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 301-710-0267. 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. 

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