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Abstract

Background. Inherited BRCA gene mutations convey a high risk for breast and ovarian cancer, but current guidelines limit BRCA mutation testing to women with early-onset cancer and relatives of mutation-positive cases. Benefits and risks of providing this information directly to consumers are unknown. Methods. To assess and quantify emotional and behavioral reactions of consumers to their 23andMe Personal Genome Service® report of three BRCA mutations that are common in Ashkenazi Jews, we invited all 136 BRCA1 and BRCA2 mutation-positive individuals in the 23andMe customer database who had chosen to view their BRCA reports to participate in this IRB-approved study. We also invited 160 mutation-negative customers who were matched for age, sex and ancestry. Semi-structured phone interviews were completed for 32 mutation carriers, 16 women and 16 men, and 31 non-carriers. Questions addressed personal and family history of cancer, decision and timing of viewing the BRCA report, recollection of the result, emotional responses, perception of personal cancer risk, information sharing, and actions taken or planned. Results. Eleven women and 14 men had received the unexpected result that they are carriers of a BRCA1 185delAG or 5382insC, or BRCA2 6174delT mutation. None of them reported extreme anxiety and four experienced moderate anxiety that was transitory. Remarkably, five women and six men described their response as neutral. Most carrier women sought medical advice and four underwent risk-reducing procedures after confirmatory mutation testing. Male carriers realized that their test results implied genetic risk for female relatives, and several of them felt considerably burdened by this fact. Sharing mutation information with family members led to screening of at least 30 relatives and identification of 13 additional carriers. Non-carriers did not report inappropriate actions, such as foregoing cancer screening. All but one of the 32 mutation-positive participants appreciated learning their BRCA mutation status. Conclusions. Direct access to BRCA mutation tests, considered a model for high-risk actionable genetic tests of proven clinical utility, provided clear benefits to participants. The unexpected information demonstrated a cascade effect as relatives of newly identified carriers also sought testing and more mutation carriers were identified. Given the absence of evidence for serious emotional distress or inappropriate actions in this subset of mutation-positive customers who agreed to be interviewed for this study, broader screening of Ashkenazi Jewish women for these three BRCA mutations should be considered.

Authors

Uta Francke;  Cheri Dijamco;  Amy K. Kiefer;  Nicholas Eriksson;  Bianca Moiseff;  Joyce Y. Tung;  Joanna L. Mountain

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  • Basic reporting

    There are several tables in this manuscript; at the very least, I think Table 7 can be deleted and summarized in the text.

    Experimental design

    Methods – Please describe the development of the interview guide – were the questions adapted from other studies (several studies referenced about patients’ responses to BRCA1/2 testing), particularly how were the six options constructed to ascertain emotional response, was the guide piloted for understandability and clarity, was the interviewer allowed to ask follow-up questions not included in the guide, etc.

    There is no information about how the authors analyzed the data. I’m assuming the interviews were recorded and transcribed. How did they identify themes, how did they code the data, etc? Were participants’ comprehension/recall of results compared to actual results?

    While gender and BRCA-carrier status are the major variables analyzed, can the authors provide more insight about the effect of age – presumably responses were different from individuals in their 20’s compared to those in their 70’s? Also, is it possible to link some of responses? For example, was the woman who misunderstood that she would be getting a definitive answer about carrier status and then her anxiety was increased following genetic counseling session also one of the respondents who indicated being ‘moderately upset, surprise, or shocked.’

    Could the authors comment on how long after the receipt of results that the interview was conducted? This could impact the many of the comments by the consumers, as well as comprehension and behaviors.

    Validity of the findings

    RESULTS – some of the sections seem a bit redundant; some reorganization could limit data from being repeated and shorten this section overall. For example, in the section “Actions taken or planned in response…” , the sharing of data is mentioned again. The quotes only appear in the latter half of Results section – can it be more balanced throughout, such as including some in the Emotional Response section? Maybe have a section on Familial Implications?

    Regarding comment on perceived worth of PGS, I think it should be clarified whether their response was based on the BRCA finding or overall. There certainly may have been other data that would influence this response.

    Comments for the author

    This manuscript presents some interesting data about consumers’ responses to receipt of BRCA1/2 mutations from their purchase of the 23andMe Personal Genome Services. Some further information on their methods and analyses would be helpful as suggested.

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  • Basic reporting

    The authors do not provide information about the educational level of participants (in demographics Table 1), which would be useful if available.

