Download WHI Cancer Survivor Cohort Research Strategy

Program Director/Principal Investigator (Last, First, Middle):
Anderson, Garnet L.
RESEARCH STRATEGY
A.
COHORT OVERVIEW
This application proposes to establish the Women’s Health Initiative Cancer Survivor Cohort (WHI-CSC), a
resource for studies of factors related to cancer outcomes (defined as recurrence, second primary cancer, and
overall and cancer-specific mortality) among women diagnosed with cancer during their participation in WHI.
This section summarizes the history of the WHI from its beginning in 1993 to the present including its design,
key findings, cancer survivor population, and results from key pilot studies conducted within the WHI. In
addition, we briefly describe our experience in other large cohorts.
A.1
The Original Women’s Health Initiative (WHI) Program (1993-2005)
A.1.1 Overview of the History, Design, and Data Collection
The WHI, a NHLBI-sponsored program was launched in 1993 to
study the etiology and prevention of the major causes of morbidity
and mortality in postmenopausal women including cancer. The focus
of the program was a partial factorial randomized controlled clinical
trial testing three chronic disease prevention hypotheses: does
hormone therapy (HT) reduce the risk of coronary heart disease and
improve overall health; does a low-fat eating pattern (Dietary
Modification or DM) reduce the risk of breast cancer and colorectal
cancer; do calcium and vitamin D (CaD) supplements reduce the
risk of hip fractures. In all, 68,132 women were randomized into one
or more of the clinical trial (CT) components and 93,676 women
enrolled into a parallel observational study (OS) with nearly identical
data collection procedures (Figure 1). The objective of the OS was
to provide a resource for examining other risk factors and molecular
markers of disease (1, 2).
DM
HT
48,835
27,347
CaD
36,282
OS 93,676
Figure 1: Design of WHI partial factorial trial
and observational study of 161,808
postmenopausal women.
The WHI program overall represents a large, population-based sample. Between 1993 and 1998, 40 WHI
clinical centers (three of which were led by Drs. Caan, Paskett, and Chlebowski) recruited 161,808
participants, primarily by mass mailings to age-eligible populations identified through insurance lists, major
health care providers (e.g., Kaiser Permanente), and voter registration, motor vehicle, or purchased mailing
lists (3). Eligibility for the overall program was broadly defined to increase generalizability. Postmenopausal
women age 50-79 years with no conditions predictive of <3 year survival, and willing to provide written
informed consent were eligible. Trial-specific eligibility requirements excluded women with prior invasive
cancer, already consuming a low-fat diet, unwilling to discontinue current HT use, contraindications for the
interventions, and factors predictive of poor adherence. Women found to be ineligible for the trials or unwilling
to be randomized were offered enrollment into the OS. Participants of racial/ethnic minorities were specifically
recruited using clinical centers in regions with large populations of minority women. Among the original
enrollees, 83% were white, 9% black/African American, 4% Latina, 3% Asian/Pacific Islander, and <1% Native
American.
WHI participants have been well-characterized with high quality data. Extensive baseline data were collected in
a series of three clinic visits (see data collection schedule, Appendix A) and have been published (3-7). All
protocols, procedures, data collection forms, and a study-wide comprehensive data dictionary are available
online (www.whiscience.org). Fasting bloods were collected at the first visit, prepared as serum, plasma and
buffy coat, and preserved at -70C within two hours and subsequently shipped to a central repository. Women
were asked to bring all of their usual medications and nutritional supplements to the clinic where a complete
inventory was taken with real-time coding using a pharmacy database (Medispan). An in-person interview of
prior HT and oral contraceptive use was administered and a brief physical exam was conducted to measure
height, weight, hip and waist circumference, blood pressure, and pulse. Numerous self-administered
questionnaires were collected covering most major aspects of medical, family and reproductive histories, diet
(food frequency questionnaire), physical activity, demographics, personal habits as well as a baseline
assessment of common symptoms, quality of life, social support, and activities of daily living. All instruments
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Program Director/Principal Investigator (Last, First, Middle):
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were translated into Spanish to encourage participation of Latina women. Additional procedures were
conducted in large subsamples: bone densitometry and urine collection in three centers (over 11,000
participants); physical function (grip strength, chair stand and timed walk) among 25% of CT participants 65+
years of age at randomization; and cognitive status (modified mini-mental exam) among all HT participants 65+
years of age at randomization. Among CT participants, a baseline mammogram within the last 12 months was
required. Clinical breast exams, EKGs, and for HT participants, pelvic exams, were conducted. All DM trial
participants completed 4-day food records.
CT participants were followed semi-annually, with annual clinic visits required through 2005. OS participants
were followed annually by mail with a clinic visit at year 3. At each clinic visit height, weight, blood pressure,
and pulse were measures. Fasting bloods were collected from CT participants at year 1 and from OS
participants at year 3, using the protocol described above. Six percent of participants had repeat blood
collections at years 3, 6, and 9, with oversampling of minorities to provide additional precision for racial/ethnic
specific results. Throughout follow-up, updates of key exposure data were obtained, particularly those relevant
to the trial interventions, medication and supplement use, quality of life and activities of daily living (Appendix
A). In the OS, the annual contacts updated key exposures and assessed emerging areas of interest over time.
Prospective follow-up of WHI participants for incident cancer and comorbidities was comprehensive and
retention rates were high (>93% response rates annually). All follow-up contacts assessed new primary
diagnoses of cancer, cardiovascular disease (CVD), and fractures, the primary study endpoints, as well as
overall and cause-specific mortality. Incident events of study endpoints were documented with medical records
and adjudicated locally, and often centrally, by blinded physician adjudicators (8). Self-reports of new
diagnoses of many other conditions (e.g., diabetes, hypertension, hypercholesterolemia, autoimmune
diseases, arthritis, osteoporosis/osteopenia) and cancer screening were assessed at each contact.
Mammogram reports were obtained in the CT at least every 2 years (annually for HT participants). Periodic
searches of the National Death Index (NDI) have been conducted to identify deaths in women who are lost-tofollow-up.
For incident cancer events, medical records, including pathology reports, were obtained and reviewed by the
local physician adjudicator to confirm the diagnosis. Records for a subset of these cancer events (incident
breast, colorectal, endometrial, and ovarian cancer) were sent to the WHI Clinical Coordinating Center at Fred
Hutchinson Cancer Research Center (FHCRC) (Drs. Ross Prentice and Garnet Anderson, Principal
Investigators) for centralized cancer coding according to SEER standards. Centralized cancer coding
according to SEER standards for all other cancers was done retrospectively during the 2005-2010 Extension
Study period as described below WHI participants with cancer continued to be followed annually for new
primary cancer diagnoses at different sites, incidence of other monitored disease events, quality of life
assessments, and mortality.
A.1.2
Key Results of the Original WHI Program
WHI CT results have provided important, practice-changing data on some key health concerns of
postmenopausal women. Best known are the two HT components: the trial of estrogen alone (E-alone) in
women with prior hysterectomy and the trial of estrogen plus progestin (E+P) in women with an intact uterus.
Both were terminated early for adverse effects, E+P in 2002 (9) and E-alone in 2004 (10). Intervention effects
on cancer incidence and in some cases mortality for breast, colorectal, lung and gynecological cancers have
been published in major medical journals (11-17). In contrast to the primary hypothesis, no HT benefit was
seen for cardiovascular diseases (18-23) as had been hypothesized. These results led to dramatic changes in
HT usage in the general population (24) which subsequently has been linked to reductions in population-based
breast cancer incidence rates internationally (25-29). In a series of innovative joint OS/CT analyses led by Dr.
Prentice, the discrepancies between the WHI randomized trials and the observational study for breast and
colorectal cancer and cardiovascular outcomes were examined, revealing limitations of previous observational
studies in their acknowledgement of important aspects of timing of exposure and treatment effects (30-35).
The DM trial of a low-fat dietary eating pattern, completed in 2005, revealed an overall 9% reduction in breast
cancer incidence that was not statistically significant but appeared stronger in women who made larger
changes to their fat consumption, and some evidence of differential effects by hormone receptor status (36),
indicating the importance of analyses in biologically relevant subtypes. Risks of colorectal cancer (37) and
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cardiovascular disease (38) were not affected. Secondary analyses revealed a nominally significant 17%
reduction in ovarian cancer (39). Additional work led by Dr. Prentice is proceeding with the goal of developing
nutrition biomarkers and appropriate analytic tools to improve the inference that can be made from nutritional
epidemiological studies (40, 41).
The effect of calcium (1000 mg/d) and vitamin D (400 IU/d) on hip fracture incidence was a modest 13%
reduction which was not statistically significant but appeared stronger in women who were adherent to study
pills (42). These supplements also provided no benefit for colorectal cancer (43) or breast cancer (44). With
increasing interest in health effects of vitamin D, serum vitamin D levels were measured in a series of casecontrol studies, revealing possible relationships between endogenous levels and risk of breast cancer (44),
colorectal cancer (43), and melanoma (45), but control for physical activity levels substantially reduced this
association for breast cancer (44). There was no indication of interaction between endogenous levels and
supplement use on risk.
The observational study has been used extensively for cancer studies. For example, WHI investigators have
examined the role of race/ethnicity in cancer risk (46,47), the insulin and IGF pathways for breast (48),
colorectal (49) and endometrial cancer (50), common medications such as NSAIDS (51) and bisphosphonates
(52), the glycemic index (53), and selected micronutrients (54) in relation to risks of various cancers. Patterns
of cancer screening have been studied. WHI data have been used to validate refinements in the well-known
Gail model for breast cancer risk (55-57) and are being used to develop risk models for other tumor sites. The
WHI has provided a unique opportunity to examine health-related quality of life among African-American and
white breast cancer survivors and among women without a history of cancer, thus eliminating many of the
methodological problems of prior studies (58).
A.2
The (First) WHI Extension Study (2005-2010)
A.2.1 Overview of the History, Design and Data Collection
Prior to the end of planned follow-up in 2005, the NHLBI decided that extended follow-up of all participants was
warranted to assess the longer-term intervention effects and maximize the value of the WHI resource through
support for additional studies using the vast database and specimen repository. During close-out contacts in
2004-2005, WHI Clinical Centers re-consented 115,407 participants (76.9% of living participants who had not
previously refused further contact) to 5 more years of follow-up. The CCC assumed responsibility for
participant follow-up via annual centralized mailings, achieving response rates to mailings of 89-95%. Clinical
Centers conducted phone follow-up of non-responders and those who could not be followed by mail, yielding
overall annual response rates greater than 96%.
During the 2005-2010 ES, WHI adjudicated 53,151 clinical outcomes cases, including 11,052 cardiovascular
events, 5,846 strokes, 17,877 cancers, 2,889 fractures, and 12,019 deaths. The abnormally high number of
cancers coded during this interval (relative to the other health events) was a result of retrieving and SEERcoding all incident cancers reported from the beginning of WHI, a modification of the WHI workscope approved
by the WHI Steering Committee and the NHLBI at our request. Medical records from all previously reported
cancers were retrieved by Clinical Center staff and sent to the CCC for coding, yielding 20,763 confirmed
invasive cancers. Of these, approximately 1/3 had died by September 2010 (Table 1). For the cancer sites
selected for inclusion in the proposed Cancer Survivor Cohort (breast, colorectal, endometrial, lung, and
ovarian cancers, lymphoma, leukemia, and melanoma), there are 16,727 centrally confirmed cases. The vast
majority (79%) were 65+ years of age at diagnosis. Nearly 4800 deaths were observed in these women by
2010, but of those who survived, 75% consented to continued follow-up. Many of these cancers (n=5179) have
been included in GWAS studies, primarily as a result of WHI participation in larger consortia. WHI is also
participating in a National Human Genome Research Institute (NHGRI) sequencing consortium (MPIs: Drs.
Rebecca Jackson, Ulriki Peters, Christopher Carlson, and Kari North) currently examining a more limited set of
phenotypes. All genomic data and all the accompanying phenotype data have been deposited in dbGaP for
broader use. A complete listing of disease phenotype events by age and race for the CT and OS component
through September 2010 may be found in Appendix B.
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Table 1. Centrally confirmed invasive cancers through September 2010, by site, age at diagnosis, inclusion in
GWAS and consent status for active follow-up
Confirmed cancers diagnosed through Sept 2010
Age at diagnosis
Confirmed cancer cases re-consented in 2010
Total
Cancer Site
N
N
N
%
N
N
%
N
%
N
N
%
N5
Breast
7787
1720
5819
75%
1968
1169
15%
5033
76%
1051
3689
73%
1344
Colorectal
2211
1949
1867
84%
344
706
32%
1070
71%
915
909
85%
161
Endometrial
1321
195
1020
77%
301
236
18%
839
77%
97
625
74%
214
Ovary
685
110
548
80%
137
391
57%
221
75%
37
181
82%
40
Melanoma (skin)
769
101
595
77%
174
109
14%
547
83%
61
411
75%
136
Lung
2246
518
1962
87%
284
1530
68%
491
69%
94
437
89%
54
Lymphoma
1133
433
964
85%
169
359
32%
555
72%
211
469
85%
86
Leukemia
575
153
499
87%
76
291
51%
229
81%
68
195
85%
34
Total CSC cohort
16727
5179
13274
79%
3453
4791
29%
8985
75%
2534
6916
77%
2069
Other sites
4036
1560
3487
86%
549
2251
56%
1360
76%
485
1142
84%
218
Total invasive cancers
20763
6739
16761
81%
4002
7042
34%
10345
75%
3019
8058
78%
2287
> 65 years
< 65
Died <2010
consent
With
GWAS
Age at diagnosis
With
GWAS
Total
> 65
< 65
Selected exposures were updated during this interval. In
2010, the medications inventory was repeated, primarily by
mail, with a very good (89.9%) response rate among those
in active follow-up (n=108,296). These data demonstrate
high prevalence of regular use of calcium supplements
(59%), multivitamins with minerals (58%), salicylates
(51%), statins (40%), NSAIDs (30%), vitamin D (28%), and
thyroid hormones (25%) (Figure 2). A separate
questionnaire was included for participants who previously
reported a breast cancer diagnosis to ascertain use of
hormonal therapies. Among the 88% of 6584 breast
cancer survivors who responded to this survey, 44% had
taken tamoxifen (22% for 5+ years), 28% had used
anastrozole, 14% letrazole, 6% for exemestane, and 6%
for raloxifene.
