Molecular Genetic Characterization of a Subset of Women With Early Breast Cancer Followed Up for 25 Years in the Stockholm Tamoxifen Clinical Trial

Abstract

The Dar et al 1 secondary analysis of data from the Stockholm tamoxifen randomized clinical trial published in this issue of JAMA Network Open was conducted in the context of life-long follow-up of women with early breast cancer who received treatment with surgery and adjunct biological therapy, endocrine therapy, and/or chemotherapy. Dar and colleagues 1 performed an immunohistochemical analysis of estrogen receptor (ER), progesterone receptor (PR), ERBB2 (formerly HER2), and cellular proliferation marker Ki-67 status using archival formalin-fixed paraffin-embedded tissue samples from the primary breast cancer tumor; these tissue samples were available for 808 of the 1780 women randomized in the Stockholm tamoxifen clinical trial, which was conducted from 1976 to 1990. Among 808 women, 565 were diagnosed with ER-positive and ERBB2-negative (ER-positive/ ERBB2-negative) breast cancer and were included in the secondary analysis. 1 In this selected subgroup, the outcome measure, distant recurrence-free interval at 25 years, was reported as significantly better among women who received tamoxifen therapy for 5 years compared with women who did not. 1 The authors compared this selected subgroup of women with the total clinical trial cohort and concluded that, although highly selected, the patients in the subgroup were representative of all women with respect to primary tumor size and ER status. Nevertheless, the reported conclusions can only directly apply to this subpopulation of women with ER-positive/ ERBB2-negative breast cancer, which was subsequently recategorized by the immunohistochemical analysis performed in 2014. 1 Lifelong follow-up of breast cancer treatment in randomized clinical trials began with the International Breast Cancer Study Group (IBCSG) clinical trials I to V, which have included lifetime follow-up of all participants since 1978. 2 The IBCSG reported in 2016 that the duration of breast cancer-free interval, the primary outcome measure, from diagnosis and attempted curative treatment for women with ER-positive operable breast cancer remained significantly higher than that of women with ER-negative breast cancer for a median follow-up of 24 years. 2 In the IBCSG clinical trials I to IV, participants received adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil for 6 months and adjuvant endocrine therapy with tamoxifen for 12 months; in clinical trial V, participants also received prednisolone for 6 months. 2 The only breast cancer molecular markers measured were the hormone receptors for estrogen and progesterone. 2 The current long-term follow-up report from Dar and colleagues 1 is in the context of adjuvant tamoxifen administered for 5 years to all participants who survived for 2 or more years, 1 which would be expected to improve on the long-term outcome findings reported in the IBCSG clinical trials.The Dar et al 1 study was also performed in the context of increasing recognition that breast cancer is a very complex cancer and that mammographic screening, which is b...