Genetic Education in BRCA Families

Women who carry a pathogenic BRCA variant (PV) have a lifetime breast cancer risk of 55-70%
and a lifetime ovarian cancer risk of 16-45%. Men with a PV are at increased risk for
prostate, pancreatic and breast cancer. BRCA testing typically begins with a family member
(proband) who is affected with cancer. If a PV is identified, probands are encouraged to
communicate this test result with at risk relatives. Unaffected first- and second-degree
relatives (FSDR), who are at 50% and 25% risk for carrying the PV, may then pursue genetic
counseling and testing for the specific variant identified in the proband (targeted testing).
Targeted testing is far less complex and expensive than testing probands and definitively
distinguishes carriers from non-carriers. Such testing allows carriers to reduce their cancer
incidence, morbidity and mortality through risk reduction and screening while non-carriers
can avoid unnecessary medical intervention and their offspring can safely forgo testing.
Despite these well-recognized significant benefits and clear guideline-based recommendations
for genetic counseling and testing, only 28-57% of FSDRs undergo BRCA testing. This low rate
of participation occurs despite high rates of result communication by probands, calling into
question the quality of the information communicated and the accuracy of FSDRs understanding
of the importance of the information. Additional barriers to counseling and testing include:
limited access, lack of referral, time and travel commitment, and lack of proactive clinical
approaches to facilitate uptake.

Remarkably, there have been no randomized trials focused on increasing use of guideline
consistent genetic counseling and targeted testing. Guided by the Informed Choice (ICM) and
Health Belief Models (HBM), the investigators will conduct a randomized controlled trial of
proactive Web-based pre-test education plus streamlined telephone genetic counseling (W+T) vs
usual care (UC) for unaffected FSDRs of PV carriers. Web-based pre-counseling education
followed by streamlined telephone genetic counseling will be proactively delivered. Following
counseling, participants will have the option to proceed directly to targeted testing. By
proactively providing access to accurate genetic information and reducing barriers to genetic
services, W+T is predicted to yield increased uptake of genetic counseling and testing.

Aim 1: Evaluate the impact of web-based intervention plus brief telephone counseling (W+T)
vs. Usual Care (UC) on uptake of genetic counseling and targeted genetic testing.

Aim 2: Evaluate the impact of W+T vs UC on psychosocial outcomes.

Aim 3: Evaluate mechanisms and moderators of W+T.

Research Overview. The aim of this RCT is to evaluate the efficacy of proactively delivered
Web Pre-Test Education plus Streamlined Telephone Counseling (W+T) for first- and
second-degree relatives (FSDRs) of individuals who have recently received a positive BRCA
test result (i.e., probands). The W+T intervention is designed to facilitate access to
genetic education and counseling, foster informed decisions and reduce barriers to targeted
genetic testing. The primary hypotheses are that W+T participants will have increased uptake
of genetic counseling and targeted genetic testing relative to UC participants. Eligible
FSDRs will be contacted for a baseline assessment. One-month following the baseline
assessment, all participating FSDRs will be randomized (by family) to either W+T or UC. FSDRs
will be reassessed at 1- and 6-months post-randomization and probands will be reassessed at
6-months post-randomization to enumerate additional testing in the family.

Identification and Enrollment. Probands will be recruited within the clinical genetics
programs at LCCC and George Washington University (GWU). The genetic counselor will obtain
permission to recontact BRCA probands at the time of their test result disclosure. Three
months following disclosure, eligible probands will be contacted for enrollment. At that time
they will be asked for consent to access their genetic counseling/testing records and provide
the names, addresses, and telephone numbers of all potentially eligible FSDRs. Participating
probands will be asked to inform all potentially eligible FSDRs about the planned study
contact.

After obtaining contact information, potentially eligible FSDRs will be mailed a recruitment
packet (introductory letter, study brochure, informed consent document, opt-out
e-mail/address/telephone number). Two weeks later, a research assistant will call all FSDRs
who have not opted out of the study. The RA will explain the study and answer any questions.
At enrollment participants will be informed that written consent is required prior to
randomization. They will also be informed of the randomization date and that they must
complete their baseline survey before that date in order to participate in the study.

