Endocrine Therapy for Cancer Treatment

Endocrine Therapy in Context

• Endocrine therapy is a systemic therapy used to treat solid malignancies, including breast cancer.
• Other systemic therapies include chemotherapy, targeted therapy, and immunotherapy.
• Local therapies include surgery and radiotherapy.

Principles of Endocrine Therapy

• Endocrine therapy involves:
  • Oestrogen deprivation
  • Anti-oestrogens
  • Pharmacological interventions
• These strategies target the ER (oestrogen receptor) pathway.
• AIs (Aromatase Inhibitors) are also used.

Targeting the ER Pathway

• The ER pathway is targeted by:
  • Oestrogen deprivation.
  • Anti-oestrogens (SERMs and SERDs).
  • Aromatase inhibitors (AIs).
• This pathway is modulated by:
  • Oestrogen receptor co-activators/co-repressors.
  • Growth factor receptors (MAPK, Akt kinase, Tyrosine kinase).
  • Growth factor inhibitors.

Tamoxifen

• Tamoxifen was first synthesized in 1962 as a contraceptive pill (ICI 46,474).
• The Nolvadex Development Programme spanned from 1962 to 1980, including:
  • Synthesis of ICI 46,474 (1962-1967).
  • Bench and clinic investigation (1967-1971).
  • X-ray analysis (1971).
  • The First Collaborative Trials (1973-1975).
  • The Final Years of ICI's Tamoxifen Project (1975-1980).
• Evolved from palliative care to adjuvant therapy.

Fulvestrant

• Fulvestrant is an oestrogen receptor (ER) antagonist.
• Down-regulates the ER.
• Has a distinct mechanism of action from tamoxifen.
• Chemical structure includes HO, OH, and a complex chain: $(CH₂),SO(CH2)3CF2CF3$

Treatment Strategies

• Strategies involve:
  • LHRHa (LHRH agonists).
  • Gonadotrophins (FSH + LH).
  • Aromatase Inhibitors.
• The Hypothalamus releases LHRH, which acts on the Pituitary gland, which releases Gonadotrophins (FSH + LH).
• Ovaries produce Oestrogens.
• Adrenal glands produce Androgens and Oestrogens stimulated by ACTH.
• Peripheral conversion via aromatase enzyme also produces Oestrogens.
• ACTH, adrenocorticotrophic hormone. FSH, follicle-stimulating hormone. LH, luteinising hormone. LHRH, LH-releasing hormone.

Clinical Uses

• Endocrine therapy is used in:
  • Prevention
  • Neoadjuvant settings (before surgery)
  • Primary treatment
  • Adjuvant settings (after surgery)
  • Advanced disease

Prevention

• Double mastectomy is a preventive option.
• Recommendations for chemoprevention in women at moderate risk of breast cancer:
  • Consider tamoxifen for 5 years for premenopausal women without a history of thromboembolic disease or endometrial cancer.
  • Consider anastrozole for 5 years for postmenopausal women without severe osteoporosis.
• Women with or at risk of osteoporosis should have their bone mineral density assessed regularly.
• For postmenopausal women with severe osteoporosis or who do not wish to take anastrozole:
  • Consider tamoxifen for 5 years if no history or increased risk of thromboembolic disease or endometrial cancer.
  • Consider raloxifene for 5 years for women with a uterus and no history or increased risk of thromboembolic disease who do not wish to take tamoxifen.
• Refer to NICE guidelines (CG164) for familial breast cancer classification, care, and managing breast cancer and related risks.

Neoadjuvant

• Treatment before surgery.
• Aims:
  • Downstage the tumor.
  • Downsize the tumor.
  • Potentially postpone surgery.
• Alternative to neoadjuvant chemotherapy.
• Neoadjuvant endocrine therapy involves:
  • Biopsy.
  • 2 weeks of AI (anastrozole or letrozole).
  • Assessment of Ki-67 gene expression changes.
  • Surgery.
  • Standard adjuvant therapy.
• Endpoints include RFS (Relapse-Free Survival).

Primary

• Evaluation of primary endocrine therapy based on age groups and H-score:
  • >/=35 yrs (n = 109)
  • >35-50 yrs (n = 903)
  • >50-70 yrs (n = 1,662)
  • D>70 yrs (n = 1,557)
• Cheung KL et al, Crit Rev Oncol Hematol 2008.
• Surgery versus primary endocrine therapy:
  • Cochrane Database of Systematic Reviews Intervention: Surgery versus primary endocrine therapy for operable primary breast cancer in elderly women (70 years plus).
  • Meta-analysis of studies comparing surgery to primary endocrine therapy (PET).
  • Studies included EORTC 10851, Nottingham 1, and St Georges.
  • Other studies CRC, GRETA,Nottingham 2.

