Chapter  179:  Clinical Utility of Cancer Family History Collection in Primary Care

Breast Cancer

Five systematic reviews synthesized evidence on chemoprevention (antioxidants and statins) and screening (breast self-examination (BSE) and screening mammography).

Antioxidants. One review¹⁸ evaluated supplements that contained any combination of ß-carotene, vitamin C, vitamin E, selenium, zinc, and other antioxidants, and concluded no evidence of a protective effect of any combination against breast cancer (RR 1.00, 95 percent CI 0.90–1.09) at one year followup. A second review¹⁹ examined vitamin E alone or in any combination in three high quality randomized controlled trials (RCT) and concluded no evidence of a reduction in breast cancer incidence (RR 0.99, 95 percent CI 0.90–1.10).

Statins. One review,²⁰ suggested that statins appeared to confer neither a protective nor a harmful effect on breast cancer incidence (RR 1.01, 95 percent CI 0.79–1.30).

BSE. One review²¹ showed no impact of BSE on breast cancer mortality (RR 1.05, 95 percent 0.98–1.14).

Screening mammography. The most recent comprehensive review,²² suggested that screening mammography was associated with reduced breast cancer mortality at 13 years (RR 0.80, 95 CI 0.73–0.88), although concerns were raised about inadequate bias control in some primary trials. No effect on overall mortality was noted (RR 1.00, 95 percent CI 0.96–1.04).

Colorectal Cancer

Six reviews evaluated interventions in colorectal cancer (CRC) prevention, four on chemoprevention (antioxidants, NSAIDS, statins) and two on screening (fecal occult blood testing (FOBT) and flexible sigmoidoscopy (FS)).

Antioxidants. One review¹⁸ evaluated supplements which contained any combination of ß-carotene, vitamin C, vitamin E, selenium, zinc, and showed no evidence of a protective effect against CRC incidence (RR 1.00, 95 percent CI 0.90–1.10). A second review¹⁹ evaluated vitamin E given in any combination and found no evidence of an effect on CRC incidence (RR 0.95, 95 percent CI 0.81–1.12).

NSAIDS. One review evaluated low dose ASA,²³ and found no evidence of an effect on CRC incidence (RR 1.02, 95 percent CI 0.84–1.25), CRC mortality (RR not reported) or adenoma incidence (RR 0.85, 95 percent CI 0.68–1.1) at 5 years.

Statins. One review²⁰ showed neither a protective nor harmful effect of statins on CRC incidence (pooled RR 1.02, 95 percent CI 0.89–1.16) or CRC mortality (RR 0.33, 95 percent CI 0.07–1.63).

FOBT. One review²⁴ examined FOBT (guaiac or immunochemical) in studies of at least two rounds of screening were compared with no screening. A statistically significant effect of screening on CRC mortality was observed (RR 0.84, 95 percent CI 0.78–0.90), and no effect on all-cause mortality (RR 1.00, 95 percent CI 0.99–1.01).

FS. A single review²⁵ examined the evidence for FS in CRC screening, identifying a single RCT comparing FS plus FOBT against FOBT alone. No statistically significant effect was found on CRC mortality or incidence (RR 0.78, 95 percent CI 0.36–1.73 and 1.37, 95 percent CI 0.88–2.15, respectively).

Prostate Cancer

Five reviews synthesized evidence in relation to prostate cancer prevention: four relating to chemoprevention (antioxidants, calcium, and statins) and one relating to screening (prostate-specific antigen (PSA) with digital rectal examination (DRE) and trans-urethral ultrasound (TRUS) biopsy).

Antioxidants. One review¹⁸ evaluated supplements that contained any combination of ß-carotene, vitamin C, vitamin E, selenium, zinc, and other antioxidants. The pooled analysis of all antioxidants showed no effect on prostate cancer incidence (RR 0.87, 95 percent CI 0.74–1.02), and a reduced risk associated with vitamin E specifically (RR 0.82, 95 percent CI 0.67–0.99). A second review¹⁹ of vitamin E in any combination showed a negative association with prostate cancer incidence (RR 0.85, 95 percent CI 0.74, 0.96).

Calcium. One review evaluated calcium supplementation and prostate cancer risk,²⁶ where this was a secondary outcome in a single colorectal adenoma prevention trial.⁴⁷ It suggested a statistically significantly lower incidence of prostate cancer in the supplement group until 2 years after supplementation was discontinued (rate ratio 0.52, 95 percent CI 0.28–0.98), at which point the risk in both groups converged.

Statins. One review²⁰ examined the effectiveness of statins on prostate cancer. The results indicated that statins appeared to neither increase nor decrease the risk of prostate cancer incidence or mortality (RR 1.00, 95 percent CI 0.85–1.17 and RR 0.99, 95 percent CI 0.14–7.01, respectively).

PSA-based screening. One review²⁷ examined the effectiveness of PSA-based population screening (with DRE and TRUS biopsy) in two trials, one with an annual and the other a three times yearly, screening cycle. No statistically significant impact of screening on prostate cancer mortality was found (RR 1.01, 95 percent CI 0.80–1.29).

Conclusions

• 1

  The evidence for the predictive accuracy of algorithms in primary care populations was very limited. Although many tools were identified that incorporated some family history information, no evaluations of solely family history-based tools. The tools on which it was possible to comment related mainly to breast cancer.

  Recommendations for future research:

  • The actual performance of tools based only on family history should be formally examined in primary prospective studies, and/or in secondary analysis of large cohort studies.

  • The performance of individual family history components of different risk stratification models which use a wider range of factors (including those examined in this report) should be examined separately from the non-family history components, in order to determine whether they provide sufficient predictive power in the absence of the non-family history factors.

  • For clinical relevance, the focus of validation should be discriminatory accuracy at the individual patient level.

  • More definitive evaluation should examine the effect on health outcomes when risk stratification systems are used in combination with preventive interventions, in actual practice settings. This cannot be done with secondary analyses of observational data and requires well-designed intervention studies.

• 2

  The evidence establishing the efficacy of interventions for primary and secondary prevention based on systematic reviews of randomized or controlled clinical studies in unselected populations is very limited. Interventions for which there were reviews include chemoprevention (antioxidants, calcium, NSAIDS, and statins) and screening interventions (BSE, mammography, FBOT, FS, and PSA) for breast, colorectal and prostate cancers. No reviews were found for ovarian cancer. It is likely that this review excluded effectiveness data available from RCTs of interventions which have not yet been the subject of systematic reviews.

  Recommendations for future research:

  • The large amount of evidence on potential primary cancer preventive interventions obtained from observational studies of cancer risk factors should continue to be further evaluated in well-designed randomized controlled trials.

  • Further systematic reviews should be conducted to examine the full range of potentially preventive interventions

• 3

  Within primary care populations, there is very limited evidence to support or refute the effect on risk-reducing behavior changes (e.g., lifestyle changes or uptake of recommended clinical interventions) of taking a family history and using it to personalize risk of breast, ovarian, colorectal or prostate cancer.

  Recommendations for future research:

  • Well-designed trials are required that compare family history-based, personalized risk advice with standard of care on risk reducing behaviors in populations at different risk levels (including population risk).

• 4

  In primary care populations, there is very limited information to evaluate direct harm incurred from the routine practice of taking family history and using it to personalize risk information.

  Recommendations for future research:

  • Trials of family history taking as an intervention should include capture of data to examine the full range of potential impacts on individuals. Baseline data on psychological status should be captured so that this can formally be adjusted for in outcome analyses.

• 5

  Research on the use of family history tools, risk stratification systems, and family history-based personalized prevention advice should take into account evidence on the factors likely to promote their effective use in practice, such as the educational needs of primary care practitioners and issues which act as barriers or constraints to their implementation in practice.

The Potential of Family History Information in Preventing Cancer

Family history has always been a core tool in medical practice. A person's family history reflects the combined influences of genetics, environmental exposures, and behaviors within families.¹ A large number of reports demonstrate that a positive family history is a risk factor for many chronic diseases of clinical importance, including cardiovascular disease, diabetes mellitus, stroke, and several cancers.^{2, 3} The greater the number of relatives affected by a disorder, the younger their ages of onset, and the closer the relationship to the individual in question, the more likely it is that the family's disease experience has a genetic basis. However, given the low population prevalence of genetic forms of common, complex disorders, a screening approach based on identifying fairly extreme family histories offers very limited public health or clinical utility in practice.

Historically, the practice of clinical genetics has been largely predicated on detecting individuals marked out by membership in families with unusual patterns of disease, and who are at significantly elevated individual risk as a result of rare genetic disorders that have relatively high penetrance. The alternative approach, which is the focus of this review, is to recognize that family clustering of disease risk reflects combinations of lower penetrance, and moderate risk alleles which are reasonably common within a population. The latter example, a high prevalence of people with slightly or moderately elevated inherited disease risk, would lead to a much higher total disease burden within a population than that associated with a low prevalence of people at very high risk.⁵² Under the right circumstances, a ‘genomic test’ - such as the presence of particular family history characteristics - could have a significant positive predictive value.

Several years ago, Yoon and colleagues¹ illustrated this point. They demonstrated how even fairly simple family history information could be used to clarify the risk of a number of common, complex disorders. Based on published data, they suggested that a healthy 23 year old man could have the following lifetime risks of:

• 60 percent for cardiovascular disease (based on one male first degree relative (1DR) diagnosed after age 60)

• 50 percent for colorectal cancer (based on two 1DRs diagnosed before age 50); and

• 30 percent for type 2 diabetes (based on one 1DR diagnosed after age 60

Importantly, their risk prediction was based on family history information which would not be considered extreme. This application of family history information complements the vision of ‘personalized medicine’ which physician-geneticist Francis Collins M.D., PhD., predicted would be available in 2010, in the form of DNA-based genome profiling tests.⁵³ While recent research indicates that such profiling is possible in principle,⁵⁴ it is evident that this is not yet a technology ready for routine implementation in health care.^{52, 55} Until such time, family history represents a potential source of useful predictive information already available to any health care provider.

Discussing the role of family history in coronary heart disease risk, Kardia and colleagues describe the family history as “compressed information” which integrates risks arising from shared genomic components, and social and physical environments.⁴ They expand:

• “For, example, we know that parents and children share exactly half their genes. This translates practically into sharing one copy of the 30,000 to 50,000 genes estimated to be in the human genome in the nucleus of each nucleated cell in the human body. ... it is quite possible that even with our ability to measure hundreds and thousands of genes and environments we may find that family history is the best, low-cost way to identify the at-risk subgroups in the population. This will be especially true if gene-gene and gene-environment interactions play a major role in determining risk of future disease.”

Table 1

Pooled relative risk estimates (95% confidence intervals) (more...)

Table 1

Pooled relative risk estimates (95% confidence intervals) for cancers of interest3

Cancer	≥1 1DR	≥2 1DRs	Age cut-off younger, older	Younger affected relative	Older affected relative
Colorectal	2.24 (2.06, 2.43)	3.97 (2.60, 6.06)	<50, ≥50	3.55 (1.84, 6.83)	2.18 (1.56, 3.04)
Breast	1.80 (1.70, 1.91)	3.01 (2.46, 3.69)	<40, >60	2.22 (1.71, 2.87)	1.55 (1.38, 1.74)
Ovarian	2.85 (2.41, 3.37)	14.74 (5.78, 37.60)	<50, ≥50	3.98 (2.53, 6.26)	2.90 (2.10, 4.01)
Prostate	2.42 (2.25, 2.60)	4.27 (3.13, 5.84)	<60, ≥60	2.91 (2.12, 4.01)	1.88 (1.47, 2.40)

1DR=first degree relative

These meticulous analyses provide direct evidence to support the association between family history and risk of cancer even when family history is captured in a less specific or extensive way than is the case in a specialist genetics consultation.

Figure 1. Family history-based primary care activities (more...)

   Figure 1. Family history-based primary care activities

Figure 1

Domain A represents the assessment of a patient in whom clinical suspicions of an inherited disorder or predisposition have arisen, for example in response to concerns about several relatives affected by cancer. In this situation, the main clinical goal would be to assess whether the individual met the criteria for referral for specialist genetics assessment and/or genetic testing. A family history ‘tool’ in this situation would be represented by guidelines for genetic referral or testing. Here, the focus would be on capturing specific family history information which might be rather extensive and specific, requiring attention to, for example, different combinations of diseases in the family, the lineage of affected relatives, and so forth, as illustrated in the Bethesda criteria for non-polyposis colorectal cancer.⁵⁶

Domain B might typically represent a periodic health assessment in an otherwise healthy individual, where there would be no suspicion of underlying genetic disease and no particular indications of illness or disease susceptibility. Here, the goal would be to conduct a broad brush assessment across a range of common disorders, to identify issues which warrant further probing by the primary care practitioner. The most useful family history tool might incorporate a limited range of the most sensitive family history markers or “red flags” across a range of disorders, in the expectation that more detailed information would be collected for those conditions where an indicator item was positive.

In domain C, the primary care practitioner's goal would be to incorporate family history with other clinical and personal information to assess future risk of a specific chronic disease, with a view to ordering further investigations and advising on appropriate risk reduction strategies. In this situation, the focus would be on family history items which were either independently highly predictive of disease risk, or added useful incremental predictive value to other, established risk factors. A family history “tool” in this context might actually consist of a short set of questions within a more comprehensive disease-specific risk assessment guideline. An example of this approach would be the incorporation of information on parental history of myocardial infarction in the National Cholesterol Education Program III guidelines.⁵⁷

These three domains are clearly not mutually exclusive. However, this approach illustrates that the demands of extensiveness and specificity of the type of information that is necessary is not uniform across all contexts. Until comprehensive and current family history information is available for patients through, for example, electronic records systems, a primary care practitioner's approach to family history-taking may be influenced by external constraints (e.g., time), their prior assessment of the patient's risk of disease, and the way in which the information will actually be used for decisionmaking.

Although this report borrows from the language and concepts of genetics and genomics (see below), its approach reflects the perspective on family history exemplified particularly by domain C described above. Its focus is on the utility of using family history information to stratify the risk of common, complex diseases in individuals who are not specifically selected for suspicion of high genetic risk.

Evaluating Family History for use in the Prevention of Cancers

Table 2

Elements and key components of evaluation framework (more...)

Table 2

Elements and key components of evaluation framework for family history as screening tool [reproduced from Yoon, Scheuner, and Khoury 2003]59

Element	Definition	Components
Analytic validity	An indicator of how well a test or tool measures the property or characteristic (disease status among relatives) that it is intended to measure	Analytical sensitivity Analytical specificity
Clinical validity	A measurement of the accuracy with which a test or tool identifies or predicts a clinical condition	Clinical sensitivity Clinical specificity Positive predictive value Negative predictive value
Clinical utility	Degree to which benefits are provided by positive and negative test results (presence and absence of family history for disease)	Availability of effective interventions Health risks and benefits Economic assessment
Ethical, legal, and social implications	Issues affecting data collection and interpretation that might negatively impact individuals, families, and society	Stigmatization Discrimination Psychological harms Risks to privacy and confidentiality

Yoon P.W., Scheuner M.T., Khoury M.J. Research priorities for evaluating family history in the prevention of common chronic diseases. Am J Prev Med 2003;23(2)128–135. Used with permission.

• (a)

  Does a positive family history (however defined) predict future risk of cancer in an individual patient sufficiently accurately to be useful in a clinical setting?

• (b)

  If so, are there interventions available which reduce the risk of cancer? Do these interventions also carry risks?

• (c)

  If there are interventions which help prevent cancer, does information on family history-based disease risk mean a person is more likely to adhere to them (compared with advice which is not based on knowledge of family history)?

• (d)

  Are there any direct harms which arise from the process of taking a family history and feeding back personalized risk based on family history?

In terms of efficient health care resource use, it is also legitimate to examine the incremental benefits and costs associated with capturing and using family history information, whether it substitutes for, or adds informational value to, other risk factor information, and whether it is easier and/or cheaper to obtain.

In a previous effectiveness report,⁵ evidence regarding the accuracy of reporting by individuals of their family history of breast, ovarian, colorectal, and prostate cancer was synthesized, and a large number of family history tools and family history-based risk assessment tools identified and reviewed. The current review is designed to inform issues (a) to (d) above, which address the issues of clinical validity and, in part, clinical utility.

Risk Stratification

Table 3

Family history-based risk stratification guidelines (more...)

Table 3

Family history-based risk stratification guidelines for breast, ovarian, colorectal, prostate cancers60

High risk

1 Premature disease* in a 1DR 2 Two affected 1DRs 3 A 1DR with late/unknown onset of disease and an affected 2DR with premature disease from the same lineage 4 Two 2DRs, maternal or paternal, with at least one having premature onset of disease 5 Three or more affected aternal or paternal relatives 6 The presence of a ‘moderate risk’ family history on both sides of the pedigree 7 Pedigree demonstrating clustering of different primary cancers consistent with a family cancer syndrome

Moderate risk

1 A 1DR with late or unknown disease onset 2 Two 2DRs from the same lineage with late or unknown disease onset

Average (population) risk

1 No affected relatives 2 Only one affected 2DR 3 No known family history 4 Adopted individual with unknown family history

Scheuner M.T., Wang S.J., Raffel L.J., Larabel S.K., Rotter J.I. Family history: a comprehensive genetic risk assessment method for the chronic conditions of adulthood. Am J Med Genet 1997;71(3):315–324. Used with permission of John Wiley & Sons, Inc.

Abbreviations: 1DR=first degree relative; 2DR=second degree relative

*

Breast, ovarian: premenopausal or ≤50 years; colorectal, prostate ≤50 years

Effectiveness of Cancer Risk Reduction Interventions

Even the most highly predictive and practical risk stratification system cannot change health outcomes unless effective cancer prevention interventions are available for patients at risk. While there is extensive epidemiological literature on a wide range of cancer risk factors, much of the evidence regarding cancer prevention is based on observational studies. Contradictory evidence has emerged when some apparently protective factors, identified through observational studies⁷¹–⁷³ were associated with increased risk of cancer in experimental studies, as was the case for alpha-tocopherol.⁷⁴ It is crucial that any assessment of the clinical utility of family history-based risk stratification take into account the highest quality evidence on the benefits and risks of recommended preventive interventions.

Effect of family history taking on uptake of interventions. Assuming that proven preventive interventions are available, the question remains whether individualized, family history-based advice actually promotes uptake of such interventions by patients. Simplistically, it might be assumed that individuals would be more motivated to act on a health care provider's advice if they know they are at higher than average risk. However, there is a body of literature in the area of predictive and predisposition genetic testing which cautions that knowledge of genetic risk might lead to fatalism in those at higher risk (failing to take up available interventions because of the ‘inevitability’ of disease) or complacency in those at average risk (failing to take up available interventions because of lower perceived personal risk - the ‘certificate of health’ effect).⁷⁵ Like any healthcare intervention, family history taking may incur incremental costs in time, energy, and money over and above standard care, therefore an examination of the incremental benefits is important.

Risks inherent in family history-based risk assessment. No healthcare intervention should be assumed to be safe without formal assessment of harms as well as benefits. While family history taking is seen as a standard activity in all areas of healthcare, the systematic capture of more extensive information, and its purposeful use in individual risk assessment, merits objective review. The ACCE framework⁵⁸ emphasizes the assessment of both harms and benefits, and there is substantial literature that examines the impacts of predictive genetic tests beyond simple accuracy.⁷⁶ While some guidelines⁷⁷ suggest a cautionary approach, with cancer family history collection undertaken only in response to patients' enquiries, many other observers argue that family history taking is an integral part of good clinical practice.^{78, 79} Objective evidence on the prevalence of specific harms of family history taking, and of its use in advising patients about disease risk reduction, is necessary in order to clarify the appropriate level of caution to be exercised, and the types of situations in which patients might be most vulnerable to potential harms.

