On the strength of this study, I will consider adjuvant zoledronic acid for high-risk patients treated with endocrine therapy alone (which would typically apply only to patients with major contraindications to chemotherapy, or patients declining chemotherapy). However, this is a single study, which did not address the benefit of adjuvant bisphosphonates among young women receiving chemotherapy. Further trials in this area are clearly needed, and data are anticipated from the AZURE trial (Does Adjuvant Zoledronic acid redUce REcurrence in patients with high-risk localised breast cancer?), which included women with stage II/ III breast cancer receiving chemotherapy and/or endocrine therapy.
Do All Young Women With Breast Cancer Require Chemotherapy?
Given that young women with breast cancer tend to be otherwise healthy (able to tolerate therapy) and face a higher risk of recurrence, there is frequently a strong rationale for administering chemotherapy. For triple- negative patients, chemotherapy is the only proven effective systemic therapy, and for HER2-positive patients, chemotherapy is standard in all regimens. For endocrine receptor– positive patients, age is often a factor that moves physicians and patients toward chemotherapy.
However, several studies have shown that tumor biology as predicted by multigene assays can predict risk of recurrence better than traditional prognostic factors, including age, and may also predict response to chemotherapy.[39,40] For patients with low (and possibly even intermediate) risk of recurrence, Paik and colleagues found minimal to no benefit from additional treatment with CMF (cyclophosphamide, methotrexate, fluorouracil [5-FU]) chemotherapy, in contrast to small benefits predicted by traditional models.[41]
Ongoing studies are addressing the predictive value of the 21-gene recurrence score (the Trial Assigning Individualized Options for Treatment [Rx], or TAILORx) and the Amsterdam 70-gene panel (the Microarray in Node-Negative Disease May Avoid Chemotherapy Trial, or MINDACT) for modern chemotherapy regimens, with patients at intermediate risk randomized to chemotherapy vs no chemotherapy. At this time, testing for biologic recurrence risk using one of these commercially available multigene assays, or within a clinical trial, is appropriate for young women with lymph node–negative, endocrine receptor– positive breast cancer.
This approach may also have value among patients with lymph node–positive disease. It appears likely that biology, as determined by these genetic tests, will prove to be a major predictor of response and benefit from adjuvant chemotherapy, but further data are needed, given the relatively high risk of recurrence (approximately 40% in one study) even for patients classified as low risk.[42]
Selection of Chemotherapy
Several choices confront the clinician considering chemotherapy regimens in this setting. First, one must consider whether to use a more or less intensive regimen in terms of duration of therapy and combination/ sequencing of chemotherapeutic agents, and second, there is the question of precisely which regimen to use. For patients at greatest risk of recurrence—for example, those with multiple positive lymph nodes or those with triple-negative breast cancer, for whom chemotherapy is the only effective systemic therapy— several third-generation regimens offer large reductions in risk of recurrence through the addition of a taxane to an anthracycline-based regimen. For patients at lower risk of recurrence, either anthracycline-based or taxane-based chemotherapy might be appropriate.
With regard to the more intensive regimens, common considerations include (1) dose-dense chemotherapy with AC (doxorubicin [Adriamycin] and cyclophosphomide) followed by paclitaxel (AC-T), (2) FEC (5-FU, epirubicin [Ellence], and cyclophosphomide) followed by docetaxel (FEC-D), or (3) TAC (docetaxel [Taxotere], doxorubicin, and cyclophosphomide). All have proved superior to non–anthracycline- containing regimens in large phase III randomized trials, and have not been compared directly to each other, making any of the above an acceptable choice of therapy (see Table 2).[20]
