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CLINICAL EPIDEMIOLOGIC STUDIES IN HEREDITARY BREAST/OVARIAN CANCER

NIH GUIDE, Volume 26, Number 32, September 26, 1997

PA NUMBER:  PA-97-109

P.T.

National Cancer Institute

PURPOSE

The Division of Cancer Epidemiology and Genetics (DCEG) of the
National Cancer Institute (NCI) invites investigator-initiated grant
applications (R01s) and applications for competing supplements to
existing NIH-funded research project grants (R01s, P01s) or
cooperative agreements (U01s, U10s) for innovative epidemiologic
studies to address clinical issues facing women with inherited
predisposition for breast and/or ovarian cancer.

With increasing public awareness of genetic contributions to cancer
risk and the commercial availability of testing for mutations
predisposing to breast and ovarian cancer, women at inherited risk
for these cancers must make decisions about preventive interventions
- and often cancer-directed therapy - with only limited scientific
information about the natural history of disease associated with
predisposing mutations, the efficacy of prophylactic surgery and
other preventive measures, and the appropriateness of standard
oncologic care for cancers developing in mutation carriers.  While
prospective studies will eventually provide definitive answers to
these questions, there is an immediate need to address these issues
through retrospective studies based on existing resources such as
tissue banks and high- risk clinic registries and through concurrent
studies added to ongoing clinical or epidemiologic research projects.
This initiative seeks to enhance informed decision-making among women
at hereditary cancer risk by strengthening and expanding the
scientific knowledge about preventive and therapeutic options.

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 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. 017-001-10473- 1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign institutions
for-profit and non-profit organizations, public and private, such as
universities, colleges, hospitals, laboratories, units of state or
local government, and eligible agencies of the Federal government.
The total requested project period for an application submitted in
response to this PA may not exceed five years. Competing supplements
should not extend beyond the funding period of the parent grant; the
parent grant must have at least one year remaining in its project
period after award of the supplement. Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as principal investigators.

MECHANISM OF SUPPORT

The mechanism of support will be the individual research project
grant (R01) and competing supplements to existing NIH-funded research
project grants and cooperative agreements.  Responsibility for the
planning, direction, and execution of the proposed project will be
solely that of the applicant.

RESEARCH OBJECTIVES

Background

The identification of numerous genes that contribute to inherited
predisposition to cancer has generated cautious enthusiasm for
presymptomatic genetic testing within both scientific and lay
communities. While the cloning of each new cancer susceptibility gene
brings hope that mutation carriers can ultimately decrease their
cancer risk through preventive interventions, the potential for
psychosocial complications and discrimination against mutation
carriers has led numerous professional organizations to recommend
that predictive genetic testing should be limited to the research
setting (1-4).  However, the recent identification of an increased
prevalence of specific mutations of BRCA1 and BRCA2 among defined
population subgroups (5,6) has made presymptomatic testing clinically
relevant and commercially attractive, and several laboratory
companies now offer predictive genetic testing for BRCA1 and BRCA2
mutations.

Progress in genetic technology and molecular diagnostics has rapidly
outpaced scientific information about cancer prevention and
management in individuals with a genetic predisposition to cancer.
This knowledge gap translates into significant decision- making
dilemmas for unaffected individuals found to be carriers of
predisposing mutations and for cancer patients with germline
mutations of these genes: risks for developing primary and second
primary cancers may be extremely high; options for cancer prevention
are limited, with most involving radical surgical procedures for
which preventive efficacy is unknown; recommendations for preventive
measures are variable and may conflict with each other; and optimal
treatment and post-treatment management for mutation carriers who
develop cancer has not been well explored.  Specific examples for
BRCA1/2 mutations include:

Cumulative risks of breast cancer may approach 85% and of ovarian
cancer, 60%, by age 70 years (7) for BRCA1 mutation carriers from
strictly-defined breast/ovarian kindreds; while risk associated with
specific alleles may be lower, it is still markedly elevated (8).
Investigations of penetrance are just beginning for other high risk
or general population groups toward which commercial testing is
marketed.

Methods for more accurately assessing individual risk for mutation
carriers are largely unexplored.  Molecular markers such as ploidy
and ER/EGFR over-expression (9) or altered breast DNA patterns on
infrared spectroscopy (10), potentially useful in assessing
individual breast cancer risk for women in general, have not been
systematically studied for mutation carriers.

