Recent clinical studies have found that adding gemcitabine to neoadjuvant taxane and anthracycline regimens does not improve pathologic complete response (pCR), a prognostic endpoint associated with patient survival. But findings from the phase 3 Neo-tAnGo trial bolster the case for administering neoadjuvant taxanes ahead of anthracyclines to modestly improve pCR. Experts are now calling for future clinical trials to investigate tailored neoadjuvant regimens for specific patient populations in order to clarify the importance of taxane/anthracycline sequencing.

Historically a treatment for women with inoperable breast tumors, neoadjuvant chemotherapy is now commonly employed to downstage tumors ahead of breast-conserving surgery.1,2 In addition to reducing mastectomy rates, contemporary anthracycline and taxane neoadjuvant chemotherapy for human epidermal growth factor receptor 2 (HER2)-negative breast cancer can yield important prognostic information. pCR was determined to be sufficiently predictive of survival outcomes in patients with breast cancer according to a 2012 meta-analysis by the US Food and Drug Administration (FDA); as a result, the agency suggested its use as a surrogate endpoint in order to accelerate studies of new neoadjuvant agents.3-5 Although pCR is a suitable surrogate endpoint for most breast tumor subtypes, patients with luminal A tumors can enjoy better survival outcomes despite lower pCR rates, and pCR is not considered a suitable endpoint for luminal A or luminal B/HER2-positive tumors.6,7

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Gemcitabine is effective in metastatic breast cancer, but two recent clinical trials that used pCR endpoints have yielded disappointing results when gemcitabine was added to neoadjuvant chemotherapy regimens.3,8 NeoGem, a phase 2 efficacy and safety trial, found that adding gemcitabine to docetaxel after epirubicin and cyclophosphamide did not improve pCR rates in HER2-negative breast tumors.8 Authors of the phase 3 randomized Neo-tAnGo clinical trial similarly reported no significant improvement in pCR when gemcitabine was added to neoadjuvant paclitaxel, epirubicin, and cyclophosphamide chemotherapy.3

But the Neo-tAnGo study findings do seem to bolster previous reports that sequencing taxanes ahead of anthracyclines for neoadjuvant chemotherapy can improve pCR.3 Patients randomly assigned to receive the taxane paclitaxel (with or without gemcitabine) before standard anthracycline experienced a modest but statistically significant increase in pCR: from 15% to 20% (P = 0.03) at a median follow-up of 47 months.3

“These findings confirm the benefit of taxane-first sequencing that was noted in a large retrospective non-randomized study from the M.D. Anderson Cancer Center,” the Neo-tAnGo authors concluded.3

The regimen used in the study “cannot be regarded as a present standard for patients with HER2-positive disease, because no targeted anti-HER2 agent was used,” cautioned Marco Colleoni, MD, and Aron Goldhirsch, MD, of the International Breast Cancer Study Group in Milan, Italy.6