Following the discovery of theBRCA1 and BRCA2 genes justa decade ago, many felt it prematureto introduce these predictivemolecular markers into clinical practice.At the time, there were concernsregarding perceived limitations ofcancer genetic tests, including the limitedaccuracy of risk estimates associatedwith mutations of BRCA (andother susceptibility genes), the complextechnology needed for sequenceanalysis of large genes, the unprovenoptions for cancer prevention and earlydetection for mutation carriers, thelimited number of cancer genetic specialists,and the potential for adversesequelae following cancer genetic testing.The review by Peshkin and Isaacsprovides an excellent summary of theprogress over the past decade in addressingthese concerns. Nonetheless,as will be summarized here, importantchallenges remain in each of theseareas.
Following the discovery of the BRCA1 and BRCA2 genes just a decade ago, many felt it premature to introduce these predictive molecular markers into clinical practice. At the time, there were concerns regarding perceived limitations of cancer genetic tests, including the limited accuracy of risk estimates associated with mutations of BRCA (and other susceptibility genes), the complex technology needed for sequence analysis of large genes, the unproven options for cancer prevention and early detection for mutation carriers, the limited number of cancer genetic specialists, and the potential for adverse sequelae following cancer genetic testing. The review by Peshkin and Isaacs provides an excellent summary of the progress over the past decade in addressing these concerns. Nonetheless, as will be summarized here, important challenges remain in each of these areas. Clinical Relevance of BRCA-Related Risk
Regarding the cancer risk associated with BRCA mutations, Peshkin and Isaacs point to one recent large cohort study. The cancer risks associated with BRCA mutations in that study remain a topic of hot controver sy among cancer epidemiologists.[1,2] However, a point often overlooked in this debate is its clinical relevance. Even the "lowest" risk estimates for BRCA mutation carriers-approximately 20% for ovarian cancer and approximately 40% for breast cancer- are significantly elevated from baseline. For most women, in our experience, this range of risks does not have a substantial impact on the preventive and surveillance options ultimately chosen. But why the range of risks? As noted by the epidemiologists, ascertainment bias in these studies is clearly a factor. In addition, however, there are a range of risks associated with the same mutation, sometimes in the same family. In the absence of clearly documented environmental or hormonal influences, this suggests that other genetic modifiers are at play. Future BRCA testing may well be accompanied by genotyping for such risk modifiers. There also remains a group of women with hereditary breast cancer and no documented BRCA mutations.[3,4] The CHEK2 allele 1100delC accounts for some of this risk in European studies, but the incidence of this mutation in North America appears to be almost negligible. Among the Ashkenazim, however, a novel CHEK2 founder mutation is relatively common and is associated with a twofold risk of breast cancer. Should such testing for low penetrance breast cancer alleles be included in clinical practice? If so, how will this modify our clinical recommendations? Technologic Issues
With regard to the technologic challenges of testing, high-quality genotyping incorporating automated sequencing and large deletion analysis is now commercially available. Despite patent limitations, academic laboratories have thus far been allowed to provide BRCA testing to patients in a research context. There remains a need for a BRCA genotyping approach that is less costly and more rapid than automated sequencing. And until a functional assay for BRCA1 and BRCA2 mutations is developed, the substantial frequency of missense variants of unknown significance will remain a strong disincentive to test individuals outside of clearly defined "high-risk" groups. Along these lines, the recent emergence of direct-to-consumer BRCA testing poses new concerns. For example, incomplete counseling of selfreferred probands may result in "false-positive" results and unproven interventions based on detection of such missense variants. Similarly, there may be incomplete counseling resulting in false reassurance of a "soft negative" BRCA wild-type individual in the absence of proven segregation of a BRCA mutation in the kindred. Peshkin and Isaacs document the significant advances made in the area of establishing an evidence-based approach to surgery and prevention in BRCA mutation carriers. At our institution, based on prospective followup of over 500 BRCA mutation carriers, our current research protocols offer surveillance consisting of breast magnetic resonance imaging alternating with mammography staggered at 6-month intervals, as well as discussion of risk-reducing mastectomy or salpingo-oophorectomy and/or ovarian screening options.[3,4] Women who undergo risk-reducing salpingo-oophorectomy must be counseled regarding, and surgeons must be prepared for the 3% chance that an ovarian cancer will be detected in these patients at the time of "preventive" surgery. For hereditary breast cancer families without BRCA mutations-an important and understudied group- our prospective experience has thus far failed to detect an increased ovarian cancer risk. Data on the most rational use of hormonal and novel chemoprevention agents in BRCAand non-BRCA-linked hereditary breast cancer kindreds is just beginning to emerge. Need for Genetics Services
With regard to the projected shortfall of cancer genetics professionals, the authors of the Peshkin/Isaacs review serve as testimony to the multidisciplinary teams that have emerged to provide needed genetics services, pairing experienced oncologists with cancer genetic counselors. The training of oncologists and genetic counselors in cancer genetics has been facilitated by a decade of educational support from a number of professional societies, with the American Society of Clinical Oncology playing a leading role in creating teaching tools available to all health-care providers (see cancer genetics CME listings at www.asco.org). With educational empowerment also come new responsibilities and liabilities. Several lawsuits have already been filed against physicians who failed to warn family members of the hereditary nature of certain cancers. Finally, despite the dire predictions of a decade ago, BRCA testing has been integrated into oncologic practice with minimal stigma or penalty. Both the genetic testing and the preventive procedures described by Peshkin and Isaacs have generally been reimbursed by insurance companies- and this has included prophylactic surgeries. Similarly, while genetic discrimination remains a potential barrier to uptake, there has been scant evidence of genetic discrimination based on BRCA mutation status. The leadership of a physician as Senate majority leader resulted in the rapid and unanimous passage of a genetic antidiscrimination bill in the US Senate. Unfortunately, the prospects for passage in the House of Representatives remain uncertain. As summarized by Peshkin and Isaacs, the integration of BRCA testing into the practice of clinical oncology remains a work in progress. After a decade of clinical experience in BRCA testing and counseling, this new application of molecular medicine merits our continued commitment.
The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Easton DF, Hopper JL, Thomas DC, et al: Breast cancer risks for BRCA1/2 carriers. Science 306:2187-2191, 2004.
2. Wacholder S, Struewing JP, Hartge P, et al: Breast cancer risks for BRCA1/2 carriers. Science 306:2187-2191, 2004.
3. Narod SA, Offit K: Prevention and management of hereditary breast cancer. J Clin Oncol 23:1656-1663, 2005.
4. Garber JE, Offit K: Hereditary cancer predisposition syndromes. J Clin Oncol 23:276- 292, 2005.
5. Offit K, Pierce H, Kirchhoff T, et al: Frequency of CHEK2*1100delC in New York breast cancer cases and controls. BMC Med Genet 4:1. Epub Jan 15, 2003.
6. Shaag A, Walsh T, Renbaum P, et al: Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population. Hum Mol Genet 14:555-563, 2005.
7. Robson ME, Offit K: Breast MRI for women with hereditary cancer risk. JAMA 292:1368-1370, 2004.
8. Kauff ND, Satagopan JM, Robson ME, et al: Risk-reducing salpingo-oophorectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 346:1609-1615, 2002.
9. Kauff N, Mitra N, Robson ME, et al: Risk of ovarian cancer in BRCA1 and BRCA2 mutation negative hereditary breast cancer families. J Natl Cancer Inst. In press.
10. Offit K, Groeger E, Turner S, et al: The "duty to warn" a patient's family members about hereditary disease risks. JAMA 22:1469- 1467, 2004.