“Father of tamoxifen” foresees challenges and successes for endocrine therapy

Reporting from the 27th Miami Breast Cancer Conference, ONCOLOGY spoke with internationally renowned breast cancer scientist, V. Craig Jordan, OBE, PhD, DSc. Dr. Jordan highlighted some of the fundamental clinical issues that he explored during his presentation, "Challenges to Improve Adjuvant Endocrine Therapy."

"Adjuvant endocrine therapy for estrogen receptor (ER) positive stage I and Stage II breast cancer has been an important advance and has increased breast cancer patient survivorship. The question to be addressed is whether we can build on our successes and improve adjuvant endocrine therapy," said Dr. Jordan.

Asked about the role of Aromatase inhibitors, Dr. Jordan responded…

"Aromatase inhibitors have demonstrated improved efficacy vs tamoxifen for the adjuvant endocrine treatment of postmenopausal patients with hormone receptor-positive breast cancer. However, recent genomic research on the metabolism of tamoxifen has revealed that variants of CYP2D6 could be important in the success of therapy," said Dr. Jordan.

He added, "High metabolizers of tamoxifen can produce response rates equivalent to aromatase inhibitors. In other words, removal of poor metabolizers can improve the efficacy of tamoxifen. A simple test can be used to identify these patients, thereby improving adjuvant tamoxifen therapy. Another approach is the consideration of the mechanism of drug resistance to tamoxifen and to use drugs to subvert this process."

A major problem in hormonal therapy is primary and acquired resistance to endocrine manipulations. The possible ways to delay or avoid this phenomenon are only allusively understood. Dr. Jordan addressed this issue…

"Drug resistance to tamoxifen implies that the growing tumor can now create angiogenesis. Current research on inhibitors of angiogenesis, particularly those targeted to the kinases that control the activation of receptor 2 (R2) for vascular endothelial growth factor (VEGF), have demonstrated activity that can stop the growth of tamoxifen-stimulated tumors. It is therefore possible to consider using low doses of small molecules either continuously or intermittently during adjuvant tamoxifen therapy to block VEGFR-2. Obviously the strategy would need to be tested in metastatic breast cancer as a prelude to adjuvant clinical trials," said Dr. Jordan.