Search Strategy

Bibliographic databases searched for this review included: MEDLINE®, EMBASE®, CINAHL®, Cochrane Controlled Trials Register (CCTR)® (Q1, Q3, Q4), Cochrane Database of Systematic Reviews (Q2), and PsycINFO (Q3). Years searched were 1990 to June 2008 inclusive (Q1, Q3, and Q4). We searched for cancer guidelines and recommendations from 2002 forward to ensure that the guidelines were reasonably current. We also searched the grey literature, including the National Clearing House for guidelines. Based on input from our Technical Expert Panel we searched the Guide to Community Preventive Services published by the CDC⁸⁰ and other appropriate guidelines (e.g., U. S. Preventive Services Task Force recommendations for the prevention and screening interventions for the cancers of interest).

Finally, we restricted the search for systematic reviews (Q2), from 2003 to June 2008 (Q2). As per the recommendations of our content experts, we reviewed the methods and content of the report “Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective” published by World Cancer Research Fund’ from American Institute for Cancer Research (updated for breast cancer only in Spring 2008).⁸¹ This report reflects an international initiative that has systematically reviewed the literature to evaluate the cancer prevention evidence for a range of interventions broadly including exercise and related behaviors, food and food supplements (including vitamins), and screening interventions for different types of cancer (including breast, ovarian, colorectal, and prostate cancers). Since this World Cancer Review comprehensively captured and evaluated the literature on these interventions from root to the end of 2006), we did not include any reviews on these particular interventions for this time period.

In addition we retrieved and evaluated references from eligible articles. Hand searching was not undertaken, but we reviewed the publication type “letters” (normally excluded from reviews); the investigators suggested that, within the content area of cancer genetics, primary data information might be published as letters in some journals. Finally, we formally reviewed all articles suggested by peer reviewers of the draft evidence report and incorporated those which met eligibility criteria. Detailed search strategies are listed in Appendix A.

Eligibility Criteria

A list of eligibility criteria was determined and standardized forms were developed in Systematic Review Software (SRS, 3.0, TrialStat Corporation, Ottawa, Ontario Canada) and Microsoft Excel for the purposes of this systematic review.

Eligibility Criteria for Research Q1

Eligibility Criteria for Research Q2

Comparator/Study Design

Eligibility Criteria for Research Q3

Population

Any patient or general populations not specifically selected for known or suspected pre-existing elevated risk of breast, ovarian, colorectal, and/or prostate cancer

Eligibility Criteria for Research Q4

Outcome

Inclusion

• psychological status

  • anxiety/distress

  • cancer worry

  • depression

  • inaccurate risk perception

  • other psychological outcome

• quality of life

• social impacts

  • family functioning including dynamics/communication, etc.

  • insurance or employment discrimination

  • other

Exclusion

• outcomes not listed above

FIgure 3. Flow of studies to final number of eligible studies (more...)

   FIgure 3. Flow of studies to final number of eligible studies

Figure 3 illustrates the flow of studies based on the eligibility criteria described.

Study Selection

A team of study assistants was trained to apply the eligibility criteria for screening the title and abstract lists and the full text papers. All levels of screening were done in web-based Systematic Review Software (SRS) (TrialStat Corporation, Ottawa, Ontario Canada). Standardized forms and a training manual explaining the criteria were developed and reviewed with the screeners (Appendix B). For the title and abstract phase, two reviewers evaluated each citation for eligibility. Articles were retrieved if either one of the reviewers judged it as meeting eligibility criteria or if there was insufficient information to determine eligibility. For screening of full text articles, two screeners came to consensus on the identification, selection, and abstraction of information. Disagreements that could not be resolved by consensus were resolved by one of our McMaster research team members.

Data Extraction

Appropriate data collection forms were developed for use in the SRS (Appendix B). All eligible studies from the selection phase (full text screening) were abstracted onto a data form according to predetermined criteria. One data extractor transferred the data onto these forms, and another checked the answers for accuracy before they were entered into SRS. Data entries were verified by the investigators responsible for summarizing the different report results sections.

Quality Assessment and Peer Review

Quality assessment of studies was undertaken in varying forms. Studies eligible for (Q1) were evaluated for potential bias in relation to the model variables and selection bias. For the systematic reviews identified for (Q2), a modified version of the Oxman-Guyatt Overview Quality Assessment Questionnaire, a validated, 10-item assessment scale was used.⁸² Studies for (Q3 and Q4) were evaluated using the Jadad scale for randomized trials.⁸³

A draft version of this report was circulated to 14 peer reviewers (see Appendix E). Where possible, comments and suggestions were incorporated.

General Approach

We reviewed published studies which examined the ability of models (or algorithms, or guidelines) which used family history information to accurately predict individual risk of breast, ovarian, colorectal, or prostate cancer. To be eligible, the model had to include systematic collection of specified family history information, either alone or with other personal or clinical information which would be available for all patients and routinely available to a primary care practitioner. We examined the performance of models in relation to populations not selected for known or suspected high risk of cancer.

Model performance was assessed by predictive accuracy, in terms of calibration and discrimination. “Calibration” is a model's ability to correctly predict the number of observed events (incidence of cancer) in a population and is generally evaluated by its goodness-of-fit to observed events. The ratio of observed to expected cases provides an overall epidemiological assessment of how well a model might perform for a defined population.

“Discrimination” is the assessment of how well a model separates out individuals who will go on to develop different outcomes. Discriminatory accuracy for dichotomous outcomes (e.g., disease/no disease) is best examined through metrics such as sensitivity and specificity, predictive value, likelihood ratio, and the area under the receiver operator characteristic (ROC) curve (or area under the curve (AUC)). The AUC is also referred to as the c-statistic and is defined in the unit square with a range of 0 to 1.0. Since chance alone will follow a perfect diagonal from (0,0) to (1,1), the subsequent AUC will be 0.5 (no apparent discrimination), whereas an AUC of 1.0 indicates perfect discriminatory accuracy.

Discriminatory accuracy is a more relevant evaluation than calibration from the point of view of clinical practice, as it directly indicates how well the model predicts an individual patient's likelihood of developing cancer within a defined time scale. A model that is well calibrated at a population level may not necessarily be highly discriminating when used for individual prediction.

Studies Reviewed

Eight evaluation studies were retained for data abstraction after full text review.⁷–¹⁴ All except one focused on breast cancer risk assessment. The individual breast cancer models were all conceptually related: the “original” Gail model,¹⁵ the modified Gail model,⁸⁴ the modified Gail model for African American populations,¹⁰ the modified Gail model for Italian populations,^{11, 12} and the model developed from the Contraceptive and Reproductive Experiences (CARE) study.⁷ The exception was Harvard Cancer Risk Index (HCRI),¹⁶ which was developed for calculating the risk of a several cancers, including breast, ovary, colon, and prostate. An eligible validation¹⁴ of the HCRI was published only for colon cancer.

Table 4

Details of risk prediction models

Table 4

Details of risk prediction models

System	Cancer	Family history items	Other items	Output	Relevant studies	Comments
Gail model (GM)15	Breast	1DRs with BC Age at first birth <20y (0, 1, ≥2) 20–24y (0, 1, ≥2) 25–29 y or nulliparous (0, 1, ≥2) ≥30y (0, 1, ≥2)	Age Ethnicity Age at menarche Age at first live birth # previous breast biopsies (0, 1, >1) Presence of atypical hyperplasia on biopsy	Risk of BC	Adams-Campbell10 (2007) Spiegelman8 (1994)	Assumes annual screening Cancer incidence rates derived from BCDDP15
Modified GM (MGM)84	Breast	As for GM	As for GM	Risk of invasive BC	Chlebowski13 (2007) Adams-Campbell10 (2007) Rockhill9 (2001) Boyle11 (2004) Decarli12 (2006)	Assumes annual screening Cancer incidence rates derived from SEER data
MGM for black/African Americans (GM-B)10	Breast	As for GM	As for MGM	As for MGM	Adams-Campbell10 (2007)	MGM revised using age-specific invasive rates and specific attributable risk estimates for African-American women
MGM for Italian population (IT-GM)11,12	Breast	As for GM	As for MGM, except # previous breast biopsies replaced by any breast biopsy (no, yes)	As for MGM	Boyle11 (2004) Decarli12 (2006)	MGM revised using age-specific invasive rates and specific attributable risk estimates for Italian women
CARE model for African American population7	Breast	Number of affected relatives (mother, sisters)	Age Age at menarche # previous breast biopsies, (<50y, ≥50y) Presence of atypical hyperplasia on biopsy (Age at first live birth)	As for MGM	Gail 7 2007	MGM re-developed for African American populations using age-specific invasive rates and specific attributable risk estimates from control data from the CARE Study and SEER program.
Harvard Cancer Risk Index 16	Colon	Brother/sister/parent with colon cancer	Red meat intake Vegetable intake Alcohol intake Multivitamin use Physical activity Body mass index Height Colonoscopy/sigmoidoscopy screening (Aspirin use)	10 year cancer risk	Kim 14 2004	Designed to assess risk of multiple cancers Validation using family history data published only for colon cancer

Abbreviations: 1DR=first degree relative; AUC=area under the curve; BC=Breast cancer; BCDDP=Breast Cancer Detection Demonstration Project; CI=confidence interval; CRC=Colorectal cancer; E=Expected events; GM=Gail Model; GM-B=GM for blacks/African Americans; IT-GM=GM for Italian population; MGM=Modified GM; O=Observed events; NHS= National Health Service; RCT=Randomized controlled trial; RR=Relative risk; SEER=Surveillance, Epidemiology and End Results; y=years;

Outcomes

Table 5

Evaluations of risk prediction models

Table 5

Evaluations of risk prediction models

Study Design	Tool(s)	Participants	Outcome measure(s), timing ascertainment	Algorithm performance	Conclusions
Spiegelman8 1994	GM	n=115,172	12 y BC incidence	Calibration O, E E/O (95% CI) O=2,396, E=3,196 E/O=1.33 (1.28–1.39) Discrimination Correlation coefficient (Pearson) 0.67 (Spearman) 0.04	Significant overestimation of overall BC risk Modest discriminatory accuracy
Rockhill9 2001	MGM	n=82,109	5 y BC risk	Calibration O, E E/O (95% CI) O=1,354, E=1,273.42 E/O=0.94 (0.89–0.99) Discrimination AUC (95% CI) 0.58 (0.56–0.60) RR=(95% CI) 2.83 (2.19–3.65) Sensitivity, specificity (cut point=1.67% 5 y risk): Se=0.44, Sp=0.66	Fairly well calibrated model Modest discriminatory accuracy
Chlebowski13 2007	MGM	n=147,916 Mean age 63 y (range 50–79 y) “Ethnically diverse” Excluded: History of BC, mastectomy Suspicious baseline mammogram <5 y followup	5 y invasive BC risk, assessed by annual or semi-annual ascertainment by mail or telephone questionnaire Cancer verified through pathology reports	Calibration O, E E/O O=3,236, E=2,562 E/O=0.79 (p<0.001) Discrimination AUC (95% CI) 0.58 (0.56–0.60)	Poorly calibrated, underestimated number of invasive BCs in 5 years by about 20% Modest discriminatory accuracy
Adams-Campbell10 2007	MGM GM-B	n=1,450 Age: 21–69 y Enrolled 1995 Diagnosed with BC 1995-2003, aged ≥35 y (cases) Age-matched, no BC by 2003	5 y invasive BC risk, assessed by biennial questionnaires	Discrimination Sensitivity, specificity (cut point=1.7% 5 y risk) MGM Se=0.18, Sp=0.86 MGM-B Se=0.04, Sp= 0.97	The MGM and MGM-B perform poorly at predicting risk of invasive BC in African American women Limited discriminatory accuracy
Boyle11 2004 Secondary analysis of RCT data 172	IT-GM MGM	n=5,383 Women had hysterectomies and no benign breast disease	5 y BC incidence	Calibration O, E E/O (95% CI) IT-GM O=79, E=82.5 E/O=0.92 (0.68–1.16) MGM O=79, E=88.4 E/O=0.86 (0.64–1.08) Discrimination AUC IT-GM 0.58	Reasonably well calibrated Modest discriminatory accuracy in the population studied Data were missing on atypical hyperplasia on biopsies
Decarli12 2006	IT-GM MGM	n=10,031 Age: 35–64	5 y invasive BC risk Method of ascertainment not reported in this paper.	Calibration O, E E/O (95% CI) IT-GM O=194, E=186.11 E/O=0.96 (0.84–1.11) MGM O=194, E=180.1 E/O=0.93 (0.81–1.08) Discrimination Average age-specific AUC (95% CI) IT-GM 0.59 (0.54–0.63) MGM 0.58 (0.55–0.63)	MGM and IT-GM both well calibrated Modest discriminatory accuracy in the population studied
Gail7 2007	CARE	n=14,059 Age:≥50	5 y age-specific invasive BC risk	Calibration O/E ratio (95% CI):1.08 (0.97–1.20) Discrimination Unweighted average age-specific AUC (95% CI): 0.555 (0.535–0.575)	Good calibration, very modest discriminatory accuracy.
Kim14 2004	HCRI	n=52,668 Females Age: median 52	10 y colon cancer incidence	Calibration O/E(95% CI) Overall O/E not reported By HCRI category:2.10≤RR≤5.10 1.79 (0.89–2.70) 1.10≤RR≤2.10 1.39 (1.12–1.67) 0.90≤RR≤1.10 1.00 (0.66–1.34) 0.50≤RR≤0.90 0.89 (0.68–1.09) 0.20≤RR≤0.50 0.58 (0.37–0.79) Discrimination AUC (95% CI): 0.67 (0.64–0.70)	Good calibration, moderate discriminatory power
Kim 14 2004	HCRI	n=38,953 Males Age: median 51	10 y colon cancer incidence	Calibration O/E(95% CI) Overall O/E not reported By HCRI category:2.10≤RR≤5.10 2.35 (1.12–3.59) 1.10≤RR≤2.10 1.34 (1.02–1.66) 0.90≤RR≤1.10 1.01 (0.64–1.39) 0.50≤RR≤0.90 0.75 (0.56–0.95) 0.20≤RR≤0.50 0.83 (0.60–1.07) Discrimination AUC (95% CI): 0.71 (0.68–0.74)	Poor calibration (possibly due to potential misclassification - older cohort at baseline), moderate discrimination

Abbreviations: 1DR=first degree relative; AUC=area under the curve; BC=Breast cancer; CI=confidence interval; CRC=Colorectal cancer; E=Expected events; GM=Gail Model; GM-B=GM for blacks/African Americans; IT-GM=GM for Italian population; MGM=Modified GM; O=Observed events; NHS= National Health Service; RCT=Randomized controlled trial; RR=Relative risk; Se=sensitivity; SEER=Surveillance, Epidemiology and End Results; Sp=specificity; y=years;

1

Performance by other cut-off points also reported

Gail Model

The first published version of the ‘Gail Score’¹⁵ used information on a woman's age at menarche, her age at the time of the birth of her first child, the number of her first degree relatives who had had breast cancer, and the number of previous breast biopsies that she had undergone. It was designed for women with no personal history of breast cancer who were being followed by annual screening mammography. It estimates the absolute probability of developing invasive or in situ breast cancer over a defined age interval. The model uses estimates of baseline hazard and attributable risk derived from the Breast Cancer Detection Demonstration Project (BCDDP).⁸⁹ The authors indicated that its primary application would be to “determine eligibility for entry to breast cancer prevention trials, where an important determinant of sample size is the absolute risk of breast cancer” in the study population.¹⁵

We identified a single study⁸ which evaluated the original Gail model,¹⁵ a secondary analysis of data from the NHS.^{85, 86} The ratio of expected to observed breast cancer cases was 1.33 (95 percent CI 1.28-1.39), which was a significant overestimation. Only modest discriminatory accuracy was demonstrated (Pearson correlation coefficient 0.67).

Modified Gail Model

The modified Gail model incorporated revisions to improve its validity and applicability to the North American population.⁸⁴ The key revisions were a focus on the absolute risk of invasive breast cancer only (i.e., in situ cancer was excluded): the inclusion of a diagnosis of atypical hyperplasia on biopsy as an additional risk factor; and the substitution of age-specific invasive breast cancer rates from the Surveillance, Epidemiology, and End Results (SEER) Program of the National Cancer Institute (NCI) for the BCDDP-based data used in the original model.

We identified five studies which evaluated the performance of the modified version of the Gail model, either in its originally published form, or adjusted to take account of different underlying breast cancer incidence patterns in different populations (African American,¹⁰ Italian^{11, 12}). The ratios of expected to observed invasive cancer cases ranged from 0.79 to 0.96, mostly not statistically significantly different from unity. Validations, performed in a predominantly white U.S. population⁹ and two Italian populations,^{11, 12} suggested reasonably good calibration, but poorer performance in “more diverse”¹³ and African American¹⁰ U.S. populations. These studies all suggested that the standard and modified versions all had very modest discriminatory accuracy (concordance statistic 0.58-0.59).

CARE Model

The CARE Model⁷ was developed as an African American adaptation of the Gail model, using data from the Women's Contraceptive and Reproductive Experiences (CARE) Study,⁹⁰ the SEER program, and National Center for Health Statistics. It is a simpler model, in that two variables in the modified Gail model were removed and one was dichotomized.

We identified one study that validated this model, in a subset of African American women in the WHI. The model showed good calibration, with an expected observed ratio of cases not statistically significantly differently from unity. The discriminatory accuracy, expressed as AUC, was 0.555, which suggests only very modest predictive ability at best.

The authors compared the CARE Model with the MGM in classifying eligibility for a chemoprevention trial, and found that it doubled the proportion of women who met inclusion criteria (30.3 percent compared with 14.5 percent).

Harvard Cancer Risk Index

The HCRI was developed as a tool to assist clinicians in counseling patients about cancer risk reduction.¹⁶ It addressed prediction of the most common cancers in American men and women (prostate, breast, lung, colon, bladder, endometrium, non-Hodgkin's lymphoma, ovary, kidney, leukemia, cervix, pancreas, skin melanoma, and stomach). The tool was developed using a consensus-based process in which available evidence was used to assign points for different levels of defined risk factors. Risk was stratified into a seven point categorical scale, set relative to the average U.S. population risk for each cancer. Several risk factors contributed to the score for each cancer, family history being included in all except leukemia and cervical cancer.

We identified one validation study,⁸⁷ in which the HCRI's predictive validity for colon cancer was assessed in two cohorts, the NHS (women) and the HPFS (men). Results pertaining to ovarian cancer were also reported in this publication, but family history items were lacking, therefore these data were excluded from the current review. In addition to family history, eight variables for men and eleven for women were included in the HCRI for colon cancer.

The overall ratios of observed and expected cases were not reported. For women, the ratios by initial risk stratum ranged from 0.58 to 1.79, and for men 0.75 to 2.35. A better fit was observed for women than men. The AUC was 0.67 for women and 0.71 for men, suggesting moderately good discriminatory accuracy.

Conclusion

There were essentially two families of tools on which relevant performance data were available, those based on the Gail model, and the HCRI. None of the identified studies evaluated the performance of a predictive tool or algorithm, designed for use in populations not already pre-selected for higher risk, and using family history information alone. No validation studies of tools designed for risk prediction for ovarian or prostate cancer were found.

Most, but not all models demonstrated good calibration for the populations for which they were developed. However, none of the models identified demonstrated more than moderate ability to correctly discriminate risk at an individual level. The highest concordance presented was 0.71: this is equivalent to the correct classification of future disease (present or absent) in 71 percent of individuals, and incorrect classification of 29 percent.

General Approach

Table 6

Target interventions for review

Table 6

Target interventions for review

Cancer	Intervention
Breast	Chemoprevention Breast self-examination Clinical breast examination Screening mammography Screening MRI
Ovarian	Screening ultrasound
Colorectal	Chemoprevention FOBT screening Screening colonoscopy Screening sigmoidoscopy
Prostate	Chemoprevention PSA screening Digital rectal examination
All	Regular exercise/physical activity Dietary interventions high fiber diet high fruit and vegetables low fat Vitamin and micronutrient supplementation Limitation of alcohol intake Smoking cessation Seeking health care advice Referral for genetic counseling and/or genetic testing, where criteria are met

Abbreviations: FOBT=fecal occult blood test; MRI=magnetic resonance imaging; PSA=prostate specific antigen

Where multiple reviews addressing the same intervention were identified, they were scrutinized to determine the degree of overlap, as well as for quality. We selected the most recent and/or most comprehensive review for reporting, bearing in mind any differences in quality.¹⁷

Studies Reviewed

Twenty-nine systematic reviews fulfilled eligibility criteria after full text review. These eligible reviews addressed evidence for four chemoprevention interventions (antioxidant supplementation, calcium supplementation, non-steroidal anti-inflammatory drugs (NSAIDS), in the form of aspirin, but not COX-2 inhibitors and statins) and five screening interventions (breast self-examination (BSE), screening mammography, fecal occult blood testing (FOBT), flexible sigmoidoscopy (FS), and prostate specific antigen (PSA), for three cancers (breast, colorectal, and prostate).

