Cohort Analysis Shows Adjuvant Tamoxifen Reduces Risk of Contralateral Breast Cancer in BRCA1 and BRCA2 Mutation Carriers
In a study reported in Journal of Clinical Oncology, Kelly-Anne Phillips, MD, of Peter MacCallum Cancer Centre and University of Melbourne, and colleagues analyzed the association of adjuvant tamoxifen use and risk of contralateral breast cancer among women carrying BRCA1 and BRCA2 mutations in the International BRCA1 and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Use of tamoxifen was associated with reduced risk of contralateral disease, with the benefit appearing to be independent of estrogen receptor (ER) status of first breast cancer.
Study Details
The study used pooled observational cohort data, self-reported at enrollment and at follow-up. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral breast cancer since 1970 who had no other invasive cancer and no tamoxifen use before first breast cancer and did not develop contralateral breast cancer within 6 months after first breast cancer diagnosis. Two primary analyses were performed. One combined retrospective (ie, time before cohort entry) and prospective (ie, time after cohort entry) follow-up, with follow-up starting at the date of diagnosis of first breast cancer. The second analysis included only data beginning from the time of cohort entry (left truncation of analysis time).
The retrospective/prospective analysis included 1,583 BRCA1 and 881 BRCA2 mutation carriers, of whom 383 (24%) and 454 (52%), respectively, took tamoxifen after first breast cancer diagnosis. Prospective follow-up data (since date of cohort entry) were available for 1,083 women (44%), comprising 657 BRCA1 and 426 BRCA2 mutation carriers, of whom 176 (27%) and 235 (55%), respectively, took tamoxifen after first breast cancer diagnosis. Overall, the median time since diagnosis of first breast cancer was 6.6 years, and the median time since cohort entry was 3.2 years.
ER status of the first breast cancer was known for 44% of patients; the first breast cancer was ER-negative for 76% of BRCA1 mutation carriers and ER-positive for 77% of BRCA2 mutation carriers; 67% of those with an ER-positive first breast cancer used tamoxifen (60% and 71% for BRCA1 and BRCA2 mutation carriers, respectively) compared with 17% of those with an ER-negative first breast cancer (15% and 25%, respectively). A total of 37% of BRCA1 mutation carriers and 33% of BRCA2 mutation carriers underwent bilateral oopherectomy, usually after their first breast cancer. Tamoxifen users tended to be older at diagnosis of first breast cancer (P < .001), which was more likely to be ER-positive (P < .001) and have lobular histology (P = .01). Tamoxifen users were also more likely to have received chemotherapy (P = .001) and to have had bilateral oopherectomy (P < .001).
Reduced Risk With Tamoxifen
In the combined retrospective/prospective analysis, there were 520 contralateral breast cancers over 20,104 person-years of observation, including disease in 24% of BRCA1 and 17% of BRCA2 mutation carriers. In the prospective-only analysis, there were 100 contralateral breast cancers over 4,392 person-years of follow-up. In the combined analysis, after adjustment for age at diagnosis, year of diagnosis, bilateral oophorectomy, and country, hazard ratios for contralateral breast cancer for women taking tamoxifen were 0.38 (95% confidence interval [CI] = 0.27–0.55, P < .001) for BRCA1 mutation carriers and 0.33 (95% CI = 0.22–0.50, P < .001) for BRCA2 mutation carriers. In the prospective analysis, after adjustment for age at diagnosis and country, respective hazard ratios were 0.58 (95% CI = 0.29–1.13, P = .1) and 0.48 (95% CI = 0.22–1.05, P = .07). There were no significant differences in the hazard ratios between BRCA1 and BRCA2 mutation carriers using the combined data (P = .7 for heterogeneity), prospective data only (P = .9 for heterogeneity), or retrospective data only (P = .7 for heterogeneity).
Effect of ER Status
In the combined analysis, hazard ratios for contralateral breast cancer for tamoxifen users were 0.33 (95% CI = 0.13–0.79) for ER-negative status and 0.59 (95% CI = 0.23–1.52) for ER-positive status among BRCA1 carriers and 0.44 (95% CI = 0.14–1.35) and 0.30 (95% CI = 0.15-0.62), respectively, among BRCA2 carriers. However, analysis adjusting for or stratifying on ER status of the first breast cancer showed that the observed associations were not accounted for by this tumor characteristic; hazard ratios for tamoxifen use did not significantly differ by ER status (P = .3 for heterogeneity for both BRCA1 and BRCA2 mutation carriers), although the overall numbers of ER-positive breast cancers in BRCA1 mutation carriers and ER-negative breast cancers in BRCA2 mutation carriers were small.
The investigators concluded: “This study provides observational evidence that, for BRCA1 and BRCA2 mutation carriers, tamoxifen use for first breast cancer might reduce the risk of contralateral breast cancer. Further follow-up of these cohorts will provide increased statistical power for prospective analyses and thus a more definitive answer to this important question in the future.”
The authors reported no potential conflicts of interest.
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