Hormonal Agents in Cancer Therapy

Hormonal Agents in Cancer Therapy

1. Definition, principle & scope

• The growth of several cancers — most notably breast and prostate carcinoma — is hormone-dependent / hormone-regulated; interrupting steroid-hormone signalling extends survival and delays or prevents tumour recurrence (G&G 14e Ch.73, p.1435).
• Hormonal (endocrine) agents are not cytotoxic; they modify the growth of hormone-dependent tumours and are essentially palliative / cytostatic rather than cytocidal — hence they must be given for prolonged periods (e.g. tamoxifen ≥5 years) (KDT 8e Ch.64, p.931; Katzung 16e Ch.54, p.1024).
• Three broad pharmacological strategies interrupt steroid-hormone action in cancer (G&G 14e Ch.73, p.1435):
  • Inhibit hormone production — GnRH analogues/antagonists (↓ gonadal output); aromatase inhibitors (↓ peripheral estrogen); abiraterone (↓ adrenal/tumoral androgen).
  • Inhibit binding of hormone to its receptor — SERMs (tamoxifen), AR antagonists (bicalutamide, enzalutamide).
  • Destabilise / degrade the receptor — SERDs (fulvestrant).
• The steroid hormone receptors (ER, PR, AR, GR) are ligand-activated transcription factors of the nuclear-receptor family; blocking their activation reduces expression of gene networks that promote tumour growth and survival (G&G 14e Ch.73, p.1435).
• Two organs are the principal targets because they are dependent on steroid hormones for growth, function and morphological integrity: prostate (androgen-dependent) and breast (estrogen-dependent) (G&G 14e Ch.73, p.1435).
• Glucocorticoids occupy a separate niche — used for antiproliferative and lympholytic effects in haematological malignancies, and to mitigate treatment-related and cancer-related symptoms (G&G 14e Ch.73, p.1435).
• Historical note: breast cancer was the first neoplasm shown to respond to hormonal manipulation; prostate cancer was the second (Katzung 16e Ch.54, pp.1024, 1026). The critical role of androgens in driving prostate cancer was demonstrated by Charles Huggins in 1941, earning the 1966 Nobel Prize and establishing androgen-deprivation therapy (ADT) as the mainstay of advanced prostate-cancer treatment (G&G 14e Ch.73, p.1436).