STUDIES ON THE PREVENTION, ETIOLOGY, CONTROL, BIOLOGY, DIAGNOSIS, ORTREATMENT OF BREAST CANCER



NIH GUIDE, Volume 22, Number 19, May 21, 1993



PA NUMBER:  PA-93-083



P.T. 34



Keywords:

  Cancer/Carcinogenesis 

  Etiology 

  Disease Control+ 

  Disease Prevention+ 

  Treatment, Medical+ 



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 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 mortality rates.  The long-term threat to

women's health cannot be understated, since the incidence of breast

cancer rises with age.  Without vigorous efforts to develop improved

cancer prevention, detection and treatment strategies, as advances in

other areas of medicine extend average lifespan, the nation faces a

continuing breast cancer crisis of increasing magnitude as the baby

boom population cohort ages.



The United States Congress has expressed continued concern about the

growing epidemic of breast cancer in the United States.  In the most

recent appropriation, the Conferees have urged, in the strongest way,

that the National Cancer Institute (NCI) make breast cancer one of

its highest priorities.  This disease is expected to be a continuing

priority and focus of the Congress for the foreseeable future.  The

NCI has devoted, and will continue to devote, significant resources

to studies of breast cancer.  However, not only does a great deal

remain to be accomplished so that more effective preventive,

diagnostic, and therapeutic modalities can be established, but much

more emphasis on pertinent basic research is also necessary.



This program announcement (PA) is one of several ongoing or planned

initiatives that should, in the strongest way possible, 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.



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,

Studies on the Prevention, Etiology, Control, Biology, Diagnosis, or

Treatment of Breast Cancer, 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.

Further, the institute 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) award (R29).



MECHANISMS OF SUPPORT



Support of this program will be through the research project grant

(either single or interactive R01), program project grant (P01),

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

to currently active research project grants (R01, P01), Cooperative

Agreements (U01) or Method to Extend Research in Time (MERIT) Awards

(R37).  Unless otherwise noted, all PHS grants policies apply.



RESEARCH OBJECTIVES



The purpose of this program is to provide support for investigators

to pursue promising avenues of research addressed to all areas of

basic, clinical and applied research relevant to breast cancer.

Applications will be accepted within all of NCIs extramural program

areas relevant to breast cancer as outlined below.  In addition to

basic research projeres, the NCI strongly urges the submission of

competing applications proposing novel projects that represent

laboratory-to-clinic transitions in breast cancer or that offer the

opportunity for participation of women or under-represented minority

individuals. Interdisciplinary collaborations between geneticists,

molecular biologists, epidemiologist, environmental health

scientists, public health officials and others are especially

encouraged, either through the program project mechanism, or through

the interactive research project grant (NIH Guide for Grants and

Contracts, Vol. 21, No. 1, January 10, 1992; Announcement PA-92-29).



The NCI is composed of four programmatic Divisions that support

extramural research relevant to this program announcement.  The

spectrum of research relevant to breast cancer encouraged by these

Divisions is as follows:



The Division of Cancer Etiology plans and directs a national program

of basic and applied research, including laboratory, field,

epidemiologic and biometric research on the cause and natural history

of breast cancer and the means for preventing such cancer, and

evaluates mechanisms of cancer induction and promotion by chemicals,

radiation, viruses and environmental agents.  Epidemiologic research

activities appropriate to this Program Announcement include

assessment of the relative contributions and interactions of

lifestyle, diet, environment, occupation, genetic factors, viruses,

radiation, and/or metabolism on breast cancer risk; identification,

validation and epidemiological assessment of markers/indicators of

environmental, occupational, dietary, radiation, chemical and/or

hormonal exposures likely to play a role in the etiology of breast

cancer.  Appropriate studies in biological carcinogenesis include:

elucidation of the potential role of viruses and/or other biological

agents in human breast cancer, including initiation of animal model

systems, investigations of the changes in the structure or regulation

of viral oncogenies, tumor suppressor genes, and other cellular genes

relevant to the development of breast cancer, and development of

microbial vectors such as bacteria and viruses that target breast

tissues.  Studies in chemical and physical carcinogenesis include

integrated multidisciplinary laboratory investigations in

carcinogenesis and its prevention using human tissues, whole animal,

or in vitro systems; identification, quantitation and validation of

biological, chemical, cellular and molecular markers for temporal

stages of preneoplasia and neoplasia and their inhibition; synthesis,

identification, characterization and mechanism of action of

inhibitors of breast carcinogenesis, including natural inhibitors in

the human environment;  determination of the role of changes in the

structure/regulation of oncogenies, tumor suppressor genes, and other

cellular genes to the development, progression and biologic behavior

of breast cancer induced by chemical and physical agents; and studies

on the roles of protein, peptide and steroid hormones, and growth

factors, in the development and progression of breast cancer.