During the 2005-2010 ES, the CCC was approved to
purchase and link Medicare data from Center for
Medicare/Medicaid Services (CMS) and link it to the WHI
database. After a successful pilot, showing high linkage
rates for the years 2006-2007, the CCC obtained Medicare
data for the years 1991-2005, assuring coverage for at
least 2 years pre-enrollment through the most currently
Figure 2: Percent reporting regular use of medications in 2010
available data at that time. The datasets requested were
the MedPar (Inpatient Standard Analytical File [SAF] and Skilled Nursing Facility SAF), Outpatient SAF, Home
Health SAF, Hospice SAF, Carrier SAF, Durable Medical Equipment, and the Denominator file, which
documents intervals of Medicare enrollment.
Of the original 161,808 WHI participants, 151,116 (93%) provided adequate personal identifiers to support
linkage, 132,685 (82%) were perfectly matched, and 2305 (1%) had adequate matches giving a total of
134,900 (83%) with valid links. Matching rates varied significantly by baseline age, race/ethnicity, study
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component (CT vs. OS), and geographic region. The complexity of claims data is suggested by enrollment
intervals: 73% of WHI participants had a single enrollment interval between January 1991 and December
2007; 22% had two intervals; and one participant appeared to have 18. Women who receive health care
through a health maintenance organization (HMO) appear in the denominator files as enrolled in Medicare but
do not typically have claims data in other Medicare files since Medicare payments are capitated, making
Medicare data uninformative for HMO members with regard to most health information. CCC use of these
data, as directed by NHLBI, is currently limited to evaluating the feasibility of relying on Medicare data for
passive follow-up of participants for CVD endpoints.
A.2.2 Key Results of the (First) WHI Extension Study
Figure 3: Time-trends for E+P hazard ratios for breast cancer in the
intervention and post-intervention phase (61)
A.3
Post-intervention HT trial results have demonstrated
attenuation of effects, both beneficial and adverse, for most
outcomes with one exception--HT effects on breast cancer
have persisted (59, 60). Although E+P-associated breast
cancer risk declined in the 3 years after intervention was
stopped (Figure 3) (61), an overall increased risk remained
and in longer-term follow-up, increased breast cancer
mortality was found (62). For E-alone, the early suggestion
of reduction (10, 16) remained in the post-intervention
follow-up (60, 63), which is also now supported by a
reduction in breast cancer mortality (63). Manuscripts
describing results of extended follow-up of DM and CaD
trial participants are in progress.
The (Second) WHI Extension Study (2010-2015)
In 2009, the NHLBI again decided to extend follow-up of the overall WHI cohort. Objectives for 2010-2015 are:
1) to maximize the knowledge gained from the WHI resource by conducting studies addressing the etiology,
biologic mechanisms, and risk factors for morbidity and mortality in postmenopausal women, particularly as
they relate to CVD, as well as for healthy and exceptional aging; and 2) to expand the WHI resource through
longer-term follow-up of consenting participants, through additional data collection via linkage mechanisms
with external data sources such as the National Death Index (NDI) and Medicare, or other NHLBI-designated
activities that may be approved.
At NHLBI’s direction, several aspects of the program were streamlined. The 40 original Clinical Centers were
consolidated into 4 Regional Centers and 6 satellite sites, all former WHI Clinical Centers. We refer to these 10
centers here as Regional Centers (RCs). The CCC assumed participant follow-up responsibility for 2 former
Clinical Centers. The NHLBI-funded workscope was reduced, reorganized, and refocused on cardiovascular
and aging endpoints. In the 2010-2015 Extension Study, all consenting participants are followed annually for
self-reported events, as in 2005-2010, but documentation and adjudication of WHI endpoints is limited to
former HT trial participants and all Black/African-American and Latina participants (referred to as the Medical
Records Cohort or MRC). Among remaining participants (referred to as the Self-Report Cohort or SRC), WHI
collects self-reported endpoints but no documentation of outcomes or adjudication is planned to occur unless
additional ancillary funding is obtained to support this effort. We are fortunate and grateful, however, that NCI
contributed funds to NHLBI to support documentation and SEER coding of all incident primary cancers for all
continuing WHI participants through 2015, making cancer incidence the most complete, high-quality clinical
event data in WHI for the foreseeable future.
Consent for extended follow-up was administered in 2010 by the CCC and the FHCRC now serves as the
central IRB for all participating centers. As of November 2011, 93,541 women had consented to continued
follow-up, including 22,309 (82% of eligible) women in the MRC and 71,232 (88.5% of eligible) women in the
SRC. Overall, 87% of continuing participants are white, 6133 (7%) are Black/African-American, 2470 (3%) are
Latina, 1880 (2%) are Asian/Pacific Islander, and 317 are Native American.
Under the 2010-2015 Extension Study protocol, all participants in active follow-up are contacted annually,
primarily by mail to obtain a medical history update (F33, Appendix C) and an assessment of aging and quality
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Anderson, Garnet L.
of life related issues. As part of F33 completion, participants are asked to sign a medical release of information
annually, permitting WHI to obtain medical information including pathology reports and specimens,
operative/procedure reports, lab tests and results, discharge summaries, physician notes, and progress
reports. The follow-up protocol, requiring repeat mailings and telephone follow-up by RCs to non-responders
has maintained very high annual response rates (>96%). For all incident cancers reported through this
mechanism, WHI RCs request medical records (i.e., pathology reports) to confirm cancer diagnoses.
This ongoing data collection will support our broader research agenda. In most years, participants will be
asked to complete a brief questionnaire assessing a variety of aging-related issues, in addition to their health
status updates on clinical events. During 2012, participants are being asked to complete a more detailed
assessment of their quality of life, physical, social, and emotional functioning, particularly in relation to aging. In
2013, participants will again be asked to complete the medications inventory.
The NHLBI has obtained an interagency agreement with CMS that will provide the CCC with Medicare data for
WHI participants for the foreseeable future. In February 2012, we received the 2008-2010 data. Since nearly
all (>98%) WHI participants are currently 65+ years of age, NHLBI is interested in determining whether
algorithms applied to Medicare data have adequate sensitivity and specificity for WHI events to strengthen
outcome data in the Self-Report Cohort. Algorithms to ascertain acute myocardial infarction, stroke, and
venous thromboembolism are being developed or refined from the literature, tested against the traditional WHIadjudicated outcomes. The interagency agreement also allows us to request Medicare Part D (prescription
drug) claims data for our participants and this application is in process. Medicare Part D, which began in 2008,
will provide ongoing supplements to our periodic medications inventory although we are aware of considerable
complexities in using these data (e.g., the so-called “donut hole” in coverage).
During 2012-2013, a national firm (Examination Management Services, Inc.), under contract to the CCC, will
conduct a home visit for all consenting Medical Records Cohort participants over 72+ years of age. Many
aspects of the baseline brief physical exam will be reassessed: height, weight, blood pressure, pulse, grip
strength, chair stand, and timed walk. A new fasting blood specimen will be collected, centrally processed and
stored, primarily for subsequent ancillary studies although CBC and selected cardiovascular risk markers will
be measured prospectively. An ancillary study (Dr. Andrea LaCroix, PI, 5R01HL105065-02) will assess
physical activity among consenting MRC participants by having them complete a self-administered
questionnaire and wear an accelerometer for 7 days. Another ancillary study (Dr. Jeannette Beasley, PI) will
re-assess nutrient intake in these aging women using the WHI food frequency.
A.4
Broader Usage of the WHI Resource
The WHI database described above has been supplemented with information collected from numerous
ancillary studies, many accessing the vast WHI biorepository which currently contains more than 5 million vials
of specimens held at -80C in 140+ freezers in Rockville MD. In total, 387 ancillary studies have been reviewed,
197 have been approved, and 146 have been funded. Of the funded studies, 37 are directly related to cancer
(listing available at www.whiscience.org). Most have focused on the more common cancers but increasingly
the accumulation of cancer cases within the entire cohort of 161,000 women has been sufficient to support
studies of rarer tumors (e.g., pancreas, melanoma, and ovary). The breadth and depth of this resource has
also made the WHI a valuable contributor to GWAS consortiums (colorectal, pancreas, kidney, bladder,
stomach). These studies, primarily examining molecular markers of risk using baseline blood specimens, have
enriched the scientific yield of WHI and supplemented the WHI database for use by other investigators.
Complete blood counts (CBC) are available at baseline from nearly all participants. 170 biomarkers have been
measured on at least 2000 participants and 15 biomarkers have been measured in at least 10,000 participants
(Figure 4). Over 22,000 participants have been in GWA studies, including over 6700 cancer cases (Table 1)
and all African American and Latina women who consented. More recently, these specimens have been used
for early detection biomarker discovery and validation studies and for proteomic analyses assessing the
differential effects of E+P and E-alone on the proteome (64, 65).
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Other funded ancillary studies have expanded the scope of possible
studies within WHI. In work funded by the National Institute of
Environmental Health Sciences (RO1-ES012238, Dr. Eric Whitsell,
PI), participant address histories throughout follow-up have been
geocoded and linked to air pollution databases and “built
environment” databases (RO1HL084425, Dr. Chloe Bird, PI) for
association studies with cardiovascular disease (66, 67).
The overall WHI database is being accessed for a broad group of
investigators with diverse interests, many of whom were not
previously associated with WHI. Overall, 1633 manuscript proposals
have been reviewed, 1320 approved and 619 published, including
320 reviewed, 209 approved and 104 published in the past year. The
619 published papers have been led by 293 different investigators
representing institutions beyond the originally funded sites (complete
listing available at www.whiscience.org).
Figure 4: Number of participants with results
for most commonly measured biomarkers
A.5
Summary – An Opportunity for Cancer Survivorship
Research
0
1000
2000
3000 4000 5000
An opportunity for greater contributions from WHI comes in the area of cancer survivorship studies. The WHI
database provides a tremendous foundation for studies of the association of diverse exposures and medical
conditions with cancer outcomes. Although some groups have better inherent designs to address specific
issues of cancer treatment (e.g., randomized trials of a small
number of specific treatment regimens), the extensive WHI
database of pre-diagnostic demographics, lifestyle, genetic and
environmental exposures, prospectively assessed comorbidities,
and longitudinal assessments of symptoms and quality of life
provides a powerful and complementary resource with over
20,000 confirmed incident cancers and follow-up for a mean of 12
years. In this proposal we seek to extend the utility of the
database with the addition of treatment data recurrence and
patient-reported outcome measures. WHI would then be in the
position to examine the broader issues of the diffusion of
treatment advances and assess their effects in an aging cohort
60
70
80
90
100
(Figure 5), a group very much under-represented in randomized
Figure 5: Current age distribution of 2010-2015
trials (68), despite the fact that cancer is primarily a disease of
WHI Extension Study participants
aging.
Data collected in parallel from WHI participants without cancer also provide an uncommon opportunity to
control for secular and aging effects when examining post-diagnosis trends among women with cancer. Making
these analyses robust and interpretable, however, requires data on cancer treatment and outcome. By
supplementing the existing database with this information, WHI would become a much more comprehensive
resource for studies of the effects of cancer prognosis and other cancer outcomes of significance to both
clinicians and cancer survivors.
While the infrastructure developed in WHI over the past two decades provides a rich environment to examine
potential causes, cofactors, and molecular markers associated with cancer incidence and mortality, limitations
of this resource will become increasingly apparent. Studies of cancers defined only by the SEER annotations
of histology, grade, stage, tumor size, and lymph node status will become increasingly obsolete. Molecular
profiling of tumors is becoming critical for etiologic, prognostic, and survival studies. WHI has captured
standard tumor markers for breast cancer (ER/PR/Her2), but many more markers will become part of routine
clinical care over the next few years. If WHI could obtain and store the tissues for the cancers already
diagnosed, the extensive WHI database could contribute to discovering, validating, and assessing the role of
novel molecular tumor markers in cancer diagnosis and treatment over the next decade.
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The timeframe for addressing these gaps is critical. Approximately 22% of cases were diagnosed before 2000.
While most providers maintain records and tissue for 10 years (some indefinitely), many will not. If we want to
collect an adequate sample, both in numbers and representativeness, the retrospective collection of these
tissues and records must begin very soon.
A.6
WHI Pilot Studies
We have conducted two pilot studies that address our ability to collect tumor tissue retrospectively, on a
national basis, and to recruit breast cancer survivors into a prospective cohort study within the WHI.
A.6.1 WHI Breast Tumor Tissue Pilot
WHI investigators (Drs. Anderson, Caan, and Chlebowski) conducted a pilot study in 2010-2011 to assess the
feasibility of collecting fixed breast tumor tissue from WHI participants diagnosed with cancer throughout the
US. We tested procedures for collecting formalin-fixed paraffin-embedded tumor tissues on a national level
from a variety of facilities and identified the administrative and logistical infrastructure needed to support a
broader tissue collection effort. We identified 1765 invasive breast cancers diagnosed between 1999 and 2007
in the DM trial. Among those, we selected the 370 cases where data were not available for all 3 tumor markers
(ER, PR, and HER2) and 133 cases of known “triple negative” invasive breast cancer. To be eligible for the
pilot study, a tumor specimen had to be collected from the women prior to any treatment other than surgery.
Thus, 503 clinical records and pathology reports collected through the standard WHI protocol were reviewed,
yielding 420 eligible participants. Tissue specimens were identified by accession number, surgery date, and
laboratory/hospital. A core needle biopsy was selected only if it was the only eligible tissue available.
Eligible participants were contacted either by the WHI Clinical Centers (n=248) or by the CCC (n=172)
according to Clinical Center preference. These participants were mailed a consent form and a medical release
form (prior to the 2010-2015 Extension Study Consent) that requested permission to access tumor specimens
and their accompanying pathology reports. Of the 420 women, 334 (80%) consented or we received proxy
consent, 29 (7%) actively refused, 20 (5%) did not respond, 24 (5%) could not be located, 7 (2%) were not
approached at clinic discretion, and 6 participants (1%) were deceased and did not require consent.
The Clinical Centers or the CCC requested tumor blocks or slides for 340 eligible cases from over 200
hospitals/laboratories. If the participant was deceased, proxy consents were obtained, although some
institutions did not require them. Tissue was received for 278 cases (82%), either as tumor blocks or slides.
Tumor tissue was no longer available or could not be located for 56 women (16%), and there was no response
from the hospital/laboratory for six cases (2%).
Tumor tissues were sent to the Anatomic Pathology Lab at the University of Washington Medical Center. Of
278 specimens received, 257 (92%), were available for histologic review, performed on H&E slides either sent
to or created by the lab. IHC testing was performed for ER, PR, CK5/6, EGFR, HER2, and if needed, FISH.
