Release Date:  May 14, 1998

RFA:  CA-98-017


National Cancer Institute
National Institute of Environmental Health Sciences

Letter of Intent Receipt Date:  June 30, 1998
Application Receipt Date:  August 25, 1998


The Division of Cancer Control and Population Sciences of the National Cancer
Institute (NCI) and the Division of Extramural Research and Training of the
National Institute of Environmental Health Sciences (NIEHS) invite grant
applications for interdisciplinary epidemiologic studies to better understand
determinants of regional variations in breast cancer incidence and mortality
rates in the U.S.  Studies are to be designed to take known risk factors into
consideration and to utilize biological markers or indicators, e.g., of
exogenous exposures, individual susceptibility to environmental factors,
intrinsic physiological processes or risk-related behavior, for elucidating
the role of geographic-specific elements in the natural history and
progression of breast cancer.  The ultimate objective is to gain knowledge
that could lead to effective prevention and cancer control strategies.

The NCI is the principal Federal funding agency that supports laboratory and
clinical investigations relating to the cause, prevention, diagnosis, and
treatment of cancer.  Of special interest are epidemiological studies
incorporating quantitative methods or markers to identify and evaluate the
role of etiological factors of cancer, including environmental and
occupational agents.

The NIEHS is the principal Federal funding agency to support research
examining the human health consequences of exposure to physical and chemical
toxicants in our environment.  Epidemiologic studies that seek to identify
exposed populations and understand the role of environmental and occupational
risk factors in the development of breast cancer and other diseases are a
major thrust of the NIEHS research program.


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 Request for Applications (RFA),
Regional Variation in Breast Cancer Rates in the 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 Summary Report: Stock
No. 017-001-00473-1) through the Superintendent of Documents, Government
Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800).


Applications may be submitted by 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.  Foreign institutions are not eligible for cooperative
agreement awards.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as principal investigators.


The administrative and funding instrument to be used for this program will be
the cooperative agreement (U01), an "assistance" mechanism (rather than an
"acquisition" mechanism), in which substantial NIH scientific and/or
programmatic involvement with the awardee is anticipated during performance of
the activity.  Under the cooperative agreement, the NIH purpose is to support
and/or stimulate the recipient's activity by involvement in and otherwise
working jointly with the award recipient in a partner role, but it is not to
assume direction, prime responsibility, or a dominant role in the activity. 
Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant.  Details of the
responsibilities, relationships and governance of the study to be funded under
cooperative agreement(s) are discussed later in this document under the
section "Terms and Conditions of Award."

The total project period for an application submitted in response to this RFA
may not exceed 4 years.  The earliest feasible start date will be April 1,
1999.  Because the nature and scope of the research proposed in response to
this RFA may vary, it is anticipated that the sizes of awards will vary also. 
The average award is expected to be approximately $500,000 total (direct plus
indirect) costs per year.

This RFA is a one-time solicitation.  Future unsolicited competing
continuation applications will compete with all investigator-initiated R01
applications and be reviewed according to the customary peer review
procedures.  If the NCI and NIEHS determine that there is a sufficient
continuing program need beyond the initially awarded period of performance, a
request for new and renewal applications may be announced.


Approximately $3.0 million per year in total costs for four years will be
committed by the NCI and NIEHS to specifically fund applications submitted in
response to this RFA.  The expected number of awards is five to seven.  This
funding level is dependent on the receipt of a sufficient number of
applications of high scientific merit.  Although this program is provided for
in the financial plans of the NCI and NIEHS, the award of cooperative
agreements pursuant to this RFA are contingent upon the availability of funds
for this purpose.



Geographical variations in cancer rates have been observed for decades, and
described spatial patterns and trends have provided clues for generating
hypotheses about the etiology of cancer.  In the case of breast cancer,
investigators have demonstrated that some variation can be explained by
differences in the population distribution of known breast cancer risk factors
such  as menstrual and reproductive variables (1-3).  However, regional
patterns may also reflect an aggregate of diverse factors including, for
example, varying presence of hazards in the environment, demographics and
lifestyle of a mobile population, subgroups of susceptible individuals, and
changes and advances in medical practice and health care management. 
Disentanglement of these factors is necessary to assess associations, singly
or jointly, with breast cancer risk in individuals and populations.