Recognized risk factors for sporadic cancers may modify
susceptibility differently for mutation carriers.  For example, in
contrast to sporadic ovarian cancer, the risk of ovarian cancer in
BRCA1 mutation carriers is reported to increase significantly with
increasing parity (11).

Clinical and histologic patterns of carcinogenesis may differ for
sporadic and hereditary breast cancers.  Recent studies suggest that
ductal carcinoma in situ (DCIS) may not be a usual component of the
BRCA1 spectrum of disease (12, 13) and that cytogenetic changes may
occur without histologic atypia (14); the implications of this
finding for surveillance technologies and interpretation of breast
biopsies have not been studied.

The preventive efficacy of prophylactic mastectomy is poorly defined
and may vary according to surgical procedure (15).  While case series
report cancer rates as low as 0.5% following subcutaneous procedures
among women at "high risk," surgical complications (e.g., skin flap
necrosis,  nipple loss) are reported in as many as 25% of procedures
(16).

A 1994 NIH Consensus Statement recommends prophylactic oophorectomy
for women in ovarian cancer families (17), despite failure of this
procedure to prevent intra-abdominal carcinomatosis in mutation
carriers (18).  The Task Force on Follow-Up Recommendations of the
NIH-funded Cancer Genetics Studies Consortium concluded that evidence
is insufficient to recommend prophylactic oophorectomy at this time
(19).

Surgical Oncologists may empirically advise  against breast-
conserving surgical procedures for known or suspected mutation
carriers with early stage breast cancer, while breast conservation is
encouraged for women with early stage sporadic cancers.

While definitive answers to these problems will eventually become
available from prospective follow-up studies of persons currently
undergoing predictive testing, there is an immediate need to address
these issues through existing resources such as tissue banks,
high-risk clinic registries, and ongoing clinical research projects.
This PA requests applications for innovative retrospective
epidemiologic studies that utilize existing clinical and pathology
resources or for concurrent research projects that supplement ongoing
studies in related scientific areas (e.g., cancer
prevention/treatment clinical trials), to provide information for
decision-making about predictive testing, preventive strategies, and
treatment options for persons at inherited risk for breast/ovarian
cancer.

Research Scope and Goals

The goal of this PA is to enhance informed clinical decision- making
among  (1) individuals with gene mutations predisposing for breast
and ovarian cancer risk and (2) individuals from high- risk families
who do not wish to be tested for predisposing mutations.  Its major
objective is to provide scientific information about efficacy of
cancer prevention and treatment measures among untested members of
high risk families, and known mutation carriers, that will serve as a
knowledge base for medical decisions by persons who are, or may be,
at genetic risk for these cancers.

This PA requests  applications which use innovative epidemiologic
approaches to address clinical issues critical to informed decision-
making by persons in the groups described above.  Applications should
address at least one question from either A or B below:

A.  Options for Cancer Prevention among Mutation Carriers

1) Do women with mutations predisposing to breast cancer have the
same patterns of preinvasive disease (atypical hyperplasia, LCIS,
DCIS) as women without mutations?

2) Can the use of histologic findings, molecular changes, or serum
markers more accurately predict individual risk of developing breast
or ovarian cancer for carriers of predisposing mutations?

3) Does use of hormonal or other therapy (e.g., oral contraceptive
use, hormone replacement therapy, antiestrogens, calcium/vitamin D
supplementation) or differences in  reproductive behavior (e.g.,
delaying birth of first child, forgoing childbearing) impact risk of
breast and/or ovarian cancer for women with predisposing mutations?

4) Can retrospective natural history data be used to mathematically
model optimal screening methodologies and intervals for women with
mutations predisposing to breast and/or ovarian cancer?

5)What are the acceptability, efficacy, and complication rates of
bilateral prophylactic mastectomy procedures among women with gene
mutations predisposing to breast cancer?

6) What are the acceptability, efficacy, and long-term effects of
prophylactic oophorectomy procedures among women with gene mutations
predisposing to breast/ovarian or ovarian cancer?  Does prophylactic
oophorectomy decrease breast cancer risk among women with gene
mutations predisposing to both breast and ovarian cancer?

B)  Clinical Management of Cancer Patients with Germline Mutations

1) Is breast-conserving therapy of equivalent efficacy to mastectomy
for women with germline mutations who develop early stage breast
cancers with respect to traditional (e.g., disease- free survival,
overall survival) and non-traditional (e.g., quality of life)
outcomes?

