Enhancing endocrine response with novel targeted therapies: why have the clinical trials to date failed to deliver on the preclinical promise?
Acquired resistance to endocrine therapies has severely limited their long-term effectiveness in breast cancer. In recent years a clear rationale has developed for combining signal transduction inhibitors (STIs) with endocrine therapies to delay the emergence of acquired resistance and enhance endocrine responsiveness. A variety of biologic agents have been developed to target key proteins along the EGFR, HER2, MAPK, and P13K/Akt signal transduction cascades. While several of these agents have shown early promise in selected breast cancer models, translating these data into convincing clinical results has been generally disappointing to date. By applying more rigorous trial design and tumor selection criteria to future trials, it is much more likely that adding the new generation of targeted therapies can fulfill its promise in enhancing endocrine responsiveness and our ability to treat breast cancer patients.
Johnston
Stephen R D
SRD
Department of Medicine, Royal Marsden Hospital, Fulham Road, Chelsea, London, UK.|Academic Biochemistry Royal Marsden NHS Foundation Trust, Chelsea, London, UK.
Leary
Alexandra
A
Academic Biochemistry Royal Marsden NHS Foundation Trust, Chelsea, London, UK.
Martin
Lesley-Ann
LA
Breakthrough Breast Cancer Centre, Institute of Cancer Research, London, UK.
Smith
Ian E
IE
Department of Medicine, Royal Marsden Hospital, Fulham Road, Chelsea, London, UK.|Academic Biochemistry Royal Marsden NHS Foundation Trust, Chelsea, London, UK.
Dowsett
Mitch
M
Academic Biochemistry Royal Marsden NHS Foundation Trust, Chelsea, London, UK.
D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D006801:Humans
D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors