Does the Sequence of Anthracycline and Taxane Matter? The NeoSAMBA Trial.

BACKGROUND: Taxanes usually follow anthracyclines in breast cancer neo/adjuvant treatment, likely because of their later introduction into clinical practice. However, there is no biological rationale that justifies this current standard of care. We compared a taxane followed by an anthracycline-based regimen with the reverse sequence in the neoadjuvant setting. PATIENTS AND METHODS: In a randomized, open-label, single-center phase II trial, women with inoperable, locally advanced, HER2-negative breast cancer were stratified by hormone receptor status and randomized to three cycles of docetaxel (T) followed by three cycles of fluorouracil, doxorubicin, and cyclophosphamide (FAC) versus three cycles of FAC followed by three cycles of docetaxel. Surgery, radiotherapy, and adjuvant hormonal therapy were administered as per local guidelines. The primary endpoint was pathological complete response (pCR), and secondary endpoints included toxicity, event-free survival (EFS), and overall survival (OS). RESULTS: Treatment sequence did not improve pCR, which was 7% with T-FAC and 3% with FAC-T. However, after a median follow-up of 79 months, the 5-year EFS rate was 75.7% (95% confidence interval [CI], 65.4%-87.7%) with T-FAC and 48.2% (95% CI, 37.0%-62.7%) with FAC-T (hazard ratio [HR], 0.46; 95% CI, 0.26-0.81; log-rank p = .0054), and the 5-year OS rate was 89.7% (95% CI, 82.2%-97.8%) with T-FAC and 64.7% (95% CI, 53.6%-78.1%) with FAC-T (HR, 0.41; 95% CI, 0.22-0.78; p = .0052). There were no unexpected toxicities. CONCLUSION: We showed for the first time an improvement in EFS and OS with taxane-first compared with anthracycline-first sequencing chemotherapy in HER2-negative, locally advanced breast cancer. Confirmation of these results may have implications for clinical practice. This trial was registered with Clinicatrials.gov identifier NCT01270373. IMPLICATIONS FOR PRACTICE: The NeoSAMBA trial showed a benefit for taxane-first sequencing chemotherapy consistent with the systematic review of the literature as well as the larger Neo-tAnGo study. Many recent and current ongoing clinical trials have already followed this treatment strategy. As a taxane-before-anthracycline sequence carries neither an incremental cost nor an increased toxicity, and given the available literature on this issue, reinforced that taxane-first regimen can be easily incorporated into daily clinical practice while awaiting confirmation of these findings from larger trials.

Neoadjuvant zoledronic acid for HER2-positive breast cancer: the Zo-NAnTax trial.

BACKGROUND: Preclinical evidence suggests that zoledronic acid (ZOL) works synergistically with chemotherapy by enhancing anti-tumor activity. ZOL blocks the mevalonate pathway and may indirectly interact with human epidermal growth factor receptor 2 (HER2) pathway activation. The clinical efficacy and biological rationale of chemotherapy plus anti-HER2 therapy and ZOL as a part of neoadjuvant therapy has not been previously tested. PATIENTS AND METHODS: We conducted a phase II clinical trial to evaluate the efficacy and safety of ZOL as part of a neoadjuvant treatment in patients with HER2-positive breast cancer (BC). The protocol consisted of four cycles of doxorubicin/cyclophosphamide with ZOL, followed by four cycles of docetaxel with trastuzumab and ZOL prior to surgery. The primary endpoint was the pathologic complete response (pCR) rate. Secondary endpoints were safety and the identification of clinicopathological characteristics associated with pCR. RESULTS: A total of 71 patients with stage IIA to IIIB BC were included, with 60 eligible for the safety assessment and 58 for the efficacy analysis. Overall, the pCR rate was 42%, with higher rates in hormone receptor (HR)-positive tumors (40%), which contrasts with the results of pivotal trials. The most commonly observed grade 3 and 4 events were febrile neutropenia (grade 3, 20%; grade 4, 3%) and diarrhea (grade 3, 12%). CONCLUSIONS: The addition of ZOL as a repositioning drug in neoadjuvant treatment was an effective and well-tolerated therapy. This drug combination might overcome endocrine and anti-HER2 resistance. The higher pCR rates in the HR-positive subgroup deserve further translational investigation.