2) What is the efficacy of post-surgical adjuvant therapy among
mutation carriers with early stage breast cancer compared to patients
without germline mutations?

3)What is the risk of bilateral and contralateral breast cancer among
mutation carriers who develop an invasive breast neoplasm?  Does
systemic adjuvant therapy impact this risk?  Does prophylactic
mastectomy or oophorectomy decrease this risk?

Applications should be based on retrospective or concurrent
methodologies:

Retrospective studies.  Applications for retrospective studies should
build upon existing resources (e.g., pathology specimens, tissue
repositories, cancer registration/tracking systems) or clinical
facilities (e.g., high-risk clinic registration logs, ongoing
predictive testing projects or programs, prevention/treatment
clinical trial cohorts).

Concurrent studies.  Applicants may propose supplemental studies of
targeted individuals participating in ongoing NCI-funded clinical
trials or epidemiologic studies by submitting applications for
competing supplements to the parent projects.  The research proposed
in competing supplements must not extend beyond the funding period of
the parent project.

Support for initiation of prospective studies or clinical trials
testing preventive or therapeutic interventions in the target
populations is beyond the scope of this initiative.

Investigators are encouraged to incorporate innovative epidemiologic
approaches, laboratory procedures, and statistical methods as
appropriate to the study question.  An interdisciplinary research
team, including expertise in basic sciences (e.g., human genomics,
carcinogenesis),  clinical cancer research (cancer and/or genetic
epidemiology, preventive and therapeutic oncology), social and
behavioral sciences, and biomedical ethics is strongly recommended.
Multi-site collaborations are encouraged as appropriate to study
hypothesis and/or design.

Applications may include genetic counseling and predictive testing of
participants, as appropriate to study design.  For applications in
which results of genetic studies are made available to participants,
investigators must demonstrate that genetic counseling protocols meet
established standards/guidelines and that testing procedures are
performed in a certified clinical laboratory by appropriately trained
personnel.  Applications in which results of genetic studies are not
made available to participants may utilize research laboratory
facilities but must describe procedures to assure accuracy and
reliability of laboratory results.  Applications which rely on
previously collected tissue specimens must assure that study
procedures are consistent with published guidelines for the use of
stored tissue samples.

Because of the sensitive nature of genetic data, applications must
include a clear description of methods for securing research records
and protecting confidentiality and privacy of study data. Procedures
for informed consent must conform to federal requirements for
protection of human research subjects (45 CFR 64), with special
attention to ethical, legal, and social implications for participants
and their family members.

The proposed R01 research projects should not exceed five years
duration, and competing supplements should not extend beyond the
funding period of the parent grant.  All studies must be completed
within the specified grant period; the PA will not support
establishment of disease or risk registry systems or participant
contact beyond the specified study period.

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 subpopulations must be included in all NIH supported
biomedical 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 Vol. 23, No. 11, March 18, 1994.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) 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 Division of Extramural Outreach and Information
Resources, National Institutes of Health, 6701 Rockledge Drive, Suite
6095, MSC 7910, Bethesda, MD 20892-7910, telephone 301-435-0714.  The
title and number of the program announcement must be typed in Item 2
on the face page of the application and the "YES" box marked.

The completed original application and five legible copies must be
sent or delivered to:

DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD, 20817 (for courier/overnight service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS
referral guidelines.  Applications that are complete will be
evaluated for scientific and technical merit by an appropriate peer
review group convened in accordance with the standard 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.

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 comment on the following aspects of the
application in their written critiques 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 by the reviewers 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 a 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.

Review Criteria

The five criteria to be used in the evaluation of grant applications
are listed below.

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 tactics?

3.  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?

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 support?

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.

AWARD CRITERIA

Applications will compete for available funds. The following will be
considered in making funding decisions: quality of the proposed
project as determined by peer review, availability of funds, and
program priority.

