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© 2002 American Society for Clinical Oncology
Risk Management in BRCA1 and BRCA2 Mutation Carriers: Lessons Learned, Challenges Posed
University of Pennsylvania Cancer Center THE DISCOVERY of the breast cancer susceptibility genes BRCA1 and BRCA2 in the early 1990s was heralded as a breakthrough in our understanding of breast cancer etiology and risk. It stood to reason that if we could identify the genetic abnormalities responsible for the high rate of breast cancer in certain families, we could use that information to identify specific individuals at particularly high risk. Furthermore, we could develop detection and prevention strategies that would reduce the incidence and mortality of breast cancer in high-risk women. We could envision a day when women from such families were spared the experience of living with the fear of breast cancer as an inevitable occurrence. Now, a decade after the localization of BRCA1, substantial progress has been made in realizing the first of these goals: the ability to identify individuals at high risk. Refined statistical models accurately stratify women based on the risk of carrying a deleterious mutation, and we now routinely use this information to guide choices about genetic testing. The testing is reliable, commercially available, and often partially or fully reimbursed by insurers. Additionally, experience has shown that the risk of genetic discrimination is negligible, thanks in part to both state and federal legislation protecting the rights and insurability of those with known mutations. However, more limited progress has been made toward realizing the second goal, a reduction in breast cancer incidence and mortality in mutation carriers. The report by Scheuer et al1 in this issue of the Journal of Clinical Oncology provides important information in this regard. The study describes a cohort of 267 women with deleterious BRCA1 or BRCA2 mutations from the Memorial Sloan-Kettering Cancer Center. Patients were provided with a standard set of recommendations for breast and ovarian cancer surveillance that included annual mammography (or later, magnetic resonance imaging), clinical breast examination two to four times annually, biannual transvaginal ultrasound (TVU), serum CA-125 screening, and monthly breast self-examination (BSE). Patients also received information on bilateral prophylactic mastectomy (BPM), bilateral prophylactic oophorectomy, and chemoprevention with tamoxifen, although the strength of the recommendations for these options was not clear. Among the 195 patients with breast tissue at risk at the time of evaluation, 165 opted for breast screening and 29 underwent BPM. Twelve of 165 screened women were diagnosed with incident breast cancers over the 2-year follow-up period: six were detected by routine mammograms (screen-detected) and six were interval cancers. Thus the sensitivity of breast cancer screening (defined as the ratio of screen-detected to screen-detected plus interval cancers) was only 50%. Five of six interval cancers (83%) were identified by patient self-examination; only four of six interval cancers could subsequently be identified radiographically. Eleven of 12 breast cancers were less than 2 cm in size, and only one was node-positive (detected by a screening mammogram). Among the 29 patients undergoing BPM, two occult breast cancers were found at surgery; both were ductal carcinoma-in-situ without an invasive component. These findings are consistent with the only other published data on breast cancer screening in BRCA1 and BRCA2 mutation carriers and emphasize the limitations of the current screening approach. A study published earlier this year in the Journal of Clinical Oncology2 on breast cancer surveillance of 1,198 high-risk women, including 128 BRCA1 or BRCA2 mutation carriers, used a screening protocol similar to that reported by the group at Memorial Sloan-Kettering Cancer Center. In the known mutation carriers, nine incident breast cancers were found over 3 years: four were interval cancers and five were node-positive. Thus, even with annual screening, interval cancers were a significant problem, and as with screening in the general population, some screen-detected cancers had spread to regional lymph nodes at the time of diagnosis. The finding of occult cancers in specimens from prophylactic surgery1,3,4 further emphasizes the difficulties of breast cancer screening in this very high-risk group. The data on ovarian cancer surveillance presented by Scheuer et al1 are intriguing but more limited. Of the 179 women with intact ovaries at the time of evaluation, 62 opted for ovarian cancer screening and 90 underwent BPO. Among those undergoing screening, five incident ovarian cancers were diagnosed during the 2-year follow-up period, and one of the five was a primary peritoneal carcinoma. Ovarian cancers were detected either by TVU, serum CA-125, or both. No interval cancers were identified based on symptoms. Notably, concordance between the two screening modalities (serum CA-125 and TVU) was only 40% (two of five), reflecting the low specificity of both tests. Among those undergoing prophylactic surgery, two occult ovarian carcinomas were found. Both were stage I tumors, and neither was seen on TVU performed within the month before surgery. Preoperative serum CA-125 was within the normal range in one of these women and it was not performed on the other. As the first published study on the efficacy of TVU screening and serum marker surveillance in BRCA1 and BRCA2 mutation carriers, these data provide valuable insight into the severe limitations of both current screening approaches and of the evaluation of the efficacy of screening. Early detection of ovarian cancer is substantially more difficult than of breast cancer.5 Furthermore, clinical symptoms almost always are associated with ascites, with mortality exceeding 80% at 5 years. Because ovarian cancer often remains occult