No reviews were identified which examined evidence for magnetic resonance imaging in breast screening, ultrasound ovarian screening, colonoscopy as a stand-alone screening intervention, regular exercise, dietary interventions other than supplements (reviewed under chemoprevention), reduction in alcohol consumption, smoking cessation, seeking health care advice or referral for genetic counseling and/or genetic testing. As mentioned in chapter 2, we did not search for reviews for food, nutrition or physical activity interventions before 2006 as these were well evaluated in the World Cancer Research Fund/ American Institute for Cancer Research Second Expert Report.⁸¹

Table 7

Breast cancer preventive interventions

Table 7

Breast cancer preventive interventions

Study	Specific intervention(s) evaluated	Type of SR	Eligible populations	Eligible study designs	Number and type of trials	Followup duration (years)	Sample sizes	Ages	Summary effect sizes	Main conclusion
Type of intervention: Chemoprevention (antioxidants, NSAIDS, and statins)
Bardia18 2008	Antioxidant supplementation: β-carotene Selenium Zinc Vitamin C Vitamin E or any others	Quant	People at average risk of cancer	RCTs; Supplements with fully disclosed components and not dietary increases in nutrients; placebo-controlled; ≥1 y of followup; reported overall cancer incidence	≤12 (n not reported for cancer-specific analyses)	NR	88,392 (total across all trials)	NR	BC incidence (any antioxidant) RR=1.00 (0.90–1.09)	No evidence of protective effect of antioxidants against risk of BC
Alkhenizan19 2007	Vitamin E alone Vitamin E as part of other supplements	Quant	≥18 y; range of pre-existing health states, but not high risk for BC	RCTs; Supplementation in capsule or tablet form; control = placebo or no intervention; reported total mortality, cancer mortality, cancer-specific mortality	3	≥510 days – ≤10 y (not reported separately for individual cancers)	62,158 (total across all studies)	NR	BC incidence (Vit E in any combination) RR=0.99 (0.90–1.10)	No evidence of protective effect of Vitamin E against BC
Browning20 2006	Statins	Quant	All populations except highly specific statin-using patients (e.g. familial hypercholesterolemia, renal transplant)	RCTs; Control = placebo; Reported all cancer, site-specific cancer incidence or mortality	1–7 (depending on analysis)	Median followup: Trials: 3.6 y Observational studies: 6.2 y	RCTs: n = 103,573 Observational studies: n = 826,854	RCTs: 18–82 y Observational studies: 30–89 y	BC incidence from use of statins: 1 All studies RR=1.01 (0.79–1.30) 2 LI (3 trials) RR=0.89 (0.62–1.27) 3 LO (4 trials) RR=1.15 (0.81–1.64) 4 LP (1 trial) RR=1.44 (0.62–3.37) 5 MP (4 trials) RR=1.15 (0.81–1.64) 6 HP (2 trials) RR=0.80 (0.54–1.19)	No evidence of protective effect
Type of intervention: Screening
Kosters21 2003	BSE	Quant	General population	RCTs	3 trials, 1 discontinued China Russia	10–12	122,471–266,064	30–74	1. BC mortality (longest available followup) RR=1.05 (0.90–1.14)	The trials are based on large sample sizes and the findings are robust. Uptake was high and the findings are applicable to BSE practice generally. There is no effect of BSE on breast cancer mortality, but evidence that women taught BSE were more likely to be referred for a biopsy.
Gøtzche22 2006	SM	Quant	Women without previously diagnosed BC	RCTs; Controls with no SM	3 ‘adequately randomized’ trials Canada 7 ‘suboptimally randomized’ trials	7–13	42,482–92,934	39–74	All trialsBC mortality (13 y): RR=0.80 (0.73–0.88) Suboptimally randomized' trials RR=0.75 (0.67–0.83) Adequately randomized' trials RR=0.93 (0.80–1.09) All cause mortality RR=1.00 (0.96–1.04) Suboptimally randomized' trials RR=0.99 (0.97–1.01) All cancer mortality RR=1.02 (0.95–1.10)	Screening likely reduced BC mortality, with a reasonable risk reduction estimate of about 15%. Screening also leads to over diagnosis and over treatment. “It is not clear whether screening does more good than harm”

Abbreviations: BC=breast cancer; BSE=breast self-examination; DRE=digital rectal exam; e.g.=example; FOBT=fecal occult blood test; HP=High potency; LI=Lipophilic; LO=Lipophobic; LP=Low potency; mg=milligrams; MP=Medium potency; NR=not reported; PHS=Physician's Health Study; PSA=prostate specific antigen; Qual=Qualitative; Quant=Quantitative; RCT=Randomized controlled trial; RR=Relative risk; SM=Screening mammography; SR=systematic review; TRUS=transrectal ultrasound; y=year; WHS=Women's Health Study

Table 8

Colorectal cancer preventive interventions

Table 8

Colorectal cancer preventive interventions

Study	Specific intervention(s) evaluated	Type of SR	Eligible populations	Eligible study designs	Number and type of trials	Followp duration (years)	Sample sizes	Ages	Summary effect sizes	Main conclusion
Type of intervention: Chemoprevention (antioxidants, NSAIDS, and statins)
Bardia18 2008	Antioxidant supplementation: β-carotene Selenium Zinc Vitamin C Vitamin E or any others	Quant	People at average risk of cancer	RCTs; Supplements with fully disclosed components and not dietary increases in nutrients; placebo-controlled; ≥1 y of followup; reported overall cancer incidence	≤12	NR	178,086 (total across all studies)	NR	CRC incidence (any antioxidant) RR=1.00 (0.90–1.10)	No evidence of protective effect of antioxidants against CRC
Alkhenizan19 2007	Vitamin E alone Vitamin E as part of other supplements	Quant	≥18 y; range of pre-existing health states, but not high risk for colorectal cancer.	RCTs; Supplementation in capsule or tablet form; control = placebo or no intervention; reported total mortality, cancer mortality, cancer-specific mortality	2–4 depending on outcome	≥510 days – ≤10 y (not reported separately for individual cancers)	24,114 – 91,099 (across all trials, depending on analysis)	NR	1 CRC incidence (Vit E any combination) RR=0.95 (0.81–1.12) 2 CRC incidence (Vit E alone) RR=1.05 (0.79–1.39)	No evidence of protective effect of Vitamin E against CRC
Dubé23 2007	ASA	Quant and Qual	“Average’ risk	RCTs, controlled clinical trials	2 PHS 325mg every other day WHS 100mg/day	5–10	22,071–39,876	NR	1 CRC mortality (WHS) “No statistically significant benefit of ASA on CRC mortality” 2 CRC incidence RR=1.02 (0.84–1.25) 3 Adenoma incidence (PHS only) RR=0.86 (0.68–1.10)	Observational data appear to indicate that ASA use reduces the risk of colorectal neoplasia, but this effect is not seen in large trials of low dose ASA use
Browning20 2006	Statins	Quant	All populations except highly specific statin-using patients (e.g. familial hypercholesterolemia, renal transplant)	RCTs; Control = placebo; Reported all cancer, site-specific cancer incidence or mortality	1–9 (depending on analysis)	Median followup: Trials: 3.6 y	RCTs: n = 103,573	RCTs: 18–82 y	CRC incidence from use of statins: 1 All studies RR=1.02 (0.89–1.16) 2 Mortality (1 trial) RR=0.33 (0.07–1.63) 3 LI (4 trials) RR=1.0 (0.85–1.18) 4 LO (5 trials) RR=1.04 (0.85–1.30) 5 LP (2 trials) RR=1.07 (0.61–1.85) 6 MP (5 trials) RR=1.04 (0.84–1.30) 7 HP (2 trials) RR=0.99 (0.83–1.18)	No evidence of protective effect
Type of intervention: Population-based screening
Hewitson24 2006	FOBT (Hemoccult) investigation following positive screen result - colonoscopy or sigmoidoscopy and double contrast barium enema, with removal of colorectal cancers or adenomas found at diagnostic investigation	Quant, Qual	Adults; volunteers or individuals/households identified from primary care records or population registries	RCTs (individual or groups); control = no screening; report results based on participation in >1 screening round; report colorectal cancer mortality	4	10–17	46,551–150,251 Total 329,642	45–80 y	1 CRC mortality (all groups) RR=0.84 (0.78–0.90) 2 CRC mortality (biennial screening groups) RR=0.85 (0.78–0.92) 3 All cause mortality (all groups) RR=1.00 (0.99–1.01) 4 All cause mortality without CRC mortality (all groups) RR=1.01 (1.00–1.03). 5 CRC mortality (attended ≥1 screening) RR=0.75 (0.66–0.84)	15–16% reduction in relative risk of CRC mortality for individuals allocated to receive screening, rising to 25% risk reduction for those who actually participated at least once. No evidence of reduction in overall mortality, and borderline evidence of increased non-CRC mortality
Kerr25 2007	Once-only flexible sigmoidoscopy in addition to FOBT test, followed by colonoscopy for investigation of positive screen result*	Quant	Not specified, but population-based implied	RCTs; control = no screening control for this study was FOBT alone	1	2–5	10,978	50–75	1 CRC mortality RR=0.78 (0.36–1.73) 2 CRC incidence RR=1.37 (0.88–2.15)	The trial was limited by short followup period and no repeat screening. Results do not support benefit of combined screening strategy of FS with FOBT over FOBT alone in asymptomatic populations Poor compliance with combined screening group

Abbreviations: ASA=acetylsalicylic acid; BC=breast cancer; BSE=breast self-examination; DRE=digital rectal exam; e.g.=example; FOBT=fecal occult blood test; HP=High potency; LI=Lipophilic; LO=Lipophobic; LP=Low potency; mg=milligrams; MP=Medium potency; NR=not reported; PHS=Physician's Health Study; PSA=prostate specific antigen; Qual=Qualitative; Quant=Quantitative; RCT=Randomized controlled trial; RR=Relative risk; SR=systematic review; TRUS=transrectal ultrasound; y=year; WHS=Women's Health Study

*

Kerr review also examines FOBT screening alone, but results overlap, and are consistent, with those of Hewitson & Heresbach, therefore not reported here.

Table 9

Prostate cancer preventive interventions

Table 9

Prostate cancer preventive interventions

Study	Specific interventions evaluated	Type of SR	Eligible populations	Eligible study designs	Number and type trials	Followup durations (years)	Sample sizes	Ages	Summary effect sizes	Main conclusion
Type of intervention: Chemoprevention
Bardia18 2008	Antioxidant supplementation: β-carotene Selenium Zinc Vitamin C Vitamin E or any others	Quant	People at average risk of cancer	RCTs; Supplements with fully disclosed components and not dietary increases in nutrients; placebo-controlled; ≥1 y of followup; reported overall cancer incidence	≤12	NR	55,709 (total over all trials)	NR	Prostate cancer incidence: Any antioxidant RR=0.87 (0.74–1.02) Selenium alone (200µg daily): “decreased incidence’. [Estimated RR26=0.37 (0.20–0.70)]	No evidence of protective effect of antioxidants on prostate cancer risk
Alkhenizan19 2007	Vitamin E alone Vitamin E as part of other supplements	Quant	≥18 y; range of pre-existing health states, but not high risk for prostate cancer.	RCTs; Supplementation in capsule or tablet form; control = placebo or no intervention; reported total mortality, cancer mortality, cancer-specific mortality	2–4 (depending on outcome reported)	≥510 days – ≤10 y (not reported separately for individual cancers)	24,114–71,759 (total over all trials analyzed, depending on outcome reported)	NR	Prostate cancer incidence: 1 Any dose/combination RR=0.85 (0.74–0.96) 2 Vit E alone RR=0.86 (0.70–1.06) 3 Vit E plus other supplements RR=0.79 (0.67–0.93) 4 Vit E ≥300mg/day RR=0.94 (0.79–1.11) 5 Vit E <300mg/day RR=0.69 (0.55–0.87)	Vitamin E may be protective against prostate cancer
Bristol SLR Team26 2006*	Calcium supplements	Quant	NR; presumed cancer free	All	1 RCT	11 (intervention duration plus followup)	672	61.8 (mean)	RR=0.83 (0.52–1.32)	No evidence of protective effect of calcium supplementation
Browning20 2006	Statins	Quant	All populations except highly specific statin-using patients (e.g. familial hypercholesterolemia, renal transplant)	RCTs; Control = placebo; Reported all cancer, site-specific cancer incidence or mortality	1 or 4 (depending on analysis	Median followup: Trials: 3.6 y Observational studies: 6.2 yrs	RCTs: n =103,573 Observational studies: n=826,854	RCTs: 18–82 yrs Observational studies: 30–89 yrs	1 Prostate cancer incidence RR=1.00 (0.85–1.17) 2 Prostate cancer mortality (1 trial) RR=0.99 (0.14–7.01)	No evidence of protective effect
Type of intervention: Screening
Ilic27 2007	Any of PSA DRE TRUS biopsy	Quant	All men	RCTs, quasi-randomized, controlled trials; screening versus no screening	2 RCTs Quebec Annual screening Round 1 = PSA + DRE + TRUS where PSA >3.0ng/ml and/or abnormal DRE Later rounds = PSA with TRUS biopsy of PSA >3ng/ml or increased by >20% 3-yly screening Rounds 1&2=DRE&sftret;Rounds 3&4=DRE + PSA.&sftret;TRUS biopsy if DRE abnormal or PSA >4.0ng/ml	11–15	9,026–46,486 Total 55,512	45–80	Prostate cancer mortality RR=1.01 (0.80–1.29)	Insufficient evidence to either support or refute the routine use of mass, selective, opportunistic, or no screening to reduce prostate cancer mortality

Abbreviations: NR=not reported; Quant=Quantitative

*

This review also reported data relating to antioxidants; not included under this review's data as included in more recent included review¹⁸

Breast Cancer

Chemoprevention. ‘Chemoprevention’ refers to the use of chemical compounds to arrest or reverse the earliest stages of carcinogenesis or development of pre-cancerous lesions. We apply it very broadly in this review to include the use of both recognized pharmaceutical agents (drugs) and supplements of naturally occurring elements and compounds administered in doses above those naturally encountered in typical diets, and/or administered in tablets or capsule.

Antioxidants. Antioxidants are molecules which inhibit or prevent damage to cells caused by oxidizing agents such as oxygen free radicals. It is suggested that such damage (oxidative stress) is an important early step in the development of many diseases, including cancer. It is hypothesized that antioxidant compounds could act as cancer prevention agents by preventing or inhibiting DNA damage, the earliest stage of carcinogenesis. Many observational epidemiological studies have found an inverse relationship between consumption of foods with high antioxidant content, such as fruits and vegetables, and incidence of cancer.⁷¹–⁷³

Antioxidants are a diverse group of compounds and different reviews have assessed them collectively and individually. Among the many antioxidants associated with food, the most commonly studied are vitamins (A, C, and E), their precursor molecules (e.g., alpha-tocopherol and ß-carotene), and minerals (e.g., selenium and zinc).

We report the findings of two reviews that examined antioxidants and breast cancer incidence. The first review¹⁸ evaluated supplements which contained any combination of ß-carotene, vitamin C, vitamin E, selenium, zinc, and other antioxidants, and the second review¹⁹ focused on vitamin E in any combination. Both of these reviews also evaluated outcomes related to colorectal and prostate cancer, the results for which are presented in the relevant sections below.

The first review¹⁸ included only placebo-controlled trials where antioxidants were given as supplements where the ingredients were fully disclosed, and which had followed up participants for at least one year. Their breast cancer analysis was based on 1,753 cancers in a total of 88,392 participants enrolled in the primary trials. No evidence was found of a protective effect of any combination of antioxidants against breast cancer (RR 1.00, 95 percent CI 0.90–1.09).

The second review¹⁹ examined vitamin E alone or in any combination. It included randomized controlled trials (RCTs) where vitamin E, in tablet or capsule form with or without other components, was evaluated against a control group receiving placebo or no intervention. They assessed the methodological quality of all included trials as high. They identified three trials, involving 62,158 participants, in which breast cancer incidence was reported as an outcome. They concluded that there was no evidence of a protective effect of vitamin E supplementation against breast cancer (RR 0.99, 95 percent CI 0.90–1.10).

Statins. Statins (hepatic 3-hydroxy-3-methylglutaryl coenzyme A [HMG-CoA] reductase inhibitors) are a class of lipid-lowering drugs that are widely prescribed for people at risk of cardiovascular disease. Interest in whether use of statins is associated with cancer risk was prompted by safety monitoring findings from cardiovascular prevention trials.⁹¹ Some studies suggest that they may also have a protective effect against cancer,⁹²–⁹⁸ while others suggest the opposite.⁹⁹–¹⁰¹ Setoguchi et al., (2007)¹⁰² observed that longterm statin users tend to be healthier overall than non-users, and suggested that this might explain the positive associations.

Screening. Breast self-examination (BSE). It has been believed for many years that the practice of regular BSE allows women to detect breast tumors at an early stage, and thus to seek early treatment and improve their chances of cure. It is also considered inexpensive, non-invasive, and can be done in private.^{103, 104} Observational evidence suggests that women diagnosed with breast cancer who have practiced BSE are more likely to have found the tumor themselves, to have smaller tumors (on average) at the time of diagnosis, and to have benefited from longer survival.¹⁰⁵ Critics of such analyses point to the possibility of lead-time bias, and the need to examine mortality rates as a more valid method of examining outcomes.

We report the findings of one systematic review²¹ which identified primary reports of three large randomized controlled trials, in two of which the intervention was teaching BSE in general populations and, in the third, clinical breast examination followed by teaching BSE. The latter was discontinued after the first screening round because of poor compliance, so data were available for only two trials. A total of 587 breast cancer deaths were observed in a total group of participants of 388,535 across the two trials. The relative risk of breast cancer mortality was 1.05 (95 percent CI 0.90–1.14). There was no statistically significant effect on the total number of cancers identified. There was a non-significant trend towards the detection of smaller tumors (carcinoma in situ RR 1.32, 95 percent CI 0.82–2.14, tumors ≤2cm RR 1.13, 95 percent CI 0.99–1.28). There was a statistically significant increase in total number of breast biopsies and biopsies with benign pathology (RR 1.53, 95 percent CI 1.47–1.60, and 1.88, 95 percent CI 1.77–1.99, respectively). These two large, longterm, population-based trials provide robust evidence that teaching women to perform regular BSE does not translate into a lower mortality rate from breast cancer, and is associated with a higher rate of invasive investigation.

Screening mammography. Mammography as an investigative technology for suspected breast pathology has been available for several decades, and has been gradually introduced, and evaluated, as a potential screening strategy for breast cancer. The rationale for mammography is that screening may detect tumors at a stage before they are palpable through self- or clinical examination, and that these smaller tumors are less likely to have become locally invasive or metastasized. Screening mammography aims to detect early malignant tumors and, if effective, would be expected to reduce breast cancer, and overall, mortality, but not breast cancer incidence.

Screening mammography has been the focus of a relatively large number of controlled trials in a range of countries, and between 1992 and 2002, 22 systematic reviews of screening mammography were published.¹⁰⁶–¹²⁷ This level of scrutiny reflects ongoing controversies about the quality of the primary trials, and the possibility for harm which some experts consider inadequately examined and appreciated.^{106, 128}

This review examined data from 10 completed RCTs involving about half a million women. Of these, the reviewers considered only three trials to have been adequately randomized, and conducted a meta-analysis for these three separately. The trials covered a wide range of age groups, from 39 to 74 years, although most studies focused on women within the 40–59 age group. The reported screening intervals ranged from annual to about 2 years. In some studies, screening was accompanied by clinical breast examination, physical examination, or encouragement to perform monthly BSE. In most trials, the control intervention was usual care.