    Is there information on which participants had children? This would be helpful to interpret the results regarding men’s concerns about passing mutations to their daughters. Did these men already have children? What about the women?

    Experimental design

    The authors do not specify what type of software (if any) was used to code and analyze the data.

    The authors also do not specify how the four coders 'reconciled' their coding. Can they provide intercoder reliability scores (if used), or further information on how reconciliation was achieved?

    Validity of the findings

    This article makes an important contribution to the literature by providing much needed empirical evidence from individuals who have received 'high impact' genetic information via DTC testing. While the data is encouraging, the small sample size and broad conclusion that population wide screening should be considered require further qualifications. Therefore my main comments are in relation to the discussion and conclusions drawn, and I suggest the authors acknowledge/address the issues below more fully:

    1. The evidence does indicate that there did not appear to be detrimental emotional effects for the individuals who received mutation positive results, however it is important to note that many of the carriers (22/32) had family histories, had already been tested, had cancer themselves...etc and therefore were aware of their increased risk prior to testing. It is likely that this pre-existing sense of risk helped prepare them for results and led to less stress or shock. Those individuals who are completely unprepared or unaware of their risk may find results more distressing as indicated by the fact that 3 out of 4 who were ‘moderately upset’ were not expecting the results and reported feeling shock or surprise. If the author’s recommendation is population wide screening, more research is required about the implications for individuals who are completely unprepared.

    2. The authors note that 23andMe customers are not representative of the population. More should be said here, in particular regarding the fact that this may be a very unique, proactive, and highly educated group (it would be nice to see information on educational level if available) that does not necessarily reflect the larger population.

    3. The authors note that BRCA mutation testing is valuable because it is clinically actionable. This is true, however it is important not to understate the difficult decisions and deliberations for women considering undergoing prophylactic bilateral mastectomy and oophorectomy (especially at a young age). There remain considerable uncertainties about the effectiveness of screening (MRI vs mammography, ovarian screening) especially for women below 25. If population screening is being recommended, it is likely more young women will be tested and these women may find the available options more difficult to cope with emotionally.

    4. The authors report the surprising and 'remarkable' number of carriers who reported feeling 'neutral' after receiving their mutation positive results. There does not appear to be enough evidence to determine if individuals were indeed 'neutral' or if these were the individuals who already were known mutation carriers, had strong family histories, or perhaps felt no change to their pre-existing feelings which are unknown.

    5. One of the concerns about DTC testing is that it will put an undue burden on healthcare system (as mentioned by the authors in the introduction). This needs to be addressed further, as 60% of individuals who were mutation carriers did seek further medical advice and are advised to do so by 23andMe. The authors suggest that this high number may be related to the actionability of the results, however this may put a strain on the health care system especially if population wide screening is being recommended.

    6. Related to the point above, it would be useful for the authors to address the fact that physicians were not necessarily prepared to handle DTC information, gave inappropriate advice, or did not know what to do with the reports. This points to a need for physician education as well.

    7. The authors touch upon, but do not go any further, in discussing the presence of these mutations in non-Ashkenazi individuals, and the deficiencies of using self identified Ashkenazi ancestry to determine who should be tested. Do the authors have a suggestion for how to deal with this? Do they suggest testing all individuals in the population, only self-identified Ashkenazi Jewish individuals, Sephardi Jews as well…etc? This also relates to an additional, and unaddressed, point regarding the fact that other populations, such as Latino/as and African Americans may not benefit from this population screening despite the fact that they may also carry particular founder mutations. Is there potential to increase health disparities?

    8. The authors suggest that the results of this study will be important especially as whole genome/exome sequencing is increasingly available. This study does provide important data about individual responses to DTC testing for serious genetic conditions, however BRCA testing is significantly different from much of the information that is currently available from whole genome/exome studies where results may be of unknown significance or create a very small and multi-factorial increased risk. BRCA mutations are highly penetrant and transmitted in an autosomal dominant fashion, and management options are available. The authors could make this distinction more explicit.

    9.The authors report that males, rather than females, had greater concern about passing on mutations to their daughters. This interpretation appears overly simplistic. There is increasing literature about the impact of mutation status on reproductive decision making for women (Ormondroyd et al, Julian-Reynier et al 2012, Fortuny et al 2009). I think it is slightly misguided to conclude that this is a greater concern for men than women. Rather I think it is the primary or initial concern for men who do not have to consider risk management options for breast/ovarian cancer, whereas women are faced with their own risk management as well as their children’s risks.