The remaining 21 tumor specimens were not tested because the tissue sent did not contain invasive tissue, the
tissue was <5mm in size, or the ER/PR stains were inadequate with a lack of positive controls.
This feasibility study provided us with experience and data in tumor tissue collection on a national basis that
will facilitate our success in the proposed application. We now propose that the CCC alone contact the
laboratories and/or hospitals throughout the country to request tumor specimens. In our pilot study, each
Clinical Center had to obtain approval from their local IRB to request the tumor tissue, and this resulted in
significant time delays. The CCC had an 85% success rate in obtaining tissue from 138 women and thus
demonstrated expertise in requesting large numbers of tumor specimens. We anticipate a similar response
rate in this research initiative given a single IRB approval process, the consistency of approach, dedicated
staffing, and more uniform staff training for follow up with non-responsive facilities.
A.6.2
WHI Breast Cancer Survivor Cohort - Pilot Study
The WHI Breast Cancer Survivor Cohort (BCSC) is a prospective cohort pilot study being conducted in 4 of the
40 original WHI Clinical Centers. The overall goals of this pilot are to determine the feasibility of the full WHI
Cancer Survivor Cohort study by: 1) refining procedures, forms, questionnaires, collection, and processing
methods; 2) establishing participation rates ; 3) refining and validating procedures for exposure and outcome
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assessments (medical records and new events using data from WHI) for both living and deceased women with
cancer.
Women were eligible if they had not history of cancer at enrollment in WHI, were diagnosed with invasive
breast cancer during their WHI follow-up, and they consented for the WHI Extension Study. Among 402
potentially eligible breast cancer survivors, 323 (80.4%) agreed to participate, 35 (8.7%) were eligible and
refused, 15 (3.7%) were found to be ineligible, 18 (4.5%) could not be contacted, and 11 (2.7%) were
deceased. Overall, 90% of potentially eligible women who were contacted agreed to participate. Of the 310
who returned the baseline survey, 36 (11.6%) reported a “new event” (local recurrence, distant recurrence, or
new primary. In 4 rounds of subsequent annual follow-up surveys, approximately 90% have returned their
questionnaires and 45 “new cancer events” or deaths have been reported. These four sites are in the process
of collecting medical records from the facilities where the incident cancer was treated. To date records have
been obtained for 50% of eligible women and verification of self-reported outcomes (new events) is underway.
Information from this pilot will inform the final data collection plan for the larger WHI-CSC. We believe the
response rates for the WHI-CSC may be even better since the proposed protocol is less burdensome (no clinic
visit or blood draw). In addition, centralized consent and follow-up rates have been consistently higher than
the average across the multiple centers, because of increased standardization and quality control.
A.7
Experience in Other Cancer Cohorts
WHI investigators, including those leading this proposed project, have extensive experience in developing and
maintaining large cohorts, including some specifically in cancer survival. A few of these are described here.
A.7.1 Breast Cancer Survivorship Studies within the Kaiser Permanente Medical Program
Several NCI funded studies, led by Drs. Caan or Kushi, form the basis of a large research program in breast
cancer prognosis and survivorship from two cohorts housed within the Kaiser Permanente Medical Program :
The Life after Cancer Epidemiology study (LACE), a study of 2200 women diagnosed between 1996 and 2000
and followed for up to 15 years; the Pathways study of 4000 women diagnosed between 2006 and 2011; the
Behavioral Correlates of Breast Cancer Recurrence (R01CA080027 Caan-PI, completed); the Long Term
Health Outcomes in Breast Cancer Survivors (R01CA106764 Caan –PI, completed); the Molecular Profiles
and Lifestyle Factors in Breast Cancer Prognosis (R01CA129-059, Caan-PI, 2010-2014); and the Prospective
Study of Breast Cancer Survivorship (R01CA105274, Kushi-PI, Caan- Co–I, funded 2006-2014). Together,
these examine medical, behavioral, lifestyle, genetic and molecular risk factors on breast cancer prognosis.
Data from these collective studies have demonstrated that modifiable behaviors such as activity (69-72), diet
(73, 74), multivitamin use (75, 76), alcohol use (77), and body weight (78, 79) can all affect quality of life and/or
breast cancer prognosis. Physical health and functional limitations (80) are also important predictors of breast
cancer outcomes. Additionally, we have observed that adherence to adjuvant hormonal therapy (81, 82), use
of ibuprofen and other NSAIDS (83), or lipophilic statins (84) reduced the risk of recurrence, while ACE
inhibitor therapy was associated with an increased risk of recurrence (85). Studies using these data have also
recently examined risk factors associated with molecular factors such as methylation profiles (86) and intrinsic
subtypes (87). The LACE study also participates in 2 large pooling projects of breast cancer survivors of which
Dr. Caan is one of the Co-Investigators: The After Breast Cancer (ABC) pooling project, a study of over 15,000
breast cancer survivors from 4 cohorts and the California Breast Cancer Survivor Study Consortium, a study of
over 12,000 breast cancer survivors from 6 cohort or case-control studies.
Dr. Caan was also the site PI of Oakland Clinical Center of the Women’s Healthy Eating and Lifestyle Study
(WHEL) study, a randomized clinical trial to test the effects of a low-fat, increased fruit and vegetable diet on
breast cancer prognosis. Since the trial ended in 2006, the study has continued as a prospective cohort of over
3000 breast cancer survivors, examining important environmental risk and genetic and molecular markers for
breast cancer prognosis.
A.7.2 Breast Cancer Survivorship Studies within the CALGB
Dr. Paskett has led several breast cancer survivorship studies within the CALGB cooperative oncology group.
CALGB 70305: A Randomized Study to Prevent Lymphedema in Women Treated for Breast Cancer (Dr.
Paskett, Study Chair) is a group randomized trial testing lymphedema prevention education versus the same
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prevention education plus a tailored exercise intervention in women with stage I-III breast cancer in whom an
axillary dissection (either full or sentinel) is planned. Each of the 34 participating institutions is randomly
assigned a treatment, which is then given to the eligible enrolled patients. The primary endpoint is incidence of
lymphedema at 18 months; secondary endpoints include lymphedema assessed by self-report and limb
measurements; health-related quality of life; adherence to the exercise intervention protocol; body image; fear
of recurrence; self-efficacy, lymphedema knowledge, range of motion, grip and arm strength. This trial is
currently accruing with a sample size goal of 560 and 406 women are currently enrolled.
CALGB 79804: Issues of Survivorship Among Breast Cancer Survivors (R01AG016602, Paskett, Study Chair)
was a breast cancer survivorship study among CALGB 8541 trial participants who were 6-16 years postdiagnosis. The study used a quality-of-life model adapted for cancer survivors to determine the prevalence of
physical, economic, psychosocial, and spiritual consequences of survivorship, including issues related to
reproduction, menopause, osteoporosis, post-mastectomy/lumpectomy pain, and lymphedema among a cohort
of 245 (78% of invitees) long-term disease-free breast cancer survivors, and to determine how these problems
affect overall health related quality of life (HRQL). Lower global HRQL was associated with decreased energy
levels, having heart disease, or having two or more comorbidities, and lower social support (88). The most
prevalent problems reported were menopausal symptoms (64%), osteoporosis (25%), and lymphedema (23%).
Other factors such as economic outcomes (89), physical activity and dietary changes (90), lymphedema,
perceived physical functioning and mental health (91), behavior and psychosocial (92), and health related
quality of life (93) have been examined.
A.7.3 Experience in Other Breast Cancer Survivor Cohorts
The Menstrual Cycle Maintenance and Quality of Life After Breast Cancer Treatment (DAMD17-96-1-6292, Dr.
Paskett, Co-I), is a prospective cohort of 627 breast cancer patients, funded by the US Department of Defense,
to identify determinants of menstrual cycle maintenance after breast cancer treatment, examine survivor’s
quality of life longitudinally, track reproductive events among those attempting pregnancy, and ultimately to
investigate the effect of subsequent pregnancy on survival. Women were identified using tumor/surgical
registries or physician referrals. Eligibility was defined as ages 18-45 years with stage I-III invasive breast
cancer within the previous 8 months, and having regular menstrual cycles at the time of diagnosis.
Participation rates were very high (93% of eligible women). To date, menstrual bleeding after treatment (94,
95) and lymphedema (96, 97) has been examined in this young breast cancer survivor cohort.
B.
INFRASTRUCTURE DESIGN AND RESEARCH PROGRAM
B.1
Broad Research Agenda: The Women’s Health Initiative Cancer Survivor Cohort (WHI-CSC) –
the tremendous potential survivorship research
Overview: Why the Women’s Health Initiative Cancer Survivor Cohort (WHI-CSC) study is needed
The need to identify ways to reduce the burden of cancer, throughout the spectrum of prevention, early
detection, improved and targeted therapies, and symptom control remains an urgent element of the nation’s
health research agenda. Among women between the ages of 35 and 74, cancer takes a larger fraction of lives
than any other condition (98) and is associated with tremendous morbidity and cost. With the growing
population, particularly in the oldest age-groups, cancer-related medical expenditures in the US are projected
to reach $158 billion in 2020, an inflation-adjusted 27% increase from 2010, and may reach $207 billion if
trends in costs for newly developed diagnostic, treatment and monitoring technologies persist (99). With
increasing survival has come an awareness of the longer-term impact of the disabilities associated with cancer
and its treatment. Previous studies of cancer outcomes have often been limited by the lack of data on preclinical and environmental factors. Significant gaps remain on how modifiable factors (e.g., diet, smoking,
physical activity, co-morbid conditions, and use of other medications) influence choice of treatment and risk of
recurrence, progression, and survival.
Increasingly, cancer treatment is based on the molecular characterization of the tumor. To be relevant, future
analyses of cancer recurrence and survival will require characterization of the patient’s tumor, beyond classical
information on histology, stage, grade and the few markers currently used in clinical practice. Next-generation
sequencing and other evolving technologies are increasingly being used to build catalogues of somatic
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mutations, methylation patterns, gene expression, and miRNA expression for each major cancer type (100,
101). These will allow tumors to be characterized in more detail and create new, more informative subclassifications of diseases based on molecular taxonomies and altered pathways (99, 101-104). This new
information on specific targets and their role in disease has already been used successfully to develop new,
targeted cancer therapies (106-112).
Testing hypotheses that relate lifestyle and genetic factors on disease outcomes within the context of the new
knowledge on molecular heterogeneity will help to better target interventions. The very comprehensive
database developed by WHI in support of cancer risk and prevention studies provides a strong foundation for
assessing the contribution of these factors to the evaluation of treatment and prognosis.
B.2
Specific Aims
The WHI has the ability to become a much more comprehensive resource configured to address specific
questions of prognosis and outcome, and through this, speed the translation of emerging biomarker findings
into meaningful interventions. The size and diversity of the WHI study population, the extensive database of
pre-clinical, clinical and epidemiological factors, the extensive repository of preclinical blood specimens and the
length of follow-up, yielding over 20,000 centrally confirmed cancer cases, thus far, support the concept that
the WHI can become a powerful platform for survivor studies. To facilitate a broad research agenda on risk
factors for cancer recurrence, new primary cancers and cancer-specific survival, with a particular emphasis
evaluating the contribution of comorbidities, lifestyle factors, molecular and genetic markers, and treatmentrelated factors, we propose:
1) To collect information on cancer treatment, clinical and patient-reported outcomes in women diagnosed
with selected cancers (breast, colorectal, endometrial, lung, and ovarian cancers, lymphoma, leukemia,
and melanoma) during their WHI participation, using surveys, Medicare linkage, whenever possible, or
direct medical record abstraction;
2) To expand the WHI biorepository by collecting paraffin-embedded tumor tissue from selected cancers sites
(colorectal and ovarian cancers, melanoma, lymphoma, and breast and lung cancer subtypes);
3) In addition, with an intent to find ways to reduce costs further, we further propose to evaluate the potential
to streamline methods and reduce the costs of data collection by:
a) developing and refining algorithms to extract cancer treatment and outcomes data from administrative
databases for analytic purposes;
b) assessing the comparability and validity of these data collected from administrative sources with those
obtained from direct medical record review; and
c) exploring the opportunities, mechanisms, data availability and costs of collecting cancer treatment and
outcome data from administrative databases such as the Cancer Research Network (CRN), a branch
of the Health Maintenance Organization Research Network (HMORN), and cancer registries.
This enhancement of the existing WHI resource with cancer treatment and outcomes and tumor samples,
coupled with extensive pre-diagnosis data and multiple blood specimens collected months or years prior to
diagnosis, will enable WHI to become one of the premier resources for studies of survivorship across multiple
cancers.
B.3
Rationale for Emphasis on Selected Cancers
Our broad scientific agenda in the WHI-CSC focuses on integrating pre- and post- diagnosis data and
specimens to investigate factors related to prognosis for colorectal, endometrial, ovarian, breast, lung cancers
and melanoma, leukemia and lymphoma. Although WHI investigators and collaborators are interested in a
range of cancers, in this proposal, we focus on relatively common, but understudied cancers. WHI has a large
number of breast cancers that can be studied, but we propose to prioritize the development of this resource for
these other cancers where WHI has sufficient numbers to conduct well-powered studies, and where studies of
variation in recurrence and survival are relevant and timely. We also include some critical research on BlackWhite survival differences in breast cancer.
Examples of research that will be conducted under this broad scientific agenda are described below and
grouped into two general categories: those that are part of the long-range agenda and necessitate tumor
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specimens and molecular profiling, as well as treatment and outcome data, and those that can be conducted in
the shorter-term with the collection of treatment and outcome data proposed within the framework of this
infrastructure grant. These concepts provide the rationale for specific types of research that require these
resources for a given cancer site to illustrate the broader questions of interest for multiple cancer sites.
B.4
Examples of High Priority Studies that Require Tumor Tissue
B.4.1 Biomarkers of Lung Cancer Prognosis
Clinical determinants of lung cancer prognosis, including tumor histopathology and stage, are insufficient to
capture the heterogeneity in survival and other outcomes observed among patients (113-116). Furthermore, it
has recently been established that lung cancer, similar to breast and colorectal cancer, is a heterogeneous
disease with different molecular subtypes. To improve the management of lung cancer, the leading cause of
cancer mortality in men and women (116), there is a critical need to identify molecular biomarkers associated
with tumor progression and response to therapeutic agents, notably ones that can be reliably assessed in noninvasively collected specimens (117). Establishing the proposed WHI resources will permit extensive
investigation of the prognostic relevance of various blood-based biomarkers, such as microRNA, and
telomeres, among patient subgroups defined by histologic and molecular subtype.