The overall analysis suggested that screening mammography is associated with reduced breast cancer mortality at 13 years (RR 0.80, 95 percent CI 0.73–0.88), but the association is more marked for the trials considered ‘sub-optimally randomized’ (RR 0.75, 95 percent CI 0.67–0.83) than for ‘adequately randomized trials (RR 0.93, 95 percent CI 0.80–1.09). When all cause mortality outcomes are considered (which would incorporate serious harms caused by over-treatment), the pooled estimates are very similar for trials considered ‘adequately randomized’ (RR 1.00, 95 percent CI 0.96–1.04) and ‘sub-optimally randomized’ (RR 0.99, 95 percent CI 0.97–1.01).

Colorectal Cancer

Chemoprevention. The rationale for chemoprevention is described in previous section on breast cancer.

Antioxidants. The background to antioxidants is described in previous section on breast cancer.

We report the findings of two reviews which examined antioxidants and CRC incidence. The first¹⁸ evaluated supplements which contained any combination of β-carotene, vitamin C, vitamin E, selenium, zinc, and other antioxidants, and the second¹⁹ focused on vitamin E in any combination. Further details of these reviews are included in the section on breast cancer.

The first review¹⁸ conducted an analysis of 1,523 cancers in a total of 178,086 participants enrolled in the primary trials. No evidence was found of a protective effect of any combination of antioxidants against CRC incidence (RR 1.00, 95 percent CI 0.90–1.10).

The second review¹⁹ identified four trials focusing on CRC. For vitamin E given in any combination (91,099 total participants), they found no evidence of an association with CRC incidence (RR 0.95, 95 percent CI 0.81–1.12). Similarly, there was no association when they examined data from two trials (24,114 participants) which evaluated vitamin E alone (RR 1.05, 95 percent CI 0.79–1.39).

Together, these reviews provide no evidence of a positive or negative association between antioxidant or vitamin E supplementation, and CRC risk.

NSAIDS. NSAIDs are a group of compounds which have an anti-inflammatory effect generally due to their action as non-selective inhibitors of the enzyme cyclooxygenase. Their potential protective effect against CRC has been observed in a number of case-control and cohort studies;¹²⁹–¹³⁶ there is also evidence of their effectiveness in preventing recurrence of colorectal adenomatous polyps.^{137, 138}

We identified two systematic reviews that examined one specific NSAID only, ASA, in CRC prevention. We report the findings of the single review that conducted a formal meta-analysis.²³ This review identified two primary studies that evaluated CRC incidence (one at 5 years, the other at 10 years) in individuals at average risk (including no personal history of adenomas); one of these trials also reported CRC mortality and the other examined the incidence of colorectal adenomas. The intervention in both of these studies was ASA at doses recommended for cardiovascular protection (i.e., 325 mg every other day or 100 mg/day). Apparently no primary studies of standard doses (i.e., ≥325 mg/day) have examined cancer outcomes in average risk individuals. The combined number of participants in these two studies was 61,947. No statistically significant association was identified between low dose ASA and CRC incidence (pooled RR 1.02, 95 percent CI 0.84–1.25), CRC mortality (RR not reported) or adenoma incidence at 5 years (RR 0.86, 95 percent CI 0.68–1.10). These results provide no direct information on the effectiveness of either higher doses of ASA, or other NSAIDS, on colorectal neoplasia.

Statins. The background to statins is described in previous section on breast cancer. A comprehensive systematic review²⁰ examined the evidence for statins in reducing the risk of CRC as well as breast (reported above) and prostate cancer (reported below). Data was synthesized for nine trials which examined CRC incidence, and one which evaluated CRC mortality, as outcomes. The overall analysis indicated that statins appeared to confer neither a protective nor a harmful effect on CRC incidence (pooled RR 1.02, 95 percent CI 0.89–1.16) or mortality (RR 0.33, 95 percent CI 0.07–1.63). The findings were unaltered in sub-group analyses comparing lipophilic and lipophobic statins, and low, medium and high potency statins.

Screening. Evidence from a wide range of studies¹³⁹–¹⁴¹ suggests that CRC results from complex interactions between genetic and environmental factors, and that most cancers evolve from small adenomas over a period of years.^{140, 141} The possibility of preventing CRC cases and deaths by early intervention to remove colorectal adenomas and/or early stage cancers has led to a large number of studies of a range of screening strategies, specifically involving FOBT, colonoscopy and sigmoidoscopy.¹⁴² There is no consensus on the optimum combination of these modalities, or on the ideal screening interval.

FOBT. The most widely used approach to FOBT is the stool guaiac test, in which the presence of heme (from haemoglobin) is indicated by a color change when hydrogen peroxide is added. This is a result of the oxidation of guaiac by the peroxide. A newer class of occult blood tests (immunochemical) rely on the detection of globin rather than heme, and it is suggested that these are more sensitive and specific than guaiac tests.¹⁴³

A number of reviews examined FOBT-based screening strategies, of which one is reported here.²⁴ This review examined RCTs only of FOBT (guaiac or immunochemical) in which at least two rounds of screening were compared with no-screening controls. This review analyzed data from four trials involving a total of 329,642 participants. A statistically significant effect of screening on CRC mortality was observed (pooled RR 0.84, 95 percent CI 0.78–0.90), which remained when the three trials with biennial screening were examined separately. No effect on all-cause mortality was observed (pooled RR 1.00, 95 percent CI 0.99–1.01), but a statistically borderline association with non-CRC mortality was noted (pooled RR 1.01, 95 percent CI 1.00–1.03). The interpretation of these combined results is difficult. It is argued that effective CRC screening would have little impact on all-cause mortality because CRC makes only a small contribution to overall mortality in these populations (and screening trials are therefore inadequately powered to detect such an effect). There is also an argument that biased attribution of cause of death between screened and control groups can lead to an overestimate of the true effect of screening on mortality, therefore an assessment of all-cause mortality would provide a more valid assessment of effectiveness.¹⁴⁴

Flexible sigmoidoscopy. Flexible sigmoidoscopy (FS) is an endocopic technique which allows visualization of the colon and rectum distal to the splenic flexure. FS has a very low complication rate.^{145, 146} The majority of CRCs arise in the distal colon, thus are theoretically detectable with FS, and detection of distal adenomas is an indication for full colonoscopy.¹⁴⁷ It is suggested that a combined strategy such as this can detect about 80 percent of CRC cases in men and about 50 percent of those in women, without recourse to more invasive colonoscopy as a primary screening modality.¹⁴⁸–¹⁵⁰

We identified one review²⁵ which examined the evidence for FS in CRC screening. One RCT was identified which compared FS in addition to FOBT against FOBT only (positive screens being followed up by colonoscopy). This review also considered FOBT alone as a screening strategy, but the data were not extracted as they are similar to the review reported above.²⁴ This trial involved 10,978 participants and showed no statistically significant effect of the combined FS plus FOBT strategy on CRC mortality or incidence (RR 0.78, 95 percent CI 0.36–1.73 and 1.37, 95 percent CI 0.88–2.15, respectively). No formal intervention studies comparing FS alone with either no screening, or FOBT only, have been identified.

Prostate Cancer

Chemoprevention. The rationale for chemoprevention is described in previous section on breast cancer.

Antioxidants. The background to antioxidants is described in previous section on breast cancer.

We report the findings of two reviews which examined antioxidants and prostate cancer incidence. The first¹⁸ evaluated supplements which contained any combination of β-carotene, vitamin C, vitamin E, selenium, zinc, and other antioxidants, and the second¹⁹ focused on vitamin E in any combination. Further details of these reviews are included in the section on breast cancer.

The first review¹⁸ conducted an analysis of 2,143 new cancers in a total of 55,709 participants enrolled in the primary trials. Overall, the pooled analysis indicated a small, non-statistically significant decrease in prostate cancer incidence when all antioxidants were considered together (pooled RR 0.87, 95 percent CI 0.74–1.02). Noting high heterogeneity, a sensitivity analysis suggested that vitamin E in particular was associated with a reduced risk (pooled RR 0.82, 95 percent CI 0.67–0.99), based on three trials. The authors of this review also noted that “one trial report a decreased incidence of prostate cancer with selenium,” although they did not provide relative risk data. Reporting on the same trial,¹⁵¹ another review²⁶ (included below) estimated that, for a daily dose of 200μg of selenium (compared with placebo), the relative risk for prostate cancer incidence was 0.37 (95 percent CI 0.20–0.70).

The second review¹⁹ evaluated the effect of vitamin E alone or in combination, and performed a meta-analysis on three primary trials. For vitamin E given in any combination (71,759 total participants), the pooled estimate for effect on prostate cancer incidence also indicated slightly reduced risk (pooled RR 0.85, 95 percent CI 0.74–0.96). Two trials examined vitamin E alone, with no evidence of an association (pooled RR 0.86, 95 percent CI 0.70, 1.06). Similarly, there was no association when they examined data from two trials (24,114 participants) which evaluated vitamin E alone (RR 1.05, 95 percent CI 0.79–1.39).

Together, these reviews suggest no evidence of an effect of combined antioxidant supplementation on prostate cancer risk, but potentially a small protective effect of vitamin E supplementation.

Calcium. The association between calcium intake and prostate cancer risk has been examined both from risk increasing and risk reducing perspectives. Observational studies have indicated a positive association between calcium intake and prostate cancer, the suggested mechanism being that calcium lowers circulating vitamin D concentrations, and this in turn alters prostate cell proliferation.¹⁵²–¹⁵⁵ In contrast, some studies have suggested that dietary calcium decreases prostate cancer risk.¹⁵⁶–¹⁶²

We identified one review which analyzed intervention study data relating to calcium and prostate cancer risk.²⁶ This review identified a single primary trial of calcium supplementation, designed to evaluate calcium as a protective agent against recurrence of colorectal adenomas, where prostate cancer incidence was evaluated as a secondary outcome.⁴⁷ Supplements equivalent to 1,200 mg elemental calcium daily were given for 4 years and participants followed up for another 7 years. This trial observed 70 prostate cancers in 672 men with an RR for prostate cancer incidence of 0.83 (95 percent CI 0.52–1.32). Detailed review of the results suggested a statistically significantly lower incidence of prostate cancer in the supplement group until 2 years after supplementation was discontinued (RR 0.52, 95 percent CI 0.28–0.98), at which point the risk in both groups converged. It is suggested that calcium may have a slight protective effect, which is maintained only by ongoing supplementation. This finding from a single trial is insufficient to recommend calcium supplementation specifically for the purpose of prostate cancer prevention, particularly given the contradictory findings of previous observational studies.

Statins. The background to statins is described above in previous section on breast cancer.

We present data from the comprehensive systematic review described in previous sections,²⁰ which examined the effectiveness of statins in reducing the risk of several cancers. Four trials examined prostate cancer incidence, and one evaluated prostate cancer mortality. The overall analysis indicated that statins appeared to neither increase nor decrease risk of prostate cancer incidence or mortality (pooled RR 1.00, 95 percent CI 0.85–1.17 and RR 0.99, 95 percent CI 0.14–7.01 respectively). No data were presented with regard to lipophilic versus lipophobic, or low, medium and high potency statins.

Screening. Prostate-specific antigen-based strategies (PSA). Strategies for screening for early prostate cancer have revolved around the combined use of PSA with or without DRE of the prostate, followed by needle biopsy guided transrectal ultrasound (TRUS). Digital rectal examination has limited sensitivity because it is not possible to palpate the entire prostate gland, while PSA testing produces high rates of false positive and false negative results.¹⁶³ In addition, although reductions in prostate cancer mortality have been demonstrated with early treatment,^{164, 165} there remains considerable concern about lead and length time bias, the overtreatment of men who have indolent disease (tumors which were never destined to be fatal),¹⁶⁶ and harms associated with treatment.¹⁶⁷–¹⁷⁰

We identified a single review²⁷ which examined the effectiveness of population-based screening in preventing death from prostate cancer. This study identified two trials of screening strategies that combined PSA testing, DRE and TRUS biopsy for diagnostic investigation, one of which used an annual, the other a 3 times yearly, screening cycle. The total number of participants randomized was 55,512, and 345 prostate cancer deaths were observed over followup periods of at least 11 years. No statistically significant impact of screening on prostate cancer mortality was found (pooled RR 1.01, 95 percent CI 0.80–1.29). No data were presented in relation to all-cause mortality. The authors of the review considered that both trials had a high risk of bias. The overall findings indicate that PSA-based screening cannot be considered to be an effective secondary prevention intervention in prostate cancer.

Quality Assessment of Studies

Standardized quality assessment checklists using a modified scoring version of the Oxman and Guyatt criteria⁸² were employed for all systematic reviews. The range of scores was 11–17 out of a possible 18. The major area of weakness was failure to describe adequate control of bias in the selection of studies for review.¹⁸–^{20, 22, 23, 27} Other issues encountered in a minority of reviews were incomplete description of search methods,^{23, 27} and failure to describe criteria for assessing the validity of primary studies,^{20, 25, 26} or to cite the validity assessments of included studies.^{20, 26}

Overall, the potential for bias in these reviews appears quite low. It is impossible to say whether failing to adequately describe search strategies, methods for controlling selection bias, or assessing validity of studies reflects methodological shortcomings or only failure to report these in published articles.

Conclusion

We were able to locate relevant systematic reviews relating to prevention, in average risk populations, of breast, colorectal, and prostate cancers, but not ovarian cancer. For all three cancers, the core primary prevention strategy for which reviews could be identified was chemoprevention. For breast and CRC, no evidence of an effect on cancer incidence of antioxidant supplements in general, vitamin E supplements in particular, or statins. For CRC, data on NSAIDS were available, with no evidence of an effect on cancer incidence. For prostate cancer, equivocal evidence was found of a possible protective effect of vitamin E supplements, selenium, and calcium supplements.

Screening strategies were also examined. For breast cancer, a review of three large population-based trials, confirm that BSE is not an effective strategy for reducing mortality from breast cancer and may increase morbidity through unnecessary investigations. Screening mammography has been evaluated in a large number of meta-analyses, which indicate that population-based screening appears to consistently reduce breast cancer mortality by about 15 percent, although there is still an open debate on whether all-cause mortality is a more valid measure of benefit of this intervention. There is concern that screening leads to higher rates of investigation and over treatment which undermine overall benefits. The analyses are based on studies with participants with a wide range of age ranges, which makes it difficult to discern the extent to which the profile of benefits and risks change according to target age. Both the technical performance of the screening test, in terms of sensitivity and specificity, and the prior risk of breast cancer, vary according to age, therefore the predictive value is not constant across all age groups. Also, the level of any risks associated with overtreatment will depend on local protocols for diagnostic investigation and treatment.

For CRC, FOBT-based screening strategies (which generally include diagnostic investigation using colonoscopy) appear to be associated with a decrease in CRC mortality, and the limited evidence available suggests that adding FS does not improve their effectiveness. As with breast screening, it is argued that all-cause mortality may provide a more valid assessment of screening effectiveness; however, since the proportion of overall mortality attributable to CRC is low, screening studies are generally underpowered to detect an effect.

With respect to prostate cancer, we found no evidence that PSA-based screening strategies are effective in reducing mortality.

General Approach

We reviewed published intervention studies (RCTs, controlled trials, and before-after studies) that examined the impact of systematic collection of family history information on one or more risk-reduction behaviors for breast, ovarian, colorectal, or prostate cancer. To be included, the intervention had to comprise systematic collection of individual family history information, and also communication of personal risk of one or more of the cancers of interest. This could be accompanied by individualized advice on specific risk reduction behaviors, although this was not necessary for a study to be included. The target behaviors of interest were both personal/lifestyle, and adherence to recommended clinical preventive interventions such as screening; the interventions were those considered standard of care when the primary study was conducted.

Studies Reviewed

Table 10

Details of family history and personalized risk interventions (more...)

Table 10

Details of family history and personalized risk interventions

Study and study design	Target population	Target behavior	Family history collection component of intervention	Risk personalization component of intervention	Other components	How individualized risk reduction advice communicated
Curry49 1993 RCT	Women eligible for SM	Having SM	Mailed self-completion questionnaire: 1 Information on 1DR and 2DR with BC 2 Other risk factors: age, age at menarche, age at first birth, menopause status, age at menopause, previous mammography, history of biopsy	Insertion of following text into a generic mammography invitation letter: “BC affects 1 in 10 women over their lifetime, but is more common with a personal history of particular risk factors. The recommendation that you schedule a comprehensive visit now is based on the answers you provided on the BC Screening Survey. From your responses, we were able to determine that your personal screening schedule is affected by your age [plus other risk factors if present]...”	None	Letter
Giles48 2001 BA	General female population	Having SM BSE CBE	Interviewer-administered survey: 1 Number of 1DRs with BC 2 Other risk factors: age at menarche, age at first live birth, number of breast biopsies 3 Other: history of practicing BSE, formal instruction in BSE, confidence in performing BSE, history of mammography	1 RR for developing BC in next 5y 2 RR for developing cancer in her lifetime	Encouragement to follow ACS guidelines for mammography, BSE, CBE ACS instruction card on BSE NCI brochure on BC risk factors	Individual consultation with a pharmacist
Bastani 50 1999 RCT	Female relatives of breast cancer patients	Having SM	Current age age at menarche, age at first live birth, number of breast biopsies, and number of first-degree relatives with breast cancer age at first biopsy, age of the index case (first degree relative listed in cancer registry) with cancer, age at menopause	List of personal risk factors for breast cancer and classification of risk in comparison with other women of the same age (“slightly”, “moderately”, or “substantially” higher risk)	Other materials tailored for high-risk women” plus message regarding the importance of regular screening mammography	Letter

Abbreviations: 1DR=first degree relative; 2DR=second degree relative; ACS=American Cancer Society; BA=before-after; BC=breast cancer; BSE=breast self-examination; CBE=clinical breast examination; FH=family history; NCI=National Cancer Institute; RCT=randomized controlled trial; RR=relative risk; SM=screening mammogram;

The sample sizes ranged from 188 to 2,076, and participants were recruited from a health maintenance organization (HMO),⁴⁹ community pharmacies/health promotion events,⁴⁸ and as first degree relatives (1DR) of breast cancer patients.⁵⁰ Family history information was captured by computer-assisted telephone interview,⁵⁰ postal questionnaire,⁴⁹ and interviewer-administered questionnaire.⁴⁸ In all three studies, information relating to personal medical history was collected as well as family history information. The 1DR and community pharmacy studies^{48, 50} specified use of the Gail model for risk calculation, which requires information on the number of 1DRs with breast cancer; the HMO study⁴⁹ used a risk stratification algorithm developed in-house, which included information on first and second degree relatives with breast cancer.¹⁷¹

The HMO study⁴⁹ had four groups, with two levels of collection of family history information (collected or not collected) and three levels of risk information included in screening invitation letters (no reinforcement, general risk messages, personalized risk messages) in the following combinations:

• no collection of individual risk information plus generic invitation for mammography

• no collection of individual risk information plus general risk messages embedded in invitation for mammography

• collection of individual risk information plus general risk messages embedded in invitation for mammography

• collection of individual risk information plus personalized risk messages embedded in invitation for mammography.

Data on the outcome of mammography uptake by 12 months were captured using the HMO's databases.

The 1DR study⁵⁰ had two groups, both of which had individual family history information collected, and personalized information on risk of breast cancer fed back. The two groups had different levels of reinforcement of the importance of, and reminders to undertake, the target behavior of screening mammography. Data on the outcome of uptake of mammography was assessed by self-report at 12 months, captured by mail or telephone survey.

The community pharmacy study⁴⁸ had one group of participants, all of whom had individual family history information collected and personalized information on risk of breast cancer fed back, along with reminders of recommended screening behaviors. Data on the outcomes of self-reported uptake of mammography, and adherence to BSE and clinical breast examination (CBE) recommendations, was captured at 6 months using telephone survey.

It should be noted that the two controlled studies (1DR and HMO^{49, 50}) both examined different levels of personalization of risk information, but only the HMO study⁴⁹ examined the capture of family history information as an intervention in itself. The community pharmacy study⁴⁸ did not have a control group without family history capture.

