Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Symptoms and General Pathology

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Digestive System Diseases

Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Rare Diseases

Breast Neoplasms

Syndrome

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Peutz-Jeghers Syndrome

Li-Fraumeni Syndrome

Hamartoma Syndrome, Multiple

Carcinoma

Endocrine Gland Neoplasms

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Endocrine System Diseases

Gonadal Disorders

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Ovarian Cancer

Ovarian Epithelial Cancer

Cowden Syndrome

Bannayan-Riley-Ruvalcaba Syndrome

Individuals and families with known or suspected syndromes that include breast, ovarian or genetically-related cancers are enrolled in this family study.

Sharon A Savage, M.D.

Individuals and families with known or suspected syndromes that include breast, ovarian or genetically-related cancers are enrolled in this family study, which is a syndrome-specific sub-set of the long-standing DCEG Human Genetics Program umbrella family studies protocol (78-C-0039). Cancer outcomes are documented through review of medical, vital, and pathology records. Selected individuals and family members are asked to complete questionnaires to assess etiologic risk factors and to undergo clinical evaluations specifically tailored to the relevant familial syndrome. Study participants are monitored prospectively for the development of outcomes of interest, typically by means of periodic mail or telephone contact. In selected instances, subjects may return to the Clinical Center periodically for study-specific follow-up examinations. Study participants are asked to donate biologic specimens to be used in the laboratory search for cancer etiology and mechanisms of carcinogenesis. DNA and serial serum samples will be collected. Tumor tissue will be obtained whenever feasible.

Clinical genetic testing for tumor susceptibility gene(s) mutations and risk notification will be offered consistent with ASCO guidelines when reasonable individual cancer risk estimates can be delivered, and only to those participants who choose to know their individual genetic status after appropriate education and counseling. The testing will be conducted exclusively in Clinical Laboratory Improvement Amendments (CLIA)-licensed laboratories. Clinical genetic testing and risk notification are entirely optional and do not affect subject eligibility for other aspects of the protocol. A separate consent procedure and consent form will be used for genetic testing and risk notification.

This protocol, developed in response to recommendations developed by the Clinical Center IRB, is intended to:

1. Provide a mechanism under which the Clinical Genetics Branch can honor the commitment made to the members of over 60 hereditary breast/ovarian cancer families which have been participated in various Human Genetics Program research studies conducted over the past 3 decades to provide genetic counseling,

   clinical germline mutation testing, and consultative services now that several of the major breast/ovarian cancer susceptibility genes have been identified;
2. Provide a mechanism through which new families with various familial syndromes associated with an increased risk of breast and ovarian cancer can be studied, as research interests in these syndromes evolve over time; and
3. Create a resource of well-characterized, carefully documented high-risk families to facilitate the development of new etiologic and translational research studies in the future.

While we do not offer specific anti-cancer therapy as part of this protocol, we provide assistance to ensure that study participants who require treatment for problems that develop during the course of the study are referred to appropriate health providers. We

remain available to provide advice and consultation related to the management of the familial cancer syndrome to study participants and their health care providers.

Individuals and families with known or suspected syndromes that include breast, ovarian or genetically-related cancers are enrolled in this family study, which is a syndrome-specific sub-set of the long-standing DCEG Human Genetics Program umbrella family studies protocol (78-C-0039). Cancer outcomes are documented through review of medical, vital, and pathology records. Selected individuals and family members are asked to complete questionnaires to assess etiologic risk factors and to undergo clinical evaluations specifically tailored to the relevant familial syndrome. Study participants are monitored prospectively for the development of outcomes of interest, typically by means of periodic mail or telephone contact. In selected instances, subjects may return to the Clinical Center periodically for study-specific follow-up examinations. Study participants are asked to donate biologic specimens to be used in the laboratory search for cancer etiology and mechanisms of carcinogenesis. DNA and serial serum samples will be collected. Tumor tissue will be obtained whenever feasible.

