify personal, social, and lifestyle

factors known to contribute to the development and/or increased risk

of cancer, and multidisciplinary intervention research aimed at

addressing minority, underserved, and other special populations.



The Division of Cancer Treatment plans, directs, and coordinates an

integrated program of preclinical and clinical cancer treatment

research with the objective of curing or controlling cancer in humans

by utilizing single or combination treatment modalities.  The tumor

site addressed by this program announcement currently requires

multimodality treatment for optimal management of all stages and

presentations of disease, but these treatment methods cause serious

morbidity and fail to cure most patients with advanced disease.  In

preclinical cancer treatment research, there is an urgent need to

translate recent developments in the molecular biology of cancer into

the discovery of new anticancer treatments whose actions will be

highly specific for particular genes or gene products.  Exciting

areas that may be exploited include oncogenes such as the HER-2/neu

oncogene in breast cancer, suppressor genes, signal transduction,

cell cycle regulation, growth factors/receptors, metastasis, and

angiogenesis.  Several approaches will be necessary to take advantage

of these new opportunities.  Additional topics include, but are not

limited to, drug discovery of new anticancer agents, biochemical and

molecular mechanisms of antitumor drug action, and pharmacology and

toxicology of antitumor agents.  Studies to circumvent individual and

multiple drug resistance and prevent metastasis of these cancers to

other organs are included.  Clinical research opportunities exist in

the areas of high-dose chemotherapy followed by autologous bone

marrow rescue, multidrug resistance, radiosensitizers, adjuvant

chemotherapy, innovative surgical or multimodality approaches,

particle beam irradiation, novel immune therapies and genetic

manipulations of host or malignant tissues, therapy with biological

products, such as interleukins, monoclonal antibodies, and/or

retinoic acid.  Applications that address these opportunities and

these particular tumors are specifically solicited.



STUDY POPULATIONS



SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH

POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL

RESEARCH STUDY POPULATIONS



NIH policy is that applicants for NIH clinical research grants and

cooperative agreements are required to include minorities and women

in study populations so that research findings can be of benefit to

all persons at risk of the disease, disorder or condition under

study; special emphasis must be placed on the need for inclusion of

minorities and women in studies of diseases, disorders and conditions

that disproportionately affect them.  This policy is intended to

apply to males and females of all ages.  If women or minorities are

excluded or inadequately represented in clinical research,

particularly in proposed population-based studies, a clear compelling

rationale must be provided.



The composition of the proposed study population must be described in

terms of gender and racial/ethnic group.  In addition, gender and

racial/ethnic issues should be addressed in developing a research

design and sample size appropriate for the scientific objectives of

the study.  This information must be included in the form PHS 398 in

Sections 1-4 of the Research Plan AND summarized in Section 5, Human

Subjects.  Applicants are urged to assess carefully the feasibility

of including the broadest possible representation of minority groups.

However, NIH recognizes that it may not be feasible or appropriate in

all research projects to include representation of the full array of

United States racial/ethnic minority populations (i.e., Native

Americans (including American Indians or Alaskan Natives),

Asian/Pacific Islanders, Blacks, Hispanics).  The rationale for

studies on single minority population groups must be provided. For

the purposes of this PA, it is expected that women residing in the

states or jurisdictions cited in the Senate Report (H.R. 5677) will

be the focus of the proposed research project.



For the purpose of this policy, clinical research is defined as human

biomedical and behavioral studies of etiology, epidemiology,

prevention (and preventive strategies), diagnosis, or treatment of

diseases, disorders or conditions, including but not limited to

clinical trials.



The usual NIH policies concerning research on human subjects also

apply.  Basic research or clinical studies in which human tissues

cannot be identified or linked to individuals are excluded. However,

every effort should be made to include human tissues from women and

racial/ethnic minorities when it is important to apply the results of

the study broadly, and this should be addressed by applicants.



For foreign awards, the policy on inclusion of women applies fully;

since the definition of minority differs in other countries, the

applicant must discuss the relevance of research involving foreign

population groups to the United States' populations, including

minorities.



If the required information is not contained within the application,

the review will be deferred until the information is provided.

 Peer reviewers will address specifically whether the research plan

in the application conforms to these policies.  If the representation

of women or minorities in a study design is inadequate to answer the

scientific question(s) addressed AND the justification for the

selected study population is inadequate, it will be considered a

scientific weakness or deficiency in the study design and will be

reflected in assigning the priority score to the application.



All applications for clinical research submitted to NIH are required

to address these policies.  NIH funding components will not award

grants or cooperative agreements that do not comply with these

policies.



APPLICATION PROCEDURES



Applications are to be submitted on the grant application form PHS

398 (rev. 9/91) and will be accepted at the standard application

deadlines as indicated in the application kit.  Application kits are

available at most institutional offices of sponsored research and may

be obtained from the Office of Grants Inquiries, Division of Research

Grants, National Institutes of Health, Westwood Building, Room 449,

Bethesda, MD 20892, telephone 301/496-7441.  The title and number of

the announcement must be typed in line 2a on the face page of the

application.



The completed original application and five legible copies must be

sent or delivered to:



Division of Research Grants

National Institutes of Health

Westwood Building, Room 240

Bethesda, MD  20892**



REVIEW PROCEDURES



Applications will be assigned on the basis of established Public

Health Service referral guidelines.  Applications will be reviewed

for scientific and technical merit by study sections of the Division

of Research Grants (DRG), NIH, in accordance with the standard NIH

peer review procedures.  Applications for supplements to ongoing

awards will be assigned to DRG study sections on the basis of current

NIH referral guidelines, and reviewed according to criteria

applicable to the mechanism of the ongoing award.  Following

scientific-technical review, the applications will receive a

second-level review by an appropriate national advisory council or

board.



AWARD CRITERIA



Applications will compete for available funds with all other approved

applications.  Applicants are encouraged to seek matching funds from

state or municipal sources wherever these might be appropriate to

augment the institutional or investigational resources available in

support of the proposed project.  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 balance among research areas of the announcement



INQUIRIES



The opportunity to clarify any issues or questions from potential

applicants is welcome.  Written and telephone inquiries concerning

the objectives and scope of this program announcement are encouraged

and may be directed to:



NCI Referral Office

National Cancer Institute

Westwood Building, Room 850

Bethesda, MD  20892

Telephone:  (301) 496-7173

FAX:  (301) 402-0275



Inquiries will be referred to the appropriate NCI Program Director in

one of the program Divisions noted above in the RESEARCH OBJECTIVES

section of this announcement.



Direct inquiries regarding fiscal matters to:



Ms. Jean Cahill

Grants Administration Branch

National Cancer Institute

Executive Plaza South, Room 243

6120 Executive Boulevard

Bethesda, MD  20892

Telephone:  (301) 496-7800, extension 47

FAX:  (301) 496-8601



AUTHORITY AND REGULATIONS



This program is described in the Catalog of Federal Domestic

Assistance under one or more of the applicable sections:  No. 93.393,

No. 93.394, No. 93.395, No. 93.396, and No. 93.399. 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.



.

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