Traceback: A Proposed Framework to Increase Identification and Genetic Counseling of BRCA1 and BRCA2 Mutation Carriers Through Family-Based Outreach

Abstract

In May 2016, the Division of Cancer Prevention and the Division of Cancer Control and Population Sciences, National Cancer Institute, convened a workshop to discuss a conceptual framework for identifying and genetically testing previously diagnosed but unreferred patients with ovarian cancer and other unrecognized BRCA1 or BRCA2 mutation carriers to improve the detection of families at risk for breast or ovarian cancer. The concept, designated Traceback, was prompted by the recognition that although BRCA1 and BRCA2 mutations are frequent in women with ovarian cancer, many such women have not been tested, especially if their diagnosis predated changes in testing guidelines. The 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 to provide appropriate reassurances to noncarriers. The Traceback program could provide an important opportunity to reach families from racial, ethnic, and socioeconomic groups who historically have not sought or been offered genetic counseling and testing and thereby contribute to a reduction in health disparities in women with germline BRCA mutations. To achieve an interdisciplinary perspective, the workshop assembled international experts in genetics, medical and gynecologic oncology, clinical psychology, epidemiology, genomics, cost-effectiveness modeling, pathology, bioethics, and patient advocacy to identify factors to consider when undertaking a Traceback program. This report highlights the workshop deliberations with the goal of stimulating research and providing a framework for pilot studies to assess the feasibility and ethical and logistical considerations related to the development of best practices for implementation of Traceback studies.

Fig 1.

Three phases of Traceback. Phase I: potential previously diagnosed, unreferred probands are identified through searches of pathology or tumor registry records or through self-referral. Phase II: consent is obtained for BRCA1/2 genetic testing according to method used to identify potential probands. If proband is living and contactable, direct consent is obtained, and blood is tested in a clinically and molecularly certified laboratory. If archived pathology specimen is used to test potential proband because individual is deceased or cannot be contacted, consent is sought from next of kin (which also allows investigators to determine whether family members have already been tested). Phase III: variants of unknown significance are by definition not clinically actionable and, thus, should not be considered with respect to decision making. As such, a Traceback approach to genetic testing should only return pathogenic or likely pathogenic variants. If the potential proband is confirmed to have a BRCA1/2 pathogenic mutation, cooperation of the proband or next of kin is enlisted to reach relatives to offer education, counseling, and testing. If potential proband is not found to carry a BRCA1/2 pathogenic mutation or is found to have a variant of unknown significance, participants are informed about residual familial empirical and genetic risk. If a variant of unknown significance is later reclassified as a pathogenic mutation, relatives are contacted to offer education, counseling, and testing.