Use of Pemetrexed in Breast Cancer

Pemetrexed, a new antifolate drug, has shown broad-spectrum activity in multiple tumor types. Single-agent activity against breast cancer in untreated patients reached 31% and, depending on the type and degree of prior chemotherapy, response rates tended to decrease stepwise from 28% in lightly pretreated patients (ie, with only adjuvant chemotherapy or at maximum one chemotherapy treatment for metastatic disease) to 8% in heavily pretreated patients after exposure with anthracyclines, taxanes, and capecitabine. No clear dose-response relationship could be established. The results from an ongoing prospective, randomized, double-blind phase II study of two different doses (600 mg/m2 and 900 mg/m2 of single-agent pemetrexed) may elucidate this further. In addition, analysis of specific gene profiles and clinical outcome with special emphasis on pathways known to be important for antifolate activity is ongoing. Combinations of pemetrexed with doxorubicin, epirubicin, or cyclophosphamide have also been evaluated in separate phase I/II trials. For the combination of pemetrexed with carboplatin or gemcitabine, dose recommendations from phase I trials that are not restricted to breast cancer have been used. The combination of pemetrexed with gemcitabine or carboplatin has shown remarkable activity. Further results on the use of a pemetrexed-plus-cyclophosphamide combination will be provided by an ongoing prospective, randomized phase II study.