MicroRNA (miRNA) studies. Multiple lines of evidence clearly implicate miRNAs – a class of short non-coding
RNA molecules that function as post-transcriptional gene regulators – in cancer: 1) miRNA expression levels
differ between normal and tumor tissue (118); 2) miRNA expression profiles uniquely characterize various
types of cancer (118), including histologic subtypes of non-small cell lung cancer (NSCLC) (119-121); 3)
miRNAs act as both tumor suppressors and oncogenes (122); and 4) over 50% of all human miRNAs reside in
cancer-associated genomic regions or fragile sites (123). Through genome-wide and selected miRNA
expression profiling, primarily of resected tissue from lung cancer patients, distinct (but not necessarily
overlapping) miRNA expression signatures associated with clinical outcomes, including survival and response
to treatment, have been identified (124, 125). With the recent demonstration of miRNA stability in body fluids
(126, 127), studies identifying miRNAs in serum and plasma as prognostic markers for lung cancer have
started to emerge (128-135). Most have been limited with respect to the number of miRNAs and specimens
examined. Only one has analyzed plasma collected 1-2 years before and at lung cancer diagnosis, revealing
that miRNA profiles in pre-diagnostic specimens may be useful in identifying persons with the poorest
prognosis (128). The extent to which serum or plasma miRNA profiles change over time in relation to health
status is currently unknown (136). Expanded WHI resources would present an opportunity to conduct genomewide expression profiling of all human miRNAs in pre-diagnostic specimens, discover potentially novel miRNA
expression signatures associated with lung cancer detection of particular subtypes and progression, and
investigate the degree to which such signatures vary by time from specimen collection to lung cancer onset
and death in a large, well-characterized population.
Telomere length. Telomeres are repetitive DNA sequences capping the ends of chromosomes that help to
maintain cellular genomic integrity. With each cycle of cell division, telomeres progressively shorten until the
cell encounters senescence, apoptosis, or sustained genetic damage that favors carcinogenesis (137). Studies
examining telomere length in relation to lung cancer risk have yielded suggestive, but conflicting, results. In
three small case-control studies (<250 cases), telomere length was inversely related to lung cancer risk (138140). Conversely, in a nested case-control study of Finnish male smokers (229 cases), telomere length
(measured in prospectively collected specimens) was positively associated with lung cancer risk (141).
Analyses of telomere-related gene expression and telomere length in paired tumor and normal tissue from lung
cancer patients also suggest that telomere maintenance might influence disease progression and survival
(142-145). However, no known studies have evaluated these measures in both tissue and pre-diagnostic blood
specimens in relation to lung cancer outcomes. The proposed WHI-CSC infrastructure would provide the
opportunity to conduct a larger, well-designed study to clarify the role of telomeres in lung cancer prognosis.
B.4.2 Methylation and Ovarian Cancer
Epigenetic modifications (e.g., DNA methylation) refer to heritable and modifiable markers that regulate gene
expression without changing the underlying DNA sequence. Aberrant DNA methylation in specific genes can
activate or silence genes, which may be critical to tumor development and growth (146-150), while lower
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overall genomic DNA methylation can lead to genomic instability. Both gene-specific and overall lower
genomic DNA methylation can increase cancer risk (146-150). If these changes also impact prognosis after a
cancer diagnosis, it is not yet known. These abnormal changes in DNA methylation are crucial, yet
understudied, tissue-specific epigenetic events. Evidence is emerging that lower overall genomic methylation
and aberrant DNA methylation in select genes is important to a number of cancers (e.g., breast, colorectal,
prostate, and blood cancers) (150-154).
Gene-specific and genomic methylation. Recent studies in cell lines and retrospective ovarian tumor series
have shown that gene-specific methylation differences measured in selected genes such as BRCA1 (155,
156), OPCML (157-159), RASSF1A (158, 160-163), ARLTS1 (164), ARH1 (165, 166), and TCEAL7 (167) are
important to ovarian cancer (168). A study on genome-wide measures of methylation in four ovarian tumors
compared to two normal tissue samples found that 367 CpG islands (an enrichment of methylated genes
related to cell differentiation and proliferation inhibition) were specifically hypermethylated in cancer cells (169).
In addition, in a study of 137 ovarian samples of varying malignancy from normal tissue to stage IV cancer),
659 CpG islands showed significant loss or gain of methylation. These DNA methylation profiles distinguished
between stage III ovarian tumors and normal and low malignant potential tissue (170). Further, SNPs involved
in DNA methylation and synthesis reactions are associated with risk of ovarian cancer (171). Changes in CpG
island methylation have been shown to be cumulated and associated with tumor grade (171), but their role in
prognosis has not been examined. Furthermore, animal and in-vivo studies suggest that hypomethylation is
significant in ovarian cancer development (168). Two studies have shown that genomic hypomethylation is
correlated with tumor progression and invasiveness (172, 173). Using 59 pairs of microdissected tissues
obtained from patients with epithelial ovarian cancer, one study showed that LINE-1 methylation was
significantly lower in cancer tissue compared to normal ovarian tissues (174). In addition, LINE-1 level of
methylation has been shown to be inversely associated with stage (173, 174), histological subtypes (174), and
ovarian cancer survival (174). Recent studies have begun to examine the potential of DNA methylation as a
predictive (161, 175, 176) or prognostic (177-179) biomarker for ovarian cancer.
Having the ability to assess methylation in tumor tissue will help us identify key pathways and/or mechanisms
relevant to cancer which may in turn aid in developing preventive and therapeutic targets and risk prediction
models. Tissue measures of DNA methylation are essential to our understanding of whether less invasive
blood biomarkers actually map to tissue-specific changes. Thus, we believe it is important to investigate both
tissue-specific and less invasive and more easily collected measures (e.g., WBC, plasma, urine). To date: 1)
no epidemiologic studies have examined genomic and gene-specific DNA methylation in WBC or plasma with
ovarian cancer risk or prognosis; 2) no epidemiologic studies have assessed the correlation between
measures of genomic and gene-specific DNA methylation in tumor tissue with WBC or plasma; and 3) these
novel markers have not been examined prospectively. Measurement of methylation in plasma DNA may be
useful as a tumor and/or disease marker as we may be measuring the DNA that tumors release into the
bloodstream, while WBC, due to its rapid turnover, may represent an early biomarker for biological processes
that systematically influence DNA methylation.
By focusing on measuring DNA methylation patterns in tissue and correlating these with blood measures, we
can robustly examine the feasibility of performing biomarker tests using peripheral blood, rather than tissue, to
inform risk prediction and prognosis. These same biomarkers may ultimately prove important for earlier
diagnosis, risk prediction, and prognosis. This knowledge may lead to development of alternative preventive
factors and treatment modalities for this highly fatal and largely understudied disease.
B.4.3
Vitamin D and Melanoma
WHI participants have a 5 fold-increased incidence of melanoma compared to published SEERs incidence
rates (180). It is unclear whether this increased melanoma incidence is associated with higher education,
ultraviolet (UV) exposure, or other dietary/lifestyle factors. WHI recently reported that women with prior skin
cancer who were randomized to active calcium plus 400 IU vitamin D had a significantly reduced melanoma
risk compared to women receiving placebo and higher baseline serum vitamin D levels correlated with lower
risk (45). These results suggest that vitamin D may be important in melanoma development (181). As of
August 2010, 769 melanomas of the skin have been confirmed in WHI. With more detailed information on
treatment and outcomes and tissue specimens, we will be able to better determine the role of vitamin D in
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melanoma development and prognosis by: 1) assessing whether vitamin D expression in melanomas
correlates with melanoma stage, recurrence and survival; and 2) examining gene-environment interactions for
melanoma risk and prognosis by evaluating differences in vitamin D receptor polymorphisms (182), serum
vitamin D levels, prior UV exposure, and vitamin D supplementation. With the collection of paraffin embedded
tumor tissues, we will be able to determine tumor gene expression levels for the purposes of discovering new
transcriptomes that may correlate with melanoma risk, recurrence and survival. New gene expression
technologies using 3’-RNA sequencing now allow us to interrogate the transcriptome using paraffin-embedded
tumor samples (183). We will determine whether the expression of known genes such as BRAF predict
melanoma subtype, stage at diagnosis, recurrence, and survival (184) and query the transcriptome for new
genes that correlate with melanoma stage and survival.
B.4.4 Immune Function and Non-Hodgkin’s Lymphoma
It is estimated that 30,300 women will be diagnosed with non-Hodgkin’s lymphoma (NHL) in 2011, and onethird of these will die (185). Risk of NHL may be augmented both by immune suppression and immune
activation. In a recent WHI study, investigators found that several biomarkers of immune activation were strong
predictors of incident NHL. Women with baseline serum levels in the highest-versus-lowest quartile categories
of IL10, CD23, CD27, CD30, CXCL13 were at 2.3 to 5.5-fold increased risk of NHL, and there were significant
trends of risk by increasing levels of these markers (De Roos, 2011, unpublished).These findings are similar to
risks observed for the same biomarkers in HIV patient cohorts with pronounced immune activation (186-190).
The associations observed in WHI were strongest for cases with the shortest lag time between blood draw and
diagnosis (<3 years), suggesting a possible role of these molecules in NHL progression in addition to the
hypothesized role in disease etiology. High levels of CXCL13 and IL10 have been found to correlate with poor
NHL prognosis in preliminary studies (191), and further characterization of immune activation markers in NHL
patient groups may be useful for identifying individuals who may not respond optimally to standard therapy.
In a previous study, these WHI investigators found that although the immune activation markers studied were
associated with NHL risk overall, the strength of the association differed by NHL subtype. With the addition of
paraffin-embedded tumor tissue, we will be able to further classify NHL subtypes based on characteristics
related to an activated immune environment. For example, the most common NHL subtype, diffuse large B-cell
lymphoma (DLBCL), could be further subtyped based on molecular lesions in the BCL-6 oncogene and
Epstein-Barr virus in tumor tissue–both characteristics associated with immune activation and commonly seen
in HIV-associated NHL (191, 192). The addition of such tumor-specific markers would allow us to define more
homogenous patient subgroups enabling us to clearly distinguish host characteristics (serum biomarkers,
exposures from WHI questionnaires) and tumor characteristics associated with response to treatment.
Strategies are in development for suppression of immune activation in AIDS patients to improve patient
outcomes (193), and findings from proposed follow-up of NHL patients in WHI may indicate whether such
approaches could prove useful in a broader population of NHL patients as well.
B.4.5
Energy Balance and Colorectal Cancer and Breast Cancer Prognosis
Obesity, physical activity and diet, all modifiable risk factors, have been related to the incidence of many
cancers (194), but their effects on survival after cancer diagnosis are equivocal (195-198). Few populations
have adequate data on all components of energy balance (weight, physical activity, and diet) both prediagnosis, which may be more representative of lifetime exposure, and post-diagnosis, when modifications to
behavior or changes in weight may have occurred as a result of the cancer. Studies examining post-diagnosis
obesity and colorectal cancer survival have reported modest or no associations (195, 199-202). In one study
among colon cancer survivors that examined both pre- and post-diagnosis weight (203), pre-diagnosis weight
was significantly positively related to increased death from colorectal cancer. Breast cancer survivor studies
demonstrate that underweight and severely obese women have poorer prognosis (71) than normal or
overweight women. Similarly, both weight gain (204-207) and weight loss are related to poor prognosis (78,
205-207), suggesting that weight-stable women have the most favorable outcomes for breast cancer (207) and
colon cancer (202, 203). Although pre-diagnosis obesity was associated with worse prognosis (203), postdiagnosis obesity has not related to worse survival in either breast or colon cancer. With the prospective
collection of body size, physical activity and diet in the WHI, we propose to examine the influence of weight,
diet, and physical activity jointly, in both pre- and post-diagnosis on breast and colon cancer prognosis.
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We will examine the role of these modifiable behaviors on survival for a range of cancer subtypes as defined
by tumor expression. Two recent studies (208, 209) in colon cancer highlight the value of these analyses. In
both studies, they found an interaction between a patient's body mass index (BMI) and tumor expression on
cancer survival. In the first study (208), TP53 positivity was associated with shorter cancer-specific survival in
non-obese patients but not in non-obese patients. In the second study (209), activation of CTNNB1 was
associated with better colorectal cancer-specific survival and overall survival in obese patients, but not in
patients who were not obese. Similarly, post-diagnosis physical activity was associated with better colorectal
cancer-specific survival but only among patients with negative status for nuclear CTNNB1. The opportunity to
examine these relationships in the WHI-CSC extends beyond colorectal, to breast and lung cancer, where
tumor gene expression appears to have a significant impact on survival.
B.4.6
African Ancestry and Breast Cancer Molecular Characteristics
Although breast cancer is less frequent in African-American (Black) women compared to white women,
African-American women have a higher age-adjusted breast cancer death rate (47, 210, 211). Despite
socioeconomic factors that lead to later stage at diagnosis and limited access to health care, differences in
outcomes are still observed after accounting for stage, socioeconomic status, and age (211).
African-American women more commonly present with biologically aggressive tumors including estrogenreceptor negative (ER-) tumors and “triple negative” (TN) breast cancers. More recently, findings from
international studies indicate that African natives are at substantial risk for such aggressive breast cancers. In
a recent report, 82% of breast cancers in Ghanaian women were triple negative compared to 26% in AfricanAmericans and 16% in white women (212). In Nigeria, about 25% of breast cancers are triple negative
compared to 61-66% in the US and UK (213).
Rapidly growing triple negative cancers commonly present as interval cancers even with appropriate screening
and could be responsible for a sizable component of black/white survival differences. To address this issue,
the difference in the frequency of such tumors will be explored based on degree of African Ancestry. In this
regard, WHI investigators have determined proportional European, sub-Saharan African, and American-Indian
admixture using ancestry gene markers in the WHI African-American population of 10,147 participants eligible
for genetic studies. Such analyses have found that degree of African Ancestry, assessed in quintiles, is
strongly related to increased hypertension risk and bone mineral density (214, 215).