until its later stages, evaluation of the efficacy of screening strategies is hampered by difficulty in determining the true denominator of incident and prevalent cases in the screened population. Without this information, it is impossible to accurately calculate sensitivity (true-positives ÷ true-positives + false-negatives) and specificity (true-negatives ÷ true-negatives + false-positives). Scheuer et al1 claim that ovarian cancer screening in their study had a sensitivity of 71% and a specificity of 91%. However, only 10 of 22 patients with abnormal screening tests subsequently underwent surgery, the gold standard in evaluating the accuracy of a screening test. Without data on the surgical findings in the other 12 patients with initially positive tests, the accuracy of ovarian cancer screening cannot be evaluated. The fact that screening tests in these 12 women normalized over time contributes no useful information to the assessment of the screening test characteristics—follow-up is short and definitive diagnostic procedures were not performed. What lessons, then, can we take from the current data on cancer surveillance in BRCA1 and BRCA2 carriers? First, the data suggest an important role for BSE in mutation carriers, a procedure that has become surprisingly controversial in recent years. In evaluating BSE, both the United States Preventative Services Task Force6 and the Canadian Task Force on Preventive Health Care7 found few data to support benefit, and fair evidence to suggest harm, in the form of excess biopsies. The situation may be very different for BRCA1 and BRCA2 mutation carriers, because a much higher event rate likely will lead to fewer false-positive results. Thus we strongly recommend monthly BSE for women with BRCA1 or BRCA2 mutations. Second, there is evidence for an unacceptably high rate of interval breast cancers even with annual screening in BRCA1 and BRCA2 mutation carriers. Interval cancers can occur either because lesions present at the time of screening were not detected (due to dense breast tissue, for example) or because the rate of tumor growth is sufficiently rapid to result in transition from radiographically subclinical to clinically detectable within the screening interval. Both factors may be important in BRCA1 or BRCA2 mutation carriers because of the young average age at screening8 and the aggressive biologic features suggested by the histopathology of BRCA1-associated cancers.9 These data compel us to recommend a systematic reassessment of the breast cancer screening recommendations provided to women known to carry mutations in BRCA1 or BRCA2.10 Appropriate screening interval and imaging modality (mammography v magnetic resonance imaging) as well as the role of BSE must be addressed. It is possible that screening in this very high-risk group may need to be reduced to 6-month intervals, regardless of the modality used. Finally, retrospective studies of screening practices have limited ability to fully assess the efficacy of risk management strategies in BRCA1 and BRCA2 mutation carriers. Prospective trials specifically designed to assess the efficacy of cancer screening in these high-risk women are clearly needed. These challenging studies will require large numbers of mutation carriers, with rigorous assessment of quality assurance and adherence. Such studies will require a multicenter approach, as no single institution will achieve the needed sample size, and the time and expense involved will be substantial. Most importantly, future studies must not only evaluate the impact of preventive and surveillance strategies on cancer incidence, but also must be powered to determine whether these approaches will translate into meaningful reductions in mortality without undue medical, economic, or psychologic costs. When we attain the goal of a marked reduction in cancer mortality in women with BRCA1 and BRCA2 mutations, then we truly will have begun to exploit the promise of these spectacular genetic discoveries. REFERENCES
1.
Scheuer L, Kauff N, Robson M, et al: Outcome of preventive surgery and screening for breast and ovarian cancer in BRCA mutation carriers. J Clin Oncol 20: 1260-1268, 2002
2.
Brekelmans C, Seynaeve C, Bartels CC, et al: Effectiveness of breast cancer surveillance in BRCA1/2 gene mutation carriers and women with high familial risk. J Clin Oncol 19: 924-930, 2001
3.
Hartmann L, Schaid DJ, Woods JE, et al: Efficacy of bilateral prophylactic mastectomy in women with a family history of breast cancer. N Engl J Med 340: 77-84, 1999
4.
Meijers-Heijboer H, van Geel E, van Putten WL, et al: Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 345: 159-164, 2001
5.
Lu K, Garber JE, Cramer DW, et al: Occult ovarian tumors in women with BRCA1 or BRCA2 mutations undergoing prophylactic oophorectomy. J Clin Oncol 18: 2728-2732, 2000 6. Moore M, DiGuiseppi C: Neoplastic diseases: Screening for breast cancer. United States Preventive Services Task Force: Guide to Clinical Preventive Services (ed 2). Http://odphp.osophs.dhhs.gov/pubs/guidecps/
7.
Baxter N: Preventive health care, 2001 update: Should women be routinely taught breast self-examination to screen for breast cancer? Canadian Task Force on Preventive Health Care. CMAJ 164: 1837-1846, 2001
8.
Kerlikowske K, Grady D, Barclay J, et al: Positive predictive value of screening mammography by age and family history of breast cancer. JAMA 270: 2444-2450, 1993 9. Breast Cancer Linkage Consortium: Pathology of familial breast cancer: Differences between cancers in carriers of BRCA1 and BRCA2 mutations and sporadic cases. Lancet 349: 1505-1510, 1997[CrossRef][Medline]
10.
Burke W, Daly M, Garber J, et al: Recommendations for follow-up care of individuals with an inherited predisposition to cancer: II. BRCA1 and BRCA2. JAMA 277: 997-1003, 1997
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Copyright © 2002 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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