It is unclear what the determinants of geographic differences in breast cancer
rates may be and whether spatial variation of environmental factors is
contributory in areas with elevated breast cancer incidence and mortality. 
Biologic data relating environmental pollutants to breast cancer risk are
sparse, and epidemiologic studies have been challenged by methodological
limitations, most often in determining past exposure levels.  To date, the
scientific literature on the association of measurable exposures, e.g.,
organochlorine pesticides, and breast cancer is conflicting.

Based on the known importance of endogenous hormones in breast cancer
development, a leading question remains whether environmental factors, such as
xenoestrogens and other hormone-mimicking pollutants, may also exert an
effect.  A multidisciplinary workshop, "Hormones, Hormone Metabolism,
Environment, and Breast Cancer," convened by the National Action Plan on
Breast Cancer (NAPBC), the NCI, Tulane University, and the U.S. Public Health
Service's Office of Women's Health, in September 1995 discussed the complexity
of factors, unresolved controversial issues, and the need for improved
methodology to measure hormones and their metabolites (4).  The power of
molecular and bioinformatic technology could potentially provide biologic
probes and sensitive methods for epidemiologic studies to gain insights into
the relationship between environment, the individual, and breast cancer.

Research Scope and Goals

The purpose of this RFA is to stimulate innovative epidemiologic studies that
include assessment of markers or indicators of exposures, susceptibility or
other factors relevant to human breast carcinogenesis.  Major consideration
will be directed to studies, including those that are transitional (from
laboratory-based to population-based), that incorporate validation of
utilizable markers, e.g., hormone-related, in human populations. 
Collaborations among multiple disciplines and research institutions are
particularly encouraged, and research designs can make use of existing
resources, such as specimen repositories.  Supplementary research to expand an
ongoing investigation (i.e., parent study) may be proposed, contingent upon
the continuation of the parent study for at least two years.  There is special
interest in understudied populations, particularly those subgroups with
unusually high breast cancer incidence and mortality rates, and in study
populations of contrasting risk.

Investigators are encouraged to involve appropriate community/advocacy groups
interested in breast cancer research.  These groups could be comprised, for
example, of breast cancer survivors, health care professionals involved in
breast cancer care or women at high risk of the disease.  The type and degree
of participation by the group members could vary depending upon the proposed
research activities; e.g., members could serve as advisors to the
investigative team or assist in research implementation such as informing and
recruiting eligible study participants in the community.

Studies responding to this initiative may propose, for example, research in
areas listed below, but are not limited to:

-- Evaluation of joint effects of environmental factors, intrinsic host
characteristics or susceptibility, and behavioral patterns;

-- Assessment of mechanisms by which exogenous exposures, e.g., occupational,
could act in initiation and progression of breast cancer.  This may include
the evaluation of such exposures on hormonal or metabolic pathways,
consideration of the timing of exposures during critical windows of
development, and modulation of risk due to environmental exposures by genetic

--Comparison of populations with substantial regional differences in breast
cancer incidence or mortality rates using parameters such as, for example: 
(1) host-specific factors related to health (e.g., comorbidity), 
socioeconomic status (e.g., income, residence in the inner city or rural
geographic areas); (2) tumor-specific characteristics (e.g., histology types,
tumor aggressiveness in susceptible subpopulations); or (3) related to medical
care utilization;

--Improvement and validation of methodology, e.g., for detecting steroid
hormones, their metabolites, and xenohormones in biologic media, for use in
large population studies;

--Application of computer technology, e.g., geographic information systems,
and development of innovative statistical methods for improving estimates of 
historical environmental exposures;

--Investigation of environmental interaction and modulation of age-related
markers of hormone activity related to normal and malignant breast physiology.


It is critical that each applicant include specific plans for responding to
the Terms and Conditions of Award described below.  Plans should describe how
the applicant will comply with the program staff involvement as well as how
all the responsibilities of awardees will be fulfilled.

