Clinical Experience With Pemetrexed in Breast Cancer

Alimta (pemetrexed) is a novel multitargeted antifolate that inhibits several enzymes in the de novo pathways of pyrimidine and purine biosynthesis, including thymidylate synthase, dihydrofolate reductase, and glycinamide ribonucleotide formyltransferase. Pemetrexed possesses antitumor activity in several solid tumors, including non–small cell lung cancer, malignant pleural mesothelioma, pancreas, colorectal, gastric, bladder, breast, and head and neck cancers. The main toxicities of the drug are myelosuppression, skin rash, and mucositis. Both myelosuppression and mucositis are more frequent in patients with high homocysteine plasma levels (an indicator of deficient vitamin B₁₂ and folate pools). Supplementation with vitamin B₁₂ and folic acid greatly reduces most severe toxicities and has been implemented in pemetrexed trials since December 1999. Pemetrexed has been tested in five phase II trials in locally advanced or metastatic breast cancer. The drug has shown an activity of around 30% in advanced breast cancer patients with minimal or no prior chemotherapy. In patients who received prior anthracyclines, response rates of 21% were reported. Responses have also been observed in a moderate proportion of patients who had been pretreated with anthracyclines, taxanes, and capecitabine. Some studies have suggested that a correlation exists between thymidylate synthase tumor expression with pemetrexed antitumor activity; this attractive hypothesis should be confirmed in further studies. The optimal dose when combined with vitamin supplementation is under current investigation in patients with breast cancer. A randomized phase II study comparing pemetrexed 600 and 900 mg/m² with vitamin supplementation as first-line treatment for metastatic breast cancer is ongoing.