Full Text CA-92-20


NIH GUIDE, Volume 21, Number 27, July 31, 1992

RFA:  CA-92-20

P.T. 34


National Cancer Institute

Letter of Intent Receipt Date:  October 15, 1992
Application Receipt Date:  November 12, 1992


The Division of Cancer Etiology of the National Cancer Institute (NCI)
invites grant applications for innovative interdisciplinary
epidemiologic studies to better understand the etiology of ovarian
cancer and the means of prevention.


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), Epidemiology of Ovarian Cancer, is related to
the priority area of cancer.  Potential applicants may obtain a copy of
a "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 20402-9325 (Telephone 202/783-3238).


Applications may be submitted by domestic and foreign non-profit and
for-profit institutions, public and private, such as colleges,
universities, hospital, research laboratories, units of State and local
governments, and eligible agencies of the Federal Government.
Applications from or involving minority institutions, individuals, and
women are encouraged.


This RFA will be supported through the NIH traditional research project
grants (R01) and the Interactive research project grants (IRPG) (R01).
Awards will be administered under PHS grants policy as stated in the
PHS Grants Policy Statement, DHHS Publication No. (OASH) 90-50,000,
revised October 1, 1990.

This RFA is a one-time solicitation.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that of
the applicant.  The total project period for applications submitted in
response to the present RFA may not exceed five years.  Competitive
continuation applications will compete with all other unsolicited
applications and be reviewed by standing Division of Research Grants
study sections.  If the NCI determine that there is a sufficient
continuing program need, the NCI may announce a request for renewal


The estimated funds (total costs) available for the first year of
support for this initiative is $2.0 million.  The expected number of
awards is five to eight.  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 plan of
the NCI, the award of grants pursuant to this RFA is contingent upon
the availability of funds for this purpose.



Ovarian cancer is the most lethal gynecologic malignancy.  On a
worldwide basis, it is estimated that over 140,000 cases are diagnosed
annually, representing more than 4 percent of all cancer cases in
women.  In the United States, incidence and mortality estimates for
1990 indicated that approximately 20,500 new cases were diagnosed and
12,000 women died.  Overall, the probability that a woman will be
diagnosed with ovarian cancer in her lifetime is 1 in 70.  The
incidence rate is currently 46 percent higher in whites than in blacks.
The incidence of ovarian cancer seems to have decreased slightly since
1973, but the survival rate has changed very little. Survival is
related to age.  During the period 1981-86, women diagnosed prior to
age 65 had a 5-year relative survival rate of 48 percent compared to 24
percent for those diagnosed at age 65 and older.

The highest ovarian cancer rates are reported from industrialized
countries, with the exception of Japan.  The age-adjusted mortality
rates are 1.69, 3.02, 7.04, and 11.02 per 100,000 for Japan, Italy, the
United States, and Denmark, respectively.  Japanese migrants to Hawaii
and their first-generation offspring have a higher incidence of ovarian
cancer than women in Japan, suggesting environmental influences.  The
trends in ovarian cancer over the last two decades indicate increasing
rates in low-risk areas such as Japan and Singapore.

A few aspects of ovarian cancer epidemiology are well documented, such
as an inverse association with parity and oral contraceptive use.  A
role for other menstrual, reproductive, and hormonal factors and diet
has been suggested, but remains to be confirmed.  Cancers of the breast
and ovary appear to share some etiologic factors. For example, women
with breast cancer have twice the expected risk of ovarian cancer, and
women with ovarian cancer have a three-to-fourfold increase in the risk
of subsequent breast cancer.

Epithelial carcinomas account for 80-90 percent of ovarian neoplasms.
The remaining ovarian tumors originate from the germ or stromal cells.
Epithelial tumors are classified as benign, malignant (invasive), and
tumors of low malignant potential (or borderline malignancy).  The peak
incidence of benign epithelial tumors occurs in the 20-40-year-old
group, whereas the peak incidence for malignant neoplasms, occurs in
the 40-70-year-old group.  The peak incidence of tumors of low
malignant potential is between ages 30 and 40.  The 5- and 10-year
survival rates for patients with low malignant potential tumors are 98
percent and 74 percent, respectively, compared with 34 percent and 29
percent for patients with invasive epithelial tumors.  Although the
ovary is not the primary target tissue for estrogens, estrogen
receptors (ER) and progesterone receptors (PGR) have been found in both
benign and malignant ovarian tumors.  The ER and PGR content in ovarian
carcinomas has not yet been correlated with the histologic type and
grade of the tumor, or with risk factors.

It has been proposed that repeated minor trauma to the epithelial
surface of the ovary, caused by incessant ovulation, allows promotion
of cells bearing allele loss and, by inference, those carrying
inactivated tumor-suppressor genes.  This may lead to uncontrolled cell
division and malignant transformation.  A molecular basis for this
hypothesis comes from the studies of variable number tandem repeat
(VNTR) probes used to analyze DNA from ovarian tumors.  Allele loss was
observed on the long arm of chromosome 17 in more than 80 percent of
malignant ovarian tumors.  Such allele losses have been shown to
represent loss of tumor-suppressor genes.  It is conceivable that
another as yet unidentified gene(s) may play an essential role.