This initiative is designed to enhance cooperation between investigators and
NCI.  The role of NCI will be that of the provider of technical assistance and
facilitator for cross-project collaborations.  Applicants will be assessed for
the ability to conduct research projects under the conditions of this
cooperative agreement and must demonstrate an understanding of the research
process and responsibilities as partners in the cooperative agreement.  For
example, each applicant should propose the study design most appropriate for
the project and be responsible for selecting and recruiting appropriate
patient/control populations.  A description of the characteristics of the
population should be included.  Evidence should be presented indicating the
likelihood of recruiting study participants and the feasibility of achieving
significant participation rates.  This should include data on the likelihood
of subject availability for interview, if appropriate.  Applicants should
discuss any factors which they believe should exclude a participant from the

Applicants should discuss: a) what data should be collected, b) how, when,
where and by whom the data are to be collected, c) the numbers of study
subjects to be enrolled, d) data management procedures, e) the procedures for
assuring timeliness, completeness and accuracy of the data, and f) plans for
data analyses.

Failure of an awardee to meet the performance requirements, including these
special terms and conditions of award, or significant changes in the level of
performance, may result in a reduction of budget, withholding of support,
suspension and/or termination of the award.

The following TERMS AND CONDITIONS, pertaining to the scope and nature of the
interaction between the NCI and the investigators, will be incorporated in the
Notice of Award and are in addition to, and not in lieu of, otherwise
applicable OMB administrative guidelines; HHS grant administration regulations
at 45 CFR 74 and 92, and 42 CFR 52; other HHS, PHS, and NIH grant
administration policy statements and other NCI administrative terms of award.


Nature of Participation of NCI and NIEHS Staff

It is expected that the dominant role and primary responsibilities for the
research activities will reside with the awardees, although specific tasks and
activities in carrying out the studies may be shared among the awardees and
NCI and NIEHS Program Coordinators.  There will be a partnership among the
awardees and NCI/NIEHS with the role of the NCI and NIEHS Program Coordinators
being one of assisting, supporting, stimulating, and participating with the
awardees in conducting the projects.  The NCI and NIEHS Program Coordinators
or Assignees will:

-- Participate in Steering Committee meetings as voting members, assisting in
development of operating guidelines and policies for dealing with recurrent
situations that require coordinated action;

-- Assist in development of ad hoc protocols which specify  methods of
research determined by the Steering Committee;

-- Serve as liaison, helping to coordinate activities among the awardees;

-- Assist, if applicable, in the monitoring of field data collection, helping
to ensure standardization in methods across study sites;

-- Participate in any group analyses as determined by the Steering Committee;

-- Assist in the interpretation and reporting of information collected

-- Monitor study progress.  This may include periodic site visits for
discussions with awardee research teams, observation of field data collection
and management techniques, fiscal review, and other matters.  Decisions for
continued funding will be based on overall study progress, as well as
sufficient participant and/or data accrual, cooperation in carrying out the
research (e.g., attendance at Steering Committee meetings, implementation of
group decisions, compliance with reporting requirements), and maintenance of a
high quality of research which will allow pooling of data and comparisons
across Cooperative Agreements for common data elements.  The inability of a
cooperative agreement recipient to meet the performance requirements, or
significant changes in the level of performance, may result in an adjustment
of funding, withholding of support, suspension or termination of the award;

-- Assist by providing advice in the management and technical performance of
the investigation;

-- In conjunction with grants management, provide advice on administrative
issues, including funding.

Nature of Participation of Cooperative Agreement Recipients

The recipients of Cooperative Agreement awards will cooperate with each other
and the NCI and NIEHS in the conduct of this research.  Each awardee will:

-- Designate the Principal Investigator or assignee to participate in the
Steering Committee.  This committee will meet periodically during the course
of the study.  The first meeting will be called by the NCI Program Coordinator
shortly after award of the agreements with  subsequent annual meetings planned
and scheduled at this meeting.  Accordingly, sufficient funds must be included
within the submitted budgets to accommodate travel expenses for one yearly
trip to the Washington D.C. area for the principal investigator or designee.

-- Retain primary authorities and responsibilities to define objectives and
approaches, and to plan, conduct, analyze, and publish results,
interpretations, and conclusions of the study as was originally proposed in
the grant application and approved by the reviewers.

-- Cooperate in development of any common research instruments (e.g.,
questionnaire) or study documents (e.g., medical record abstract forms, field
procedures manuals) as determined by the Steering Committee.  With the
Steering Committee's approval, the awardee will utilize common instruments and
documents, but additional elements could be appended by individual
institutions to address issues of unique interest or capabilities;

-- Establish and maintain quality control in all data and materials collection
and management procedures.