With the availability of tumor specimens, we could determine, using breast cancer molecular subtypes (luminal
A, luminal B, HER2 overexpressing, basal-like, or low claudin), whether a particularly high risk population
related to African-American Ancestry admixture can be identified. Specifically, we would: 1) describe the
pathological and molecular subtypes of invasive breast cancers in the overall population of African-American
women, and in women in the highest quintile of African-American ancestry, compared with White women; and
2) define risk of rapidly developing proliferative cancers defined by tumor grade and molecular characteristics
regardless of breast cancer subtype. The achievement of the first objective will allow optimal characterization
of the nature of breast cancers in women with African ancestry. Achievement of the second objective could
directly lead to change in clinical screening procedures for subgroups of African-American women. If a
population with an extraordinarily high (60-80%) risk of developing a rapidly proliferating tumor is identified,
altered screening approaches (age initiation and/or frequency), incorporating additional modalities (ultrasound,
MRI), could be proposed that could impact prognosis and mortality.
B.5
Studies that Require Treatment and Recurrence Information
As stated above, our short-term agenda for the WHI-CSC infrastructure involves studies that will use the
newly-collected treatment and outcome data, but take advantage of the existing extensive WHI data resource
so that hypotheses can be investigated in a timely and cost-efficient manner. Below are examples of the types
of questions that will be investigated in relation to cancer recurrence and survival with the addition of the WHICSC infrastructure. More specifically, we will be able to ask questions about genetic, social, physical, and
clinical factors, and their influence on post-diagnosis outcomes.
B.5.1 Medication Use
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Prescription and over-the-counter (OTC) medications are widely used in the US, especially among cancer
survivors (216-218). Given their widespread exposure and possible influence on outcomes, it is crucial to
identify their role in cancer survival. Extensive preclinical data in cell culture and animal models show that
NSAIDs/COX inhibitors decrease breast, colorectal and lung cancer cell growth (219) decrease angiogenesis
and suppress cytokines (51, 220, 221). In vitro studies of statins have shown that lipophilic statins inhibit
mammary tumor growth by 50% at doses equivalent to those used in humans for reducing cholesterol (222,
223), and some studies have now demonstrated a protective effect of statin use for incidence of colorectal
cancer (224), melanoma, endometrial cancer, and non-Hodgkin lymphoma (225). There is more limited data on
statin effects on cancer survival but at least one study has found a decreased risk in breast cancer recurrence
associated with statin use (84). Antihypertensives (calcium channel blockers, angiotensin-converting enzyme
inhibitors [ACE inhibitors], and beta-adrenergic blocking agents/antagonists [beta blockers]) are also commonly
used in older populations but there is little information on their role in cancer outcomes. In breast cancer, the
majority of studies reported no association with calcium channel blockers for either risk or mortality (226-229),
while one study reported elevated risk with ever use of calcium channel blockers (230) . Beta blockers may be
associated with better breast cancer prognosis, but evidence to date has been mixed (85, 231). In one study
beta blocker intake was associated with a significantly better recurrence-free survival, especially among
patients with triple negative breast cancer (231). In another study, beta blocker use was associated with a nonsignificant reduction in recurrence and cause-specific mortality (85). In a network meta-analysis of
antihypertensive drugs, and cancer risk and mortality in 324,168 participants from randomized trials, there was
no increase in the risk of cancer-related death (from any cancer) with use of any of these anti-hypertensive
medicines (232). WHI has a comprehensive database with periodic medication inventories to support timedependent analyses of a wide range of medications such as NSAIDs, statins, metformin, and bisphosphonates
that may have the potential influence cancer recurrence.
B.5.2
Comorbidities
Comorbid medical conditions, including hypertension, myocardial infarction, angina/coronary artery disease,
heart failure, stroke, diabetes occur at a 2-3% greater prevalence among persons with, than in those without,
cancer (233). The presence of comorbidities often results in less aggressive treatment (234), and is associated
with lower survival and higher mortality. Using SEER data collected from 1992-2000 among 64,034 women
with breast cancer who were 66 years of age and older, Patnaik et al (235) demonstrated that numerous
comorbid conditions were associated with increased mortality. Diabetes has been shown to confer increased
risk of mortality in cancer patients generally (236). In a United Kingdom study, data were obtained
retrospectively from >350 primary care practices including 112,408 men and women with a cancer diagnosis of
whom 7.5% also had a diabetes diagnosis. Among breast cancer patients, mortality was increased by 32%
among those who had diabetes compared to those who did not. Interestingly, mortality from lung cancer was
somewhat decreased among those with vs. those without diabetes, but associations also differed by type of
diabetes treatment (237). With extensive data on comorbidities both before and after cancer diagnosis, and
data on blood glucose and insulin, WHI is particularly well-suited to investigate hypotheses related to
comorbidities, cancer recurrence and survival, and to investigate whether these relationships may be modified
by levels of insulin resistance. We will be able to examine the relationship between existing comorbidities and
treatment decisions, rates of treatment complications, functional status, cancer prognosis and occurrence of
second cancers and development of new co-morbid conditions compared to similar women without cancer.
B.5.3 Physical Function
Poor self-reported physical function predicts total mortality among patients with lung cancer (238), breast
cancer (239, 240) and colorectal cancer (241). It has been hypothesized that women with cancer and low
physical function may have suboptimal lean body mass and higher levels of inflammation (242). In one study of
breast cancer survivors, improvement in physical health among women >2 years after a breast cancer
diagnosis was associated with reduced mortality (240). In a second study of 1511 women, higher role
functioning (degree of impairment of work and/or leisure/hobby related activities) was significantly related to
decreased overall death (239). Findings in colorectal and lung cancer patients have been similar. In a study of
396 stage III-IV colorectal cancer patients, every 10-point improvement in physical function between diagnosis
and 3 months post-treatment was associated with a 14% reduction in risk of death (241). In 230 lung cancer
patients, physical function at baseline was inversely related to overall mortality (238). Change in physical
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function over 3 months was marginally related to a decreased risk of death. Data on self-reported physical
function were collected at two points in time (at baseline and study close-out) for all WHI women and objective
data (grip strength, ability to get out of a chair, a timed walk) are available for a subset of women who were
greater than 65 years at study entry. With rich data on longitudinal patterns of both self-reported and objective
physical function, combined with cancer recurrence and survival data, the WHI would be able to examine
associations of physical function, as well as change in physical function before and after cancer diagnosis, with
cancer recurrence and survival. These data could inform intervention to improve cancer survival by evaluating
correlates of physical function trajectories associated with survival, addressing a clearly unmet need (241).
B.5.4 Social Risk Factors in Latina Women
According to the US Census Bureau, 45.5 million Americans, or 15% of the total US population, identified
themselves as Hispanic or Latino in 2007. There is a substantial cancer mortality burden in the population of
Hispanic women (age-adjusted death rate of 104 per 100,000 in 2006) (243). Despite surveillance regarding
cancer incidence and mortality, there has been no specific study of social risk factors and outcomes in
Hispanic female cancer survivors. Despite a greater representation of Latina women among those of low
socioeconomic status, which has been consistently related to a higher burden of adverse cancer-related
outcomes, incidence and death rates are lower among Hispanics than among non-Hispanic whites for all
cancers combined, and for the most common cancers in women (breast, colorectal, and lung), part of the
phenomenon known as the Hispanic Paradox (244). A few studies that have examined social ties in Latina
women suggest that issues with social isolation related to immigration status or lack of partner knowledge
could lead to poorer prognosis through lower levels of screening. However, better outcomes in Hispanic
women are thought to be related in part to higher levels of social cohesion among families (245) and in
neighborhoods in which women reside (246). However, this potential effect has never been studied with regard
to cancer outcomes in Latina women. In the WHI-CSC we are proposing to collect more comprehensive social
network data from our cancer survivors which will enable us to examine the influence of social networks and
neighborhood social cohesion on post-cancer outcomes in these women.
B.5.5
GWAS Studies of Survival
While over 200 loci have been discovered for various cancer sites, not a single variant has been identified for
cancer survival (247). GWAS data for colorectal, breast, and other cancers site are already available within
WHI and next-generation sequencing data are increasingly becoming available, which would allow genomewide scans for common and rare genetic variants that are associated with survival at no additional genotyping
costs. The infrastructure is in place and expertise available to rapidly extend the GWAS and next-generation
sequencing studies to cancer survival. For instance, WHI is part of the Genetics and Epidemiology of
Colorectal Cancer (GECCO, U01-CA137088, PI Peters) consortium and the Colorectal Cancer Translational
Study (CORECT, U19, MPI: Peters, Gruber, Casey and Thomas) including about 40,000 samples with GWAS
data. GECCO is expanding the focus from colorectal cancer incidence to survival. Currently, lack of treatment,
recurrence, and tumor characteristic data substantially compromise the usability of WHI data for cancer
survival studies.
B.5.6
Potential for Health Services Research in Cancer Survivorship
The growth in US health care spending over the last ten years has raised major concerns surrounding
sustainability, and a renewed interest in understanding how various preventive detection and treatment
strategies, coupled with inherent and modifiable risk factors, mitigate healthcare use and expenditure over
time. With a link to etiology, biologic mechanisms, and risk factors for morbidity and mortality in
postmenopausal women, the WHI presents an extraordinary opportunity to understand the relationship
between health, health behaviors, the use of new and established medical interventions, and—ultimately—
health care expenditures and health-related quality of life over time. Such information is an essential step in
assessing the economic implications of specific interventions aimed at health-related behaviors and therapies
with long term consequences. Use of Medicare data linked to the WHI database, the specimen repository and
the proposed tissue repository strategically positions the WHI to engage in a range of investigations into health
services resource utilization, health related quality of life, cost and cost-effectiveness as they relate to cancer
diagnosis, treatment, and outcomes. At the core of these studies is a unique opportunity to explore the
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Medicare expenditure devoted to postmenopausal women in terms of its growth, the determinants of that
growth, and its relationship to health benefits.
The Medicare-WHI linked database provides an opportunity to undertake comparative effectiveness and cost
effectiveness analyses for a range of cancer-related topics, including investigations of the determinants of
uptake of genetic testing for breast and ovarian cancer and associations of testing and future healthcare use
and expenditure; evaluating the cost-effectiveness of the HT, DM, and CaD interventions for cancer outcomes;
and assessing the cost-effectiveness of commonly used cancer therapies in subgroups defined by
demographic, clinical, or molecular subgroups.
B.6
Summary of the WHI-CSC Research Potential
In summary, the WHI-CSC would be a unique resource for examination of risk factors for cancer recurrence
and survival, with data on pre- and post-diagnosis exposures, data from randomized trials of diet, hormone
therapy, and vitamin D; complete case ascertainment of 16,727 confirmed cancer cases; with the proposed
addition of data on treatment and recurrence; and data on tumor tissue, enabling examination of questions
regarding cancer survival that may not be possible in any other cohort.
The expansion of the WHI to support cancer survivorship studies, as proposed, leverages the current
investment to create a comprehensive cancer research infrastructure capable of supporting the entire
spectrum of cancer studies in older women. The size of WHI permits us to include less common tumor types
and expand and strengthen the portfolio of the existing NCI cohorts. In addition, the WHI program is well
known for its accessibility to outside investigators and for data sharing through direct collaboration and through
systems such as dbGaP and the NHLBI data repository, thereby maximizing opportunities for these resources
to be used effectively. For the proposed expansion to be successful, however, this new phase of activity needs
to begin now. Most (~77%) of the previously diagnosed cancer cases have occurred within the last 10 years,
which suggests that for these, tumor tissue and information on cancer treatment and outcome will still be
accessible. Increasingly these sources will disappear or become much more challenging to access, which will
limit the power and generalizability of any studies using them.
B.7
Core Infrastructure Activities
Overview: The original WHI cohort of over 161,000 participants serves as the parent cohort from which the
WHI Cancer Survivor Cohort (CSC) participants will be identified. Mechanisms for active and passive followup of this cohort for incident events are in place and well-functioning, funded through contracts with the NHLBI.
At enrollment, WHI participants consented to: 1) active follow-up for a wide variety of health conditions and
related exposures, and for quality of life; 2) passive follow-up, which has permitted the WHI Clinical
Coordinating Center (CCC) to link to the National Death Index (NDI) and Medicare data; and 3) future use of
existing biological specimens for unspecified purposes consistent with the mission of WHI.
We propose to build upon the existing WHI cohort to establish a cost-efficient, integrated mechanism to
conduct studies of cancer survivorship. We will supplement the existing WHI resource with cancer treatment
and outcome data. To be strategic in the development of this resource, we will focus most efforts on a subset
of cancers: breast, colorectal, endometrial, lung, and ovarian cancers, lymphoma, leukemia, and melanoma.
Our priorities were based on an assessment of the most compelling and unique research opportunities related
to cancer prognosis, the availability of an adequate number of cases in WHI to support high quality studies,
logistical considerations, and a cognizance of the limitations in available funding. Our current priorities for
tumor tissue collection are colorectal and ovarian cancers, melanoma, lymphoma, and breast and lung cancer
subtypes. Upon funding, these priorities will be further refined by our CSC Steering Committee (SC) with input
from our External Advisory Board (EAB). The proposed mechanisms, once established, will be made available
to support similar data and specimen collection for other cancer sites if other funding became available.
B.7.1 Design and Composition of the WHI-Cancer Survivor Cohort
Among the original WHI participants, 20,763 cancer diagnoses have been reported and centrally confirmed as
of September 2010, the end of the first Extension Study (Table 1, above). (Note: Although additional cancers
have since been confirmed, September 2010 represents an important point of distinction with regard to
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consent status, so we have chosen to describe the cases before and after September 2010 for simplicity). The
subset of these women comprising the 16,727 confirmed cases of breast, colorectal, endometrial, lung, and
ovarian cancers, lymphoma, leukemia, and melanoma form the initial target population of the Cancer Survivor
Cohort (CSC). We refer to these as prevalent cases in describing the data collection processes below.
Of the 16,727 prevalent cancer cases, 4791 (29%) had died by September 2010, 8985 (75% of eligible)
consented to follow-up in the 2010-2015 Extension Study, and 2951 declined further participation (Table 1).
With a total of 93,541 WHI participants (87% of eligible) consenting to the 2010-2015 Extension Study, we
project that approximately 5155 newly diagnosed primary cancers (incident cases) will occur during the
remaining funded follow-up (through 2015), based on observed age-specific rates in SEER and the WHI
population for these cancer sites (Table 2). Thus the total projected number of eligible participants to the WHICSC is approximately 21,882.