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 and progression, and on

the transfer of basic research findings to clinical application for

improved diagnosis/prognosis of cancer.  In breast cancer biology,

areas of emphasis include, but are not limited to:  the various

growth factors and their receptors that contribute to the growth and

progression of human breast cancer, the target genes in malignant and

normal breast epithelium whose expression is regulated by the

estrogen or progesterone receptor, the cellular mechanisms

responsible for the action of tamoxifen on breast cells, the

interplay of stromal and extracellular matrix components with breast

epithelium in facilitating breast cancer growth and progression, and

the identification of genetic modifications associated with the

progression from early stage cancer to more malignant tumors and the

related functional changes that occur in the affected cells.  Of

special interest are applications that utilize human breast tumors

and tumor cells to pursue these research goals.  In the area of

cancer immunology, specific interests include, but are not limited

to:  identification and characterization of breast cancer antigens

recognized by T lymphocytes, functional significance of leukocyte

infiltrates in breast cancer, cytokine influences on immune

responsiveness to tumor, neuroendocrineimmune interactions, immune

mechanisms in tumor dormancy, immune control of tumor metastasis 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 breast cancer.  Cancer diagnosis emphasizes evaluation

of predictive markers for breast tumors to aid therapeutic decision

making, of markers for monitoring the response to therapy and the

earlier detection of recurrent tumors, and identification of

individuals at risk for developing breast cancer.



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.  Initiation, validation and clinical

testing of biomarkers, and their modulation for prevention and early

detection also are appropriate.  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, undeserved, and other special populations.

Research under the 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, particularly pertaining to

the PHS "Healthy People 2000" National Goals.



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.  Breast

cancer requires multi-modal 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 breast 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 oncogenies

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

multi-modal 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.  Studies of microbial vectors such

as vaccinia virus, retroviruses, adenoviruses and salmonellae as

potential targeting and delivery vehicles in experimental

therapeutics also are appropriate.  Applications that address these

opportunities for breast cancer 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 females will be the

major 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

the purposes of this announcement, females are expected to be major

gender under study.



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 301/710-0267.  The title and number of

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

of the application.



Applicants from institutions that have a General Clinical Research

Center (GCRC) funded by the NIH National Center for Research

Resources may wish to identify the GCRC as a resource for conducting

the proposed research.  If so, a letter of agreement from either the

GCRC program director or Principal Investigator could be included

with 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 CONSIDERATION



Applications will be assigned on the basis of established PHS

referral guidelines.  Applications will be reviewed for scientific

and technical merit either by study sections of the Division of

Research Grants (DRG), NIH, or by initial review committees convened

by the Division of Extramural Activities, NCI, in accordance with the

standard NIH peer review criteria and procedures for specific award

mechanisms.  Applications for supplements to ongoing awards will be

assigned for review 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.



AWARD CRITERIA



Although there is no specified set-aside of funds for these awards,

all meritorious applications submitted in response to this

announcement, if assigned to the NCI, will receive consideration for

a designation of high program relevance in the funding plans of the

Institute.  The President's proposed FY 1994 budget for the NCI

specifically allocates substantial funds for breast cancer.  Should

future funding appropriations contain language designating funds

specifically for breast cancer, it is anticipated that competing

applications submitted in response to this announcement would be

eligible for payment with such funds.  Award decisions will be based

on quality of the proposed project as determined by peer review,

availability of funds, and program balance among research areas of

the announcement.



INQUIRIES



Written and telephone inquiries concerning the objectives and scope

of this program announcement are encouraged and may be directed to

the NCI Referral Office at the address below.  The opportunity to

clarify any issues or questions from potential applicants is welcome.



NCI Referral Office

Division of Extramural Activities

National Cancer Institute

6130 Executive Boulevard, Room 636

Bethesda, MD  20892

Telephone:  (301) 496-3428

FAX:  (301) 402-0275



Inquiries will be referred to the appropriate NCI Program Director in

one of the program Divisions listed under RESEARCH OBJECTIVES.



Direct inquiries regarding fiscal matters to:



Ms. Susan Cook

Grants Administration Branch

National Cancer Institute

6120 Executive Boulevard, Room 243

Bethesda, MD  20892

Telephone:  (301) 496-7800, ext. 27

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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