Hormone-refractory breast cancer remains sensitive to the antitumor activity of heat shock protein 90 inhibitors.

PURPOSE: The antiestrogen tamoxifen (Tam) has been used as therapy against estrogen receptor (ER)-positive breast cancer for decades. Most tumors respond initially, but resistance frequently develops. The ER exists in a multiprotein complex containing the molecular chaperone heat shock protein (Hsp) 90, which is known to regulate the stability and activity of this receptor. Therefore, we investigated a ligand-independent approach to hormonal therapy that depletes cellular levels of the receptor by inhibiting the function of Hsp90. EXPERIMENTAL DESIGN: The activity of the Hsp90 inhibitor geldanamycin (GA) and its clinically relevant derivative, 17-allylamino-17-demethoxygeldanamycin (17AAG), was examined at the molecular and cellular levels using Tam-resistant MCF-7 breast cancer cells both in vitro and in tumor xenografts. RESULTS: The ER was depleted by GA in several Tam-resistant cell lines, as were other Hsp90 client proteins such as Akt and Raf-1. Unexpectedly, Tam inhibited ER depletion by GA but had no effect on destabilization of Akt or Raf-1. When SCID mice supplemented with Tam were treated with 17AAG, their tumors also showed no decrease in ER levels as measured by immunofluorescent staining and laser scanning cytometry. In these same tumors, however, decreased Akt and Raf-1 levels were observed. Drug administration also led to inhibition of tumor xenograft growth. The mechanism by which Tam inhibits GA-mediated ER depletion is unclear, but immunoprecipitation experiments showed that Tam does not inhibit the ability of GA to alter the ER-chaperone complex. CONCLUSIONS: Based on its ability to deplete the ER as well as other critical signaling molecules in Tam-resistant breast cancer, 17AAG may provide a useful alternative treatment for patients with recurrent, hormone-refractory breast cancer that should be explored further in Phase II trials. In this context, combined treatment with 17AAG and Tam should be avoided because Tam may inhibit the ability of 17AAG to deplete the ER, potentially reducing its anticancer activity.     

Endometrial cancer--revisiting the importance of pelvic and para aortic lymph nodes

In 1998, FIGO (International Federation of Gynecologists and Obstetricians) required a change from clinical to surgical staging in early endometrial cancer. This staging requirement raised numerous controversies around the importance of determining nodal status and its impact on outcomes. A diversity of opinions exists as to the actual benefits and toxicities associated with surgical staging which includes lymph node sampling, ranging from those whose opinion is that staging is required for all patients even when the a priori risk of nodal involvement is extremely low through to those who consider that staging is unnecessary in any patient. While knowledge of the presence or absence of extra uterine sites of disease may change treatment approaches and direct different treatment interventions in some patients, the impact of those changes on survival is much less clear. This paper examines recommendations for surgical staging in various subgroups of patients with clinically early endometrial cancer and the impact on survival and toxicity of the various approaches and the subsequent use of adjuvant irradiation and/or chemotherapy.