NIH – Traceback Testing: Increasing Identification and Genetic Counseling of Mutation Carriers through Family-based Outreach (U01 Clinical Trial Optional)

February 2, 2018 by School of Medicine Webmaster

Women with pathogenic BRCA1/2 mutations have a 45-65% risk of developing breast cancer and a 11%-59% risk of developing ovarian cancer by age 70 years. The National Comprehensive Cancer Network (NCCN) guidelines recommend genetic counseling for BRCA1/2 mutation testing to all women diagnosed with ovarian cancer. However, opportunities to counsel and test individuals at high-risk of carrying BRCA1/2 mutations are often missed, especially among minority groups. Only ~20% of cancer patients at high-risk of BRCA1/2mutations undergo genetic testing, with lower percentages among women diagnosed with ovarian cancer. This modest uptake of testing likely reflects a lack of referral, access, and follow-through by patients. It is estimated that only 48,700 of over 348,000 women who are BRCA1/2 mutation carriers have been identified, 220,000 of which have not been diagnosed with cancer. These findings highlight missed opportunities for cancer prevention and risk management through breast cancer screening, prophylactic mastectomy and risk-reducing salpingo-oophorectomy.

To address these missed opportunities, NCI developed research questions associated with a “Traceback”-type program to improve detection of families at risk for beast/ovarian cancer by identifying and genetically testing previously diagnosed but un-referred ovarian cancer patients ( Failure to identify mutation carriers among probands represents a lost opportunity to prevent cancer in unsuspecting relatives through risk-reduction intervention in mutation carriers, and provide appropriate reassurances to non-carriers. Traceback leverages limited resources by using medical records and pathology specimens as well as community and individual education to identify previously diagnosed probands and engage family members with limited awareness of genetic risk. Additionally, Traceback could provide an opportunity to reach families from rural areas and racial, ethnic and socioeconomic groups that historically have not sought or been offered genetic counseling and testing, thereby contributing to a reduction in health disparities in women with germline BRCA1/2 mutations.

Research Scope

The scope of this FOA includes genetics and other clinical projects that will improve the identification of individuals at high risk for cancer. The research scope of this FOA covers 3 major areas that are necessary to understand the feasibility and best approaches to undertake Traceback testing:

1) How to identify probands to reach untested individuals and their families?

Germline BRCA1/2 mutations are present in 15% of epithelial ovarian cancers, providing an efficient sentinel cancer to detect carriers among family members. Once identified, a carrier provides an entry point for reaching family members who could potentially benefit from genetic counseling, genetic testing and interpretation of results, and appropriate risk-management strategies.

Approaches for identifying previously diagnosed probands include: 1) searching pathology records or tumor registry databases; 2) community engagement campaigns and 3) self-referral based on family (and/or personal) cancer history. Research questions of interest for this component include but are not limited to:

  • Which approaches are most effective for identifying and testing potential carriers given the ethical issues (e.g. obtaining consent) and logistical issues (e.g. proband’s vital status and ability to contact) that would be faced in various clinical and community contexts?
  • What are the best approaches to recruit, counsel and test rural and/or minority populations? What cultural considerations need to be addressed when working with racially/ethnically diverse populations and/or rural communities? How does acceptability of these approaches differ between different races or socioeconomic populations?
  • How does community engagement impact acceptability/uptake of genetic testing?
  • How does the availability of tissue blocks differ across different sites and how does the availability of tissue blocks affect the testing rates of family members? What is the availability of tissue blocks from racially/ethnically diverse cases and how does it reflect the patient population?
  • What are the limitations of testing FFPE specimens and how can they be overcome to improve testing performance?
  • What is the accuracy of self-referrals with respect to original diagnosis of proband or level of risk for family members?

2) What is the scope of genetic testing and which results should be reported?

Uncertainties exist regarding the important issue of genetic counseling and testing, and what findings to report. Research to clarify the implications of variants of unknown significance in different clinical contexts is ongoing, and research associated with Traceback may enable the construction of research pedigrees that clarify the biological importance of these findings. Research questions of interest for this component include but are not limited to:

  • Which genes/variants should be tested?
  • How to best balance the valuable information gained from multi-gene testing with limited actionable results?
  • Which findings should be returned (e.g. actionable results only or also return variants of unknown significance)?  How should this information be communicated in different clinical and community contexts?
  • Given that our understanding of genetic/epigenetic risk changes over time, how best to handle variant re-classification and/or improved understanding of risk factors?
  • How does interpretation of variants and risk differ between testing labs?

3) What are the ethical and privacy considerations that need to be addressed?

A Traceback protocol to identify and test previously diagnosed cases engenders ethical and legal concerns related to consent to perform genetic testing and return results to probands and/or their relatives. These considerations may vary with the design of the protocol and in accordance with local, state, national and institutional mandates and applicable laws. Accordingly, applicants should conduct research addressing ethical and legal issues raised by their protocol, including approaches for resolving state and national privacy restrictions. Research questions of interest for this component include but are not limited to:

  • What are the institute-, locality-, state- and country-specific laws, informed by ethical and privacy concerns, that impact Traceback cascade testing? How do various Traceback approaches navigate these laws?
  • What are effective approaches to contact previously diagnosed cases that are still alive and/or next-of kin/personal representatives of deceased cases for consent? What cultural considerations need to be addressed to make these approaches effective in specific clinical and community contexts, including racially/ethnically diverse populations and rural communities?
  • What is the acceptability of contacting previously diagnosed cases and/or next-of kin/personal representative for consent? What factors impact the acceptability of contact?
  • What are the best approaches to improve genetic counseling and cascade testing, particularly in rural and/or minority populations (e.g. remote counseling options, telemedicine)? What sustainability factors will be implemented or leveraged to ensure that genetic counseling is available for all populations?
  • How will genetic counselors communicate with populations who do not speak or understand English? What are the most effective options for interpretation services to facilitate communication?
  • What are the ethical issues of reporting/not reporting variants of unknown significance or other non-actionable variants?

Deadlines:  standard dates and standard AIDS dates apply.


Filed Under: Funding Opportunities