Adjuvant chemotherapy is not for everyone

The history of breast cancer therapy is cyclical [1]. Each new treatment, whether surgery, hormone therapy, or chemotherapy is initially applied to all patients, but with time, usually 10–20 years, it becomes clear that the overall benefit is substantially smaller than first anticipated because only a portion of treated patients derive any benefit. With further study and time (another 10? years) the clinical, pathological, and, more recently, molecular characteristics of the tumors unlikely to benefit from the new treatment are identified. This was true for mastectomy; clinical staging was introduced to exclude inappropriate patients. With endocrine therapy it became evident after 10–20 years that patients who did not benefit had more rapidly growing tumors (e.g. those with a short disease-free interval). Ten years after that the estrogen receptor (ER) was identified and it was shown that patients without an ER did not respond to endocrine therapy. (It is easy to forget that it took yet another decade for all clinicians to accept the validity of the estrogen receptor! [2, 3]). It has been clear for some time that not all patients derive equal benefit from chemotherapy or from any specific chemotherapy. The importance of ER in determining the likelihood of responding to chemotherapy was first suggested in 1978 [4], but that hypothesis was quickly rejected by many [5–8]. Recently, however, more compelling evidence on the relationship between ER status and benefits from adjuvant chemotherapy make it difficult to ignore this relationship [9, 10] (Table 1). Oncologists are more likely to use lymph node status than estrogen receptor status to decide whether a patient should receive adjuvant chemotherapy, but the proportional reduction in risk is constant for patients in different node categories [9]. In contrast, patients with ER negative tumors derive greater benefit from chemotherapy than those with ER positive tumors. Since most older women have ER positive tumors, summary estimates of either the proportional reduction in odds of recurrence or absolute differences in disease-free survival or overall survival seriously underestimate the benefit for older women with ER negative tumors. The possibility of a similar correlation between benefit and another well-established prognostic factor, HER2/neu, was first made in studies of doxorubicin dose effect [11]. Subsequently, retrospective analyses were performed on the relationship between HER2/neu and outcome in 10 adjuvant chemotherapy studies that compared an anthracycline with a non-anthracycline regimen [12]. There was a statistically significant correlation in only three of these trials, but in a meta-analysis of the six studies that provided sufficient information, there was a significant improvement in both disease-free and overall survival for the anthracycline-treated patients among those with HER-2/neu positive tumors but no advantage for those without overexpression of HER2/neu. [Table 2] The first report of a correlation between HER2/neu and the use of taxane therapy was from a planned subset analysis of CALGB protocol 9344 in which patients were randomized to either four cycles of doxorubicin/cyclophosphamide or the same plus an additional four cycles of paclitaxel [13] (Table 3). In this analysis, those patients who had tumors that were both ER? and HER2/neu negative (52% of the patients) derived no advantage from the added paclitaxel, but there was a 20–30% reduction in the This is an invited commentary to article doi:10.1007/s10549-009-0663-z.