Baseline Assessment. Individuals who remain eligible and interested can complete the 20
minute baseline survey via telephone by a trained RA or electronically. For those who do not
return the consent document prior to the baseline, an RA will use an IRB-approved verbal
consent for telephone baselines or electronic consent for electronic baselines. Written
consent will be required prior to randomization.

Randomization. Following the baseline, participants will be provided with a randomization
date on which they will be contacted with their assignment. Participants will be randomized
by family to avoid contamination. Randomization will take place 1 month after enrollment of
the first FSDR in a family. At that point, FSDRs who have not completed a baseline will be
ineligible for the study. Participants will be informed of the randomization deadline upon
enrollment. On the randomization date, participants will be notified by email or phone,
followed by a priority letter. For W+T participants, this letter will contain log-in
information website instructions. For UC participants, this letter will include a list of
informational resources (including a list of low-cost genetic counseling options).

Interventions.

Usual Care. As part of standard clinical genetic counseling, probands with a BRCA mutation
are provided with an individualized summary letter that includes cancer risks, management
recommendations and options, a family letter that identifies at-risk relatives and encourages
them to share the test result with these relatives. All participants in both arms will
receive these standard materials. As described above, following randomization, UC
participants will be notified of their assignment and will receive a list of informational
resources. Of course, they can pursue standard clinical genetic counseling on their own at
LCCC, GWU or any other program.

The W+T Intervention. The W+T intervention includes: Interactive Pre-Test Web-Education with
direct genetic counseling scheduling; streamlined telephone genetic counseling; and for those
who opt for testing, a telephone genetic counseling disclosure session. The W+T pre-test Web
component is designed to provide comparable information to a traditional genetic counseling
session for an FSDR of a mutation carrier. A detailed description of the content of the W+T
is described in the treatment plan below. Participants will receive an individualized link to
the website that is connected to their email address. They will be able to create their own
password the first time they access the website, and then log back into the website in the
future using their email address and created password. The website has a "forgot password"
option, where participants can create a new password at any time. The study will provide
participants with a toll-free support number to call if they have any questions. After
reviewing the website, participants will be provided with the option to schedule a brief
telephone genetic counseling session with a board-certified genetic counselor. This session
will take approximately 15 minutes and is designed to supplement and reinforce the web-based
information. This session will be provided free of charge. Participants can decline

Genetic Testing. Genetic testing is not required as part of this study. Any participants who
proceed with genetic testing will receive standard clinical testing for their familial
mutation (or more extensive testing when clinically indicated). At the conclusion of the
pre-test telephone counseling session, participants who wish to proceed directly to testing
will have the process for testing explained by the genetic counselor and a test requisition
form (TRF) including insurance information will be completed. Upon completion of the TRF, a
DNA saliva collection kit will be sent via overnight mail to the participant. After
participants collect their DNA, they mail the kit and all included paperwork to the lab in a
pre-paid FedEx pack. Targeted testing will be for the specific PV identified in their family,
and if Ashkenazi Jewish (AJ), also for the 3 BRCA founder mutations. In rare instances
participants may have a particularly complex family history and will be appropriate for
broader multiplex testing. This option will be explained by the genetic counselor during the
telephone session.

Telephone Genetic Counseling Disclosure. Telephone disclosures will be delivered by the same
board certified genetic counselors who provided pretest counseling. Telephone disclosures
will utilize our existing clinical disclosure protocol that includes: result disclosure with
comprehensive interpretation; discussion of cancer risks and management options; implications
for family members; referral to specialists as needed/indicated. Within a week of the
disclosure session, participants will be provided with a copy of their results, pedigree and
an individualized summary letter.

Follow-Up Survey. Participants will be contacted for follow-up surveys at 1-month and
6-months post-randomization. These surveys will be similar to (but shorter than) the baseline
survey.

Inclusion Criteria:

- A first- (sibling, adult offspring) or second-degree (aunt/uncle, niece/nephew if
at-risk parent is deceased) biological relative of an individual with a recently
identified BRCA1 or BRCA2 mutation

Exclusion Criteria:

- Personal diagnosis of metastatic cancer

- Prior genetic testing for hereditary breast/ovarian cancer

- Have one or more children who have tested positive for a BRCA1 or BRCA2 mutation

- Cannot participate in or understand English

- Cannot provide meaningful informed consent