Cancer Risks for BRCA1 and BRCA2 Mutation Carriers
Nine hundred eighty-eight women without a previous diagnosis of breast or ovarian cancer were followed from baseline questionnaire to breast cancer or censoring. Age-specific cancer incidences for BRCA1 and BRCA2 carriers are shown in Table 2 and Table 3. The BRCA1 breast cancer incidence was estimated to be 8.7 per 1000 in the group aged 20 to 29 years, rising to 36.1 per 1000 for women in the group aged 50 to 59 years. There was one breast cancer diagnosis beyond age 60 years among BRCA1 carriers. The majority of breast tumors were invasive carcinomas. The average cumulative risk of breast cancer by age 70 years was 60% (95% confidence interval [CI] = 44% to 75%) (Figure 1A). The estimated BRCA2 incidence peaked in the group aged 40 to 49 years (41.4 per 1000) but was in the range 11.9 to 16.2 per 1000 for other age groups. The average cumulative risk of developing breast cancer for BRCA2 carriers by age 70 years was 55% (95% CI = 41% to 70%) (Figure 1B).
The analysis of ovarian cancer incidence involved 1509 women without prior diagnosis of ovarian cancer. The BRCA1 ovarian cancer incidence rose with age to 55.9 per 1000 in the group aged 60 to 69 years. There was only one case of ovarian cancer in BRCA2 carriers before age 50 years, and the incidence after age 60 years was 11.2 to 15 per 1000. The average cumulative risk of ovarian cancer by age 70 years was 59% (95% CI = 43% to 76%) for BRCA1 and 16.5% (95% CI = 7.5% to 34%) for BRCA2 carriers (Figure 1).
Six hundred fifty-one women with a previous unilateral breast cancer diagnosis were included in the analysis of CBC. The CBC incidence rates in BRCA1 carriers were substantially higher than those for a first breast cancer. For BRCA2 carriers, incidence rates were lower and the overall incidence rate was similar to that for a first breast cancer. The average cumulative risk of CBC by age 70 years was 83% (95% CI = 69% to 94%) for BRCA1 and 62% (95% CI = 44% to 79.5%) for BRCA2 carriers (Figure 1).
To obtain estimates of breast cancer incidences that more closely reflect the natural history of the disease, analyses were performed in which follow-up was stopped at oophorectomy. Estimated incidence and average cumulative risks for breast cancer in previously unaffected women and for CBC were somewhat higher when follow-up was stopped at oophorectomy than for the entire cohort (Supplementary Table 3 and Supplementary Figure 2, available online).
(Enlarge Image)
Figure 2.
Kaplan–Meier curve for breast cancer risk in unaffected BRCA2 carriers stratified by tertiles of the risk score. Tick marks indicate censoring events (apart from failure). The table below the figure indicates the number of women at risk in each age group and tertile of risk score. All statistical tests were two-sided.
To quantify the effect of bilateral prophylactic oophorectomy on cancer risk, oophorectomy was treated as a time-dependent covariable in a Cox regression model. The point estimates for the hazard ratio were less than one for breast cancer in BRCA1 (HR = 0.52, 95% CI = 0.24 to 1.13; P = .10) and BRCA2 (HR = 0.79, 95% CI = 0.35 to 1.80; P = .58) carriers and for CBC risk for BRCA1 carriers (HR = 0.77, 95% CI = 0.41 to 1.45; P = .42) but did not differ statistically significantly from one ( Table 4 ). A statistically significant reduction in CBC risk after oophorectomy was observed for BRCA2 carriers (HR = 0.16, 95% CI = 0.04 to 0.66; P = .01) ( Table 4 ). The hazard ratios were virtually identical when analyses were adjusted for parity and age at first birth (data not shown). Oophorectomy carried out at less than 45 years of age was associated with a greater reduction in cancer risks than oophorectomy carried out at ages 45 years or older (Supplementary Table 4, available online).
The combined effects of common breast cancer susceptibility alleles on breast cancer risk for BRCA1 and BRCA2 mutation carriers were assessed by constructing a risk score based on the joint distribution of these variants, under the assumption that the hazard ratios combine multiplicatively. Individuals were not followed up after oophorectomy in these analyses. Figure 2 shows the cumulative breast cancer risk in unaffected BRCA2 carriers stratified by tertiles of the risk score. BRCA2 carriers at the highest tertile of the score distribution were at statistically significantly higher risk than women at the lowest tertile (HR = 4.1, 95% CI = 1.2 to 14.5; P = .02). The risk by age 70 years for BRCA2 carriers in the highest tertile was 72%, compared with 20% for those in the lowest tertile. We also tested for trend in risk across the risk score as a continuous variable; the effect was in the same direction, although the association was not statistically significant (HR = 2.9, 95% CI = 0.74 to 11.4; P = .13). Analyses were also repeated with the entire cohort, adjusting for oophorectomy (test for trend across tertiles P = 0.07). The hazard ratios for the SNPs by tertile were consistent with those derived from the retrospective analysis in CIMBA (HR = approximately 1.9). A risk score based on four genetic variants associated with BRCA1 risk was also constructed. There was no evidence of an association, although the estimated risk was higher for women in the highest tertile of risk score (HR = 2.74 for highest vs lowest tertile; P = .41). There was no evidence for an association between risk scores and CBC risk for either BRCA1 or BRCA2 carriers (data not shown).
