Are We Ready for Online Tools in Decision Making for BRCA1/2 Mutation Carriers? D. Gareth Evans, The University of Manchester, Manchester Academic Health Science Centre, Central Manchester University Hospitals Foundation Trust, St. Mary’s Hospital; and Genesis Prevention Centre, University Hospital of South Manchester, Wythenshawe, Manchester, United Kingdom Anthony Howell, Genesis Prevention Centre, University Hospital of South Manchester, Wythenshawe, Manchester, United Kingdom See accompanying article doi: 10.1200/JCO.2011.38.6060 Decision making for female BRCA1/2 mutation carriers regard- ing when and whether to undergo risk reducing breast and or ovarian surgery is complex and involves not only the desire to stay alive longer, but to avoid the diagnosis of breast and ovarian cancer itself. These considerations are balanced against the desire for most women to have children, which in modern western society is often at a later age, as well as the impact of bilateral salpingo-oophorectomy (BSO) in causing early menopause with its attendant symptoms, increase in heart dis- ease and osteoporosis risk, and for some women a loss of sexuality and gender identity. 1-3 Bilateral risk-reducing mastectomy (BRRM) may have a greater impact psychologically than BSO since it affects body image. There are large variations in uptake of BRRM, 4 which may reflect cultural differences, whether the procedure is offered and if so the way and time at which it is offered 5,6 Decision aids are increasingly used to help in complex decision making in other areas of breast cancer management, such as the successful Adjuvant! Online program (http://www.adjuvantonline.com/index.jsp). Development of deci- sion aids addressing the complex issues faced by BRCA1 and BRCA2 mutation carriers is to be welcomed. In the article accompanying this editorial, Kurian et al 7 have extended their work with a model that predicts tumor incidence and survival in BRCA1/2 mutation carriers and have developed these data into a decision aid for female carriers of BRCA1/2 mutations who have to make complex trade offs between surgery and screening for breast and ovarian cancer. The model is based on data from the published literature, but several assumptions have to be made in the absence of firm data, including penetrance estimates of each gene mutation as a function of age, as well as survival from each cancer after diagnosis. There are two major concerns with regard to the validity of the as- sumptions made to produce the model, which may possibly affect the accuracy of the decision aid in the clinic. The first concern is the assumption that the penetrance of BRCA1 and BRCA2 germline mutations does not vary in relation to factors other than age, such as the degree of family history and other known risk factors such as age of first pregnancy or body mass index, among others. The Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) model 8 builds estimates of penetrance of BRCA1 and BRCA2 in relation to age and closeness of relatives with breast cancer and this could be included in the Kurian et al 7 model. In addition to some lack of precision based on these issues, there is also concern that Kurian et al may have underestimated penetrance since they used estimates for breast cancer from popula- tion studies 9 that assessed risk in women with birth cohorts consider- ably earlier than their own modeling for women born in 1980. Breast cancer incidence has increased markedly both in the general popula- tion and BRCA carriers as demonstrated so well in Iceland, which shows a fourfold increase in sporadic breast cancer and in the pen- etrance of the BRCA2 founder mutation over the 80 year period from 1920 to 2000. 10 Most women who are referred for genetic testing are identified through reasonably strong family histories, and their pen- etrance estimates should reflect that. 11,12 This influence of family history is likely to be partly due to the coinheritance of other lower risk genetic susceptibility alleles that have been identified in Genome Wide Association Studies (GWAS). 11 Thus far at least 18 common low risk genetic susceptibility loci have been identified using frequently occur- ring single nucleotide polymorphisms (SNPs). 13 Most of these have now been validated as affecting risk in BRCA2 mutation carriers al- though only a few for BRCA1. 14-17 Use of just five of these SNPs modifies the penetrance for breast cancer from between 95% down to as little as 45%. 17 and this type of information should be considered for inclusion in future iterations of the Kurian et al model. Another important issue in determining risk to an individual is their hormonal and reproductive history. Apart from parity, where the data are conflicting, 18,19 the remaining risk factors such as age at menarche, oral contraceptive use, and age at menopause have either similar effects to those seen in the general population or no effect. 20-22 The greatest single risk factor, mammographic density, also substan- tially affects breast cancer risk in BRCA1/2 carriers. 23 Clearly addition of both family history and nongenetic risk factors would make the algorithm in the decision aid far more complex, but ignoring these factors altogether will mean that women are given an average risk of breast and ovarian cancer, whereas in reality many women will have a substantially different risk from the average BRCA carrier. Yet another area where the assumptions made by Kurian et al 7 may be problematic is in the calculation of survival. A major concern is overestimation of survival of BRCA1 carriers with breast cancer JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L S © 2012 by American Society of Clinical Oncology 1 Journal of Clinical Oncology, Vol 30, 2012 http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2011.40.1562 The latest version is at Published Ahead of Print on January 9, 2012 as 10.1200/JCO.2011.40.1562 Copyright 2012 by American Society of Clinical Oncology Downloaded from jco.ascopubs.org on February 22, 2013. For personal use only. No other uses without permission. Copyright © 2012 American Society of Clinical Oncology. All rights reserved.