Outcomes

Table 11

Evaluations of family history and personalized risk (more...)

Table 11

Evaluations of family history and personalized risk

Study and study design	Participants	Control intervention/group	Outcome measure(s)	Effect of FH based intervention on target behavior(s)	Modified Jadad quality score (max=8)	Conclusions
Curry49 1993 RCT	Women ≥50 y registered with a single HMO, eligible for SM n=2,076	1 No risk data captured, generic invitation to schedule a mammogram (C1) 2 No risk data captured, general risk information included in invitation to schedule a mammogram (C2) 3 Risk data captured, general risk information included in invitation to schedule a mammogram (C3)	Having a mammogram within 12 months of invitation	% Received a mammogram by 12 months: I: 44.6% C1: 49.2% C2: 41.1% C3: 41.8% P=0.23 (χ2) Comparison restricted to I&C3 only (risk factor questionnaire plus general risk or personalized risk invitation), stratified by family history: No family history - I: 39.7% C3: 41.4% Positive family history: I: 66.7% C3: 42.9% P=0.005. No significant interactions of personalized feedback with other risk factors	4 Allocation concealment NR	Overall, capturing risk information and/or addition of general or personalized risk information to screening mammography invitations did not increase uptake. Findings suggest that capturing risk information and personalizing risk messages may be more effective in promoting screening behavior
Bastani50 1999 RCT	Women with a 1DR with BC n=901	1 Note thanking for participation in telephone survey 2 General information booklet on BC	SM measured by self-report at 1 y followup	% Had SM All ages:Baseline I: 55.0% C:54.9% Followup I: 65.2% C: 57.7% P=0.05 30–40Baseline I: 41.4% C:31.4% Followup I: 49.4% C:35.7% P=0.66 40–50Baseline I: 61.4% C: 57.4% Followup I: 62.3% C:67.0% P=0.26 50–64Baseline I: 58.9% C:68.8% Followup I: 76.8% C: 68.8% P=0.02	4 Allocation concealment NR	In a somewhat selected group of participants, and compared with the control intervention of FH taking and general information on BC, the active intervention of FH taking accompanied by individualized risk assessment and reinforcement of importance of target behavior appeared to improve adherence with screening recommendations to a modest level, equivalent to difference in increased uptake by 7% in absolute terms No comparison group which did not have FH information collected
Giles48 2001 BA	Women ≥18y visiting a community pharmacy or attending a health screening event n=188	None	Adherence with ACS guidelines for BSE, CBE, and mammography, assessed at 6 months	Proportions following ACS guidelines (self-report) (% (95% CI*)) BSEAll: Pre: 42/137 (31 (23–38)) Post: 77/137 (56 (48–64) P<0.001 5 y risk≥1.7%: Pre: 4/20 (20 (2–37)) Post: 12/20 (60 (38–81)) P<0.005 CBEAll: Pre:121/140 (86 (81–92)) Post:128/140 (91 (87–96)) P<0.09 5 y risk≥1.7%: Pre: 17/21 (81 (61–98)) Post: 17/21 (81 (64–98)) P=1.00 MammographyAll: ≥50y Pre: 33/44 (75 (62–88)) Post: 31/44 (70 (57–84)) P<0.48 40–49 Pre: 18/32 (56 (39–73)) Post: 21/32 (66 (49–82)) P<0.257 5 y risk≥1.7%: Pre: 17/21 (81 (64–98)) Post: 15/21 (71 (52–91)) P<0.317	NA	Findings suggest that personalized risk assessment which included family history may improve adherence with recommended screening practices The size and direction of changes were different across the three target behaviors and no uniform effect was observed in high risk participants The lack of a control intervention, the reliance on self-report data, and the small sample size for sub-group analyses severely limit the conclusions which can be drawn

Abbreviations: 1DR=first degree relative; BA=before-after; BC=breast cancer; BSE=breast self-examination; CBE=clinical breast examination; FH=family history; NA=not applicable; NR=not reported; RCT=randomized controlled trial; SM=screening mammogram;

*

Confidence intervals not provided in original article, calculated on basis of data presented

All articles reported age-specific analyses, which generally did not show meaningful differences in effectiveness of the interventions. The HMO study⁴⁹ also analyzed outcomes by breast cancer family history status (positive or negative) in the two groups that had been sent a risk questionnaire. While mammography uptake was similar between those receiving general risk and personalized risk invitations and who had a negative family history (41.4 and 39.7 percent, respectively), uptake was higher in women who had a positive family history and received a personalized invitation (66.7 percent) than women with a positive family history who received a generalized risk invitation (42.9 percent) (P=0.005). The results of the community pharmacy study⁴⁸ were unchanged when the analyses were limited to the high risk participants only.

The studies vary in the extent to which their participants were representative of the general population. The HMO study was designed to be completely representative of its own patient population, which was described in previous publication as predominantly white, slightly better educated, and having a slightly different income distribution than Washington state as a whole.¹⁷¹ The proportion of participants with a positive first or second degree family history of breast cancer was about 20 percent, which is consistent with the North American female population. In contrast, the 1DR study was confined to women who had at least one first degree relative with breast cancer. The community pharmacy study drew participants from women attending pharmacies and heart health events, and no specific data are presented regarding representativeness. Their analyses indicate that 21 of 140 (15 percent) participants were assigned to the high risk category (≥1.7 percent risk of breast cancer in 5 years), which appears higher than would be expected for an unselected female population in this age group. Also, the high baseline rates of CBE and mammography compared with published figures for the general population may indicate that this study has limited external validity.

Quality Assessment of Studies

Standardized quality assessment checklists were employed on the two studies that used a randomized trial design.^{49, 50} The modified Jadad scores were 4 out of 8 for both studies.⁸³ The main problem areas for both studies were failure to report measures to achieve blinding, and neither explicitly described randomization procedures or measures to conceal allocation. Both studies implemented the intervention through mail-outs to participants, asking them to take a specific action (schedule a mammography), and the possibility for contamination was probably rather low, particularly for the 1DR study. The potential for bias in these studies therefore appears quite low.

The third study⁴⁸ was described in the report's abstract as a ‘randomized, paired, pre-post study’, which is misleading. In our assessment, it was an uncontrolled pre-post study in which before-after outcomes for individual participants were analyzed as paired data. No control group was used and therefore no random allocation was possible. The potential for bias in this study is high, given that no assessment could be made of the influence of external factors, or placebo or Hawthorne effects.

Conclusion

Taken together, the three studies identified neither support nor refute the hypothesis that taking family history and using it to personalize risk of breast, ovarian, colorectal, or prostate cancer promotes lifestyle changes which reduce cancer risk, and/or greater adherence with preventive clinical interventions. All three studies focused on breast cancer, the interventions were heterogeneous, some including components beyond family history taking and personalization of risk. The interventions generally did not resemble the routine, personal interaction which might occur between a primary care professional and an individual patient, and the methodological rigor of the evaluations was variable.

The HMO study⁴⁹ was embedded in a routine screening invitation system, and therefore resembled regular clinical practice, albeit in a non-personal way. The evaluation was well-designed and had a large sample size. This study (the oldest of the three reviewed) provides no evidence that personalization of risk information would be an effective overall strategy, but suggests that it might be worth exploring as a way of promoting risk reduction behavior in high risk sub-groups.

The 1DR study⁵⁰ provided evidence of a possible modest effect on mammography uptake of personalizing risk information for a group already likely to have higher than average personal risk perceptions. The intervention had several components, and it is impossible to separate out the individual effects of the family history collection, the personalization of risk information, and the materials designed to reinforce the importance of mammography. Even this thoughtfully designed intervention produced only a small increase in screening behavior. The transferability of the approach to a clinical setting, and the absolute size of benefits that would be achieved, is unclear.

The community pharmacy study⁴⁸ showed some evidence that personalized risk information could promote cancer prevention behavior, but the lack of a control group, the questionable validity of the outcome measurement, and the likely selection bias of participants all make it impossible to judge the wider applicability of its findings.

General Approach

We reviewed published intervention studies, (RCTs, controlled trials, and before-after studies) which assessed negative impacts of systematically collecting family history information and providing patients with risk information for the cancers of interest based on their family history. The focus was on systematic collection of individual family history information, and communication of personal risk of one or more of the cancers of interest, in populations considered representative of primary care populations. Specialist genetic counseling (with or without genetic testing) for patients selected because of possible genetic risk was excluded from this definition.

The outcomes of interest were impaired quality of life, negative psychological effects (cognitive, affective, or behavioral), social impacts (e.g., negative impact on family well-being, discrimination, stigmatization), which could be directly attributed to this intervention, not subsequent clinical or other preventive activities.

Studies Reviewed

Table 12

Harm/risk of family history collection

Table 12

Harm/risk of family history collection

Author Year Setting	Type of cancer	Study design	Characteristic of population	1 No.recruited 2 No.completed	Time points for analysis (months)	Duration of intervention followup	Who delivered intervention?	Method of family history collection	Other intervention(s)
Leggatt51 2000	Colorectal/colon/rectal Breast	Before - After uncontrolled study	Unselected patients aged 35 to 65 years	1 666 (29% response) 2 604	Baseline 1–1.5	Postal survey followed by single session	Lower risk group: letter from family doctor Potential increased risk groups: family doctor and/or oncologist/geneticist	Postal cancer family history questionnaire	Participants provided with risk information

Outcomes

This study analyzed participants in two groups. Firstly, ‘lower risk’ (those at no more than slightly elevated risk) participants, for whom no followup was necessary, were given feedback by letter only. No statistical difference was observed in anxiety and most other cancer worry measures following the intervention, with the exception of a small reduction in participants' perception of their own risk (P<0.01).

Of the remaining participants, most were interviewed to clarify details of the family history, which led to further designation into ‘higher risk’ and ‘false positive’ groups (the latter comprising patients deemed not actually to be at high risk after further enquiry). For both ‘higher risk’ and ‘false positive’ groups, no difference between baseline and followup responses to general anxiety and cancer worries scales was observed. However, both of these groups showed higher baseline cancer risk perception scores compared to the lower risk group (P<0.001 for ‘higher risk’ group and P=0.003 for ‘false positive’ group).

Overall, the findings suggested no association between the exercise of capturing family history information and feeding back personalized risk, and anxiety or cancer worry, in patients who are close to average risk. In fact, it is possible that the intervention may have led to more realistic (lower) perceptions of personal risk. In contrast, the higher anxiety and cancer worry outcomes in the ‘true’ and ‘false positive’ high risk groups may reflect their baseline (pre-intervention) status rather than an effect of family history taking.

Conclusion

The evidence base for addressing (Q4) is limited to a single study. It suggested that structured family history collection and feedback of breast cancer risk information had no deleterious psychological effects on any of the risk groups, and in women, who were not at high risk, may have led to appropriate reductions in perceived risk. Higher average baseline levels of anxiety and cancer worry in the groups who went on to have further assessment may reflect pre-existing concerns about a positive family history and need to be taken into account when family history interventions are evaluated.

Conclusions

• 1

  The evidence for the predictive accuracy of algorithms in primary care populations was very limited. Although many tools were identified that incorporated some family history information, no evaluations of solely family history-based tools were identified. The tools on which it was possible to comment related mainly to breast cancer.

  Recommendations for future research:

  • The actual performance of tools based only on family history should be formally examined in primary prospective studies, and/or in secondary analysis of large cohort studies.

  • The performance of individual family history components of different risk stratification models which use a wider range of factors (including those examined in this report) should be examined separately from the non-family history components, in order to determine whether they provide sufficient predictive power in the absence of the non-family history factors.

  • For clinical relevance, the focus of validation should be discriminatory accuracy at the individual patient level.

  • More definitive evaluation should examine the effect on health outcomes when risk stratification systems are used in combination with preventive interventions, in actual practice settings. This cannot be done with secondary analyses of observational data and requires well-designed intervention studies.

• 2

  The evidence establishing the efficacy of interventions for primary and secondary prevention based on systematic reviews of randomized or controlled clinical studies in unselected populations is very limited. Interventions for which there were reviews include chemoprevention (antioxidants, calcium, NSAIDS, and statins) and screening interventions (BSE, mammography, FBOT, flexible sigmoidoscopy, and PSA) for breast, colorectal and prostate cancers. No reviews were found for ovarian cancer. It is likely that this review excluded effectiveness data available from RCTs of interventions which have not yet been the subject of systematic reviews.

  Recommendations for future research:

  • The large amount of evidence on potential primary cancer preventive interventions obtained from observational studies of cancer risk factors should continue to be further evaluated in well-designed randomized controlled trials.

  • Further systematic reviews should be conducted to examine the full range of potentially preventive interventions

• 3

  Within primary care populations, there is very limited evidence to support or refute the effect on risk-reducing behavior changes (e.g., lifestyle changes or uptake of recommended clinical interventions) of taking a family history and using it to personalize risk of breast, ovarian, colorectal, or prostate cancer.

  Recommendations for future research:

  • Well-designed trials are required that compare family history-based, personalized risk advice with standard of care on risk reducing behaviors in populations at different risk levels (including population risk).

• 4

  In primary care populations, there is very limited information to evaluate direct harm incurred from the routine practice of taking family history and using it to personalize risk information.

  Recommendations for future research:

  • Trials of family history taking as an intervention should include capture of data to examine the full range of potential impacts on individuals. Baseline data on psychological status should be captured so that this can formally be adjusted for in outcome analyses.

• 5

  Research on the use of family history tools, risk stratification systems, and family history-based personalized prevention advice should take into account evidence on the factors likely to promote their effective use in practice, such as the educational needs of primary care practitioners and issues which act as barriers or constraints to their implementation in practice

Ovid-MEDLINE

• 1

  claus.tw.

• 2

  gail.tw.

• 3

  BRCAPRO.tw.

• 4

  BOADICEA.tw.

• 5

  UK cancer family study group.tw.

• 6

  UKCFSG.tw.

• 7

  Myriad.ti,ab.

• 8

  tyrer Cuzick.ti,ab.

• 9

  ((Amsterdam or Bethesda or Manchester or Gilpin or Evans or Frank or Finnish or Yale or Spanish) adj5 (criteria or guideline? or scor$ or model? or protocol? or algorithm?)).ti,ab.

• 10

  FHAT.ti,ab.

• 11

  (Australia adj5 breast cancer cent$).tw.

• 12

  couch.ti,ab.

• 13

  ((mendel or LAMBDA) adj5 (criteria or guideline? or scor$ or model? or protocol? or algorithm?)).ti,ab.

• 14

  (Dutch guideline adj7 breast).ti,ab.

• 15

  (nice guideline? and breast cancer).ti,ab.

• 16

  or/1–15

• 17

  models, statistical/

• 18

  models, theoretical/ or models, genetic/

• 19

  17 or 18

• 20

  genes, brca1/ or genes, brca2/

• 21

  BRCA$.tw.

• 22

  20 or 21

• 23

  19 and 22

• 24

  16 or 23

• 25

  exp breast neoplasms/ or exp colorectal neoplasms/ or exp ovarian neoplasms/ or exp prostatic neoplasms/

• 26

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 27

  *Neoplasms/

• 28

  or/25–27

• 29

  validation.ti.

• 30

  accuracy.ti.

• 31

  validation studies/

• 32

  evaluation studies/

• 33

  exp “Sensitivity and Specificity”/

• 34

  “reproducibility of results”/

• 35

  odds ratio/

• 36

  multivariate analysis/

• 37

  exp Probability/

• 38

  predictive value?.ti,ab.

• 39

  or/29–38

• 40

  24 and 28 and 39

• 41

  animals/ not (humans/ and animals/)

• 42

  40 not 41

• 43

  limit 42 to english language

• 44

  limit 43 to yr=“1990 - 2008”

• 45

  Breast Neoplasms/

• 46

  exp Colorectal Neoplasms/

• 47

  exp Prostatic Neoplasms/

• 48

  exp Ovarian Neoplasms/

• 49

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$)).ti,ab.

• 50

  or/45–49

• 51

  exp Mass Screening/

• 52

  (surveillance or screening).ti.

• 53

  Primary Prevention/

• 54

  Preventive Medicine/

• 55

  prophylactic.ti.

• 56

  prevention.ti.

• 57

  (genetic adj2 (counsel?ing or test$)).ti.

• 58

  Risk Assessment/

• 59

  (risk adj (assessment? or stratification)).ti.

• 60

  Preventive Health Services/

• 61

  or/51–60

• 62

  exp Pedigree/

• 63

  limit 62 to humans

• 64

  exp Medical History Taking/

• 65

  ((family or familial) adj3 (histor$ or history-taking or risk$)).ti,ab.

• 66

  anamnesis.ti.

• 67

  (human adj2 pedigree).ti,ab.

• 68

  (genetic adj2 (risk adj3 (assessment or evaluation))).ti,ab.

• 69

  genogram$.ti,ab.

• 70

  ((famil$ or heredi$ or inherit$) adj3 (cancer$ or carcinom$ or neoplasm$)).ti,ab.

• 71

  (genetic adj2 (screening or test$)).ti,ab.

• 72

  Family Health/

• 73

  or/63–72

• 74

  exp Neoplasms/

• 75

  (neoplasm? or carcinoma? or cancer?).ti.

• 76

  74 or 75

• 77

  guideline.pt.

• 78

  practice guideline.pt.

• 79

  guideline?.ti.

• 80

  or/77–79

• 81

  73 and 76 and 80

• 82

  50 and 61 and 80

• 83

  81 or 82

• 84

  (note or comment or editorial).pt.

• 85

  83 not 84

• 86

  limit 85 to english language

• 87

  limit 86 to yr=“2003 - 2008”

• 88

  44 or 87

Ovid-EMBASE

• 1

  claus.tw.

• 2

  gail.tw.

• 3

  BRCAPRO.tw.

• 4

  BOADICEA.tw.

• 5

  UK cancer family study group.tw.

• 6

  UKCFSG.tw.

• 7

  Myriad.ti,ab.

• 8

  tyrer Cuzick.ti,ab.

• 9

  ((Amsterdam or Bethesda or Manchester or Gilpin or Evans or Frank or Finnish or Yale or Spanish) adj5 (criteria or guideline? or scor$ or model? or protocol? or algorithm?)).ti,ab.

• 10

  FHAT.ti,ab.

• 11

  (Australia adj5 breast cancer cent$).tw.

• 12

  couch.ti,ab.

• 13

  ((mendel or LAMBDA) adj5 (criteria or guideline? or scor$ or model? or protocol? or algorithm?)).ti,ab.

• 14

  (Dutch guideline adj7 breast).ti,ab.

• 15

  (nice guideline? and breast cancer).ti,ab.

• 16

  or/1–15

• 17

  MATHEMATICAL MODEL/ or STATISTICAL MODEL/ or CANCER MODEL/ or GENETIC MODEL/

• 18

  GENETIC ALGORITHM/ or ALGORITHM/

• 19

  or/17–18

• 20

  Brca1 Protein/ or Brca2 Protein/

• 21

  oncogene/

• 22

  brca2 gene/

• 23

  BRCA$.tw.

• 24

  or/20–23

• 25

  19 and 24

• 26

  exp breast neoplasms/ or exp colorectal neoplasms/ or exp ovarian neoplasms/ or exp prostatic neoplasms/

• 27

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 28

  *Neoplasms/

• 29

  or/26–28

• 30

  16 or 25

• 31

  29 and 30

• 32

  validation.ti.

• 33

  accuracy.ti.

• 34

  agreement.ti.

• 35

  VALIDATION STUDY/ or INSTRUMENT VALIDATION/ or VALIDATION PROCESS/

• 36

  diagnostic accuracy/

• 37

  exp statistical parameters/

• 38

  prediction/

• 39

  “SENSITIVITY AND SPECIFICITY”/

• 40

  predictive value?.ti,ab.

• 41

  or/32–40

• 42

  31 and 41

• 43

  limit 42 to human

• 44

  limit 43 to english language

• 45

  limit 44 to yr=“1990 - 2008”

• 46

  exp Neoplasms/

• 47

  (neoplasm? or carcinoma? or cancer?).ti.