    10. The fact that men were less likely to seek advice from a physician than women and felt uncomfortable sharing information with relatives speaks to a common and recognized ‘gendered’ burden of health care and sharing of information which often falls to women.

    Comments for the author

    This article makes an important contribution to the literature by providing much needed empirical evidence from individuals who have received 'high impact' genetic information via DTC testing. While the data is encouraging, the small sample size and broad conclusion that population wide screening should be considered require further qualifications. Therefore my main comments are in relation to the discussion and conclusions drawn, and I suggest the authors acknowledge/address the issues below more fully:

    1. The evidence does indicate that there did not appear to be detrimental emotional effects for the individuals who received mutation positive results, however it is important to note that many of the carriers (22/32) had family histories, had already been tested, had cancer themselves...etc and therefore were aware of their increased risk prior to testing. It is likely that this pre-existing sense of risk helped prepare them for results and led to less stress or shock. Those individuals who are completely unprepared or unaware of their risk may find results more distressing as indicated by the fact that 3 out of 4 who were ‘moderately upset’ were not expecting the results and reported feeling shock or surprise. If the author’s recommendation is population wide screening, more research is required about the implications for individuals who are completely unprepared.

    2. The authors note that 23andMe customers are not representative of the population. More should be said here, in particular regarding the fact that this may be a very unique, proactive, and highly educated group (it would be nice to see information on educational level if available) that does not necessarily reflect the larger population.

    3. The authors note that BRCA mutation testing is valuable because it is clinically actionable. This is true, however it is important not to understate the difficult decisions and deliberations for women considering undergoing prophylactic bilateral mastectomy and oophorectomy (especially at a young age). There remain considerable uncertainties about the effectiveness of screening (MRI vs mammography, ovarian screening) especially for women below 25. If population screening is being recommended, it is likely more young women will be tested and these women may find the available options more difficult to cope with emotionally.

    4. The authors report the surprising and 'remarkable' number of carriers who reported feeling 'neutral' after receiving their mutation positive results. There does not appear to be enough evidence to determine if individuals were indeed 'neutral' or if these were the individuals who already were known mutation carriers, had strong family histories, or perhaps felt no change to their pre-existing feelings which are unknown.

    5. One of the concerns about DTC testing is that it will put an undue burden on healthcare system (as mentioned by the authors in the introduction). This needs to be addressed further, as 60% of individuals who were mutation carriers did seek further medical advice and are advised to do so by 23andMe. The authors suggest that this high number may be related to the actionability of the results, however this may put a strain on the health care system especially if population wide screening is being recommended.

    6. Related to the point above, it would be useful for the authors to address the fact that physicians were not necessarily prepared to handle DTC information, gave inappropriate advice, or did not know what to do with the reports. This points to a need for physician education as well.

    7. The authors touch upon, but do not go any further, in discussing the presence of these mutations in non-Ashkenazi individuals, and the deficiencies of using self identified Ashkenazi ancestry to determine who should be tested. Do the authors have a suggestion for how to deal with this? Do they suggest testing all individuals in the population, only self-identified Ashkenazi Jewish individuals, Sephardi Jews as well…etc? This also relates to an additional, and unaddressed, point regarding the fact that other populations, such as Latino/as and African Americans may not benefit from this population screening despite the fact that they may also carry particular founder mutations. Is there potential to increase health disparities?

    8. The authors suggest that the results of this study will be important especially as whole genome/exome sequencing is increasingly available. This study does provide important data about individual responses to DTC testing for serious genetic conditions, however BRCA testing is significantly different from much of the information that is currently available from whole genome/exome studies where results may be of unknown significance or create a very small and multi-factorial increased risk. BRCA mutations are highly penetrant and transmitted in an autosomal dominant fashion, and management options are available. The authors could make this distinction more explicit.

    9.The authors report that males, rather than females, had greater concern about passing on mutations to their daughters. This interpretation appears overly simplistic. There is increasing literature about the impact of mutation status on reproductive decision making for women (Ormondroyd et al, Julian-Reynier et al 2012, Fortuny et al 2009). I think it is slightly misguided to conclude that this is a greater concern for men than women. Rather I think it is the primary or initial concern for men who do not have to consider risk management options for breast/ovarian cancer, whereas women are faced with their own risk management as well as their children’s risks.

    1. The fact that men were less likely to seek advice from a physician than women and felt uncomfortable sharing information with relatives speaks to a common and recognized ‘gendered’ burden of health care and sharing of information which often falls to women.

    Published in
    Reviewed by
    Ongoing discussion