Outcomes of Multimodality Breast Screening for Women at Increased Risk of Familial Breast Cancer: Reply to Letter
- First Online:
- Cite this article as:
- Bennett, I.C. World J Surg (2010) 34: 2788. doi:10.1007/s00268-010-0706-y
The issues raised by Dr. Roukos in his recent correspondence are relevant and important. The development of the Familial Breast Cancer Screening Clinic, whose outcomes are reported in our recent article in the World Journal of Surgery , does in fact represent a step in the direction of providing a more tailored approach to breast screening based on the new knowledge that we have acquired over the last decade of gene mutation analysis and its associated risks. It is therefore appropriate to offer an alternative and specific breast screening process to women who are identifiable as being at higher risk of familial breast cancer and that recognizes such factors as earlier potential onset of the disease and increased breast density. Hence, the addition of screening by ultrasonography and magnetic resonance imaging as well as younger age of commencement need to be considered when establishing a program for these women.
Although prophylactic mastectomy is the other major alternative management strategy for high risk women, it seems that most women in this situation do in fact prefer screening over surgery with its potential for disfigurement, surgical complications, and emotional trauma. The review by Wainberg and Husted  of women choosing preventive surgery showed a great deal of variation among countries and health care systems, but one of the largest single studies in the United States showed only 15% making this choice among women diagnosed with a predisposition gene mutation. Hence, for the significant proportion of those women who find prophylactic mastectomy unacceptable, there is an important obligation to provide a screening program that caters to their particular circumstance. Women who have a significant family history of breast cancer but who have negative testing for BRAC1/2 mutations should probably still be regarded as potentially at higher risk than the general population, as there may yet be other unproven gene site mutations that might be implicated in the future. It is also possible to have a false-negative result in relation to gene testing for BRAC1/2 gene mutations. For women without a family history of breast cancer, population-based mammographic screening would usually be recommended to all women over the age 50 years.
However, despite further extensive research and advances in gene technology, including sequencing the human genome during the past decade, we seem to have progressed only very slowly along the path of being able to prevent, diagnose, and cure potentially hereditable diseases based on genetic profiling of individuals. Progress has been slower than anticipated, and the promises of expected predictability of phenotypic expression based on genotype analysis have not been as fruitful and forthcoming as had been hoped. Indeed, the predictability of both hereditary and sporadic breast cancer development, for example, continues to remain enigmatic, a fact highlighted by the recent study by Wacholder et al.  whose analysis of risk found that despite factoring in 10 common genetic variants to traditional known risk factors in a large series of cases the level of predicted breast cancer risk changed little after the addition of this extra genetic information. It is well established that in women with known mutations of BRAC1 and BRAC2, the lifetime risk of developing breast cancer ranges widely between 60% and 85% and the risk of developing ovarian cancer between 15% and 65% . These rather crude estimates suggest that we still have a way to go in providing accurate predictability of phenotypic expression of disease based on our current knowledge of the genome structure, and we are still far from providing tailored gene therapies that might offer primary prevention. Undoubtedly, as genetic predictability becomes more certain in the future, it can be anticipated that screening programs such as being offered in the Familial Breast Cancer Screening Clinic could be tailored even further according to new genetic information. Such new information could come from genome-wide association studies, as suggested by Manolio et al.  or from the ability to sequence multiple genomes per person as predicted by Venter .
A highly critical future challenge, as indicated by Roukos, is to more fully appreciate and understand gene–environmental interactions, which will enable us to explain, for example, why some 15% to 40% of BRCA1/2 gene mutation carriers never develop breast cancer during their lifetime. Only then will we have a realistic expectation of outcomes on which to base more personalized and tailored preventive and therapeutic strategies.