Endocrine Therapy in Cancer Treatment

Endocrine Therapy in Cancer Treatment

Endocrine Therapy in Context

Endocrine therapy is a systemic treatment option for solid malignancies, sitting alongside surgery, radiotherapy, chemotherapy, targeted therapy, and immunotherapy. It is used in:

• Breast Cancer

It has limited use in:

• Thyroid Cancer
• NSCLC
• Hepatocellular Carcinoma
• Advanced Cholangiocarcinoma
• Gastric Cancer
• Colorectal Cancer
• Ovarian Cancer
• Pancreatic Ductal Adenocarcinoma
• Melanoma Cancer

Principles of Endocrine Therapy

Endocrine therapy primarily involves estrogen deprivation through surgery (oophorectomy) or pharmacological means. Pharmacological interventions include:

• Anti-estrogens like Tamoxifen
• Aromatase Inhibitors (AIs)

Targeting the ER Pathway

Endocrine therapies target the estrogen receptor (ER) pathway:

• Estrogen Receptor (ER): The target of endocrine therapies.
• AF1 & AF2: Activation function domains on the ER.
• DBD: DNA binding domain.
• SERMs: Selective Estrogen Receptor Modulators, e.g., Tamoxifen.
• SERDs: Selective Estrogen Receptor Downregulators, e.g., Fulvestrant.
• Co-activators/Co-repressors: Proteins that modulate ER activity.
• Growth Factor Receptors: Can interact with the ER pathway.
• MAPK/Akt Kinase/Tyrosine Kinase: Signaling pathways that can affect ER function.
• Growth Factor Inhibitors: Can be used in combination with endocrine therapy.
• AIs: Aromatase Inhibitors block estrogen production.

Structure of New Generation AIs

• Non-steroidal AIs:
  • Anastrozole (Arimidex)
  • Letrozole (Femara)
• Steroidal AIs:
  • Exemestane (Aromasin)

Chemical structures differentiate steroidal from non-steroidal AIs.

Tamoxifen Development

• 1962: Synthesis of ICI 46,474 as a contraceptive pill.
• 1962-1967: Bench and clinic investigation.
• 1967-1971: X-ray analysis.
• 1971: The Nolvadex Development Programme.
• 1973-1975: From Palliative Care to Adjuvant Therapy.
• 1975-1980: The Final Years of ICI's Tamoxifen Project, including the First Collaborative Trials.

Fulvestrant

Fulvestrant is an estrogen receptor (ER) antagonist that down-regulates the ER. Its mechanism of action is distinct from tamoxifen.

Treatment Strategies: The Ovary, Adrenal Glands, and Peripheral Conversion

• Ovary: Produces estrogens; targeted by LHRHa (goserelin) and gonadotrophins (FSH + LH).
• Pituitary Gland: Releases LH and FSH under the influence of LHRH from the hypothalamus.
• Adrenal Glands: Produce androgens and estrogens; influenced by ACTH.
• Peripheral Conversion: Aromatase enzyme converts androgens to estrogens; targeted by aromatase inhibitors.

Acronyms:

• ACTH: Adrenocorticotrophic hormone
• FSH: Follicle-stimulating hormone
• LH: Luteinising hormone
• LHRH: LH-releasing hormone

Clinical Uses of Endocrine Therapy

Endocrine therapy is employed in:

• Prevention
• Neoadjuvant settings (before surgery)
• Primary treatment
• Adjuvant therapy (after surgery)
• Advanced disease

Prevention

Considerations for chemoprevention in women at moderate risk of breast cancer:

• Tamoxifen: For 5 years in premenopausal women, unless there is a history or increased risk of thromboembolic disease or endometrial cancer.
• Anastrozole: For 5 years in postmenopausal women, unless they have severe osteoporosis. (Off-label use in March 2017).
  • Bone mineral density should be assessed and monitored regularly; treatment/prophylaxis for osteoporosis should be started when needed.
• For postmenopausal women with severe osteoporosis or those who do not wish to take anastrozole:
  • Tamoxifen for 5 years if they have no history/increased risk of thromboembolic disease or endometrial cancer.
  • Raloxifene for 5 years for women with a uterus if they have no history/increased risk of thromboembolic disease and do not wish to take tamoxifen. (Off-label use in March 2017).

Neoadjuvant

Treatment before surgery aims to downstage or downsize the tumor, potentially postponing surgery. It may also serve as an alternative to neoadjuvant chemotherapy.

• Neoadjuvant endocrine therapy involves:
  • 2 weeks of Aromatase Inhibitors (AIs) like anastrozole or letrozole, followed by surgery and standard adjuvant therapy.
  • Ki-67 gene expression changes are monitored.
• The effectiveness is measured by recurrence-free survival (RFS).

