Gemcitabine in breast cancer: future directions

Gemcitabine is an active drug in advanced breast cancer both as a single agent and in combination with other chemotherapeutic agents. Its unique mechanisms of action, which involve masked DNA chain termination and several self-potentiating effects on DNA and RNA synthesis enzymes, result in broad and potent activity across many cancer types. Preclinical models have suggested positive interactions with other agents such as trastuzumab, and early-phase clinical trials are exploring potential synergistic activity with another DNA-synthesis targeting drug, the multitargeted antifolate, pemetrexed (Alimta). Many small trials have confirmed the efficacy and tolerability of gemcitabine alone or in combinations with other drugs as summarized in this supplement. Furthermore, neoadjuvant clinical models have shown promising pathologic complete response rates, an endpoint that correlates with prolonged survival. These results taken together have now set the stage for more definitive phase III trials of gemcitabine combinations compared to standard combinations that will directly assess the independent contribution of gemcitabine. In the metastatic setting, survival benefits (if any) are likely to be limited, but the potential to achieve this with preservation of quality of life is good. Synergistic combinations with biological therapies or novel chemotherapeutic agents need to be further explored, and ultimately, randomized trials will be needed to define optimal regimens. The largest clinical benefits might be derived from the proper deployment of gemcitabine combinations with taxanes and/or anthracyclines in the adjuvant setting. Highly active and well-tolerated therapies, especially those that are justified based on preclinical and neoadjuvant models, represent our best hope for successors to current adjuvant regimens. Such trials are now either in the planning stages or already under way.