Lack of complete cross-resistance between different aromatase inhibitors; a real finding in search for an explanation?

While third-generation aromatase inhibitors (anastrozole, letrozole and exemestane) are successfully implemented as adjuvant and first-line therapy for hormone-sensitive breast cancer in postmenopausal women, important questions remain to be addressed. An issue of particular interest is the question about lack of complete cross-resistance between steroidal and non-steroidal compounds. Although the studies reporting this phenomenon in general contain a small number of patients, the findings across the different reports seem consistent. While several potential mechanisms have been suggested, so far we lack scientific proof what mechanisms may be responsible for this finding. Finally, we do not know whether lack of cross-resistance actually signals an improved efficacy for certain compounds or may be due to alternative mechanisms of action. Neither do we know whether some tumours are more sensitive to particular drugs. This paper summarizes clinical findings up to now with respect to lack of cross-resistance and discuss potential mechanisms involved.