Adjuvant

• Adjuvant therapy is administered after surgery for primary disease.
• Treatment targets systemic disease.
• Selection is based on risk and ER (oestrogen receptor) status.

Nottingham Prognostic Index (NPI)

• The Nottingham prognostic index is used to stratify breast cancer patients into 5 prognostic groups.
• It can be applied to study the effects of treatment regimes within groups of similar patients.
• Version: 1.39
• NPI considers:
  • Tumor size (in centimeters).
  • Lymph node stage (Stage A, B, C).
  • Histological grade (Grade I, II, III).
• NPI Score and Cancer-specific ten-year survival:
  • I (Excellent) </=2.4: 96%
  • II (Good) >2.4 but </=3.4 93%
  • III (Moderate) >3.4 but </=5.4 78%
  • IV (Poor) >5.4 44%

Adjuvant Therapy - Premenopausal

• If the patient is premenopausal at diagnosis:

  • If high-risk disease (consider chemotherapy).
  • If not high-risk, consider Tamoxifen x 5 years.
  • Can also consider OFS + Tamoxifen x 5 years or OFS + AI x 5 years.

• If the patient becomes postmenopausal:

  • Continue Tamoxifen x 5 years (Total 10 years ET).

• If the patient is still premenopausal:

  • Continue Tamoxifen x 5 years (Total 10 years ET).

Adjuvant Therapy - Postmenopausal

• Adjuvant Hormonal Therapy Options for Postmenopausal Patients:
  • TAM (Tamoxifen).
  • AI (Aromatase Inhibitor).
  • Upfront AI vs TAM (ATAC, BIG-1-98).
  • TAM to AI (IES, ABCSG, BIG-1-98).
  • AI to TAM (BIG-1-98, TEAM).
  • Extended AI (MA.17).

Advanced

• For post-menopausal HR+/HER2- metastatic breast cancer (mBC):

  • Assess for symptomatic visceral crisis.
  • If yes, chemotherapy is the preferred option.
  • If not, ET (Endocrine Therapy) is the preferred option.

• Endocrine-sensitive:

  • CDK4/6 inhibitor + NSAI (Non-Steroidal Aromatase Inhibitor).

• Endocrine-resistant:

  • post NSAI:
    • Fulvestrant.
    • CDK4/6 inhibitor + Fulvestrant.
    • Everolimus + Exemestane.
  • post TAM/NSAI:
    • Fulvestrant.(bone only)
    • NSAI
    • Everolimus + exemestane.

• If PD (progressive disease) or rapid symptomatic visceral crisis, consider chemotherapy.

Development and Challenges

• Overcoming resistance to endocrine therapy.
• Identifying new targets.
• Improving tolerability of treatments.

Targeting the ER Pathway

• The ER pathway is targeted by:
  • Oestrogen deprivation.
  • Anti-oestrogens (SERMs and SERDs).
  • Aromatase inhibitors (AIs).
• This pathway is modulated by:
  • Oestrogen receptor co-activators/co-repressors.
  • Growth factor receptors (MAPK, Akt kinase, Tyrosine kinase).
  • Growth factor inhibitors.
• The Tumor Cell and hormonal interactions:
  • AI
  • IGFR , MTOR
  • HER 1/2 , RAS, RAF, SOS,MEK , MAPK, pp90sk
  • SERM , SERD
  • CBP , ER P160, C-jun C-fos, HSP

Clinical Trials and Therapies

• MONALEESA-2 Trial: First-line Ribociclib + Letrozole in Hormone Receptor-positive, HER2-negative Advanced Breast Cancer.
• Everolimus in Postmenopausal Hormone-Receptor-Positive Advanced Breast Cancer: mTOR inhibitor everolimus added to exemestane shown to have anti-tumor activity.

Tolerability

• Comparison of adverse events between Anastrozole and Fulvestrant:
  • Hot flushes: 21.0% vs 20.6% ($P=0.91$)
  • GI disturbances: 46.3% vs 43.7% ($P=0.53$)
  • Weight gain: 0.9% vs 1.7% ($P=0.35$)
  • Vaginitis: 2.6% vs 1.9% ($P=0.51$)
  • Thromboembolic disease: 3.5% vs 4.0% ($P=0.68$)
  • Joint disorders: 5.4% vs 10.6% ($P=0.0036$)
  • Urinary tract infection: 7.3% vs 4.3% ($P=0.062$)
  • Withdrawn due to AE: 2.8% vs 1.9%

New Therapies

• Old targets with new, more potent compounds.
• New targets with novel agents.
• Combined therapies.
• Optimal sequencing of therapies.

Summary

• Endocrine therapy is established in adjuvant and advanced settings.
• ER (oestrogen receptor) is the best predictor of response to date.
• Pharmacological manipulation has replaced ablative procedures.
• Ongoing studies aim to optimise treatment strategies.