Table 2. Projected number of selected cancers among the 93540 women consenting to the WHI 2010-2015
Extension Study
Follow-up year*
Total
Total
Total
Projected
Prevalent
Projected
Rate 2010 2011 2012 2013 2014
+
Incident
Cases
Cases
Cases
/year -2011 -2012 -2013 -2014 -2015
(2010-2015)
(2010)
(2015)
Breast
0.0044
412
391
371
353
335
1862
7787
9649
Colorectal
0.0023
215
204
194
184
175
973
2211
3184
Endometrial 0.0007
26
25
24
22
21
118
1321
1439
Ovarian
0.0005
47
44
42
40
38
212
685
897
Lung
0.0027
253
240
228
217
206
1143
769
3389
Melanoma
0.0006
56
53
51
48
46
254
2246
1023
Lymphoma 0.0009
84
80
76
72
69
381
1133
1514
Leukemia
0.0005
47
44
42
40
38
212
575
787
Total
1139 1082 1028
977
928
5155
16727
21,882
*Assumes deaths/loss to follow-up of 5% per year
+Rates derived from age-specific incidence rates from SEER, with some adjustment for the historically lower rate of lung
cancer and higher rates for breast cancer and melanoma in WHI participants
Data collection will vary based on the woman’s vital and consent status and whether her specific diagnosis has
been selected for tumor collection. The schema in Table 3 outlines the general plan.
B.7.2 Approaches and Methods for Follow-up
Within the first year of funding for prevalent cases in active follow-up, and immediately after confirmation of an
incident cancer for women diagnosed with cancer between 2010 and 2015, all CSC eligible women will be
asked to complete an initial intake questionnaire (Appendix D). The questionnaire will query about initial cancer
treatment including surgery, chemotherapy, hormonal therapy, radiation therapy, biological therapies and
complementary/alternative medicine, including type, start dates and providers of these treatments; reports of
new cancer events related to their primary cancer diagnosis; reports of longer-term disabling conditions or
effects on quality-of-life that are common sequelae to many cancers or their treatments but not covered by
WHI questionnaires (e.g., lymphedema, cardiotoxicity, nephrotoxicity, neurotoxicity) and questions on
insurance coverage, income, employment status and access to care. These items were selected based on
their relevance to cancer treatment and outcomes and for being complementary to the ongoing WHI data
collection (Appendices E and F).
The initial questionnaire will be sent separately from the WHI mailings to reduce participant burden at the time
of administration. The mailing will be sent by first class mail with the out-going envelopes identified with the WHI
logo to assure recognition. The mailing will contain a personalized cover letter introducing the new data
collection, describing the previously reported cancer(s) and date(s) of diagnosis which qualifies the participant,
two copies of a consent form for the tissue acquisition, an “Authorization for release of medical information”,
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Table 3. General plan for collection of treatment and recurrence data and tumor tissue based on timing of
cancer diagnosis, vital status and consent status and linkage to Medicare information
N
Deceased
before
September
2010
Prevalent
cases
(N=16727)
Incident
cases
Consented to
2010-2015
Extension
Study
Did not
consent to
2010-2015
Extension
Study
Consented to
the 20102015
Extension
Study
4791
8985
Medicare
Linkage
Linkable at time of
diagnosis
Not linkable at time
of diagnosis
Linkable at time of
diagnosis
Not linkable at time
of diagnosis
Approach to collecting treatment and
recurrence data
Medicare linkage (51%, n=2443)
Obtain waiver of consent IRB to request
remaining medical records (n =2348)
Medicare linkage (51%, n=4582)
Request medical records (n=4403)
Request tissue if
appropriate cancer type
Yes, if waiver of consent
approved
Yes, if waiver of consent
approved
Yes with new consent and
medical release
Yes with new consent and
medical release
Linkable at time of
diagnosis
Medicare linkage (51%, n=1505)
No
Not linkable at time
of diagnosis
Unavailable (n=1446)
No
Linkable at time of
diagnosis
Medicare linkage (~64%, N=3286)
Yes with new consent and
medical release
Not linkable at time
of diagnosis
Request medical records ( n=1869)
Yes with new consent and
medical release
2951
5155
and a self-addressed, business reply envelope. For participants known to be deceased, the designated proxy
respondent may be contacted by phone or mail to complete a limited number of these items.
The annual questionnaire (Appendix G) will be included in each subsequent annual WHI follow-up (F33)
mailing for all CSC members who completed the initial questionnaire. This form will assess traditional patient
reported outcomes and it will request updates from the woman on new cancer events and cancer treatments.
In addition, a small number of new questions may be included to support newly funded ancillary studies or
other important emerging topics.
All questionnaires will be translated into Spanish for use by Spanish-speaking participants using the same
translation services employed by WHI. All English forms will be printed in optical mark recognition (bubble)
format, with large font, consistent with WHI practices for the last 15+ years. The mailings will follow the
established WHI follow-up protocol which has achieved excellent response rates (>96% annually).
Questionnaires will be returned to CCC for scanning. Women who do not respond to these attempts to contact
or indicate that they do not want to participate will be excluded from further active CSC data collection.
B.8
Cancer Treatment and Outcome Data Collection
Details of cancer treatment and outcomes will be derived from two main sources: CMS and direct medical
record abstraction, as described in Table 3. While the data from these two sources will vary considerably in
terms of the level of detail, timeliness and specificity, we propose to use the strengths of each, supported by
targeted overlap in sources, to create a pooled dataset that can support analyses of higher level variables.
Where more detailed information is required, analyses may be restricted to cases documented through a
specific source (e.g., cost analyses will be restricted to the Medicare population).
B.8.1 Use of Medicare Claims to Assess Cancer Treatment and Outcome
To reduce costs, we propose to rely on Medicare data for cancer treatment and outcome data whenever
possible. As described in A.1.3, the CCC has Medicare data files for the calendar years 1991-2010. An NHLBICMS interagency agreement will supply Medicare data to the CCC for the remaining years of WHI follow-up.
For women who were enrolled in Medicare and using a fee-for-service provider (i.e., not receiving care through
an HMO) at the time of their diagnosis, Medicare has claims data available that documents hospitalizations,
inpatient and outpatient procedures, hospice, etc. We expect records for approximately 51% of prevalent
cancer cases to be in the Medicare data files based on the following calculations. Among the 16,727 prevalent
cases, 13274 (80%) were 65+ years of age at diagnosis. Our current work with Medicare data for 1991-2007
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indicates that overall, 85% of WHI participants were linked to Medicare data during this interval. Among those
who were linked to Medicare, approximately 25% received their health care through an HMO. (HMOs do not
submit claims information to Medicare for reimbursement of services for Medicare enrollees so details of
patient care are mostly not available in Medicare data files although their enrollees are included in the
“Denominator” file.) For simplicity, we assume that these same fractions apply to prevalent cancer cases in all
three categories (deceased, consenting and non-consenting to the 2010-2015 Extension). For cases
diagnosed between 2010 and 2015, we expect to make a successful linkage with nearly two-thirds (.85*.75) of
all incident cancers through Medicare since almost all (>98%) WHI participants are now 65+ years of age.
Thus for 8531 (.8*.85*.75 *16,727) prevalent cases and 3259 (.85*.75*5155) incident cancers identified in
2010-2015, we expect to use Medicare data.
In WHI, incident cancers and deaths are initially ascertained through self or proxy-report and verified by
medical record review. We will attempt to link patients’ confirmed cancers to their corresponding diagnosis in
Medicare records, primarily through dates and medical codes (ICD-9 and HCPCS). The Medicare claims files
we will use include inpatient (MedPAR), outpatient (Outpatient SAF), and provider/supplier (NCH) claims,
taking into account enrollment intervals documented in the Denominator file. When such a link is defined, and
the Denominator file indicates enrollment in both Medicare Part A and Part B (and not an HMO member) for at
least 12 months following diagnosis, we expect to obtain reasonably complete information on the initial course
of treatment. Information on therapies, dates of administration, type of provider and costs, will be extracted.
CCC staff will work with study investigators (Ramsey, Bensink, Chlebowski, Kushi, and Liao) and other
interested investigators to define analytic approaches for identifying exposure to classes of therapy,
determining adherence to standard therapy regimens, and estimating attributable costs of disease. Our
objectives will be to define algorithms that are accurate, meaningful and useful for most analyses of interest,
and sufficiently comparable to those that can be abstracted directly from medical records to allow pooling
across data sources. Algorithms to extract information on cancer recurrence have been developed by others
with moderate success (248-250). These algorithms will serve as the starting point for developing tumor sitespecific approaches. Information derived from our direct medical records abstraction process will also inform
this process. Although some of this work can be done across all cancers, most of it will require tailoring for
each cancer site to take into account differences in preferred treatment modalities, agents, and protocols and
disease monitoring strategies. Validation studies using the overlap in Medicare and direct medical records
cases, as described in Section B.12.2, will be used to evaluate and refine these algorithms. Except for the
cases selected for the validation study, we do not plan to request medical records for cases linked to Medicare.
B.8.2 Direct Medical Records Collection
For the projected 6751 prevalent cancers and 1869 incident cancers for which treatment and clinical outcome
data are not available in Medicare, who were diagnosed in 2000 or later (77%) and for whom we are
authorized to collect medical records, we will request medical records using the approach used for WHI clinical
outcomes documentation and adjudication.
Potential Outcome Identification and Follow-up: The CCC will develop a database program, similar to one
used for WHI outcomes, to analyze baseline and annual questionnaires to determine participants for whom
medical records are to be requested. For each Regional Center (RC), a list of these participants and
corresponding event information will be presented in a report accessible in the WHI Extension Study database
(WHIX). This listing will reflect currently available information on linkage to CMS and resource development
priorities. The RCs will access the report, review the associated form image and enter the provider identities
into WHIX. Once provider identities are entered, RCs can use WHIX to create and track document requests.
RCs will use the detailed information from the baseline questionnaire to identify and request records from the
medical oncology clinic or other treatment facility responsible for the woman’s initial care using electronic
requests, when feasible, and mailed or in-person requests as needed. For women who were deceased at the
time of the 2010 consent with no claims data in the Medicare files, if a waiver of consent is obtained, RCs will
use the information from the previously obtained medical records as well as any proxy respondents, to identify
potential sources of documentation. When the documents are received, RC staff will review the records for
completeness, scan and submit them electronically to the CCC through a secure link to the WHI database
following the same procedures in place for WHI outcomes collection. A random sample of cases
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(approximately 140) for each of the 8 targeted tumor sites from the Medicare linkage set will also be requested
for validation studies (see B.12.2).
Medical Records Review and Coding: For the CSC, a CCC outcomes liaison will log each medical record into
the WHI database, review each case’s records for completeness, and send any necessary queries back to the
RC for additional documents or clarifications. Regular reports will be generated describing the timeliness and
completeness of the documentation process.
A trained medical records abstracter will review each selected record to confirm the previously documented
diagnostic information and record information on surgery date(s); biomarkers; types, and start and stop dates
of neoadjuvant and adjuvant chemotherapy, radiotherapy, biologic therapy, and hormonal therapy directly into
the WHI Extension Study database. Reports of major toxicities will also be noted when available.
Records will be selected for abstraction and coded first for validation studies. Subsequent abstraction efforts
will be prioritized based on guidance from the CSC Steering Committee and the CSC External Advisory Board
based on research priorities within the available resources. Ancillary studies may be required to support
addition abstraction charges to support their specific needs.
B.8.3 Defining Clinical Cancer Outcomes
Our primary clinical cancer outcomes are recurrence, progression, new primary cancers and cancer mortality.
The WHI data collection includes all primary incident cancers and mortality so here we propose to supplement
these data with information on recurrence and progression. We will develop coding systems that define the
criteria and minimum required evidence based on information commonly available from the medical records for
each specific tumor. These coding systems will be adapted for use in the Medicare data. As an example, for
breast cancer the criteria for recurrence are:

New primary: histologic diagnosis of new contralateral invasive breast cancer or ipsilateral invasive
breast cancer in a quadrant outside of the original location.
 Local recurrence: histologic diagnosis of recurrent ipsilateral breast cancer in the same quadrant or on
the chest wall or the axilla.
 Distant recurrence: histological or clinical evidence of metastatic breast cancer in distant sites
(including ipsilateral supraclavicular lymph nodes).
o Bone metastases: bone scan abnormalities imaged by plain x-rays, and consistent with metastases
or progressive symptomatic bone scan abnormalities over an interval of time.
o Lung metastases: radiographic evidence of metastases in the absence of infection or other likely
diagnoses. A solitary pulmonary nodule should be evaluated for a possible primary lung cancer.
o Liver metastases are defined as CT scan evidence of liver metastases with ultrasound imaging not
consistent with cysts or progressive CT scan evidence of metastases over an interval of time.
o Other metastatic sites are defined as clinical or histologic evidence of metastases in the absence of
other likely diagnoses.
Neither ductal carcinoma in situ (DCIS) nor lobular carcinoma in situ (LCIS) is considered a study outcome;
however, both will be ascertained and recorded.
B.9
Creation of a Fixed Tumor Tissue Repository
As described in the overview, collection of tumor tissue will be guided by the resource development priorities
established by the SC with input from the EAB and NCI. In general, we expect that tissue collection requests
will be most successful for cases diagnosed within the last 10-12 years. Information on the number of cases by
tumor site for which tissue is likely to be accessible (i.e., year of diagnosis) and availability of other data
needed for proposed studies (e.g., GWAS, treatment data) will inform these decisions. We propose to attempt
to collect 8200 tissues, which includes all available colorectal and ovarian cancers, melanoma, lymphoma, and
2000 each of breast and lung cancer subtypes. For breast and lung cancer, where the projected number of
available specimens exceed 2000, we propose to oversample rarer tumor types based on available molecular
markers (e.g., for breast cancer triple negative, ER-/PR-, and ER-/ PR+, Her2+) and a representative sample
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of more common subtypes. Based on our pilot work, we expect that from 8200 tissue requests, we will receive
samples from 5900 cases.
B.9.1 Tumor Tissue Collection
The WHI Breast Tumor Tissue Pilot study (A.2.1) laid the groundwork for the proposed tissue collection
protocol. The collection process is defined for 3 groups of WHI participants who have been or will be
diagnosed with these cancers: 1) Women with one of the specified cancer diagnoses who are continuing in
active follow-up and provide consent and sign a release form with the initial questionnaire; 2) Women
diagnosed with the specific cancers who died prior to the 2010 Extension Study consent. Tumor specimens
from previously deceased women will be collected after a waiver of consent is approved by the FHCRC
Institutional Review Board (IRB). Such approvals are in keeping with previous actions of the FHCRC IRB; and,
3) Women diagnosed with one of the selected cancers during the active follow-up of the 2010-2015 Extension
Study who provide updated release forms in response to our protocol questionnaire.