-- Submit periodic supplementary reports quarterly or semi-annually if
requested by NCI and NIEHS Program Coordinators;

-- Cooperate in the reporting of collaborative findings.

The NIH will have rights of access to the data under this cooperative
agreement.  The awardees will retain custody and primary rights to the data
consistent with current HHS, PHS, and NIH policies.

Collaborative Responsibilities

A Steering Committee will be the main oversight body and will be composed of
the Principal Investigators or assignees from the awardee institutions and the
NCI and NIEHS Program Staff or assignees.  An organizational meeting of the
Steering Committee will be convened by the NCI Program Staff early after
award.  A Chairperson, other than the NCI/NIEHS staff representatives, will be
selected by a vote of the members.  The Committee likely will meet annually
and, if necessary, more frequently.

Major scientific decisions regarding core data will be determined by the
Steering Committee.  All investigators selected will need to be able and
willing to implement any core data collection method and strategy
collaboratively decided upon by the Steering Committee.  Research results will
be disseminated by means of peer-reviewed publications that will be planned
and prepared by award recipients, with assistance as needed from NCI and NIEHS
program staff.


In the event of a major scientific/programmatic disagreement between NCI/NIEHS
and the awardees that cannot be resolved by appropriate negotiations, an ad
hoc arbitration panel will be assembled to consist of one awardee nominee, one
NCI/NIEHS nominee, and a third member with appropriate expertise chosen by the
other two.  This NCI/NIEHS arbitration process in no way affects the awardees'
right to appeal an adverse determination under the terms of 42 CFR Part 50,
Subpart D, and 45 CFR Part 16.


It is the policy of the NIH that members of minority groups and their
subpopulations 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 or Public
Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines on the Inclusion of Women and Minorities as Subjects in
Clinical Research," which was published in the Federal Register of March 28,
1994 (59 FR 14508-14513) and in the NIH GUIDE FOR GRANTS AND CONTRACTS of
March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.


Prospective applicants are requested to submit, by June 30, 1998, a letter of
intent that includes a descriptive title of the proposed research, the name,
address, and telephone number of the Principal Investigator, the names of
other key personnel and participating institutions, and the number and title
of the RFA in response to which the application may be submitted.

Although a letter of intent is not required, is not binding, and does not
enter into the review of subsequent applications, the information that it
contains is helpful in planning for the review of applications.  It allows NCI
and NIEHS staff to estimate the potential review workload and to avoid
conflict of interest in review.  The letter of intent is to be sent to Dr.
Kumiko Iwamoto at the address listed under INQUIRIES.


The research grant application form PHS 398 (rev. 5/95) is to be used in
applying for these grants.  Applications 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, telephone
301/710-0267, Email:

In accordance with the previously described Terms of Award for cooperative
agreements:  (1) applicants are to request sufficient funds in the budget to
accommodate expenses for one to two participants to attend Steering Committee
meetings (for approximation: round-trip travel to Bethesda, Maryland for one
day annually during duration of the study), and (2) applicants must describe
plans to fulfill requirements in the Terms and Conditions of Award.

The RFA label available in the PHS 398 (rev.9/95) application form must be
affixed to the bottom of the face page of the application.  Failure to use
this label could result in delayed processing of the application such that it
may not reach the review committee in time for review.  In addition, the RFA
title and number must be typed on line 2 of the face page of the application
form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed photocopies, in one package to:

6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, two additional copies of the application must also
be sent to:

Ms. Toby Friedberg
Division of Extramural Activities
National Cancer Institute
6130 Executive Boulevard, Room 636
Bethesda, MD  20892-7399
Rockville, MD  20850 (for express/courier service)

Applications must be received by August 25, 1998.  If an application is
received after that date, it will be returned to the applicant without review. 
The Center for Scientific Review (CSR) will not accept any application in
response to this RFA that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending application.  The
CSR will not accept any application that is essentially the same as one
already reviewed.  This does not preclude the submission of a substantial
revision of an application already reviewed, but such an application must
follow the guidance in the PHS Form 398 application instructions for the
preparation of revised applications, including an introduction addressing the
previous critique.


