Hormonal Management of Breast Cancer

Hormonal Management of Breast Cancer

1. Definition, rationale & the hormone-dependence concept

• Breast cancer growth is, in a large subset, hormone-dependent: tumour proliferation and survival are driven by oestrogen signalling through the oestrogen receptor (ER), a ligand-activated transcription factor (G&G 14e Ch.73, pp.1435).
• Endocrine therapy works by interrupting the normal feedback controls regulating steroid-hormone synthesis, inhibiting oestrogen production, or inhibiting oestrogen binding to its cognate receptor — thereby blocking expression of gene networks that promote tumour growth and survival (G&G 14e Ch.73, p.1435).
• Three complementary pharmacological strategies underpin ER+ breast-cancer therapy: (i) antagonise oestrogen at the ER (SERMs, SERDs), (ii) reduce oestrogen production (aromatase inhibitors; GnRH/LHRH analogues), and (iii) combine these with cell-cycle or pathway inhibitors (CDK4/6, PI3K, mTOR inhibitors) (G&G 14e Ch.73, pp.1435–6, 1443–4; Figure 73–1A).
• These drugs extend survival and delay or prevent tumour recurrence, and are used across the disease continuum — chemoprevention, adjuvant, and metastatic settings (G&G 14e Ch.73, p.1435; Table 73–1).
• Hormonal/endocrine agents are not cytotoxic; they modify the growth of hormone-dependent tumours. Historically described as "palliative", they are in fact the sheet-anchor of adjuvant and palliative therapy of carcinoma breast, and of primary and secondary breast-cancer prevention (KDT 8e Ch.64, pp.932–3).
• Historical note: high-dose oestrogen was itself once an effective treatment of breast cancer; the growth-inhibitory effect of oestrogens may relate to their ability to induce apoptosis in endocrine-resistant breast cancer. Oestrogens/progestins have, however, been largely replaced by SERMs, SERDs, AIs, and GnRH analogues, which are more effective and better tolerated (G&G 14e Ch.73, p.1435).
• Male breast cancer is rare and predominantly (>90%) ER+/PR+; treatment is directed at inhibiting ER with tamoxifen. Data on AIs or SERDs in males are scant (G&G 14e Ch.73, p.1435).