Once an updated release form or a waiver of consent is received, a trained data coordinator will review the
pathology report in the existing WHI cancer outcomes chart to determine which specimens (i.e., biopsies,
excisions, or more extensive surgical procedures) should be requested. Decisions will be based upon tumor
size and behavior, presence of specific histologic types of the cancer, and use of neoadjuvant chemotherapy.
Information in the pathology reports (previously obtained by WHI to confirm the cancer) such as the procedure
date, hospital/laboratory, and pathology accession number will be entered into a WHI tissue database, and a
standardized request for tumor tissue blocks will be sent to the institution. The request letter will be
accompanied by a copy of the signed release form or documentation of the IRB-approved waiver of consent.
To reduce the workload burden to large institutions with multiple specimens, requests for tissue blocks
(preferably) or slides will be batched and mailed biannually. Lack of response within 4 weeks will generate a
repeat request and follow-up phone contact with hospital/laboratory personnel. To address potential concerns
about access to specimens for continuing care, we will assure the return of any specimen to any location in US
within 48 hours if the specimen is needed for clinical care. Institutions will be reimbursed for this activity, if
requested, although our experience indicates that many will not make the request.
B.9.2 Tumor Tissue Review and Storage
Upon receipt, formalin-fixed paraffin-embedded tumor blocks and their corresponding pathology reports will be
logged into the WHI repository database, and labeled with a unique WHI specimen ID bar code that is linked to
the WHI member ID. They will be batched and transported to the FHCRC Specialized Pathology Shared
Resource, accompanied by an electronic transmittal sheet that lists the specimen IDs and the diagnostic
information from the WHI database to be verified. The specimens will be checked into the laboratory database
via barcode scanning, and given to the staff pathologist for triage.
The triage process will consist of selecting a subset of blocks for H&E sectioning based on the information in
the pathology report; up to 5 paraffin blocks most representative of the patient's primary cancer will be selected
and recorded on the triage data entry form. H&E sections of the selected blocks will be cut and stained by
trained histotechnologists and returned to the staff pathologist for review. For each block the pathologist will 1)
confirm the presence or absence of tumor and normal structures; 2) estimate the two dimensional area of the
entire tissue block; 3) estimate the amount of available tumor and normal structures as a percentage of the
area of the tissue section; 4) mark the tumor on the H&E slide for future tissue microarray construction and or
laboratory testing; and 5) rank the tissue blocks based on the amount of representative tumor. Dr. Porter will
perform the secondary pathology review, resolve any discrepancies, and sign off on the pathology review for
each case. All specimens, corresponding pathology reports, and the completed pathology review forms will be
returned to the WHI Repository co-located with the CCC staff.
Upon return, specimens will be checked back into the WHI repository database via barcode scanning, and the
data entry of the pathology results will be performed. Major discrepancies of the diagnostic information (e.g.
incorrect site) will require resolution, including possible queries to the original pathologists. Tumor specimens
will be stored in a secure, temperature controlled room designed specifically for this purpose.
B.10
Data Management and Quality Control
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Follow-up Mailings: Procedures for identifying participants eligible for mailings, preparation of materials,
mailing and receipt of completed questionnaires, and problem resolution will follow established methods of the
WHI CCC which have been in place throughout the Extension Studies. The integration of the CSC follow-up
with WHI will require a review and modification of each of the affected programs to assure the completeness
and accuracy of the sample selection, and to assure that reporting aspects allow real-time tracking of data and
progress. RCs will have access to individual level and site-level data as it is collected through the central
Oracle database (WHIX) using a secure VPN connection, assuring better coordination of efforts across sites.
Database Support for Tracking/Reserving/Accessing Specimens: The WHI database management system for
study tracking (WHIST), tracks ancillary studies and specimen usage, including all aspects of the biorepository
inventory management (logging specimens receipt and transfers, documenting locations, reserving specimens
for approved studies, etc.). This system, called WHIST, will be expanded to include inventory management of
tissue blocks and slides, and permit linkage of tissue specimens with blood specimens.
Quality Assurance of CCC Processes: The WHI CCC has a comprehensive quality assurance program to
assure the integrity and accuracy of data collection, management and analysis processes. The key
components of this system are standardized training, documentation and data collection instruments, real-time
data checks and verification incorporated at data-entry, periodic reviews of data through statistical analyses,
routine and targeted audits of data and processes. In addition, the CCC incorporates specific QA mechanisms
into all laboratory assays (e.g., blinded split-duplicates, blinded specimen analysis) in all studies.
B.11
Data Sharing
B.11.1 Mechanisms for Sharing De-identified Data
The CSC will follow the same data sharing policies and mechanisms in place for WHI. In addition to providing
data analytic expertise, the CCC provides WHI PIs and other authorized investigators with approved
manuscript or ancillary studies with access to a secure website where comprehensive de-identified WHI
datasets and associated documentation can be downloaded, under a WHI data use agreement. Identical
information, without downloading capabilities, can be viewed at the WHI public website www.whiscience.org.
During the 2010-2015 Extension Study, these will be updated approximately biennially. After WHI investigators
have had exclusive access to these data for approximately one year, the CCC will submit further anonymized
datasets to the NHLBI BIOLINCC data repository for use by other qualified investigators, as determined by
NHLBI. The CCC also provides similar data to dbGaP for those participants who were genotyped. Medicare
data and data derived under a waiver of consent are exceptions to this plan. The Medicare data use
agreement does not permit the CCC to share Medicare data with an outside entity and the FHCRC IRB will not
permit data obtained through a waiver of consent to be deposited in dbGaP. Currently the CCC is seeking
CMS permission to make the Medicare data accessible to outside investigators on a limited basis through a
virtual data enclave.
B.11.2 Data Sharing Through Outreach
The most important methods for sharing data is through publication and outreach. Multiple avenues will be
pursued, including publishing our resource development methods, actively encouraging use of the resource
within the WHI through the WHI Cancer Scientific Interest Group (SIG) (Drs. Prentice, Caan, and Chlebowski,
co-chairs), and promoting the resource to outside investigators. Dr. Paskett will be responsible for promoting
the use of the WHI-CSC resource through outreach to the broader scientific community. She will organize
efforts to publicize and educate investigators outside of the WHI about CSC resources, and encourage
proposals for its use. Investigators from outside of WHI will be offered collaborators/mentors from the Cancer
SIG to assist in manuscript or ancillary study proposal development, both scientifically and administratively.
Venues for dissemination will include: scientific meeting presentations (e.g., AACR, ASPO, APHA, SBM,
SER), cooperative group meetings (e.g., Dr. Paskett, ALLIANCE; Dr. Anderson, SWOG), and the HMO
consortium (Drs. Caan and Kushi). Training sessions will occur at major meetings and be available via the WHI
website. We will also link other organizations that can reach investigators (e.g., Associate Director/Program
Leaders from Cancer Centers, NCI Cohort Consortium, and Schools of Public Health).
B.12
Methodological Research
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Although there are multiple areas of methodologic research that would support this effort, we focus here on
finding and evaluating ways to develop the cost-efficient and sustainable aspects of this resource.
B.12.1 Developing and Testing Algorithms to Define Cancer Outcomes in Medicare
Medicare datasets contain claims data that provide information on billable services. Although these data offer
an inexpensive approach to surveillance, there are a number of issues and limitations that must be considered
when using Medicare enrollment and claims data for studies of health care use and outcomes.
A first and vital issue for research is the accuracy of using Medicare claims to identify incident cases of cancer.
Algorithms for the purposes of identifying incident breast cancer have been developed and evaluated in both
health services (251-253) and epidemiologic research (254, 255) with mixed results. The modest sensitivity
(generally 60-90% in different settings and with different algorithms) and low PPV (252-254) for incident breast
cancer have led most authors to conclude that Medicare records should be used in combination with other
sources (254, 256). More limited work has been published evaluating the incidence of cancers other than
breast cancer. One study examining the sensitivity of Medicare claims for identifying incident cancer in
multiple sites reported ranges for breast of 68%-94%, colorectal 50%-92%, endometrial 53%-91%, lung cancer
48%-88%, and pancreatic cancer 36%-86%, depending on use of inpatient data, outpatient data, or both (257).
After identifying persons with cancer, Medicare claims may be useful for identifying those receiving specific
treatments (253). Medicare HCPCS codes have been used to identify particular types of surgery and whether
the patient has undergone radiation therapy. Medicare claims (J-codes) have high sensitivity when used to
identify whether patients received office injectable chemotherapy, but sensitivity for specific agents varies.
(258). One limitation is that drugs that have been very recently approved by the FDA are frequently recorded
using nonspecific chemotherapy codes. Finally, the timing of radiation therapy administration is not reliably
recorded, although it is generally possible to determine when patients started and stopped radiotherapy (259,
260).
Fewer studies have examined the use of Medicare claims to identify recurrence or second primaries. McCLish
et al (248) developed a logistic regression model to predict second primaries and recurrence using multiple
sources of claims and achieved an area under the ROC curve of 0.90 based on all data sources. In work more
akin to that of interest to WHI, the CALGB used Medicare data to define disease-free survival in a companion
study to CALGB-9344, a breast cancer adjuvant trial. Among eligible, linked patients (N=45), their approach
produced an estimated sensitivity for 5-year (2-year) disease-free survival of 100% (83%) and specificity was
97% (95%) with an AUC of .84 for the ROC (249). In a survival and cost study among non-metastatic breast
cancer patients, Stokes et al (250) used linked SEER-Medicare data to look for evidence of recurrence or
contralateral breast cancer. The algorithm for defining new events was developed from an acute myelogenous
leukemia study (261) and was used without additional validation.
B.12.2 Validation of Medicare Data for Cancer Treatment and Outcomes
We will conduct validation studies to assess the accuracy and reliability of Medicare (and any other
administrative databases used) with direct medical record abstraction for the eight designated tumor sites. For
each site, 140 cases will be selected from the cases represented in Medicare. Efforts will be made to assure
that each sample is diverse in terms of known diagnostic features (histology, stage), age and calendar year of
diagnosis, and geographic region. RCs will be asked to obtain the associated records and submit them in
parallel to the other medical records. We expect to obtain at least 120 per site from this effort. Comparisons of
the Medicare and self-report data to those of the medical records will be made specifically for type, dates and
duration of treatments. In addition, proposed algorithms developed for defining recurrence in Medicare data will
be applied and compared to the corresponding information as routinely abstracted from the chart in terms of
sensitivity, specificity, positive and negative predictive value.
B.12.3 Exploring Access to Other Administrative Data
In the interest of improving the cost and efficiency of obtaining treatment and outcome data, we will investigate
opportunities to collect these data through linkage to other resources such as the Cancer Research Network
(CRN4-PI, Lawrence Kushi) a network of 15 organizations funded to provide an infrastructure to facilitate
cancer research in integrated health care settings. The CRN expands the cancer research enterprise with
population sciences resources that reside in integrated health care systems, enabling access to populations
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and clinical and administrative data for health plans that provide care to 10 million members—over 3% of the
US population. Much of CRN’s success is attributable to its comprehensive virtual data warehouse (VDW) that
supports multisite, multipurpose collaborative research. The VDW is a unique shared resource that translates
data from local systems into a common format, using agreed-upon data standards. It includes demographic
and clinical information from electronic medical records, insurance claims, and registries for the defined and
diverse CRN patient populations, providing some comparability to Medicare data. Work is ongoing to develop
the VDW for cancer treatments. A large number of WHI participants receive their health care from these
integrated health care systems (e.g., Kaiser Permanente) since two of the original Clinical Centers were part of
Kaiser Permanente several other Clinical Centers were located in regions with high HMO penetration. We will
work with the CRN and the FHCRC IRB to assess the feasibility of developing data sharing agreements and
mechanisms that would permit us to link identifiers from WHI with the VDW to obtain the relevant treatment
and outcomes data and estimate the costs and likely yield associated with obtaining these data from the CRN.
If this avenue proves feasible, we would propose to replace direct medical record collection with use of this
more administrative database wherever possible.
We will also investigate opportunities and efficiencies of collecting cancer treatment data from the individual
population-based cancer registries of NCI’s SEER Program. Combined, these registries cover approximately
26 percent of the US population. The cancer registries routinely collect data on patient demographics, primary
tumor site, tumor morphology and stage at diagnosis, first course of treatment, and follow-up for vital status.
Linkage to the cancer registry data can be performed using minimal data items such as name (last, first,
middle), date of birth and social security number, and these data items are available for the vast majority of
WHI participants. Available treatment data may not be as complete as those from other sources, but the first
course of treatment may provide needed data when other sources of data are unavailable.
B.13
Potential Problems and Alternative Approaches
We have anticipated some of the potential problems that may arise in this large project. Fewer women than
expected may consent to the CSC, as some survivors may not want to be reminded of their cancer
experiences. We will pilot our materials with a small number of non-WHI cancer survivors to obtain their input
on design prior to launching this effort. We will monitor our consent rates and our 1-800 call line closely in the
early mailings, making changes to the cover letter to address concerns identified. Response rates to our
requests for medical records or tumor tissue from institutions may also be lower than projected. We will look for
patterns in the response rates to determine whether different approach mechanisms or payment options are
needed. Finally, we expect that Medicare data will be adequate to determine treatment for most analytic
purposes, but they may provide a very blunt instrument for assessing recurrence in some cancers. This would
be important information generally since direct data collection is very expensive and we are all looking for costefficient alternatives. Our alternatives would then be to rely on cancer mortality as the endpoint for our studies.
B.14
Organizational Structure
B.14.1 Cancer Survivor Cohort Governance
Decisions on the conduct and priorities of the CSC will be the responsibility of the CSC Executive Committee
with input from the broader Steering Committee and the CSC External Advisory Board (Figure 6).
Executive Committee (EC): The CSC-EC will consist of the three Principal Investigators. Drs. Anderson, Caan,
and Paskett have worked together in WHI for the last 12 years on issues related to cancer, identifying the gaps
in the WHI resource for cancer survivorship studies and building the foundation for this work. They will combine
their complementary expertise and long-standing collaborations to provide effective operational and scientific
leadership for the proposed project. The EC will meet at least bi-week bi-weekly by teleconference, convened
by Dr. Anderson, during the initial 6 months of the funding period and monthly thereafter. The EC will
determine research direction, strategy, and policy, as well as develop study instruments and protocols, monitor
study progress, and coordinate with the existing WHI Committees and Scientific Interest Groups. Because EC
members will directly lead these activities, issues that arise during study implementation can be quickly
identified and a plan for resolving them can quickly be developed. The EC will actively communicate with and
seek advice and input from the CSC Steering Committee, EAB and NCI program scientists.