Clinical genetic testing for tumor susceptibility gene(s) mutations and risk notification will be offered consistent with ASCO guidelines when reasonable individual cancer risk estimates can be delivered, and only to those participants who choose to know their individual genetic status after appropriate education and counseling. The testing will be conducted exclusively in Clinical Laboratory Improvement Amendments (CLIA)-licensed laboratories. Clinical genetic testing and risk notification are entirely optional and do not affect subject eligibility for other aspects of the protocol. A separate consent procedure and consent form will be used for genetic testing and risk notification.

This protocol, developed in response to recommendations developed by the Clinical Center IRB, is intended to:

1. Provide a mechanism under which the Clinical Genetics Branch can honor the commitment made to the members of over 60 hereditary breast/ovarian cancer families which have been participated in various Human Genetics Program research studies conducted over the past 3 decades to provide genetic counseling, clinical germline mutation testing, and consultative services now that several of the major breast/ovarian cancer susceptibility genes have been identified;
2. Provide a mechanism through which new families with various familial syndromes associated with an increased risk of breast and ovarian cancer can be studied, as research interests in these syndromes evolve over time; and
3. Create a resource of well-characterized, carefully documented high-risk families to facilitate the development of new etiologic and translational research studies in the future.

While we do not offer specific anti-cancer therapy as part of this protocol, we provide assistance to ensure that study participants who require treatment for problems that develop during the course of the study are referred to appropriate health providers. We remain available to provide advice and consultation related to the management of the familial cancer syndrome to study participants and their health care providers.

Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer

To ascertain individuals and families at high risk of breast, ovarian andother syndromically related cancers due to known or suspected genetic factor(s) which predispose to neoplasia in order to:- Evaluate and define the clinical spectrum and natural history of disease in syndromes predisposing to familial breast/ovarian cancer;- Develop a resource of epidemiologic, clinical, behavioral and genetic information on individuals and families predisposed to familial breast/ovarian cancer; - Track and validate cancer occurrence and other clinical outcomes in members of these highrisk kindreds;- Create a biospecimen repository which will facilitate exploratory,etiologically-focused laboratory studies;- Evaluate potential precursor states of neoplastic disease in families atrisk of breast and ovarian cancer;- Quantify the risk of specific tumors in family members;- Map, clone, and determine the function of novel tumor susceptibilitygenes

Identify genetic determinants, and genetic and environmental modifiers of cancer risk in individuals and families predisposed tobreast/ovarian cancer; and- Evaluate gene-gene and gene-environment interactions in thepathogenesis of familial breast/ovarian cancer.

National Cancer Institute (NCI)

Breast Diseases

Skin Diseases

All familial breast cancer risk assessment services in England

Survey Administration

Some women are more likely to get breast cancer as it runs in their family, they are at risk of familial breast cancer. There are medications, called chemoprevention, which may lower their risk of developing breast cancer by a third. However chemoprevention can also cause serious side effects, like womb cancer and blood clots. This makes decision to start them difficult. Researchers found that not all women who can have these medications are on them.

The investigators want to ask familial breast cancer specialists whether they recommend general practitioners (GP) to prescribe chemoprevention, by sending them a short survey. These specialists look after women where breast cancer runs in the family. The specialists assess a women's chance of getting breast cancer and advice those with increased risk what can be done to prevent breast cancer.

The investigators will then look at whether specialist recommendation makes a difference to whether GPs prescribe chemoprevention medication. This will be done by linking the specialists' survey response to information on GP prescribing that the government regularly publishes. This may help the investigators understand why chemoprevention is not used as often as it potentially can be.

Phase I: Short survey of lead clinicians of familial cancer services, descriptive analysis of recommendations by areas of the country

Phase II: Prescribing data analysis (using OpenPrescribing) comprising:

1. t-test to compare the chemoprevention prescribing rate in general practices where chemoprevention is recommended versus not recommended;
2. interrupted times series analysis to assess the change in the chemoprevention prescribing after recommendation from specialist compared with changes occurring in practices where chemoprevention is not recommended and
3. panel regression across all practices, in order to distinguish the relative impacts of national versus local recommendation, and the change over time.

