Genetic forms of breast cancer are an issue for public health. Women with a family history of breast cancer, and especially women with genetically known forms of susceptibility, can benefit from appropriate prevention and treatment interventions. Outcomes for breast cancer are strongly associated with the stage and degree of disease progression at the time of diagnosis, and this also holds true for genetically determined forms. Because effective screening surveillance and adequate preventive measures are proven to have a dramatic effect on the survival and the quality of life of individuals with inherited breast-cancer syndromes [1, 3], specific recommendations to define high-risk individuals and appropriate screening protocols should be provided. It is essential that, given the ethical implications of genetic testing, and also in consideration of the high costs related to their administration, guidelines should provide very clear and evidence-based recommendations on who should be tested, based on their personal and family history and on clinical criteria.
In this study, we aim to evaluate the quality of methodology of guidelines dealing with the issue of genetic testing for hereditary breast cancer, using the AGREE instrument. The application of AGREE allows evaluation of various aspects of guidelines quality: 'scope and purpose', taking into account whether the objectives, the clinical questions, and the target population are properly specified; 'stakeholder involvement', assessing which professional groups have been involved in the guideline development, and whether patients' views and preferences have been sought; 'rigour of development', with a list of key items focusing on the methods used by the developers, starting from the literature search up to the external review of the recommendations; 'clarity and presentation', focusing on how easily the user is able to find the key recommendations and the possible alternatives in the guideline; 'applicability', with three key items assessing how organizational barriers, potential cost implications, and patient monitoring/audit have been discussed; and 'editorial independence', assessing independence statements and records of potential conflicts of interest of the guideline developers.
The evaluation of the quality of the evidence which the guidelines build upon was beyond our objectives. We focused on the methods used in the course of development of the guidelines, which is the purpose of the AGREE instrument, based on the rationale that high methodological quality is fundamental in terms of credibility, reproducibility and transparency of guidelines. Furthermore, in the case of genetic susceptibility syndromes for breast cancer, as of today, there is a limited body of evidence focusing on the best screening and management options.
All the guidelines considered in this review are based on the same studies, therefore the recommendations necessarily converge. The recommendations on the topic given by the guidelines analyzed are as follows.
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All individuals at high risk (individuals from known high-risk families, or with high scores on the BRCAPRO [28] or BOADICEA [29] programs, or deemed at high risk based on clinical judgment) should be offered referral for information on genetic testing.
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Counseling from training personnel should be always available.
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If a mutation is identified in one individual from a high-risk family, predictive testing should then be offered to all adult at-risk family members.
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Known carriers of a BRCA1 or BRCA2 gene mutation should be offered counseling and the option of prophylactic mastectomy, and prophylactic salpingo-oophorectomy should also be discussed.
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Individualized screening strategies for known carriers of BRCA1 or BRCA2 gene mutations should be considered, such as earlier screening, shorter intervals between screens, and possibly annual MRI surveillance.
The most important difference between guidelines, however, and we believe it to be noteworthy, is how the different developers used the same evidence to produce the guidelines. The application of AGREE detected some major flaws in the development of the 13 guidelines on the topic, as some of the aspects investigated by AGREE were not included in these guidelines. With very few exceptions, the 13 guidelines all performed poorly with regard to 'stakeholder involvement' (domain 2) and 'editorial independence' (domain 6). Regarding stakeholder involvement, target users of the guideline (general practitioners, gynecologists, oncologists) remained generally undefined (key item 6), patient representatives were seldom involved (key item 5) in guideline development, and most guidelines were not piloted among end users (key item 7). Regarding editorial independence, explicit statements of independence from funding bodies (key item 22) were often not clearly stated, and did not allow the identification of possible conflicts of interest. The application of AGREE also showed that the methodological quality of the guidelines was suboptimal in terms of 'rigour of development' (domain 3) and 'applicability' (domain 5). Most guidelines lacked explicit statements on the criteria for selecting the evidence (key item 9), on whether they were externally reviewed before publication (key item 13), and on procedures for their update (key item 14). Generally speaking, the AGREE instrument gave high scores for domains 1 (scope and purpose) and 4 (clarity and presentation), even though not all guidelines received fully positive evaluations.
Although there was a good degree of convergence between guidelines in terms of recommendations provided, our study does have implications for clinical practice as well. As mentioned above, the AGREE instrument provides six independent scores for six corresponding aspects of the guidelines; clinicians would be interested primarily in the 'applicability' domain. It is fundamental that recommendations are not only rigorous in method but also feasible when applied to a specific clinical setting. In this sense, we recommend clinicians should rely preferentially on the guidelines that performed better with regards to the 'applicability' domain [18, 23, 24, 26], as those guidelines gave more consideration to issues related to overcoming possible organizational barriers when applying the recommendation (key item 19), and to presenting criteria for monitoring and audit purposes (key item 20).
By applying the AGREE instrument to the 13 guidelines on genetic testing for breast cancer, we found that guidelines developed by the ICSI [17], the NZGG [18], the SIGN [26] and the NHS [23, 24] scored above 50% in all six domains, with the NZGG [18], who acknowledged the adoption of AGREE in the guideline development, scoring above 70% in all domains. As for the other guidelines, two [2, 25] yielded poor scores (below 50%) in one of the six domains, three [19, 20, 27] in two of the six domains, one [21] in three of the six domains, two [16, 22] in four of the six domains, and one [15] in five of the six domains.
The guidelines produced by societies with an official endorsement tended to perform better with regard to all six the AGREE domains, however, a significant difference was not detected, probably due to the small sample size.