Ovarian cancer families provide an excellent opportunity for
epidemiologic studies.  Risk estimates based upon familial ovarian
cancer aggregations suggest a three-to-fourfold excess risk for ovarian
cancer among first degree relatives of ovarian cancer patients when
compared to the risk in the general population.  Linkage studies are
needed to determine if altered germ line alleles contribute to the
familial predisposition of ovarian cancer.  Formation of an
international computerized registry of afflicted families with an
associated family member DNA bank could be a valuable asset in having
the actual genes cloned.  The correlation of ovarian and breast cancers
in some families suggests that genetic variation in steroid hormone
metabolism may be an important factor in the susceptibility to ovarian

Recently, a collaborative analysis of 12 U.S. case-control studies of
ovarian cancer was carried out to assess the influence of events
affecting ovulation, such as timing of menarche and menopause, timing
and outcome of pregnancies, duration of breast feeding, duration of
oral contraceptive use, exogenous estrogen use and prior pelvic
surgeries.  There were clear trends of decreasing ovarian cancer risk
with increasing parity, duration of breast feeding and oral
contraceptive use, and increasing number of pregnancies regardless of
outcome.  There was a weak trend relating risk to age at menarche, no
clear trend relating risk to age at menopause, and greater risk
reduction per month of pregnancy than per month of oral contraceptive
use.  Among nulliparous women, risk did not vary by marital status or
gravidity.  There was a weak association with duration of longest
pregnancy attempt, total duration of unprotected intercourse, and
history of clinically diagnosed infertility.  The risk was elevated
among women who had used fertility drugs.  A history of tubal ligation
or of hysterectomy with ovarian conservation was associated with
reduced risk.  Oral contraceptives were generally less protective
against tumors of low malignant potential.  Also, the percent risk
reduction associated with a month of pregnancy was greater for younger
women than for older women.  The percent risk reduction attributed to
a year of oral contraceptive use was greater among older women,
suggesting that older, higher potency oral contraceptive drugs may be
more protective than recent formulations.

The findings of a meta-analysis of 3 hospital-based case-control
studies of ovarian cancer conducted in Europe were similar to those in
U.S. studies.  An interesting observation in this analysis was that the
protective effect of full-term pregnancy depended upon the age at which
it occurred.  Women who bore their first child at age 35 or older were
at slightly increased risk than those who bore their first child at age
24 or earlier.

Correlation studies and international differences have suggested an
association of diet with ovarian cancer. Positive correlations with
higher intake of fats, proteins and calories and negative correlations
with frequent consumption of green vegetables, carrots and greater
vitamin A intake have been reported.  With regard to alcohol
consumption, the findings have been inconsistent.  Lactose consumption
has been suggested as a risk factor for ovarian cancer, with low
galactose transferase activity as a genetic marker for increased


The purpose of this initiative is to stimulate innovative epidemiologic
research into the origins of ovarian cancer.  Collaborations of several
disciplines and research institutions are particularly encouraged.
Whenever possible, research designs should make use of existing
resources, such as familial ovarian cancer registries and specimen
repositories.  Projects will be evaluated on the basis of the potential
for enhancing the understanding of ovarian cancer etiology and means of

The initiative permits a range of epidemiologic and interdisciplinary
investigations of ovarian cancer including, but not limited to:

o  Epidemiologic studies of

-  the long-term effect of combination oral contraceptives, with
special reference to age at initial use and age at cessation of use, on
ovarian cancer risk by pathologic type;

-  the relationship between hormone replacement therapy and ovarian
cancer risk;

-  the use of fertility-promoting drugs, ovarian stimulants, or in
vitro fertilization in relation to ovarian cancer risk;

-  the interrelationship of tubal ligation, hysterectomy, hormone
levels, and ovarian cancer risk;

-  the association of unilateral oophorectomy, age at oophorectomy, and
ovarian cancer risk;

-  the influence of diet and physical activity and their interaction on
ovarian cancer risk;

-  the relationship of exposure to potential oocyte toxins such as
talc, galactose, caffeine, smoking, and other agents to ovarian cancer
risk among women who use and those who do not use oral contraceptives.

o  Molecular epidemiology studies exploring differences in genetic
predisposition to ovarian cancer due to variations in susceptibility
genes, hormone metabolism, DNA repair activities, chromosome
sensitivity to mutagens or other factors.

o  Molecular epidemiologic studies using existing registries of ovarian
cancer families.

o  Analytic studies of ovarian cancer to determine the impact of
changes in exposure due to migration from low- to high-risk regions
and/or to secular changes in lifestyle and environment.

o  Studies of racial/ethnic differences in the histologic and cytologic
parameters of ovarian cancer that may reflect differences in exposure
or susceptibility.

o  Population-based studies of the correlation of estrogen and
progesterone receptor content of ovarian tumors with histologic type,
grade, clinical prognosis, and exposure history.



NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical
research grants and cooperative agreements will be required to include
minorities and females 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 should be placed on the need
for inclusion of minorities and females in studies of diseases,
disorders and conditions which disproportionately affect them.  This
policy is intended to apply to males and females of all ages.  If
females or minorities are excluded or inadequately represented in
clinical research, particularly in proposed population-based studies,
a clear compelling rationale should be provided.

The composition of the proposed study population must be described in
terms of gender and racial/ethnic group, together with a rationale for
its choice.  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 should be
included in the form PHS 398 in the Research Plan, 1-4, 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 should be provided.

For the purpose of this policy, clinical research includes 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 females and
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

For foreign awards, the policy on inclusion of females 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

If the required information is not contained within the application,
the application will be returned.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
females 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.


Prospective applicants are requested to submit, by October 15, 1992, 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 is being 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 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. A.R. Patel
Extramural Programs Branch
Epidemiology and Biostatistics Program
Division of Cancer Etiology
National Cancer Institute
6130 Executive Boulevard
Executive Plaza North, Suite 535
Rockville, MD  20892
Telephone:  (301) 496-9600


Applications are to be submitted on for PHS 398 (rev. 9/91) that is
available at most institutional business offices, and from the Office
of Grants Inquiries, Division of Research Grants, National Institutes
of Health, Room 449, Westwood Building, 5333 Westbard Avenue, Bethesda,
MD 20892, telephone 301/496-7441.  The format and instructions
applicable to research grant applications must be followed.

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.  In such a case, a letter of agreement from either the GCRC
program director or Principal Investigator must be included with the

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

Submit a signed, typewritten original of the application, including the
Checklist, and three signed, exact photocopies, in one package to the
Division of Research Grants at the address below.  The photocopies must
be clear and single sided.

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892**

At the time of submission, send two additional copies of the
application to:

Referral Officer
Division of Extramural Activities
National Cancer Institute
Westwood Building, Room 838
5333 Westbard Avenue
Bethesda, MD  20892

Applications must be received by November 12, 1992.  If an application
is received after that date, it will be returned without review.  If
the application submitted in response to this RFA is substantially
similar to a research grant application already submitted to the NIH
for review, but has not yet been reviewed, the applicant will be asked
to withdraw either the pending application or the new one.
Simultaneous submission of identical applications will not be allowed,
nor will essentially identical applications be reviewed by different
review committees.  Therefore, an application cannot be submitted in
response to this RFA that is essentially identical to one that has
already been reviewed.  This does not preclude the submission of
substantial revisions of applications already reviewed, but such
applications must include an introduction addressing the previous

IRPG applications may be submitted from a single institution or may
include arrangements with one or more other institutions if
appropriate.  Each application will be considered on its own merit as
an individual research project.  Therefore, applicants for IRPGs MAY
NOT concurrently submit R01 applications that represent significant
duplication of the efforts described in the applicant's IRPG.  In this
regard, it should be noted that the NCI will consider funding
meritorious individual IRPG applications if it is not possible to fund
the IRPG package as a whole.  (Interactive Research Projects Grants for
Cancer, PA-92-29, NIH Guide for Grants and Contracts, Vol. 21, No. 1,
January 10, 1992).  Concurrent submission of program project (P01)
applications is prohibited.


Upon receipt, applications will be reviewed by the Division of Research
Grants (DRG) for completeness. Incomplete applications will be returned
to the applicant without further consideration.  Preliminary evaluation
for responsiveness to the RFA is an NCI program staff function.  If an
application is judged to be nonresponsive, the applicant will be
contacted and given an opportunity to have it considered along with
other unsolicited grant applications received by the NIH.

Applications responsive to this solicitation will be reviewed by an
appropriate review group convened by the Division of Extramural
Activities, NCI.  The initial review will be for scientific merit.  The
second level of review by the National Cancer Advisory Board considers
the special needs of the NCI and the priorities of the National Cancer

Review criteria for RFAs are generally the same as those for
unsolicited research grant applications:

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal Investigator
and staff, particularly but not exclusively in the area of the proposed

o  availability of resources necessary to perform the research.

The review group will critically examine the submitted budget and will
recommend an appropriate budget and period of support for each scored


The earliest anticipated award date is July 1, 1993.

In addition to technical merit, reasonableness of the budget in
comparison with other applications, will be taken into consideration in
making an award.


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

Direct inquiries regarding programmatic issues to:

Dr. A.R. Patel
Extramural Programs Branch
Epidemiology and Biostatistics Program
Division of Cancer Etiology
National Cancer Institute
6130 Executive Boulevard
Executive Plaza North, Suite 535
Rockville, MD  20892
Telephone:  (301) 496-9600

Direct inquiries regarding fiscal matters to:

Ms. Jean M. Cahill
Supervisory Grants Management Specialist
National Cancer Institute
6120 Executive Boulevard
Executive Plaza South, Suite 243
Rockville, MD  20892
Telephone:  (301) 496-7800, ext. 47


This cancer cause and prevention research 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 PHS grants policies and Federal Regulations
42 CFR Part 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or
Health System Agency review.


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