Specialist Recommendation on FBC (Familial Breast Cancer) Chemoprevention Prescribing

Impact of Familial Cancer Specialist Recommendation on Chemoprevention Prescribing for Familial Breast Cancer (FBC) Risk in Primary Care: Short Survey and Interrupted Time Series Analysis

Prescribing analysis code and raw data (of publicly available, anonymised, primary care prescribing data) will be made freely available alongside publication of results.

Proportion of specialist service that recommends chemoprevention prescribing by areas in England, measured using survey questionnaire

2.1. The chemoprevention prescribing rate in general practices where chemoprevention is recommended versus not recommended. The rate will be measured as the number of average daily quantities (ADQs) of chemoprevention prescribed per 1000 registered female patients aged between 35 and 74 per practice. For our primary outcome we will measure only tamoxifen items, and assess other therapies used in chemoprevention in supplementary analyses.

2.2. The change in chemoprevention prescribing rate (described in outcome 2.1) in general practices after recommendation from local specialist, compared with changes occurring in practices where chemoprevention is not recommended.

2.3. The relative change in the chemoprevention prescribing rate (described in outcome 2.1) in general practice in response to local recommendation, compared with change occurring in response to national recommendation.

University of Oxford

University of Nottingham

Supportive-Expressive Group Therapy

Mary Jane Esplen, PhD

One in 10 Canadian women will be diagnosed with breast cancer (BC) and approximately 5% of all BC is believed to be hereditary. Women with a family history experience high levels of perceived risk for developing BC. Elevated risk perceptions for BC have been associated with psychological distress, which, in turn, can interfere with screening adherence. In our completed CBCRI-funded study, we developed and standardized a group intervention designed to address the psychological issues associated with having a family history of BC. Results demonstrated that the intervention led to significant improvement in levels of anxiety and depression, improved BC risk factors/genetics knowledge and was associated with optimal screening behavior. The proposed study will rigorously test the group intervention in comparison to standard risk counselling in a sample of 150 women recruited from Familial BC clinics in Toronto. The interventions will be examined for their impact on a) psychological functioning, b) BC risk/genetic knowledge and c) screening behaviors.

Keywords: Breast cancer, genetics, psychotherapy, group counselling, randomized control trial, risk counselling, women's mental health, familial breast cancer.

One in 10 Canadian women will be diagnosed with breast cancer (BC) and approximately 5% of all BC is believed to be hereditary. Women with a family history of BC experience high levels of perceived risk and vulnerability for developing BC. Elevated risk perceptions for BC are difficult to modify and have been associated with psychological distress that, in turn, can interfere with screening adherence. The specific objectives of the current randomized trial are to determine the effects of a supportive-expressive group intervention on a) psychosocial functioning (using standardized instruments), b) BC risk/genetic knowledge and c) screening behaviors in women with a family history of breast cancer receiving standard genetic risk counseling. Preliminary data will be collected to examine the cost effectiveness of the intervention.

The study is being conducted in the following University of Toronto affiliated teaching hospitals: Mount Sinai Hospital; Preventive Oncology Program, Sunnybrook and Women's College Health Sciences; Toronto Sunnybrook Regional Cancer Centre; University Health Network; North York General Hospital; Credit Valley Hospital. A total of 150 women with a family history of BC will be randomized in a ratio of 2 to 1 to participate in an 8 weekly/ 4 monthly support group or to a control arm that receives educational materials.

The study has been funded by the Canadian Breast Cancer Research Initiative (CBCRI) of the National Cancer Institute of Canada since 2001. To date 66 women have been enrolled in the study and we anticipate a total of 90 women will be enrolled by the end of the current funding year in June 2004. At this rate it is expected that recruitment will be completed in June 2005, the last intervention groups will be completed by January 2006 and that analysis of the final study results will be completed by June 2006. Analysis of baseline data will begin in September 2005 once the last study groups have been initiated and a manuscript reporting the final results will be prepared by June 2006. Two years of funding is requested for these activities.

