Using specific cytotoxics with a targeted mind.

It is largely known that clinical activity of a given cytotoxic agent may vary between different patients. This suggests that breast cancer sub-types can be identified within the endocrine-resistant cohort, each of them with a specific degree of sensitivity to different cytotoxic drugs. Pre-clinical and early clinical data suggest that in the future some molecular markers might have practical value in predicting cytotoxics activity in the clinical setting. The most relevant evidence is summarized below according to the type of cytotoxic agent: (a) Anthracyclines Topoisomerase II alpha (topo II) gene aberrations (amplification or deletion) and/or topo II protein overexpression seem to predict response to topo II inhibitors such as anthracyclines. Of note, HER-2 amplified tumors have a concomitant topo II gene aberration in approximately 50% of cases. Moreover, the majority of hyper-proliferating tumors carry topo II protein overexpression. Early clinical data suggest the existence of a direct correlation between anthracyclines activity and the presence of topo II gene aberration or topo II protein overexpression. (b) Taxanes Microtubule-associated parameters (MTAP) such as the TAU protein, HER-2 gene amplification, and p-53 gene mutations, have been suggested as potential predictive markers for taxanes. Although early clinical data support pre-clinical experiments, the lack of large prospectively designed clinical studies makes it difficult to draw conclusions on the predictive value of these molecular markers. (c) DNA-damaging agents The BRCA 1 protein seems to play a major role in activating DNA repair mechanisms. Loss-of-function BRCA 1 mutations might lead to a substantial deficit in DNA repair mechanisms. This could ultimately translate into increased tumor sensitivity to DNA-damaging agents such as alkylating compounds and platinum-derivates. Pre-clinical and early clinical data seem to suggest that some BRCA 1 gene mutations might render the tumor more sensitive to DNA-damaging agents and clinical studies have recently been activated to investigate properly this hypothesis. A new generation of ongoing clinical studies and a "focused" use of the gene micro-array technology will hopefully clarify the complex interaction existing between molecular targets and cytotoxic drug activity. This "targeted" approach to chemotherapy might ultimately lead to a more effective strategy in breast cancer medical treatment.