Department of Environmental Health Sciences and Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD

    Department of Biostatistics and Bioinformatics, Duke University, Durham, NC
　
　　The Sidney Kimmel Comprehensive Cancer Center and the Department of Biostatistics, Johns Hopkins University, Baltimore, MD

　　In Reply:

　　We would like to thank Antoniou et al for their stimulating discussion and for giving us the opportunity to reinforce a few key points from our article.1 The first is that our estimates of lifetime risk of breast and ovarian cancer are consistent with earlier studies. We have identified eight such studies2-9 and inspected the distribution of age specific estimates. For both BRCA1 and BRCA2, for both breast and ovarian cancer, and for each age group by decade, our estimates are close to the center of the distribution of estimates across studies, and do not appear to be systematically lower. There are also no systematic deviations from population-based studies or from studies that use other statistical approaches. For example, the penetrance estimates for breast cancer at age 70 years in BRCA1 carriers range from 0.37 to 0.70 with a meta-analytic mean10 of 0.58 (95% CI, 0.46 to 0.69), while our estimate is 0.46; for BRCA2, the corresponding estimates range from 0.28 to 0.81 with a meta-analytic mean of 0.48 (95% CI, 0.37 to 0.60), while our estimate is 0.43. Our CIs are overlapping with those obtained from the meta-analysis of the other studies. Antoniou et al7 did not include mutation negative families, and should therefore not be affected by potential additional genes. The most notable differences between their estimates and ours are for breast cancer penetrances in BRCA1, but in all cases the two sets of estimates have overlapping CIs.

　　Antoniou et al11 showed that a statistical model including a single third major gene or a polygenic component produced lower estimated penetrances. Postulating the presence of a third major gene is a potentially useful approach. However, given the present difficulties in identifying such a gene in the United States population,12 the extent to which the conclusions of this hypothetical calculation apply to our study is still unclear. What is emerging from recent research appears to be a constellation of many smaller contributors to the heritability of cancer risk. These include rare autosomal highly penetrant genes, as well as moderately penetrant genes and polygenic effects. In this scenario, it is hard to speculate about the effect of not accounting for this complex collection of genetic effects in our analysis. Even in Antoniou et al,11 the major gene model, which leads to a smaller penetrance estimates, is less supported by the data than the polygenic model, which only leads to minor changes in penetrance of BRCA1 and BRCA2.

　　The issue of an age-specific effect of bilateral oophorectomy in BRCA1 and BRCA2 carriers is an interesting one. Rebbeck et al13 investigated this issue and did not find a statistically significant difference in risk by age at oophorectomy. Their estimates of hazard ratios of breast cancer are 0.39 (95% CI, 0.15 to 1.04) for the younger than 35 years group, 0.49 (95% CI, 0.26 to 0.90) for the 35 years to 50 years group, and 0.52 (95% CI, 0.10 to 2.70) for the older than 50 years group.

　　Finally, Antoniou et al warned about the limitations of using average risk in individualized patient counseling. We strongly agree that this is a critical issue, and look forward to being able to include reliably characterized modifying environmental or genetic factors in risk prediction for BRCA1 and BRCA2 carriers. At the present time, the most promising direction for refinement of individualized risk prediction in untested high risk individual is provided by incorporation of tumor immunohistochemical markers,14,15 as is done in the forthcoming version of the BRCAPRO algorithm.

　　REFERENCES

　　Chen S, Iversen ES, Friebel T, et al: Characterization of BRCA1 and BRCA2 mutations in a large United States sample. J Clin Oncol 24:863-871, 2006　　

　　Ford D, Easton DF, Stratton M, et al: Genetic heterogeneity and penetrance analysis of the BRCA1 and BRCA2 genes in breast cancer families. Am J Hum Genet 62:676-689, 1998　

　　Struewing JP, Hartge P, Wacholder S, et al: The risk of cancer associated with specific mutations of BRCA1 and BRCA2 among Ashkenazi Jews. N Engl J Med 336:1401, 1997　　

　　Hopper J, Southey M, Dite G, et al: Population-based estimate of the average age-specific cumulative risk of breast cancer for a defined set of protein-truncating mutations in BRCA1 and BRCA2: Australian breast cancer family study. Cancer Epidemiol Biomarkers Prev 8:741-747, 1999　　

　　Satagopan J, Offit K, Foulkes W, et al: The lifetime risks of breast cancer in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Cancer Epidem Bio Prev 10:467-473, 2001

　　Satagopan J, Boyd J, Kauff N, et al: Ovarian cancer risk in Ashkenazi Jewish carriers of BRCA1 and BRCA2 mutations. Clin Cancer Res 8:3776-3781, 2002　　

　　Antoniou A, Pharoah PDP, Narod S, et al: Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case series unselected for family history: A combined analysis of 22 studies. Am J Hum Genet 72:1117-1130, 2003　

　　King MC, Marks JH, Mandell JB: Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2. Science 302:643-646, 2003　
　
　　Marroni F, Aretini P, D'Andrea E, et al: Penetrances of breast and ovarian cancer in a large series of families tested for BRCA1/2 mutations. Eur J Hum Genet 12:899-906, 2004
　
　　DerSimonian R, Laird N: Meta-analysis in clinical trials. Control Clin Trials 7:177-188, 1986　

　　Antoniou AC, Pharoah PDP, McMullan G, et al: A comprehensive model for familial breast cancer incorporating BRCA1, BRCA2 and other genes. Br J Cancer 86:76-83, 2002　

　　Berry DA, Iversen ES Jr, Gudbjartsson DF, et al: BRCAPRO validation, sensitivity of genetic testing of BRCA1/BRCA2, and prevalence of other breast cancer susceptibility genes. J Clin Oncol 20:2701-2712, 2002　　

　　Rebbeck TR, Lynch HT, Neuhausen SL, et al: Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 346:1616-1622, 2002　　

　　Lakhani SR, Van DV, Jacquemier J, et al: The pathology of familial breast cancer: Predictive value of immunohistochemical markers estrogen receptor, progesterone receptor, HER-2, and p53 in patients with mutations in BRCA1 and BRCA2. J Clin Oncol 20:2310-2318, 2002　　

　　Lakhani SR, Reis-Filho JS, Fulford L, et al: Prediction of BRCA1 status in patients with breast cancer using estrogen receptor and basal phenotype. Clin Cancer Res 11:5175-5180, 2005　　

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《临床肿瘤学医学期刊》2006年7月第24卷第20期