Significance: Technological advances in molecular biology and genetics are occurring rapidly. Our proposed research has direct relevance for advancing knowledge on the communication and provision of risk/genetic information to individuals with a family history of BC and has both direct and indirect relevance to individuals at all stages of cancer. Improved counselling techniques for those with a family history may impact on the prevention and management of BC through improved surveillance and preventive techniques, enhanced psychosocial functioning and wellbeing through increased psychological resilience. In addition, effective risk counselling interventions may facilitate the understanding of and decision-making around genetic testing, and the adjustment to a cancer diagnosis, should these women with family histories later develop the disease.

RCT of a Group Intervention for Women With a Family History of Breast Cancer

A Randomized Controlled Trial of a Group Intervention for Women With a Family History of Breast Cancer

Canadian Breast Cancer Research Alliance

Canadian Cancer Trials Group

University Health Network, Toronto

Dr. Mary Jane Esplen

Hereditary Breast and Ovarian Cancer Syndrome

Colorectal Neoplasms

Colorectal Neoplasms, Hereditary Nonpolyposis

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Neoplastic Syndromes, Hereditary

Genetic Diseases, Inborn

DNA Repair-Deficiency Disorders

Metabolic Diseases

Familial Colorectal Cancer

Genetic counseling according to current clinical practice

Genetic counseling according to current clinical practice with the addition of an offer from health care provider to mail letters directly to eligible at-risk relatives.

At counseling, eligible at-risk relatives (who may benefit from disclosure of risk information) are listed on a specified protocol in collaboration between health care provider and the participant.

Standard care encouraging family-mediated disclosure of hereditary cancer risk

The participant is offered that the health care provider at the cancer genetic unit mail a direct letter with personalized family risk information to all at-risk relatives that participant approve contact with.

Offer of health-care assisted disclosure by sending direct letters to at-risk relatives

This study evaluates if uptake of genetic counselling in high-risk families is increased when patients at cancer genetics clinics are being offered healthcare-assisted disclosure to at-risk relatives compared to current standard care (with family-mediated disclosure).

Patients/families who have undergone a cancer genetic investigation will be invited to participate in the study. All participants will receive standard care. Half of them will in addition be offered a healthcare-assisted disclosure with the service of direct letters to identified at-risk relatives distributed by the healthcare provider. After a year we will compare the proportion of at-risk relatives who have contacted a cancer genetic clinics in each study arm.

(When the formal study protocol is published, this section will instead refer to the published study protocol).

This study is a multi-centre open label, prospective, randomized controlled superiority trial comparing an intervention of healthcare-assisted disclosure with standard care of family-mediated disclosure of hereditary cancer risk information in high-risk families in Sweden.

SUBJECTS AND METHODS

Patients/families will be enrolled and allocated in parallel to intervention or standard care.

All participants receive standard genetic counseling and information summarizing the results of their family investigation. They are informed about preventive measures when applicable, and are encouraged to inform their at-risk relatives (t=0 months).

The intervention component is the addition of a healthcare-assisted disclosure procedure. Participants in the intervention arm will be offered the service of sending letters directly to their at-risk relatives.

If the participant approves the offer, letters will be sent to eligible at-risk relatives deemed to be recommended genetic counseling within a year.

The direct letter will inform the at-risk relative that a cancer genetic investigation has been conducted in the family and the implications for him or her, and their blood relatives.

To facilitate access to further information, contact details to the closest cancer genetics unit are included in the letter. The letters are sent with registered mail in neutral envelopes which means that recipients will have to show proof of identity to retrieve the letter from their local delivery service provider.

METHODS FOR ASSESSMENT OF STUDY OUTCOMES

For participants in both study arms, contact details of the at-risk relatives are identified in collaboration between health care provider and the participant. The health care provider records the name, approximate or exact year of birth and postal address of each at-risk relative for follow-up.

At the time of follow-up (t=12 months) the research nurse will check whether the relatives, listed one year before, have contacted a Swedish cancer genetic unit. Primary outcome data is retrieved from the patient data registries at each clinic. The research nurse will also record additional data points from CRFs, enabling analysis of the other pre-specified outcome measures in the intervention arm.

