Reply to E.J. Moylan et al

The National Surgical Adjuvant Breast and Bowel Project (NSABP) B-38 study was designed to determine whether gemcitabine (G) added to dose-dense paclitaxel (P) following dose-dense doxorubicin and cyclophosphamide (dose-dense AC followed by PG) would improve outcomes in women with node-positive breast cancer relative to both dose-dense AC followed by P and docetaxel (T) AC (TAC).1 Dose-dense AC followed by P had been defined as an optimal adjuvant chemotherapy regimen with a toxicity profile that allowed for the addition of G and represented the conventional control arm for B-38. However, it was recognized that if dose-dense AC followed by PG improved outcomes over dose-dense AC followed by P, questions about the activity of the regimen relative to an optimal T-based regimen would persist, so B-38 included TAC as a second control arm. Inclusion of what were perceived as two optimal adjuvant chemotherapy regimens as controls also provided the opportunity for direct comparison of the two regimens in a large phase III trial. Results showed no benefit with the addition of G and no statistical differences in efficacy between the control regimens. However, toxicity profiles differed; thus, physicians and patients can now choose an anthracycline and taxane regimen based on considerations of schedule and toxicity, not relative efficacy. As Moylan et al2 point out, there was no statistically significant difference between dose-dense therapy and TAC in the estrogen receptor (ER) –positive cohort, which supports our statement regarding these findings. The results from B-38 were analyzed and submitted for publication before results from the referenced Southwest Oncology Group (SWOG) study were reported. Clearly, the use of weekly paclitaxel is an acceptable alternative to the dose-dense schedule of four cycles of paclitaxel, but it may be associated with more neurotoxicity. The meta-analysis by Bonilla et al is not based on data from trials but from a literature review. In fact, the authors stated in the conclusion, “However, additional data from randomized controlled trials are needed before dose-dense therapy can be considered as the standard of care.”3 NSABP B-38 is one such trial, with almost 5,000 patients randomly assigned. Moylan et al express “grave concerns” about the characterization in our study of the control regimens with equivalent efficacy as optimal, inferring that we were advocating for indiscriminant use of these regimens in all patients with node-positive, ER-positive breast cancer. This was clearly not the theme of our discussion. B-38 was designed in 2002, was activated in 2004, and completed accrual in 2007. Perou et al4 first described their intrinsic breast cancer types by unsupervised hierarchical clustering analysis in 2000. The apparent utility of the Oncotype DX recurrence score assay to identify subgroups of patients with ER-positive breast cancer who did not derive benefit from chemotherapy was reported in 2006 by the NSABP in node-negative patients5,6 and by SWOG in 2009 in node-positive patients.7 As a result of these and other studies, it has been increasingly recognized that the degree of benefit a patient receives from chemotherapy depends on the molecular subtype of the tumor. As stated in our discussion, biology must be the most important consideration for the development of future trials. The era of large adjuvant trials that do not consider molecular subtypes has run its course. We agree that many patients with node-positive, ER-positive breast cancer may not require a third-generation adjuvant regimen or need chemotherapy at all. Trials such as RxSPONDER ({"type":"clinical-trial","attrs":{"text":"NCT01272037","term_id":"NCT01272037"}}NCT01272037), which is evaluating the role of chemotherapy in node-positive patients with low Oncotype DX recurrence scores, are needed to determine whether promising predictive markers will be able to define groups of ER-positive patients who will not benefit from chemotherapy. Conversely, we should be recruiting patients with high-risk ER-positive tumors to trials such as SWOG 1207/NSABP B-53 ({"type":"clinical-trial","attrs":{"text":"NCT01674140","term_id":"NCT01674140"}}NCT01674140), which is evaluating the addition of a mammalian target of rapamycin inhibitor to endocrine therapy, rather than continuing to address nuances of chemotherapy.