• 48

  46 or 47

• 49

  exp Breast Cancer/

• 50

  exp Colon Cancer/

• 51

  exp Ovary Cancer/

• 52

  exp Prostate Cancer/

• 53

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 54

  or/49–53

• 55

  exp anamnesis/

• 56

  ((family or familial) adj3 (histor$ or history-taking or risk$)).ti,ab.

• 57

  anamnesis.ti.

• 58

  (human adj2 pedigree).ti,ab.

• 59

  (genetic adj2 (risk adj3 (assessment or evaluation))).ti,ab.

• 60

  ((famil$ or heredi$ or inherit$) adj3 (cancer$ or carcinom$ or neoplasm$ or tumo?r$)).ti,ab.

• 61

  (genetic adj2 (screening or test$)).ti,ab.

• 62

  genogram$.ti,ab.

• 63

  or/55–62

• 64

  prevention/ or primary prevention/ or prophylaxis/ or breast care/ or cancer prevention/ or chemoprophylaxis/ or periodic medical examination/ or personal monitoring/ or secondary prevention/

• 65

  screening/ or screening test/ or mass screening/ or cancer screening/ or genetic screening/

• 66

  risk/ or genetic risk/ or risk assessment/ or risk factor/ or risk management/ or risk reduction/

• 67

  preventive medicine/

• 68

  preventive health service/

• 69

  prevention.ti.

• 70

  prophylactic.ti.

• 71

  or/64–70

• 72

  (note or comment or editorial).pt.

• 73

  practice guideline/

• 74

  guideline?.ti.

• 75

  73 or 74

• 76

  48 and 63 and 75

• 77

  54 and 71 and 75

• 78

  76 or 77

• 79

  78 not 72

• 80

  limit 79 to human

• 81

  limit 80 to english language

• 82

  limit 81 to yr=“2003 - 2008”

• 83

  45 or 82

Ovid-CINAHL

• 1

  claus.tw.

• 2

  gail.tw.

• 3

  BRCAPRO.tw.

• 4

  BOADICEA.tw.

• 5

  UK cancer family study group.tw.

• 6

  UKCFSG.tw.

• 7

  Myriad.ti,ab.

• 8

  tyrer Cuzick.ti,ab.

• 9

  ((Amsterdam or Bethesda or Manchester or Gilpin or Evans or Frank or Finnish or Yale or Spanish) adj5 (criteria or guideline? or scor$ or model? or protocol? or algorithm?)).ti,ab.

• 10

  FHAT.ti,ab.

• 11

  (Australia adj5 breast cancer cent$).tw.

• 12

  couch.ti,ab.

• 13

  ((mendel or LAMBDA) adj5 (criteria or guideline? or scor$ or model? or protocol? or algorithm?)).ti,ab.

• 14

  (Dutch guideline adj7 breast).ti,ab.

• 15

  (nice guideline? and breast cancer).ti,ab.

• 16

  or/1–15

• 17

  practice guidelines.pt.

• 18

  Practice Guidelines/

• 19

  guidelines.ti,ab.

• 20

  or/17–19

• 21

  exp Medical History Taking/

• 22

  exp Family Health/

• 23

  exp Pedigree/

• 24

  ((family or familial) adj3 (histor$ or history-taking or risk$)).ti,ab.

• 25

  anamnesis.ti,ab.

• 26

  (human adj2 pedigree).ti,ab.

• 27

  (genetic adj2 (risk adj3 (assessment or evaluation))).ti,ab.

• 28

  ((famil$ or heredi$ or inherit$) adj3 (cancer$ or carcinom$ or neoplasm$ or tumo?r$)).ti,ab.

• 29

  or/21–28

• 30

  exp Breast Neoplasms/

• 31

  exp Colorectal Neoplasms/

• 32

  exp Ovarian Neoplasms/

• 33

  exp Prostatic Neoplasms/

• 34

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 35

  or/30–34

• 36

  cancer screening/ or genetic screening/

• 37

  (surveillance or screening).ti.

• 38

  Preventive Health Care/

• 39

  Chemoprevention/

• 40

  Risk Assessment/

• 41

  prophylactic.ti.

• 42

  prevention.ti.

• 43

  (gentic adj2 (counsel?ing or test$ or screen$)).ti.

• 44

  Genetic Counseling/

• 45

  (risk adj (assessment? or stratification)).ti.

• 46

  or/36–45

• 47

  exp Neoplasms/

• 48

  (neoplasm? or carcinoma? or cancer?).ti.

• 49

  or/47–48

• 50

  20 and 29 and 49

• 51

  20 and 35 and 46

• 52

  50 or 51

• 53

  limit 52 to (book chapter or case study or commentary or editorial)

• 54

  52 not 53

• 55

  limit 54 to english

• 56

  limit 55 to yr=“2000 - 2008”

• 57

  limit 55 to yr=“2003 - 2008”

• 58

  models, theoretical/ or models, statistical/

• 59

  Genes, BRCA/

• 60

  BRCA$.tw.

• 61

  59 or 60

• 62

  58 and 61

• 63

  16 or 62

• 64

  exp breast neoplasms/ or exp colorectal neoplasms/ or exp ovarian neoplasms/ or exp prostatic neoplasms/

• 65

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 66

  64 or 65

• 67

  63 and 66

• 68

  limit 67 to english

• 69

  (book chapter or case study or commentary or editorial).pt.

• 70

  68 not 69

• 71

  limit 70 to yr=“1990 - 2008”

• 72

  57 or 71

Ovid-CCRT

• 1

  claus.tw.

• 2

  gail.tw.

• 3

  BRCAPRO.tw.

• 4

  BOADICEA.tw.

• 5

  UK cancer family study group.tw.

• 6

  UKCFSG.tw.

• 7

  Myriad.ti,ab.

• 8

  tyrer Cuzick.ti,ab.

• 9

  ((Amsterdam or Bethesda or Manchester or Gilpin or Evans or Frank or Finnish or Yale or Spanish) adj5 (criteria or guideline? or scor$ or model? or protocol? or algorithm?)).ti,ab.

• 10

  FHAT.ti,ab.

• 11

  (Australia adj5 breast cancer cent$).tw.

• 12

  couch.ti,ab.

• 13

  ((mendel or LAMBDA) adj5 (criteria or guideline? or scor$ or model? or protocol? or algorithm?)).ti,ab.

• 14

  (Dutch guideline adj7 breast).ti,ab.

• 15

  (nice guideline? and breast cancer).ti,ab.

• 16

  or/1–15

• 17

  models, statistical/

• 18

  models, theoretical/ or models, genetic/

• 19

  17 or 18

• 20

  genes, brca1/ or genes, brca2/

• 21

  BRCA$.tw.

• 22

  20 or 21

• 23

  19 and 22

• 24

  16 or 23

• 25

  exp breast neoplasms/ or exp colorectal neoplasms/ or exp ovarian neoplasms/ or exp prostatic neoplasms/

• 26

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 27

  *Neoplasms/

• 28

  or/25–27

• 29

  validation.ti.

• 30

  accuracy.ti.

• 31

  validation studies/

• 32

  evaluation studies/

• 33

  exp “Sensitivity and Specificity”/

• 34

  “reproducibility of results”/

• 35

  odds ratio/

• 36

  multivariate analysis/

• 37

  exp Probability/

• 38

  predictive value?.ti,ab.

• 39

  or/29–38

• 40

  24 and 28 and 39

• 41

  limit 40 to yr=“1990 - 2008”

• 42

  Breast Neoplasms/

• 43

  exp Colorectal Neoplasms/

• 44

  exp Prostatic Neoplasms/

• 45

  exp Ovarian Neoplasms/

• 46

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$)).ti,ab.

• 47

  or/42–46

• 48

  exp Mass Screening/

• 49

  (surveillance or screening).ti.

• 50

  Primary Prevention/

• 51

  Preventive Medicine/

• 52

  prophylactic.ti.

• 53

  prevention.ti.

• 54

  (genetic adj2 (counsel?ing or test$)).ti.

• 55

  Risk Assessment/

• 56

  (risk adj (assessment? or stratification)).ti.

• 57

  Preventive Health Services/

• 58

  or/48–57

• 59

  exp Pedigree/

• 60

  limit 59 to humans

• 61

  exp Medical History Taking/

• 62

  ((family or familial) adj3 (histor$ or history-taking or risk$)).ti,ab.

• 63

  anamnesis.ti.

• 64

  (human adj2 pedigree).ti,ab.

• 65

  (genetic adj2 (risk adj3 (assessment or evaluation))).ti,ab.

• 66

  genogram$.ti,ab.

• 67

  ((famil$ or heredi$ or inherit$) adj3 (cancer$ or carcinom$ or neoplasm$)).ti,ab.

• 68

  (genetic adj2 (screening or test$)).ti,ab.

• 69

  Family Health/

• 70

  or/60–69

• 71

  exp Neoplasms/

• 72

  (neoplasm? or carcinoma? or cancer?).ti.

• 73

  71 or 72

• 74

  guideline.pt.

• 75

  practice guideline.pt.

• 76

  guideline?.ti.

• 77

  or/74–76

• 78

  70 and 73 and 77

• 79

  47 and 58 and 77

• 80

  78 or 79

• 81

  (note or comment or editorial).pt.

• 82

  80 not 81

• 83

  limit 82 to yr=“2003 - 2008”

• 84

  41 or 83

Ovid-MEDLINE

• 1

  exp Diet Therapy/ or exp Nutrition Physiology/ or exp Nutritional Sciences/

• 2

  (diet or diets or dietetic or dietary or eating or intake or nutrient$ or nutrition or vegetarian$ or vegan$ or “seventh day adventist” or macrobiotic or breastfeed$ or breast feed$ or breastfed or breast fed or breastmilk or breast milk).ti,ab.

• 3

  exp “food and beverages”/

• 4

  (food$ or cereal$ or grain$ or granary or wholegrain or wholewheat or roots or plantain$ or tuber or tubers or vegetable$ or fruit$ or pulses or beans or lentils or chickpeas or legume$ or soy or soya or nut or nuts or peanut$ or groundnut$ or seeds or meat or beef or pork or lamb or poultry or chicken or turkey or duck or fish or fat or fats or fatty or egg or eggs or bread or oils or shellfish or seafood or sugar or syrup or dairy or milk or herbs or spices or chilli or chillis or pepper$ or condiments).ti,ab.

• 5

  (fluid intake or water or drinks or drinking or tea or coffee or caffeine or juice or beer or spirits or liquor or wine or alcohol or alcoholic or beverage$ or ethanol or yerba mate or ilex paraguariensis).ti,ab.

• 6

  fertilizers/ or exp pesticides/ or Veterinary Drugs/

• 7

  (pesticide$ or herbicide$ or DDT or fertiliser$ or fertilizer$ or organic or contaminants or contaminate$ or veterinary drug$ or polychlorinated dibenzofuran$ or PCDF$ or polychlorinated dibenzodioxin$ or PCDD$ or polychlorinated biphenyl$ or PCB$ or cadmium or arsenic or chlorinated hydrocarbon$ or microbial contamination$).ti,ab.

• 8

  exp Food Preservation/

• 9

  (mycotoxin$ or aflatoxin$ or pickled or bottled or bottling or canned or canning or vacuum pack$ or refrigerate$ or refrigeration or cured or smoked or preserved or preservatives or nitrosamine or hydrogenation or fortified or additive$ or colouring$ or coloring$ or flavouring$ or flavoring$ or nitrates or nitrites or solvent or solvents or ferment$ or processed or antioxidant$ or genetic modif$ or genetically modif$ or vinyl chloride or packaging or labelling or phthalates).ti,ab.

• 10

  Cookery/

• 11

  (cooking or cooked or grill or grilled or fried or fry or roast or bake or baked or stewing or stewed or casserol$ or broil or broiled or boiled or microwave or microwaved or re-heating or reheating or heating or re-heated or heated or poach or poached or steamed or barbecue$ or chargrill$ or heterocyclic amines or polycyclic aromatic hydrocarbons).ti,ab.

• 12

  exp Dietary Carbohydrates/ or exp Dietary Proteins/ or exp Sweetening Agents/

• 13

  (salt or salting or salted or fiber or fibre or polysaccharide$ or starch or starchy or carbohydrate$ or lipid$ or linoleic acid$ or sterols or stanols or sugar$ or sweetener$ or saccharin$ or aspartame or acesulfame or cyclamates or maltose or mannitol or sorbitol or sucrose or xylitol or cholesterol or protein or proteins or hydrogenated dietary oils or hydrogenated lard or hydrogenated oils).ti,ab.

• 14

  exp Vitamins/

• 15

  (supplements or supplement or vitamin$ or retinol or carotenoid$ or tocopherol or folate$ or folic acid or methionine or riboflavin or thiamine or niacin or pyridoxine or cobalamin or mineral$ or sodium or iron or calcium or selenium or iodine or magnesium or potassium or zinc or copper or phosphorus or manganese or chromium or phytochemical or allium or isothiocyanate$ or glucosinolate$ or indoles or polyphenol$ or phytoestrogen$ or genistein or saponin$ or coumarin$).ti,ab.

• 16

  Physical Fitness/ or exp Exertion/ or exp Physical Endurance/ or Walking/

• 17

  (recreational activit$ or household activit$ or occupational activit$ or physical activit$ or physical inactivit$ or exercise or exercising or energy intake or energy expenditure or energy balance or energy density).ti,ab.

• 18

  exp Growth/ or exp Anthropometry/ or exp Body Composition/ or exp Body Constitution/

• 19

  (weight loss or weight gain or anthropometry or birth weight or birthweight or birth-weight or child development or height or body composition or body mass or BMI or obesity or obese or overweight or over-weight or over weight or skinfold measurement$ or skinfold thickness or DEXA or bio-impedence or waist circumference or hip circumference or waist hip ratio$).ti,ab.

• 20

  or/1–19

• 21

  animals/ not (humans/ and animals/)

• 22

  20 not 21

• 23

  meta-analysis.pt,ti,ab,sh.

• 24

  (meta anal$ or metaanal$).ti,ab,sh.

• 25

  ((methodol$ or systematic$ or quantitativ$) adj3 (review$ or overview$ or survey$)).ti,ab,sh.

• 26

  (medline or embase or index medicus).ti,ab.

• 27

  ((pool$ or combined or combining) adj (data or trials or studies or results)).ti,ab.

• 28

  25 or 26 or 27

• 29

  review.pt,sh.

• 30

  28 and 29

• 31

  23 or 24

• 32

  30 or 31

• 33

  exp Neoplasms/pc “Prevention & Control”

• 34

  ((cancer or carcinoma$ or neoplasm$) adj3 (prevent$ or reduc$)).tw.

• 35

  Breast Neoplasms/

• 36

  exp Colorectal Neoplasms/

• 37

  exp Ovarian Neoplasms/

• 38

  exp Prostatic Neoplasms/

• 39

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 40

  or/33–39

• 41

  22 and 32 and 40

• 42

  limit 41 to english language

• 43

  limit 42 to ed=20060101-20080425

Ovid-Medline

• 1

  Mass Screening/

• 2

  Smoking Cessation/

• 3

  Alcohol Drinking/

• 4

  Chemoprevention/

• 5

  chemoprevention.ti.

• 6

  (surveillance or screening).ti.

• 7

  Primary Prevention/

• 8

  Preventive Medicine/

• 9

  Preventive Health Services/

• 10

  (prophylactic or preventive or risk reduc$).ti.

• 11

  risk reduction behavior/

• 12

  “Referral and Consultation”/

• 13

  medical consultation.ti.

• 14

  (health adj3 consultation).ti.

• 15

  or/1–14

• 16

  Breast Neoplasms/

• 17

  exp Colorectal Neoplasms/

• 18

  exp Prostatic Neoplasms/

• 19

  exp Ovarian Neoplasms/

• 20

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$)).ti,ab.

• 21

  or/16–20

• 22

  self exam$.ti.

• 23

  Breast Self-Examination/

• 24

  exp Mammography/

• 25

  mammog$.ti.

• 26

  Ovariectomy/

• 27

  risk reduction mastectomy.ti.

• 28

  ((prophylactic or preventive or risk reduc$) adj3 (mastectomy or oophorectomy or ovariectomy)).tw.

• 29

  ((magnetic resonance imaging or mri) adj3 breast).ti.

• 30

  breast exam$.ti.

• 31

  (ovarian adj3 screening).ti.

• 32

  exp Contraceptives, Oral/

• 33

  tamoxifen/ or raloxifene/ or toremifene/

• 34

  (tamoxifen or raloxifene or toremifene or fareston).ti.

• 35

  or/22–34

• 36

  Breast Neoplasms/

• 37

  (breast adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 38

  exp Ovarian Neoplasms/

• 39

  (ovar$ adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 40

  or/36–39

• 41

  35 and 40

• 42

  Fenretinide/

• 43

  Finasteride/

• 44

  (Fenretinide or Finasteride or proscar).ti.

• 45

  Digital Rectal Examination/

• 46

  Toremifene/

• 47

  fareston.ti.

• 48

  (avodart or dutasteride).ti.

• 49

  Prostate-Specific Antigen/

• 50

  (psa adj3 test$).ti.

• 51

  prostate specific antigen.ti.

• 52

  or/42–51

• 53

  exp Prostatic Neoplasms/

• 54

  (prostat$ adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 55

  or/53–54

• 56

  52 and 55

• 57

  Digital Rectal Examination/

• 58

  f?ecal occult blood test$.ti.

• 59

  (FOBT or fob test$).ti.

• 60

  colonoscopy/ or sigmoidoscopy/

• 61

  (sigmoidoscopy or colonoscopy).ti.

• 62

  Hormone Replacement Therapy/

• 63

  hrt.ti.

• 64

  exp Anti-Inflammatory Agents, Non-Steroidal/

• 65

  NSAID?.ti.

• 66

  (nonsteroidal adj3 inflammatory).ti.

• 67

  exp Hydroxymethylglutaryl-CoA Reductase Inhibitors/

• 68

  HMG-CoA reductase inhibitors.ti.

• 69

  statins.ti.

• 70

  or/57–69

• 71

  exp Colorectal Neoplasms/

• 72

  ((colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$)).ti,ab.

• 73

  or/71–72

• 74

  70 and 73

• 75

  genetic services/ or genetic counseling/ or genetic screening/

• 76

  21 and 75

• 77

  15 and 21

• 78

  41 or 56 or 74 or 76 or 77

• 79

  meta-analysis.pt,ti,ab,sh.

• 80

  (meta anal$ or metaanal$).ti,ab,sh.

• 81

  ((methodol$ or systematic$ or quantitativ$) adj3 (review$ or overview$ or survey$)).ti.

• 82

  ((methodol$ or systematic$ or quantitativ$) adj3 (review$ or overview$ or survey$)).ab.

• 83

  (medline or embase or index medicus).ti,ab.

• 84

  ((pool$ or combined or combining) adj (data or trials or studies or results)).ti,ab.

• 85

  or/82–84

• 86

  review.pt,sh.

• 87

  85 and 86

• 88

  79 or 80 or 81 or 87

• 89

  78 and 88

• 90

  limit 89 to english language

• 91

  limit 90 to yr=“2000 - 2008”

• 92

  limit 90 to yr=“2003 - 2008”

Ovid-EMBASE

• 1

  exp nutrition/

• 2

  (diet or diets or dietetic or dietary or eating or intake or nutrient$ or nutrition or vegetarian$ or vegan$ or “seventh day adventist” or macrobiotic or breastfeed$ or breast feed$ or breastfed or breast fed or breastmilk or breast milk).ti,ab.

• 3

  (food$ or cereal$ or grain$ or granary or wholegrain or wholewheat or roots or plantain$ or tuber or tubers or vegetable$ or fruit$ or pulses or beans or lentils or chickpeas or legume$ or soy or soya or nut or nuts or peanut$ or groundnut$ or seeds or meat or beef or pork or lamb or poultry or chicken or turkey or duck or fish or fat or fats or fatty or egg or eggs or bread or oils or shellfish or seafood or sugar or syrup or dairy or milk or herbs or spices or chilli or chillis or pepper$ or condiments).ti,ab.