Results
Incidence of Breast, Ovarian, and Contralateral Breast Cancer
Nine hundred eighty-eight women without a previous diagnosis of breast or ovarian cancer were followed from baseline questionnaire to breast cancer or censoring. Age-specific cancer incidences for BRCA1 and BRCA2 carriers are shown in Table 2 and Table 3. The BRCA1 breast cancer incidence was estimated to be 8.7 per 1000 in the group aged 20 to 29 years, rising to 36.1 per 1000 for women in the group aged 50 to 59 years. There was one breast cancer diagnosis beyond age 60 years among BRCA1 carriers. The majority of breast tumors were invasive carcinomas. The average cumulative risk of breast cancer by age 70 years was 60% (95% confidence interval [CI] = 44% to 75%) (Figure 1A). The estimated BRCA2 incidence peaked in the group aged 40 to 49 years (41.4 per 1000) but was in the range 11.9 to 16.2 per 1000 for other age groups. The average cumulative risk of developing breast cancer for BRCA2 carriers by age 70 years was 55% (95% CI = 41% to 70%) (Figure 1B).
The analysis of ovarian cancer incidence involved 1509 women without prior diagnosis of ovarian cancer. The BRCA1 ovarian cancer incidence rose with age to 55.9 per 1000 in the group aged 60 to 69 years. There was only one case of ovarian cancer in BRCA2 carriers before age 50 years, and the incidence after age 60 years was 11.2 to 15 per 1000. The average cumulative risk of ovarian cancer by age 70 years was 59% (95% CI = 43% to 76%) for BRCA1 and 16.5% (95% CI = 7.5% to 34%) for BRCA2 carriers (Figure 1).
Six hundred fifty-one women with a previous unilateral breast cancer diagnosis were included in the analysis of CBC. The CBC incidence rates in BRCA1 carriers were substantially higher than those for a first breast cancer. For BRCA2 carriers, incidence rates were lower and the overall incidence rate was similar to that for a first breast cancer. The average cumulative risk of CBC by age 70 years was 83% (95% CI = 69% to 94%) for BRCA1 and 62% (95% CI = 44% to 79.5%) for BRCA2 carriers (Figure 1).
Risk-reducing Salpingo-oophorectomy and Cancer Risks
To obtain estimates of breast cancer incidences that more closely reflect the natural history of the disease, analyses were performed in which follow-up was stopped at oophorectomy. Estimated incidence and average cumulative risks for breast cancer in previously unaffected women and for CBC were somewhat higher when follow-up was stopped at oophorectomy than for the entire cohort (Supplementary Table 3 and Supplementary Figure 2, available online).
(Enlarge Image)
Figure 2.
Kaplan–Meier curve for breast cancer risk in unaffected BRCA2 carriers stratified by tertiles of the risk score. Tick marks indicate censoring events (apart from failure). The table below the figure indicates the number of women at risk in each age group and tertile of risk score. All statistical tests were two-sided.
To quantify the effect of bilateral prophylactic oophorectomy on cancer risk, oophorectomy was treated as a time-dependent covariable in a Cox regression model. The point estimates for the hazard ratio were less than one for breast cancer in BRCA1 (HR = 0.52, 95% CI = 0.24 to 1.13; P = .10) and BRCA2 (HR = 0.79, 95% CI = 0.35 to 1.80; P = .58) carriers and for CBC risk for BRCA1 carriers (HR = 0.77, 95% CI = 0.41 to 1.45; P = .42) but did not differ statistically significantly from one ( Table 4 ). A statistically significant reduction in CBC risk after oophorectomy was observed for BRCA2 carriers (HR = 0.16, 95% CI = 0.04 to 0.66; P = .01) ( Table 4 ). The hazard ratios were virtually identical when analyses were adjusted for parity and age at first birth (data not shown). Oophorectomy carried out at less than 45 years of age was associated with a greater reduction in cancer risks than oophorectomy carried out at ages 45 years or older (Supplementary Table 4, available online).
Associations With Common Breast Cancer Susceptibility Alleles
The combined effects of common breast cancer susceptibility alleles on breast cancer risk for BRCA1 and BRCA2 mutation carriers were assessed by constructing a risk score based on the joint distribution of these variants, under the assumption that the hazard ratios combine multiplicatively. Individuals were not followed up after oophorectomy in these analyses. Figure 2 shows the cumulative breast cancer risk in unaffected BRCA2 carriers stratified by tertiles of the risk score. BRCA2 carriers at the highest tertile of the score distribution were at statistically significantly higher risk than women at the lowest tertile (HR = 4.1, 95% CI = 1.2 to 14.5; P = .02). The risk by age 70 years for BRCA2 carriers in the highest tertile was 72%, compared with 20% for those in the lowest tertile. We also tested for trend in risk across the risk score as a continuous variable; the effect was in the same direction, although the association was not statistically significant (HR = 2.9, 95% CI = 0.74 to 11.4; P = .13). Analyses were also repeated with the entire cohort, adjusting for oophorectomy (test for trend across tertiles P = 0.07). The hazard ratios for the SNPs by tertile were consistent with those derived from the retrospective analysis in CIMBA (HR = approximately 1.9). A risk score based on four genetic variants associated with BRCA1 risk was also constructed. There was no evidence of an association, although the estimated risk was higher for women in the highest tertile of risk score (HR = 2.74 for highest vs lowest tertile; P = .41). There was no evidence for an association between risk scores and CBC risk for either BRCA1 or BRCA2 carriers (data not shown).
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