Review Method

Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by NCI and NIEHS.  Incomplete and/or non-responsive
applications will be returned to the applicant without further considerations. 
Applications that are complete and responsive to the RFA will be evaluated for
scientific and technical merit by an appropriate peer review group convened by
NCI in accordance with the review criteria stated below.  As part of the
initial merit review, a process may be used by the initial review group in
which applications will be determined to be competitive or non-competitive
based on their scientific merit relative to other applications received in
response to this RFA.  Applications judged to be competitive will be discussed
and assigned a priority score.  Applications determined to be non-competitive
will be withdrawn from further consideration and the principal
investigator/program director and the official signing for the applicant
organization will be notified.  The peer review will be followed by a second
level of review by the National Cancer Advisory Board and National Advisory
Environmental Health Sciences Council.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  The
reviewers will discuss the following aspects of the application to assess the
likelihood that the proposed research will have a substantial impact on the
pursuit of these goals, specific to the objectives of the RFA.  Each of these
criteria will be addressed and considered in assigning the overall score,
weighting them as appropriate for each application.  The application does not
need to be strong in all categories to be judged likely to have a major
scientific impact.  For instance, the proposed research may not be innovative
but is essential to move a field forward.  The review criteria are:

1.  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?

2.  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 strategies?

3.  Innovation:  Does the project employ novel concepts, approaches or
methods?  Are the aims original and innovative?  Does the project challenge
existing paradigms or develop new methodologies or technologies?

4.  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)?

5.  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

The initial review group will also examine:  the appropriateness of proposed
project budget and duration; the adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific goals of the
research and plans for the recruitment and retention of subjects; the
provisions for the protection of human and animal subjects; and the safety of
the research environment.  Written summary statements of the review will be
sent by NCI to the principal investigators.


Applications recommended by the National Cancer Advisory Board and National
Advisory Environmental Health Sciences Council will be considered for award
based upon (a) scientific and technical merit; (b) program balance, including
in this instance, sufficient compatibility of features to make a successful
collaborative program a reasonable likelihood; and (c) availability of funds.


Letter of Intent Receipt Date:  June 30, 1998
Application Receipt Date:       August 25, 1998
Review by NCAB Advisory Board:  February 9, 1999
Anticipated Award Date:         April 1, 1999


Written and telephone inquiries concerning this RFA are encouraged.  The
opportunity to clarify any issues or questions from potential applicants is

Direct inquiries regarding programmatic issues to:

Dr. Kumiko Iwamoto
Division of Cancer Control and Population Sciences
National Cancer Institute
6130 Executive Boulevard, Suite 535, MSC 7395
Bethesda, MD  20892-7395
Telephone:  (301) 496-9600
FAX:  (301) 402-4279

Dr. Gwen Collman
Chemical Exposures and Molecular Biology Branch
National Institutes of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-5980
FAX:  (919) 541-4937

Direct inquiries regarding fiscal matters to:

Ms. Marie N. Moyer
Grants Administration Branch
National Cancer Institute
6120 Executive Boulevard, Suite 243, MSC 7150
Bethesda, MD  20892-7150
Telephone:  (301) 496-7800, ext. 225
FAX:  (301) 496-8601

Mr. David L. Mineo
Grants Management Branch
National Institutes of Environmental Health Sciences
P.O. Box 12233
Research Triangle Park, NC  27709
Telephone:  (919) 541-1373
FAX:  (919) 541-2860


This program is described in the Catalog of Federal Domestic Assistance No.
93.393.  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 HHS policies and grant regulations. 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.


1.  Sturgeon SR, Schairer C, Gail M et al.  Geographic variation in mortality
from breast cancer among white women in the United States.  J Natl Cancer Inst

2.  Robbins AS, Brescianini S, Kelsey JL.  Regional differences in known risk
factors and the higher incidence of breast cancer in San Francisco.  J Natl
Cancer Inst 1997;89:960-5.

3.  Laden F, Spiegelman D, Neas LM et al.  Geographic variation in breast
cancer incidence rates in a cohort of US women.  J Natl Cancer Inst

4.  Workshop on Hormones, Hormone Metabolism, Environment, and Breast Cancer,
New Orleans, Louisiana, September 28-29, 1995.  Monographs in Environ Hlth
Perspect supp 1997; 105 (3):557-688.

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