• 4

  (fluid intake or water or drinks or drinking or tea or coffee or caffeine or juice or beer or spirits or liquor or wine or alcohol or alcoholic or beverage$ or ethanol or yerba mate or ilex paraguariensis).ti,ab.

• 5

  exp Fertilizer/

• 6

  exp Pesticide/

• 7

  Veterinary Drug/

• 8

  (pesticide$ or herbicide$ or DDT or fertiliser$ or fertilizer$ or organic or contaminants or contaminate$ or veterinary drug$ or polychlorinated dibenzofuran$ or PCDF$ or polychlorinated dibenzodioxin$ or PCDD$ or polychlorinated biphenyl$ or PCB$ or cadmium or arsenic or chlorinated hydrocarbon$ or microbial contamination$).ti,ab.

• 9

  exp food preservation/

• 10

  (mycotoxin$ or aflatoxin$ or pickled or bottled or bottling or canned or canning or vacuum pack$ or refrigerate$ or refrigeration or cured or smoked or preserved or preservatives or nitrosamine or hydrogenation or fortified or additive$ or colouring$ or coloring$ or flavouring$ or flavoring$ or nitrates or nitrites or solvent or solvents or ferment$ or processed or antioxidant$ or genetic modif$ or genetically modif$ or vinyl chloride or packaging or labelling or phthalates).ti,ab.

• 11

  cooking/

• 12

  (cooking or cooked or grill or grilled or fried or fry or roast or bake or baked or stewing or stewed or casserol$ or broil or broiled or boiled or microwave or microwaved or re-heating or reheating or heating or re-heated or heated or poach or poached or steamed or barbecue$ or chargrill$ or heterocyclic amines or polycyclic aromatic hydrocarbons).ti,ab.

• 13

  *Carbohydrate/

• 14

  exp “peptides and proteins”/ or protein/

• 15

  (salt or salting or salted or fiber or fibre or polysaccharide$ or starch or starchy or carbohydrate$ or lipid$ or linoleic acid$ or sterols or stanols or sugar$ or sweetener$ or saccharin$ or aspartame or acesulfame or cyclamates or maltose or mannitol or sorbitol or sucrose or xylitol or cholesterol or protein or proteins or hydrogenated dietary oils or hydrogenated lard or hydrogenated oils).ti,ab.

• 16

  exp Vitamin/

• 17

  (supplements or supplement or vitamin$ or retinol or carotenoid$ or tocopherol or folate$ or folic acid or methionine or riboflavin or thiamine or niacin or pyridoxine or cobalamin or mineral$ or sodium or iron or calcium or selenium or iodine or magnesium or potassium or zinc or copper or phosphorus or manganese or chromium or phytochemical or allium or isothiocyanate$ or glucosinolate$ or indoles or polyphenol$ or phytoestrogen$ or genistein or saponin$ or coumarin$).ti,ab.

• 18

  exp “physical activity, capacity and performance”/

• 19

  (recreational activit$ or household activit$ or occupational activit$ or physical activit$ or physical inactivit$ or exercise or exercising or energy intake or energy expenditure or energy balance or energy density).ti,ab.

• 20

  growth/ or exp body growth/

• 21

  anthropometry/

• 22

  exp body composition/

• 23

  body constitution/

• 24

  (weight loss or weight gain or anthropometry or birth weight or birthweight or birth-weight or child development or height or body composition or body mass or BMI or obesity or obese or overweight or over-weight or over weight or skinfold measurement$ or skinfold thickness or DEXA or bio-impedence or waist circumference or hip circumference or waist hip ratio$).ti,ab.

• 25

  or/1–24

• 26

  meta-analysis.ti,ab,sh.

• 27

  (meta anal$ or metaanal$).ti,ab,sh.

• 28

  ((methodol$ or systematic$ or quantitativ$) adj3 (review$ or overview$ or survey$)).ti,ab,sh.

• 29

  (medline or embase or index medicus).ti,ab.

• 30

  ((pool$ or combined or combining) adj (data or trials or studies or results)).ti,ab.

• 31

  28 or 29 or 30

• 32

  review.pt,sh.

• 33

  31 and 32

• 34

  26 or 27 or 33

• 35

  exp Breast Cancer/

• 36

  exp Colon Cancer/

• 37

  exp Ovary Cancer/

• 38

  exp Prostate Cancer/

• 39

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 40

  exp Neoplasm/pc “Prevention”

• 41

  cancer prevention/

• 42

  ((cancer or carcinoma$ or neoplasm$ or tumo?r$) adj3 (prevent$ or reduc$)).tw.

• 43

  or/35–42

• 44

  25 and 34 and 43

• 45

  limit 44 to english language

• 46

  animal/ not (human/ and animal/)

• 47

  45 not 46

• 48

  limit 47 to em=200601-200817

Ovid-EMBASE

• 1

  cancer screening/

• 2

  genetic services/ or genetic counseling/ or genetic screening/

• 3

  prophylaxis/ or breast care/ or cancer prevention/ or chemoprophylaxis/ or periodic medical examination/ or personal monitoring/ or secondary prevention/ or smoking cessation/

• 4

  alcohol abstinence/ or behavioral risk factor surveillance system/ or drinking behavior/ or risk reduction/

• 5

  (chemoprevention or chemoprophylaxis).ti.

• 6

  (surveillance or screening).ti.

• 7

  disease surveillance/

• 8

  PREVENTIVE HEALTH SERVICE/ or PREVENTIVE MEDICINE/

• 9

  (prophylactic or preventive or risk reduc$).ti.

• 10

  patient referral/

• 11

  medical consultation.ti.

• 12

  (health adj3 consultation).ti.

• 13

  or/1–12

• 14

  exp Breast Cancer/

• 15

  exp Colon Cancer/

• 16

  exp Ovary Cancer/

• 17

  exp Prostate Cancer/

• 18

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 19

  or/14–18

• 20

  exp breast examination/

• 21

  self exam$.ti.

• 22

  Ovariectomy/

• 23

  exp mastectomy/

• 24

  mammog$.ti.

• 25

  ((prophylactic or preventive or risk reduc$) adj3 (mastectomy or oophorectomy or ovariectomy)).tw.

• 26

  ((magnetic resonance imaging or mri) adj3 breast).ti.

• 27

  breast exam$.ti.

• 28

  (ovarian adj3 screening).ti.

• 29

  exp Oral Contraceptive Agent/

• 30

  raloxifene/ or tamoxifen/ or toremifene/

• 31

  (tamoxifen or raloxifene or toremifene or fareston).ti.

• 32

  or/20–31

• 33

  exp Breast Cancer/

• 34

  (breast adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 35

  exp Ovary Cancer/

• 36

  (ovar$ adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 37

  or/33–36

• 38

  32 and 37

• 39

  Fenretinide/

• 40

  Finasteride/

• 41

  (Fenretinide or Finasteride or proscar).ti.

• 42

  digital rectal examination/

• 43

  Toremifene/

• 44

  fareston.ti.

• 45

  (avodart or dutasteride).ti.

• 46

  Prostate Specific Antigen/

• 47

  (psa adj3 test$).ti.

• 48

  prostate specific antigen.ti.

• 49

  or/39–48

• 50

  exp Prostate Cancer/

• 51

  (prostat$ adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 52

  or/50–51

• 53

  49 and 52

• 54

  digital rectal examination/

• 55

  f?ecal occult blood test$.ti.

• 56

  (FOBT or fob test$).ti.

• 57

  colonoscopy/ or sigmoidoscopy/

• 58

  hormone replacement therapy.ti.

• 59

  hrt.ti.

• 60

  exp Hormone Substitution/

• 61

  exp Nonsteroid Antiinflammatory Agent/

• 62

  NSAID?.ti.

• 63

  (nonsteroidal adj3 inflammatory).ti.

• 64

  exp Hydroxymethylglutaryl Coenzyme a Reductase Inhibitor/

• 65

  HMG-CoA reductase inhibitors.ti.

• 66

  statins.ti.

• 67

  or/54–66

• 68

  exp Colon Cancer/

• 69

  ((colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$)).ti,ab.

• 70

  or/68–69

• 71

  67 and 70

• 72

  13 and 19

• 73

  38 or 53 or 71 or 72

• 74

  meta analysis/

• 75

  meta-analysis.ti,ab.

• 76

  (meta anal$ or metaanal$).ti,ab.

• 77

  ((methodol$ or systematic$ or quantitativ$) adj3 (review$ or overview$ or survey$)).ti.

• 78

  ((methodol$ or systematic$ or quantitativ$) adj3 (review$ or overview$ or survey$)).ab.

• 79

  (medline or embase or index medicus).ti,ab.

• 80

  ((pool$ or combined or combining) adj (data or trials or studies or results)).ti,ab.

• 81

  or/78–80

• 82

  review.pt,sh.

• 83

  81 and 82

• 84

  or/74–77

• 85

  83 or 84

• 86

  73 and 85

• 87

  limit 86 to english language

• 88

  limit 87 to yr=“2000 - 2008”

• 89

  limit 87 to yr=“2003 - 2008”

Ovid-CINAHL

• 1

  Diet Therapy/

• 2

  exp Nutrition/

• 3

  (diet or diets or dietetic or dietary or eating or intake or nutrient$ or nutrition or vegetarian$ or vegan$ or “seventh day adventist” or macrobiotic or breastfeed$ or breast feed$ or breastfed or breast fed or breastmilk or breast milk).ti,ab.

• 4

  exp “food and beverages”/ or food/

• 5

  (food$ or cereal$ or grain$ or granary or wholegrain or wholewheat or roots or plantain$ or tuber or tubers or vegetable$ or fruit$ or pulses or beans or lentils or chickpeas or legume$ or soy or soya or nut or nuts or peanut$ or groundnut$ or seeds or meat or beef or pork or lamb or poultry or chicken or turkey or duck or fish or fat or fats or fatty or egg or eggs or bread or oils or shellfish or seafood or sugar or syrup or dairy or milk or herbs or spices or chilli or chillis or pepper$ or condiments).ti,ab.

• 6

  (fluid intake or water or drinks or drinking or tea or coffee or caffeine or juice or beer or spirits or liquor or wine or alcohol or alcoholic or beverage$ or ethanol or yerba mate or ilex paraguariensis).ti,ab.

• 7

  exp Pesticides/

• 8

  Veterinary Medicine/

• 9

  (pesticide$ or herbicide$ or DDT or fertiliser$ or fertilizer$ or organic or contaminants or contaminate$ or veterinary drug$ or polychlorinated dibenzofuran$ or PCDF$ or polychlorinated dibenzodioxin$ or PCDD$ or polychlorinated biphenyl$ or PCB$ or cadmium or arsenic or chlorinated hydrocarbon$ or microbial contamination$).ti,ab.

• 10

  exp Food Preservation/

• 11

  (mycotoxin$ or aflatoxin$ or pickled or bottled or bottling or canned or canning or vacuum pack$ or refrigerate$ or refrigeration or cured or smoked or preserved or preservatives or nitrosamine or hydrogenation or fortified or additive$ or colouring$ or coloring$ or flavouring$ or flavoring$ or nitrates or nitrites or solvent or solvents or ferment$ or processed or antioxidant$ or genetic modif$ or genetically modif$ or vinyl chloride or packaging or labelling or phthalates).ti,ab.

• 12

  Cooking/

• 13

  (cooking or cooked or grill or grilled or fried or fry or roast or bake or baked or stewing or stewed or casserol$ or broil or broiled or boiled or microwave or microwaved or re-heating or reheating or heating or re-heated or heated or poach or poached or steamed or barbecue$ or chargrill$ or heterocyclic amines or polycyclic aromatic hydrocarbons).ti,ab.

• 14

  exp Dietary Carbohydrates/

• 15

  exp Dietary Proteins/

• 16

  exp Sweetening Agents/

• 17

  (salt or salting or salted or fiber or fibre or polysaccharide$ or starch or starchy or carbohydrate$ or lipid$ or linoleic acid$ or sterols or stanols or sugar$ or sweetener$ or saccharin$ or aspartame or acesulfame or cyclamates or maltose or mannitol or sorbitol or sucrose or xylitol or cholesterol or protein or proteins or hydrogenated dietary oils or hydrogenated lard or hydrogenated oils).ti,ab.

• 18

  exp Vitamins/

• 19

  (supplements or supplement or vitamin$ or retinol or carotenoid$ or tocopherol or folate$ or folic acid or methionine or riboflavin or thiamine or niacin or pyridoxine or cobalamin or mineral$ or sodium or iron or calcium or selenium or iodine or magnesium or potassium or zinc or copper or phosphorus or manganese or chromium or phytochemical or allium or isothiocyanate$ or glucosinolate$ or indoles or polyphenol$ or phytoestrogen$ or genistein or saponin$ or coumarin$).ti,ab.

• 20

  Physical Fitness/

• 21

  exp Exertion/

• 22

  Walking/

• 23

  (recreational activit$ or household activit$ or occupational activit$ or physical activit$ or physical inactivit$ or exercise or exercising or energy intake or energy expenditure or energy balance or energy density).ti,ab.

• 24

  exp Growth/

• 25

  exp “Body Weights and Measures”/

• 26

  exp Body Composition/

• 27

  exp Body Constitution/

• 28

  (weight loss or weight gain or anthropometry or birth weight or birthweight or birth-weight or child development or height or body composition or body mass or BMI or obesity or obese or overweight or over-weight or over weight or skinfold measurement$ or skinfold thickness or DEXA or bio-impedence or waist circumference or hip circumference or waist hip ratio$).ti,ab.

• 29

  or/1–28

• 30

  meta-analysis.ti,ab,sh.

• 31

  (meta anal$ or metaanal$).ti,ab,sh.

• 32

  systematic review.pt.

• 33

  systematic review.ti.

• 34

  ((methodol$ or systematic$ or quantitativ$) adj3 (review$ or overview$ or survey$)).ti,ab,sh.

• 35

  (medline or embase or index medicus).ti,ab.

• 36

  ((pool$ or combined or combining) adj (data or trials or studies or results)).ti,ab.

• 37

  34 or 35 or 36

• 38

  review.pt,sh.

• 39

  37 and 38

• 40

  30 or 31 or 32 or 33

• 41

  39 or 40

• 42

  exp Breast Neoplasms/

• 43

  exp Colorectal Neoplasms/

• 44

  exp Ovarian Neoplasms/

• 45

  exp Prostatic Neoplasms/

• 46

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 47

  or/42–46

• 48

  29 and 41 and 47

• 49

  limit 48 to ew=2006$

• 50

  limit 48 to ew=2007$

• 51

  limit 48 to ew=2008$

• 52

  49 or 50 or 51

• 53

  limit 52 to english

Ovid-CINAHL

• 1

  cancer screening/ or genetic screening/

• 2

  Genetic Counseling/

• 3

  Chemoprevention/

• 4

  “Referral and Consultation”/

• 5

  Smoking Cessation/

• 6

  Alcohol Drinking/

• 7

  (chemoprevention or chemoprophylaxis).ti.

• 8

  Disease Surveillance/

• 9

  (surveillance or screening).ti.

• 10

  Preventive Health Care/

• 11

  (prophylactic or preventive or risk reduc$).ti.

• 12

  medical consultation.ti.

• 13

  (health adj3 consultation).ti.

• 14

  Risk Management/

• 15

  or/1–14

• 16

  Breast Care/

• 17

  breast examination/ or breast self-examination/

• 18

  self exam$.ti.

• 19

  Oophorectomy/

• 20

  Mastectomy/

• 21

  Mammography/

• 22

  mammog$.ti.

• 23

  ((prophylactic or preventive or risk reduc$) adj3 (mastectomy or oophorectomy or ovariectomy)).tw.

• 24

  ((magnetic resonance imaging or mri) adj3 breast).ti.

• 25

  breast exam$.ti.

• 26

  (ovarian adj3 screening).ti.

• 27

  exp Contraceptives, Oral/

• 28

  raloxifene/ or tamoxifen/

• 29

  (tamoxifen or raloxifene or toremifene or fareston).ti.

• 30

  or/16–29

• 31

  exp Breast Neoplasms/

• 32

  exp Ovarian Neoplasms/

• 33

  (breast adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 34

  (ovar$ adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 35

  or/31–34

• 36

  30 and 35

• 37

  Finasteride/

• 38

  (Fenretinide or Finasteride or proscar).ti.

• 39

  Digital Rectal Examination/

• 40

  Toremifene.ti.

• 41

  fareston.ti.

• 42

  (avodart or dutasteride).ti.

• 43

  Prostate-Specific Antigen/

• 44

  (psa adj3 test$).ti.

• 45

  prostate specific antigen.ti.

• 46

  or/37–45

• 47

  exp Prostatic Neoplasms/

• 48

  (prostat$ adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 49

  or/47–48

• 50

  46 and 49

• 51

  Digital Rectal Examination/

• 52

  f?ecal occult blood test$.ti.

• 53

  (FOBT or fob test$).ti.

• 54

  colonoscopy/ or sigmoidoscopy/

• 55

  Hormone Replacement Therapy/

• 56

  hormone replacement therapy.ti.

• 57

  hrt.ti.

• 58

  exp Antiinflammatory Agents, Non-Steroidal/

• 59

  NSAID?.ti.

• 60

  (nonsteroidal adj3 inflammatory).ti.

• 61

  exp Statins/

• 62

  HMG-CoA reductase inhibitors.ti.

• 63

  statins.ti.

• 64

  or/51–63

• 65

  exp Colorectal Neoplasms/

• 66

  ((colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 67

  or/65–66

• 68

  64 and 67

• 69

  exp Breast Neoplasms/

• 70

  exp Colorectal Neoplasms/

• 71

  exp Prostatic Neoplasms/

• 72

  exp Ovarian Neoplasms/

• 73

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti.

• 74

  or/69–73

• 75

  15 and 74

• 76

  36 or 50 or 68 or 75

• 77

  Meta Analysis/

• 78

  (meta anal$ or metaanal$).ti,ab.

• 79

  meta-analysis.ti,ab.

• 80

  ((methodol$ or systematic$ or quantitativ$) adj3 (review$ or overview$ or survey$)).ti.

• 81

  ((methodol$ or systematic$ or quantitativ$) adj3 (review$ or overview$ or survey$)).ab.

• 82

  (medline or embase or index medicus).ti,ab.

• 83

  ((pool$ or combined or combining) adj (data or trials or studies or results)).ti,ab.

• 84

  or/81–83

• 85

  review.pt,sh.

• 86

  84 and 85

• 87

  “Systematic Review”/

• 88

  systematic review.pt.

• 89

  78 or 79 or 80 or 86 or 87 or 88

• 90

  76 and 89

• 91

  limit 90 to english

• 92

  limit 91 to yr=“2000 - 2008”

• 93

  limit 91 to yr=“2003 - 2008”

Ovid-CDSR

• 1

  (diet or diets or dietetic or dietary or eating or intake or nutrient$ or nutrition or vegetarian$ or vegan$ or “seventh day adventist” or macrobiotic or breastfeed$ or breast feed$ or breastfed or breast fed or breastmilk or breast milk).ti,ab.

• 2

  (food$ or cereal$ or grain$ or granary or wholegrain or wholewheat or roots or plantain$ or tuber or tubers or vegetable$ or fruit$ or pulses or beans or lentils or chickpeas or legume$ or soy or soya or nut or nuts or peanut$ or groundnut$ or seeds or meat or beef or pork or lamb or poultry or chicken or turkey or duck or fish or fat or fats or fatty or egg or eggs or bread or oils or shellfish or seafood or sugar or syrup or dairy or milk or herbs or spices or chilli or chillis or pepper$ or condiments).ti,ab.

• 3

  (fluid intake or water or drinks or drinking or tea or coffee or caffeine or juice or beer or spirits or liquor or wine or alcohol or alcoholic or beverage$ or ethanol or yerba mate or ilex paraguariensis).ti,ab.

• 4

  (pesticide$ or herbicide$ or DDT or fertiliser$ or fertilizer$ or organic or contaminants or contaminate$ or veterinary drug$ or polychlorinated dibenzofuran$ or PCDF$ or polychlorinated dibenzodioxin$ or PCDD$ or polychlorinated biphenyl$ or PCB$ or cadmium or arsenic or chlorinated hydrocarbon$ or microbial contamination$).ti,ab.