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Steering Committee (SC): The SC will be responsible for developing the priorities for resource development,
providing guidance and assistance in identifying new research initiatives, integrating these efforts within the
WHI, developing collaborations, managing the resource and general problem solving. The SC will be
composed of the PIs, an NCI representative and 7 additional investigators who will lead the diverse areas
needed to maximize the development and use of the resource: cohort studies of cancer survivors, genetic
epidemiology, oncology, pathology, biostatistics and health services research. In the first year, the SC will have
monthly teleconferences and three in person meetings. In years 2-5, they will have quarterly calls by
teleconference and 2 in-persons meeting per year. Members include Drs. Lawrence Kushi, Rowan Chlebowski,
Ross Prentice, Li Jiao, Peggy Porter, Scott Ramsey, and Kristine Wicklund. The SC will meet in conjunction
with the external advisory committee annually.
External Advisory Board (EAB): The EAB for the WHI-CSC will provide input on goals, priorities, methods, and
progress of the program, identify other areas for methodological and scientific research and assist with
stimulating its use by investigators outside of the WHI. Members of the EAB include: Patricia Ganz, MD
(UCLA, survivorship and quality of life), David Cohn, MD (OSU, gynecologic cancers and comparative
effectiveness research), Dawn Hershman, MD (Columbia University, Oncology, Cancer Control, and Health
Services Research), William Carson, MD (OSU, breast cancer, melanoma, and immunology), Stephen Gruber,
MD (USC, molecular epidemiology and colorectal cancer), and Elizabeth Frank ( advocate). The EAB will be
coordinated by Dr. Paskett, who will be responsible for scheduling meetings, setting agendas, making
assignments, and ensuring that meeting minutes are kept and distributed. EAB meetings will be held annually
in the Washington DC area. Attendees will include the EAB members, the SC, representatives from the NCI
and NHLBI (WHI), and, as needed, any investigators who are using the WHI-CSC resource.
As the CSC is an enhancement of the existing WHI Extension Study, we will organize WHI-CSC efforts in
manner that integrates these functions with WHI leadership and operations as much as possible. We propose
that access to the resource being developed here be governed by the same policies and committees as is
currently in place for WHI. We briefly describe the WHI governance structure here .
WHI Governing Committees: The WHI Extension Study is governed by a Steering Committee (WHI-SC, Dr.
Garnet Anderson, Chair) and 3 standing advisory committees: Outcomes Adjudication Committee (OAC, Dr.
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Marian Limacher, Chair), Publications and Presentations Committee (P&P, Drs. Barbara Howard and Cynthia
Thomson, co-Chairs), and Ancillary Studies Committee (ASC, Dr. Robert Brunner, Chair). The WHI-SC is the
main decision-making body of the study, and is comprised of 4 RC PIs, the CCC PI, Committee Chairs (P&P,
ASC, OAC), an additional CCC investigator (Dr. Andrea LaCroix), 2 Scientists-at-Large (Dr. Jennifer Robinson
and Dr. Teresa Seaman), and the NHLBI Project Officer (Dr. Jacques Rossouw). The SC currently has
monthly conference calls and 2 meetings per year. Dr. Anderson will provide coordination between the WHI SC
and the CSC-SC/EC.
WHI Advisory Committees: The Outcomes Adjudication Committee (OAC) oversees adjudication of clinical
outcomes, and advises on new findings in the literature, data collection and clinical outcome coding. Dr.
Chlebowski will be the CSC liaison to the OAC. The Ancillary Studies Committee (ASC) evaluates ancillary
study proposals, using a review process modeled after NIH study sections. All proposals seeking to collect
additional data or access the WHI biorepository must be reviewed and approved by the ASC. Dr. Caan will be
the CSC representative to the Ancillary Studies Committee. The Publications and Presentations Committee
(P&P) has two primary responsibilities in WHI. The committee identifies high priority paper topics, solicits
authors from the broader WHI community and assures adequate progress towards publication. The P&P also
evaluates investigator-initiated manuscript proposals for all reports using WHI data, facilitating the assembling
of a writing group, and reviewing the manuscript before it is submitted for publication. Dr. Paskett will represent
the CSC on the P&P committee. Policies for ASC and P&P are available at www.whiscience.org.
WHI Scientific Interest Groups (SIGs): To engage the diverse interests of WHI investigators, a set of Scientific
Interest Groups (SIGS) have been developed. There are 11 identified SIGs: CVD, Cancer, Aging, Bones,
Obesity/Diabetes, Physical activity/body composition, Nutrition/energy balance, Genomics/Proteomics, Health
Services Research/CMS/comparative effectiveness research, , Environmental Exposures, and Psychosocial &
Behavioral health. The Cancer SIG is co-chaired by Drs. Prentice, Caan, and Chlebowski with Drs. Anderson
and Paskett as some of the 20+ members. Cancer SIG members strongly endorsed this proposal and
contributed their current ideas for using this resource. We will work with all relevant SIG’s to promote the use
of this resource and accomplish our broad scientific research agenda. Our previous track record in the conduct
of cancer epidemiology research exemplifies the productivity we expect in the cancer survivorship area with
the addition of data elements funded through the proposed WHI-CSC.
B.14.2 Operational Organization
The primary data collection described in this proposal will be performed at the existing WHI centers—the WHI
Clinical Coordinating Center (Dr. Garnet Anderson, PI) and the 10 WHI Regional Centers located at HarvardBrigham and Women’s Hospital in Boston (Dr. JoAnn Manson, PI), University of Buffalo (Dr. Jean WactawskiWende, PI), Medstar Research Institute in Washington DC (Dr. Barbara Howard, PI), Wake Forest University,
Winston-Salem (Dr. Sally Shumaker, PI), University of Florida, Gainesville (Dr. Marian Limacher, PI), Ohio
State University (Dr. Rebecca Jackson, PI), University of Pittsburgh (Dr. Lewis Kuller, PI), University of Iowa
(Dr. Jennifer Robinson, PI), Stanford University (Dr. Marcia Stefanick, PI) and University of Arizona (Dr.
Cynthia Thomson, PI). Dr. Caan will serve as the CSC liaison with the PIs helping to resolve issues and
managing administrative aspects of RC oversight and payments. Dr. Wicklund will be supervise all operations
at the CCC, including tissue acquisition; review and abstraction of medical records, coordination with the
pathology lab; and general data management.
C.
LEADERSHIP AND ADMINISTRATIVE CORE
C.1
Multiple PI Plan
The WHI-CSC will be led jointly by three principal investigators, Drs. Anderson, Caan, and Paskett, forming the
CSC Executive Committee (EC). The EC will be responsible for the overall scientific direction and all
administrative functions of the project. Drs. Anderson, Caan and Paskett each bring extensive knowledge and
necessary expertise in the creation, management and analysis of the WHI-CSC, as well as the commitment to
make major decisions on the project via consensus.
Dr. Garnet Anderson is a biostatistician and Full Member of the Public Health Sciences Division of the Fred
Hutchinson Cancer Research Center and Affiliate Professor in the Department of Biostatistics, University of
Washington. Dr. Anderson is also the PI of the WHI Clinical Coordinating Center, Chair of the WHI Steering
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Committee and member of the WHI Ancillary Studies Committee and has held many other leadership positions
within the WHI and the CCC since its inception over 20 year ago. She also serves in the leadership of the
Statistical Center for SWOG, an NCI-sponsored cooperative oncology group, as the Associate Director for
Cancer Prevention and Control. She has extensive experience in conducting other large-scale randomized
trials and cohort studies. She was a statistician for the NCI-sponsored Carotene and Retinol Efficacy Trial
(CARET) and as Project Director and Bioinformatics Core Director for the NCI-sponsored Pacific Ovarian
Cancer Research Consortium SPORE. Dr. Anderson will provide oversight of all CCC operations in support of
this project. She will work closely with Dr. Wicklund to assure the overall integration of the WHI-CSC data
collection efforts with the current WHI infrastructure, for the linkage and usage of Medicare data, and the tumor
tissue collection. She will be responsible for the proposed validation studies and collaboration with and input
from Drs. Prentice, Porter, and Ramsey. Dr. Anderson will be designated as the contact PI and be responsible
for obtaining consensus and submitting all necessary documents to NIH, including IRB approvals and annual
progress reports. She will serve as the liaison to the WHI Steering Committee. She will oversee the
administrative aspects of the CSC, including budget oversight and subcontract administration.
Dr. Bette Caan is a senior Research Scientist at Kaiser Permanente Northern California (KPNC), Division of
Research, and an established cancer epidemiologist who has extensive knowledge and experience related to
the research of behavioral risk factors in relation to cancer risk and prognosis and other areas of cancer
survivorship. She is a current WHI investigator, a leader for the WHI pilot study to collect tumor tissue, coleader (with Prentice and Chlebowski) of the WHI Cancer Scientific Interest Group (SIG) and a member of the
WHI Ancillary Studies committee. She is the PI of the Life after Epidemiology Study (LACE), Co-Investigator on
the Pathways as described in A.7.1. She was the initial PI of several other large cohorts or clinical trials,
including the California Men’s Health study (CMH), a cohort of 85,000 men enrolled in Kaiser Permanente of
Northern and Southern California to study etiological risk factors for multiple cancers, The Women’s Healthy
Eating and Lifestyle Trial, a clinical trial that examined the effect of a low-fat, high fruit and vegetable dietary
pattern on recurrence of breast cancer and the Polyp Prevention Trial, a clinical trial to examine effects of
dietary change on recurrence of adenomatous polyps of the colon. She has authored over 250 publications,
most in cancer research and most on issues of cancer survivorship. Dr. Caan will lead the development of
future research on the role of energy balance on survivorship and other outcomes in CSC. She will provide
scientific direction for the proposed treatment and outcome data collection and oversee administrative aspects
for WHI regional site activities. She will be responsible for exploring and developing mechanisms for obtaining
treatment and outcomes data electronically through the CRN. She will also be responsible for coordinating
WHI investigator use of the newly collected CSC resource to fulfill our Broad Research Agenda and will be the
CSC liaison to the WHI Ancillary Studies Committee.
Dr. Electra Paskett is the Marion N. Rowley Professor of Cancer Research at The Ohio State University in
2002. She is the Director of the Division of Cancer Prevention and Control in the College of Medicine, a
professor in the Division of Epidemiology in the College of Public Health and the Associate Director for
Population Sciences and Program Leader of the Cancer Control Program in the Comprehensive Cancer
Center of the Ohio State University (OSU). She is also Director of the Diversity Enhancement Program at the
James Cancer Hospital. Dr. Paskett has been conducting research in cancer prevention, detection and
survivorship among minority and underserved communities for over 20 years. Dr. Paskett is also the PI of the
OSU Center for Population Health and Health Disparities (CPHHD). Dr. Paskett has served as Principal
Investigator on several NIH, ACS and industry sponsored grants which focus on cancer survivorship. She
chaired the Cancer Control and Health Outcomes committee in CALGB (Cancer and Leukemia Group B) for 15
years. She has been a WHI investigator since 1993, first at WFUSM and now at OSUMC, and is the PI of the
current WHI Breast Cancer Survivor Cohort pilot study. Dr. Paskett will be responsible for the design and
conduct of the cancer survivor survey data collection. She will be responsible for organizing the CSC External
Advisory Board, be a CSC liaison to the WHI Publications and Presentations Committee and take the lead in
promoting use of this resource in the broader research community outside of WHI.
Dr. Kristine Wicklund is a senior staff scientist in the Public Health Sciences Division of the FHCRC and has
overseen the collection of medical records and tumor tissue for numerous studies in the Epidemiology
program. She will serve as Project Director for the WHI-CSC, overseeing the day-to-day functions of the CCC
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staff, assuring the close coordination between the CCC staff and that of the Porter Lab, serving as the pointperson for all routine inquiries from investigators wanting information about the resource.
Dr. Lawrence Kushi is a cancer epidemiologist and Associate Director of the Epidemiology and Prevention
Section of the Division of Research at Kaiser Permanente of Northern California. He is the PI of the Cancer
Research Network (CRN4)which is part of the HMO research network (HMORN) . He has nearly two decades
of research in cancer survivorship research and will provide his expertise in abstracting chemotherapy data
from the chemotherapy warehouse established by the CRN. Dr. Kushi will serve as the PI in place of Dr. Caan
if she is unable to serve.
Dr. Ross Prentice, Director of Public Health Sciences at FHCRC and co-PI (former PI) of the WHI Clinical
Coordinating Center, is a world renowned biostatistician with broad expertise in statistical methods for
epidemiological studies, with particular interest in measurement error models and bivariate survival models. He
serves on the WHI Publications and Presentations Committee and co-leads the WHI Cancer SIG. He will
provide statistical expertise on sampling and analysis issues and provide guidance on the resource
development priorities. He will serve as the back-up PI of the CCC if Dr. Anderson should be unable to serve.
Dr. Peggy Porter is a Full Member in Human Biology Division at the FHCRC and PI of an NCI-sponsored
SPORE in breast cancer, with a focus on identifying and understanding the molecular events associated with
the initiation and progression of human cancer. Her lab will be responsible for preparing H&E slides and
conducting the initial pathology review.
Dr. Scott Ramsey is an internist, health economist and Full Member of the Public Health Sciences Division at
the FHRC, with expertise in the use of Medicare data. Dr. Ramsey and his staff will work closely with the CCC
programmers and statisticians to develop analytic data from the CMS files, and will provide scientific input in
the use of these data.
Dr. Chlebowski is an oncologist at UCLA and WHI investigator (former PI of the UCLA-Harbor Clinical Center)
who has authored over 180 manuscripts, the majority of which examine cancer related hypotheses and using
WHI data. He serves on the WHI Publications and Presentations Committee, co-leads the WHI Cancer SIG
and provides expertise to the CCC on cancer outcomes coding. He will work with Dr. Caan to provide
expertise in developing the procedures and forms for abstracting and coding cancer treatment and outcome
data and the use of these data in analyses.
Dr. Li Jiao, a molecular epidemiologist and Assistant Professor of Medicine in the Department of
Gastroenterology and Hematology at Baylor Medical School, is a member of the WHI Ancillary Studies
Committee. She will provide expertise on novel molecular hypotheses and the impact they might have on the
priorities for resource development.
PHS 398/2590 (Rev. 06/09)
Page 140
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