INQUIRIES

Inquiries are encouraged, particularly during the planning phase of
the grant applications.  The opportunity to clarify any issues or
questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Susan G. Nayfield
Division of Cancer Epidemiology and Genetics
National Cancer Institute
6130 Executive Boulevard, Suite 535, MSC 7395
Bethesda, MD 20892-7395
Telephone: 301-496-9600
FAX: 301-402-4279
Email: nayfiels@epndce.nci.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Kelli Oster
Grants Administration Branch
National Cancer Institute
Executive Plaza South
6120 Executive Boulevard, Suite 243, MSC 7150
Bethesda, MD 20892-7150
Telephone: 301-496-7800, EXT. 261
FAX: 301-496-8601

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.393 and No. 93.856.  Awards are made under
authorization of the Public Health Service Act, Title IV, Part A
(Public Law 78-140, as amended by Public Law 99.158, 42 USC 241 and
285) and administered under PHS policies and Federal regulations 42
CFR 52 and 45 CFR Part 74 and Part 92.  This program is not subject
to the intergovernmental review requirements of Executive Order 12372
or Health Systems Agency review.

The Public Health Service (PHS) strongly encourages all grant
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.

References

1.  Statement of the American Society of Human Genetics on genetic
testing for breast and ovarian cancer predisposition. Am J Hum Genet
55:i-iv, 1994

2.  National Advisory Council for Human Genome Research. Statement on
the use of DNA testing for presymptomatic identification of cancer
risk.  JAMA 271:785, 1994

3.  Presymptomatic Genetic Testing for Heritable Cancer Risk. Press
release of the National Breast Cancer Coalition, Washington, DC,
September 28, 1995

4.  Statement of the American Society of Clinical Oncology: Genetic
testing for cancer susceptibility.  J Clin Oncol14:1730-1736, 1996

5.  Fitzgerald MG, MacDonald DJ, Krainer M, et al.  Germ- line BRCA1
mutations in Jewish and non-Jewish women with early-onset breast
cancer.  N Engl J Med 334:143-9, 1996

6.  Neuhausen S, Gilewski T, Norton L, et al.  Recurrent BRCA2
617delIT mutations in Ashkenazi Jewish women affected by breast
cancer.  Nature Genetics 13:126-128, 1996

7.  Easton DF, Bishop DT, Ford D, et al.  Genetic linkage analysis in
familial breast and ovarian cancer: Results from 214 families.  Am J
Human Genet 52:678-701, 1993.

8.  Easton DF, Ford D, Bishop TD, and the Breast Cancer Linkage
Consortium.  Breast and ovarian cancer incidence in BRCA1 mutation
carriers.  Am J Human Genetics56:265-271, 1995

9.  Fabian CJ, Exiles C, Kame S, et al.  Prevalence of aneuploidy,
overexpressed ER, and overexpressed EGFR in random breast aspirates
of women at high and low risk for breast cancer.  Breast Cancer Res
Treat 30(3):263-74, 1994

10. Malins DC,  Polissar NL, Nishikida K, et al.  The etiology and
prediction of breast cancer.  Fourier transform-infrared spectroscopy
reveals progressive alterations in breast DNA leading to a
cancel-like phenotype in a high proportion of normal women.  Cancer
75(2):5003-17, 1995.

11. Narod SA, Goldgar D, Cannon-Albright L, et al.  Risk modifiers in
carriers of BRCA1 mutations.  Int J Cancer64(6):39944--8, 1995.

12. Sun CC, Lenoir G, Lynch H, Nard SA.  Lancet 348:408, 1996

13. Liotta, L (personal communication)

14. Teixeira MR, Pandis N, Gerdes A-M, et al.  Cytogenetic
abnormalities in an in situ ductal carcinoma and five
prophylactically removed breasts from members of a family with
hereditary breast cancer.  Breast Cancer Res Treat38:177-182, 1996

15. Wapnir IL, Rabinowitz B, Greco RS.  A reappraisal of prophylactic
mastectomy.  Surg Gynecol Obstet 171:171- 184, 1990

16. Danforth DN Jr.  Prophylactic mastectomy to prevent cancer of the
breast in high-risk patients.  In: DeVita VT Jr, Hellman S, Rosenberg
SA (eds).  Cancer Prevention.  JB Lippincott, Philadelphia, 1990

17. Ovarian cancer: screening, treatment, and follow-up.  NIH
Consensus Statement 1994 Apr 5-7; 12(3):11-30

18. Struewing JP, Watson P, Easton DF, et al.  Prophylactic
oophorectomy in inherited breast/ovarian cancer families. Monogr Natl
Cancer Inst 17:33-35, 1995

19. Burke W, Daly M, Garber J, et al.  Follow-up recommendations for
individuals with an inherited predisposition to cancer.  II.  BRCA1
and BRCA2.  JAMA277:997-1003, 1997.