• 5

  (mycotoxin$ or aflatoxin$ or pickled or bottled or bottling or canned or canning or vacuum pack$ or refrigerate$ or refrigeration or cured or smoked or preserved or preservatives or nitrosamine or hydrogenation or fortified or additive$ or colouring$ or coloring$ or flavouring$ or flavoring$ or nitrates or nitrites or solvent or solvents or ferment$ or processed or antioxidant$ or genetic modif$ or genetically modif$ or vinyl chloride or packaging or labelling or phthalates).ti,ab.

• 6

  (cooking or cooked or grill or grilled or fried or fry or roast or bake or baked or stewing or stewed or casserol$ or broil or broiled or boiled or microwave or microwaved or re-heating or reheating or heating or re-heated or heated or poach or poached or steamed or barbecue$ or chargrill$ or heterocyclic amines or polycyclic aromatic hydrocarbons).ti,ab.

• 7

  (salt or salting or salted or fiber or fibre or polysaccharide$ or starch or starchy or carbohydrate$ or lipid$ or linoleic acid$ or sterols or stanols or sugar$ or sweetener$ or saccharin$ or aspartame or acesulfame or cyclamates or maltose or mannitol or sorbitol or sucrose or xylitol or cholesterol or protein or proteins or hydrogenated dietary oils or hydrogenated lard or hydrogenated oils).ti,ab.

• 8

  (supplements or supplement or vitamin$ or retinol or carotenoid$ or tocopherol or folate$ or folic acid or methionine or riboflavin or thiamine or niacin or pyridoxine or cobalamin or mineral$ or sodium or iron or calcium or selenium or iodine or magnesium or potassium or zinc or copper or phosphorus or manganese or chromium or phytochemical or allium or isothiocyanate$ or glucosinolate$ or indoles or polyphenol$ or phytoestrogen$ or genistein or saponin$ or coumarin$).ti,ab.

• 9

  (recreational activit$ or household activit$ or occupational activit$ or physical activit$ or physical inactivit$ or exercise or exercising or energy intake or energy expenditure or energy balance or energy density).ti,ab.

• 10

  (weight loss or weight gain or anthropometry or birth weight or birthweight or birth-weight or child development or height or body composition or body mass or BMI or obesity or obese or overweight or over-weight or over weight or skinfold measurement$ or skinfold thickness or DEXA or bio-impedence or waist circumference or hip circumference or waist hip ratio$).ti,ab.

• 11

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 12

  or/1–10

• 13

  11 and 12

Ovid-CDSR

• 1

  chemoprevention.ti.

• 2

  (surveillance or screening).ti.

• 3

  (prophylactic or preventive or risk reduc$).ti.

• 4

  medical consultation.ti.

• 5

  (health adj3 consultation).ti.

• 6

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$)).ti,ab.

• 7

  self exam$.ti.

• 8

  mammog$.ti.

• 9

  risk reduction mastectomy.ti.

• 10

  ((prophylactic or preventive or risk reduc$) adj3 (mastectomy or oophorectomy or ovariectomy)).tw.

• 11

  ((magnetic resonance imaging or mri) adj3 breast).ti.

• 12

  breast exam$.ti.

• 13

  (ovarian adj3 screening).ti.

• 14

  (tamoxifen or raloxifene or toremifene or fareston).ti.

• 15

  (breast adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 16

  (ovar$ adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 17

  (Fenretinide or Finasteride or proscar).ti.

• 18

  fareston.ti.

• 19

  (avodart or dutasteride).ti.

• 20

  (psa adj3 test$).ti.

• 21

  prostate specific antigen.ti.

• 22

  (prostat$ adj3 (cancer$ or neoplasm$ or carcinom$)).ti.

• 23

  f?ecal occult blood test$.ti.

• 24

  (FOBT or fob test$).ti.

• 25

  hrt.ti.

• 26

  NSAID?.ti.

• 27

  (nonsteroidal adj3 inflammatory).ti.

• 28

  HMG-CoA reductase inhibitors.ti.

• 29

  statins.ti.

• 30

  ((colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$)).ti,ab.

• 31

  or/1–5

• 32

  or/7–14

• 33

  or/15–16

• 34

  or/17–21

• 35

  or/23–29

• 36

  6 and 31

• 37

  33 and 32

• 38

  22 and 34

• 39

  35 and 30

• 40

  or/36–39

Ovid-Medline

• 1

  family history.ab.

• 2

  Genetic Predisposition to Disease/

• 3

  BRCA$.ti.

• 4

  (relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk).ti.

• 5

  exp Genetic Services/

• 6

  genes, brca1/ or genes, brca2/

• 7

  or/1–6

• 8

  exp breast neoplasms/ or exp colorectal neoplasms/ or exp ovarian neoplasms/ or exp prostatic neoplasms/

• 9

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 10

  *Neoplasms/

• 11

  or/8–10

• 12

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (factors or behavio?r$ or intention or increase or change or impact)).ti.

• 13

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (mammography or test$ or screen$ or exercise or physical activity or diet or food or smoking or alcohol or utili?ation or “use”)).ti.

• 14

  ((factors or behavio?r$ or intention or increase or change or impact or risk) adj8 (mammography or test$ or screen$ or exercise or physical activity or diet or food or smoking or alcohol or utili?ation or “use”)).ti.

• 15

  (uptake or motivation or compliance or adherence or seeking or practices or patterns).ti.

• 16

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (change? or impact? or modification? or influence or risk)).ti.

• 17

  ((after or following or “because of” or “due to” or “result of”) adj9 (genetic test$ or genetic counsel?ing or genetic screening)).ti.

• 18

  ((after or following or “because of” or “due to” or “result of”) adj9 (mutation test$ or mutation screen$)).ti.

• 19

  exp Health Behavior/

• 20

  risk reduction behavior/

• 21

  or/12–20

• 22

  7 and 11 and 21

• 23

  animals/ not (humans/ and animals/)

• 24

  22 not 23

• 25

  limit 24 to english language

• 26

  (note or comment or editorial).pt.

• 27

  25 not 26

• 28

  limit 27 to yr=“1990 - 2008”

Ovid-EMBASE

• 1

  exp health behavior/

• 2

  behavior change/

• 3

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (factors or behavio?r$ or intention or increase or change or impact)).ti.

• 4

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (mammography or test$ or screen$ or exercise or physical activity or diet or food or smoking or alcohol or utili?ation or “use”)).ti.

• 5

  ((factors or behavio?r$ or intention or increase or change or impact or risk) adj8 (mammography or test$ or screen$ or exercise or physical activity or diet or food or smoking or alcohol or utili?ation or “use”)).ti.

• 6

  (uptake or motivation or compliance or adherence or seeking or practices or patterns).ti.

• 7

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (change? or impact? or modification? or influence or risk)).ti.

• 8

  ((after or following or “because of” or “due to” or “result of”) adj9 (genetic test$ or genetic counsel?ing or genetic screening)).ti.

• 9

  ((after or following or “because of” or “due to” or “result of”) adj9 (mutation test$ or mutation screen$)).ti.

• 10

  or/1–9

• 11

  Familial Cancer/

• 12

  exp Breast Cancer/

• 13

  exp Colon Cancer/

• 14

  exp Ovary Cancer/

• 15

  exp Prostate Cancer/

• 16

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 17

  *Cancer/

• 18

  or/11–17

• 19

  genetic predisposition/ or genetic susceptibility/

• 20

  family history/

• 21

  (relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk).ti.

• 22

  exp genetic service/

• 23

  brca1 protein/ or brca2 protein/

• 24

  family history.ab.

• 25

  Familial Cancer/

• 26

  BRCA$.ti.

• 27

  or/19–26

• 28

  10 and 18 and 27

• 29

  limit 28 to human

• 30

  limit 29 to english language

• 31

  (note or editorial).pt.

• 32

  30 not 31

• 33

  limit 32 to yr=“1990 - 2008”

Ovid-CCRT

• 1

  family history.ab.

• 2

  Genetic Predisposition to Disease/

• 3

  BRCA$.ti.

• 4

  (relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk).ti.

• 5

  exp Genetic Services/

• 6

  genes, brca1/ or genes, brca2/

• 7

  or/1–6

• 8

  exp breast neoplasms/ or exp colorectal neoplasms/ or exp ovarian neoplasms/ or exp prostatic neoplasms/

• 9

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 10

  *Neoplasms/

• 11

  or/8–10

• 12

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (factors or behavio?r$ or intention or increase or change or impact)).ti.

• 13

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (mammography or test$ or screen$ or exercise or physical activity or diet or food or smoking or alcohol or utili?ation or “use”)).ti.

• 14

  ((factors or behavio?r$ or intention or increase or change or impact or risk) adj8 (mammography or test$ or screen$ or exercise or physical activity or diet or food or smoking or alcohol or utili?ation or “use”)).ti.

• 15

  (uptake or motivation or compliance or adherence or seeking or practices or patterns).ti.

• 16

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (change? or impact? or modification? or influence or risk)).ti.

• 17

  ((after or following or “because of” or “due to” or “result of”) adj9 (genetic test$ or genetic counsel?ing or genetic screening)).ti.

• 18

  ((after or following or “because of” or “due to” or “result of”) adj9 (mutation test$ or mutation screen$)).ti.

• 19

  exp Health Behavior/

• 20

  risk reduction behavior/

• 21

  or/12–20

• 22

  7 and 11 and 21

• 23

  limit 22 to yr=“1990 - 2008”

Ovid-CINAHL

• 1

  health behavior/ or patient compliance/ or medication compliance/ or treatment refusal/ or help seeking behavior/

• 2

  Behavioral Changes/

• 3

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (factors or behavio?r$ or intention or increase or change or impact)).ti.

• 4

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (mammography or test$ or screen$ or exercise or physical activity or diet or food or smoking or alcohol or utili?ation or “use”)).ti.

• 5

  ((factors or behavio?r$ or intention or increase or change or impact or risk) adj8 (mammography or test$ or screen$ or exercise or physical activity or diet or food or smoking or alcohol or utili?ation or “use”)).ti.

• 6

  (uptake or motivation or compliance or adherence or seeking or practices or patterns).ti.

• 7

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (change? or impact? or modification? or influence or risk)).ti.

• 8

  ((after or following or “because of” or “due to” or “result of”) adj9 (genetic test$ or genetic counsel?ing or genetic screening)).ti.

• 9

  ((after or following or “because of” or “due to” or “result of”) adj9 (mutation test$ or mutation screen$)).ti.

• 10

  attitude to change/ or attitude to risk/

• 11

  or/1–10

• 12

  exp Breast Neoplasms/

• 13

  exp Colorectal Neoplasms/

• 14

  exp Ovarian Neoplasms/

• 15

  exp Prostatic Neoplasms/

• 16

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 17

  *Neoplasms/pc “Prevention and Control”

• 18

  or/12–17

• 19

  Genetic Screening/ or Genetic Counseling/

• 20

  Family History/

• 21

  (relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk).ti.

• 22

  Genes, BRCA/

• 23

  family history.ab.

• 24

  BRCA$.ti.

• 25

  or/19–24

• 26

  11 and 18 and 25

• 27

  limit 26 to english

• 28

  limit 27 to yr=“1990 - 2008”

Ovid-PsycINFO

• 1

  health behavior/

• 2

  lifestyle changes/ or behavior change/ or health promotion/ or readiness to change/

• 3

  preventive medicine/ or health promotion/

• 4

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (factors or behavio?r$ or intention or increase or change or impact)).ti.

• 5

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (mammography or test$ or screen$ or exercise or physical activity or diet or food or smoking or alcohol or utili?ation or “use”)).ti.

• 6

  ((factors or behavio?r$ or intention or increase or change or impact or risk) adj8 (mammography or test$ or screen$ or exercise or physical activity or diet or food or smoking or alcohol or utili?ation or “use”)).ti.

• 7

  (uptake or motivation or compliance or adherence or seeking or practices or patterns).ti.

• 8

  ((relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk) adj8 (change? or impact? or modification? or influence or risk)).ti.

• 9

  ((after or following or “because of” or “due to” or “result of”) adj9 (genetic test$ or genetic counsel?ing or genetic screening)).ti.

• 10

  ((after or following or “because of” or “due to” or “result of”) adj9 (mutation test$ or mutation screen$)).ti.

• 11

  risk management/

• 12

  or/1–11

• 13

  at risk populations/ or predisposition/ or “susceptibility (disorders)”/

• 14

  family history.ab.

• 15

  genetics/ or mutations/

• 16

  (relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk).ti.

• 17

  genetic testing/ or genetic counseling/

• 18

  BRCA$.ti.

• 19

  or/13–18

• 20

  breast neoplasms/

• 21

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 22

  *neoplasms/

• 23

  or/20–22

• 24

  12 and 19 and 23

• 25

  limit 24 to human

• 26

  limit 25 to english language

• 27

  limit 26 to yr=“1990 - 2008”

Ovid-MEDLINE

• 1

  family history.ab.

• 2

  Genetic Predisposition to Disease/

• 3

  BRCA$.ti.

• 4

  (relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk).ti.

• 5

  exp Genetic Services/

• 6

  genes, brca1/ or genes, brca2/

• 7

  or/1–6

• 8

  exp breast neoplasms/ or exp colorectal neoplasms/ or exp ovarian neoplasms/ or exp prostatic neoplasms/

• 9

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 10

  *Neoplasms/

• 11

  or/8–10

• 12

  anxiety/ or fear/

• 13

  depression/ or stress, psychological/

• 14

  ((worry or anxiety or depression or distress or coping or fear) and cancer).ti.

• 15

  ((psychological or psychosocial) and cancer).ti.

• 16

  (perception and cancer).ti.

• 17

  (impact and cancer).ti.

• 18

  family relations/

• 19

  ((insurance or employment) and cancer).ti.

• 20

  insurance/ or exp insurance, health/

• 21

  insurance.ti.

• 22

  (prejudice or discrimination).ti.

• 23

  (harm? or fatalism).tw.

• 24

  or/12–23

• 25

  employment/ or workplace/

• 26

  prejudice/

• 27

  24 or 26

• 28

  7 and 11 and 27

• 29

  animals/ not (humans/ and animals/)

• 30

  28 not 29

• 31

  (note or comment or editorial).pt.

• 32

  30 not 31

• 33

  limit 32 to english language

• 34

  limit 33 to yr=“1990 - 2008”

Ovid-EMBASE

• 1

  emotional stress/ or family stress/ or interpersonal stress/

• 2

  fear/ or anxiety/

• 3

  exp Depression/

• 4

  ((worry or anxiety or depression or distress or coping or fear) and cancer).ti.

• 5

  ((psychological or psychosocial) and cancer).ti.

• 6

  (perception and cancer).ti.

• 7

  (impact and cancer).ti.

• 8

  family relation/

• 9

  family stress/

• 10

  CANCER FAMILY/

• 11

  ((insurance or employment) and cancer).ti.

• 12

  exp health insurance/

• 13

  insurance/ or exp insurance, health/

• 14

  (prejudice or discrimination).ti.

• 15

  (harm? or fatalism).tw.

• 16

  employment discrimination/

• 17

  or/2–16

• 18

  Familial Cancer/

• 19

  exp Breast Cancer/

• 20

  exp Colon Cancer/

• 21

  exp Ovary Cancer/

• 22

  exp Prostate Cancer/

• 23

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 24

  *Cancer/

• 25

  or/18–24

• 26

  genetic predisposition/ or genetic susceptibility/

• 27

  family history/

• 28

  (relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk).ti.

• 29

  exp genetic service/

• 30

  brca1 protein/ or brca2 protein/

• 31

  family history.ab.

• 32

  Familial Cancer/

• 33

  BRCA$.ti.

• 34

  or/26–33

• 35

  17 and 25 and 34

• 36

  limit 35 to human

• 37

  (note or comment or editorial).pt.

• 38

  36 not 37

• 39

  limit 38 to english language

• 40

  limit 39 to yr=“1990 - 2008”

OVID-CCRT

• 1

  family history.ab.

• 2

  Genetic Predisposition to Disease/

• 3

  BRCA$.ti.

• 4

  (relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk).ti.

• 5

  exp Genetic Services/

• 6

  genes, brca1/ or genes, brca2/

• 7

  or/1–6

• 8

  exp breast neoplasms/ or exp colorectal neoplasms/ or exp ovarian neoplasms/ or exp prostatic neoplasms/

• 9

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 10

  *Neoplasms/

• 11

  or/8–10

• 12

  anxiety/ or fear/

• 13

  depression/ or stress, psychological/

• 14

  ((worry or anxiety or depression or distress or coping or fear) and cancer).ti.

• 15

  ((psychological or psychosocial) and cancer).ti.

• 16

  (perception and cancer).ti.

• 17

  (impact and cancer).ti.

• 18

  family relations/

• 19

  ((insurance or employment) and cancer).ti.

• 20

  insurance/ or exp insurance, health/

• 21

  insurance.ti.

• 22

  (prejudice or discrimination).ti.

• 23

  (harm? or fatalism).tw.

• 24

  or/12–23

• 25

  employment/ or workplace/

• 26

  prejudice/

• 27

  24 or 26

• 28

  7 and 11 and 27

• 29

  limit 28 to yr=“1990 - 2008”

Ovid-CINAHL

• 1

  exp Breast Neoplasms/

• 2

  exp Colorectal Neoplasms/

• 3

  exp Ovarian Neoplasms/

• 4

  exp Prostatic Neoplasms/

• 5

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 6

  *Neoplasms/pc “Prevention and Control”

• 7

  or/1–6

• 8

  Genetic Screening/ or Genetic Counseling/

• 9

  Family History/

• 10

  (relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk).ti.

• 11

  Genes, BRCA/

• 12

  family history.ab.

• 13

  BRCA$.ti.

• 14

  or/8–13

• 15

  exp Coping/

• 16

  exp “Psychosocial Aspects of Illness”/

• 17

  stress/ or stress, psychological/

• 18

  anxiety/ or depression/

• 19

  Fear/

• 20

  ((worry or anxiety or depression or distress or coping or fear) and cancer).ti.

• 21

  ((psychological or psychosocial) and cancer).ti.

• 22

  (perception and cancer).ti.

• 23

  (impact and cancer).ti.

• 24

  family functioning/ or family coping/ or family relations/

• 25

  ((insurance or employment) and cancer).ti.

• 26

  insurance coverage/ or insurance, health/

• 27

  Discrimination, Employment/

• 28

  (prejudice or discrimination).ti.

• 29

  (harm? or fatalism).tw.

• 30

  or/15–29

• 31

  7 and 14 and 30

• 32

  limit 31 to english

• 33

  limit 32 to yr=“1990 - 2008”

Ovid-PsycINFO

• 1

  coping behavior/ or hopelessness/

• 2

  anxiety/

• 3

  psychological stress/

• 4

  emotional states/ or “depression (emotion)”/

• 5

  fear/

• 6

  ((worry or anxiety or depression or distress or coping or fear) and cancer).ti.

• 7

  ((psychological or psychosocial) and cancer).ti.

• 8

  (perception and cancer).ti.

• 9

  (impact and cancer).ti.

• 10

  distress/

• 11

  family relations/ or interpersonal relationships/

• 12

  emotional adjustment/ or coping behavior/

• 13

  emotional adjustment/

• 14

  or/1–13

• 15

  at risk populations/ or predisposition/ or “susceptibility (disorders)”/

• 16

  family history.ab.

• 17

  genetics/ or mutations/

• 18

  (relative? or genetic or heredit$ or famil$ or inherit$ or high$ risk or “at risk” or increased risk).ti.

• 19

  genetic testing/ or genetic counseling/

• 20

  BRCA$.ti.

• 21

  or/15–20

• 22

  breast neoplasms/

• 23

  ((breast or ovar$ or prostate or colon or colorectal) adj3 (cancer$ or neoplasm$ or carcinom$ or tumo?r$)).ti,ab.

• 24

  *neoplasms/

• 25

  or/22–24

• 26

  14 and 21 and 25

• 27

  limit 26 to human

• 28

  limit 27 to english language

• 29

  limit 28 to yr=“1990 - 2008”