Alterations in the TOP2A and HER2 Genes: Association With Adjuvant Anthracycline Sensitivity in Human Breast Cancers

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Abstract
In this issue of the Journal, O’Malley et al. ( 1 ) present important, critical, and compelling new evidence regarding the association between alterations in the human epidermal growth factor receptor type 2 ( HER2 ) amplicon and incremental sensitivity to anthracycline-based adjuvant therapy for breast cancers. This report is the latest in a series of publications that question the generalized assumption that there is an incremental benefit to all breast cancer patients who receive anthracycline-based adjuvant therapy as opposed to non–anthracycline-containing adjuvant therapy. This premise has dominated the design of studies and clinical practice utilization for the vast majority of adjuvant regimens worldwide over the past 30 years. The widespread use of adjuvant anthracyclines is almost entirely based on the well-known meta-analysis published by the Early Breast Cancer Trialists’ Collaborative Group, frequently referred to as the Oxford “Overview” ( 2 ), rather than results from any single study. Indeed, the majority of individual studies have failed to show a substantial benefit from anthracycline-based adjuvant regimens over non–anthracycline-containing adjuvant regimens in breast cancer. The “Overview” used data derived from more than 15 000 women enrolled in 17 separate trials to show that breast cancer patients who received an anthracycline as part of their adjuvant treatment who had an absolute 3 to 4.5 percentage point improvement in relapse-free survival (RFS) and overall survival (OS) compared with women who received non-anthracycline regimens ( 2 ). The magnitude of these benefits has generally been considered to outweigh the well-known, long-term, and life-threatening problems associated with anthracyclines, that is, cardiac toxicity including congestive heart failure ( 3 , 4 ) and bone marrow dysfunction including acute leukemia and myelodysplasia ( 5 ). However, we are now beginning to appreciate that our previous estimates of these major long-term safety issues were frequently assessed using follow-up times designed to measure differences in efficacy between various regimens rather than the very late toxicities that might be caused by them. Longer follow-up from registry databases of breast cancer patients who received adjuvant anthracyclines for their breast cancers indicates that our initial assessments may have underestimated these long-term toxicities ( 6–8 ). This is true for both cardiac ( 6 , 8 ) and marrow ( 7 ) toxicities, making the judicious and appropriate use of anthracyclines even more critical.