The outcome data are reported back to the national study secretariat as plain numbers without any personal details of the at-risk relatives.

SAMPLE SIZE AND STATISTICAL METHODS

For sample size calculation and statistical methods, see attached documents.

INTERNAL PILOT, AUDIT and PROGRESS CRITERIA

As this protocol has never been tested in Swedish clinical practice an internal pilot phase is included in the outline of the project.

Progress criteria at each study site are evaluated at internal pilot point and thereafter at formal audit at least yearly. Internal pilot point is set to the time when 20 individuals in total (across the 3 pilot study sites) have been included and treated according to protocol.

Continuation of the full-powered study at the specific study site will be determined by considering the criteria filled, the potentially necessary amendments, and the degree of which the amendments deviate from the original piloted study protocol.

The outcomes and process criteria are found in the attached document.

Multi-centre, parallel assignment, balanced ratio, investigator-blinded, randomised, controlled superiority trail in Sweden.

Since the intervention in this trial is an offer of sending physical direct letters to at-risk relatives, neither the health care providers nor the study participant can be blinded to the allocation. However, the final data analysis will be performed by a statistician blinded to the study arm allocations and subgroups.

Direct Information to At-risk Relatives

Direct Letters to Relatives at Risk of Hereditary Cancer- a Multi-centre Randomised Controlled Trial of Healthcare-assisted Versus Family-mediated Risk Disclosure at Swedish Cancer Genetics Clinics (DIRECT-study)

Access to aggregated data may be granted upon reasonable request to the principal investigator.

Comparing intervention and control group with respect to proportion of first-degree ARRs who have contacted a Swedish cancer genetics clinic within 12 months of the proband receiving post-test genetic counselling because the proband is a carrier of a pathogenic variant in BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2.

Comparing intervention and control group with respect to proportion of second-degree, third-degree or more distant ARRs who have contacted a Swedish cancer genetics clinic within 12 months of the proband receiving post-test genetic counselling because the proband is a carrier of a pathogenic variant in BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6, PMS2.

Number of potential at-risk relatives that proband allowed contact with, compared to total number of potential at-risk relatives for that specific patient. \[proportion\]

Number of at-risk relatives that proband allowed contact with and where contact data allowed distribution of direct letter, compared to total number of potential at-risk relatives for that specific patient. \[proportion\]

Number of at-risk relatives that proband allowed contact with, contact data was sufficient and the registered letter was collected from the post-office within 12 months, compared to total number of potential at-risk relatives for that specific patient. \[proportion\]

Number of potential at-risk relatives who have contacted a Swedish cancer genetic unit out of the total number of potential at-risk relatives for each patient.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer	NCT00040222	Familial Ovaria... Familial Breast... BRCA1-associate... BRCA2-associate...		18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Specialist Recommendation on FBC (Familial Breast Cancer) Chemoprevention Prescribing	NCT04058418	Familial Breast...	Survey Administ...	-	University of Nottingham
RCT of a Group Intervention for Women With a Family History of Breast Cancer	NCT00150917	Breast Neoplasm...	Supportive-Expr...	18 Years - 70 Years	University Health Network, Toronto
Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer	NCT00040222	Familial Ovaria... Familial Breast... BRCA1-associate... BRCA2-associate...		18 Years - 100 Years	National Institutes of Health Clinical Center (CC)
Direct Information to At-risk Relatives	NCT04197856	Familial Breast... Familial Colore... Hereditary Brea... Hereditary Brea... Lynch Syndrome	Standard care e... Offer of health...	18 Years -	Umeå University
Clinical, Genetic, Behavioral, Laboratory and Epidemiologic Characterization of Individuals and Families at High Risk of Breast/Ovarian Cancer	NCT00040222	Familial Ovaria... Familial Breast... BRCA1-associate... BRCA2-associate...		18 Years - 100 Years	National Institutes of Health Clinical Center (CC)

Spots Global Cancer Trial Database for familial breast cancer