Primary

Discussion of studies comparing primary endocrine therapy versus surgery, particularly in elderly women.

• Example Study Results:
  • EORTC 10851
  • Nottingham 1

Meta-analysis and systematic reviews (e.g., Cochrane Database) indicate:

• Hazard ratios for surgery vs. primary endocrine therapy.

Adjuvant

Adjuvant therapy is administered after surgery for primary disease. It is a treatment for ‘systemic’ disease and is selected based on ‘risk’ and ER status.

Nottingham Prognostic Index (NPI)

The Nottingham Prognostic Index is used to stratify breast cancer patients into prognostic groups. It is based on:

• Tumor size (in centimeters)
• Lymph node stage (A, B, C)
  • Stage A: Tumor absent from all nodes sampled.
  • Stage B: Tumor in low axillary node only.
  • Stage C: Tumor in apical/internal mammary nodes.
• Histological grade (I, II, III) according to Bloom & Richardson grading system.

NPI Score & Survival

NPI scores correlate with cancer-specific and all-cause ten-year survival rates:

• I (Excellent): ≤2.4
  • Cancer-specific ten-year survival: 96%
  • All-cause ten-year survival: 88%
• II (Good): >2.4 but ≤3.4
  • Cancer-specific ten-year survival: 93%
  • All-cause ten-year survival: 86%
• III (Moderate): >3.4 but ≤5.4
  • Cancer-specific ten-year survival: 78%
  • All-cause ten-year survival: 74%
• IV (Poor): >5.4
  • Cancer-specific ten-year survival: 44%
  • All-cause ten-year survival: 42%

Adjuvant Therapy - premenopausal

Decision-making algorithm for premenopausal women:

• If high-risk disease (and chemotherapy is indicated):
  • Tamoxifen x 5 years.
  • OFS (Ovarian Function Suppression) + Tamoxifen x 5 years.
  • OFS + AI (Aromatase Inhibitor) x 5 years.
• Consider Extended ET (Endocrine Therapy).
• If the patient becomes postmenopausal:
  • Tamoxifen or AI for a total of 10 years of ET.

Adjuvant Therapy - postmenopausal

Adjuvant Hormonal Therapy Options for Postmenopausal Patients include:

• AI vs. TAM (Tamoxifen) (ATAC, BIG-1-98)
• TAM to AI (IES, ABCSG, BIG-1-98)
• AI to TAM (BIG-1-98, TEAM)
• Extended AI (MA.17)

All are superior to 5 years of TAM, but the optimal approach is still under investigation.

Advanced Disease

Treatment strategies based on endocrine sensitivity:

• Endocrine-sensitive (HR+/HER2-):
  • Assess for symptomatic visceral crisis: if present, use Chemotherapy; if absent, ET is preferred.
• Endocrine-resistant:
  • CDK4/6 inhibitor + NSAI (Non-Steroidal Aromatase Inhibitor), or
  • Fulvestrant, or
  • Everolimus + Exemestane
• In cases of PD (progressive disease) or rapid symptomatic visceral crisis, chemotherapy is considered.

Development and Challenges

Key challenges include:

• Overcoming resistance to endocrine therapy.
• Identifying new therapeutic targets.
• Addressing tolerability issues.

Targeting the ER Pathway(REPEATED)

Endocrine therapies target the estrogen receptor (ER) pathway:

• Estrogen Receptor (ER): The target of endocrine therapies.
• AF1 & AF2: Activation function domains on the ER.
• DBD: DNA binding domain.
• SERMs: Selective Estrogen Receptor Modulators, e.g., Tamoxifen.
• SERDs: Selective Estrogen Receptor Downregulators, e.g., Fulvestrant.
• Co-activators/Co-repressors: Proteins that modulate ER activity.
• Growth Factor Receptors: Can interact with the ER pathway.
• MAPK/Akt Kinase/Tyrosine Kinase: Signaling pathways that can affect ER function.
• Growth Factor Inhibitors: Can be used in combination with endocrine therapy.
• AIs: Aromatase Inhibitors block estrogen production.

The Tumor Cell: Intracellular Signaling

The tumor cell's survival and proliferation are influenced by various signaling pathways:

• Steroid Hormones
• Growth Factors (HER1/2)
• IGFR
• P13K/Akt/mTOR pathway
• Ras/Raf/MEK/MAPK pathway

These pathways converge to regulate cell cycle progression, transcription (c-jun, c-fos), and other cellular processes.

Clinical Trial Examples

• MONALEESA-2: First-line Ribociclib + Letrozole in Hormone Receptor-positive, HER2-negative Advanced Breast Cancer.
• Everolimus in Postmenopausal Hormone-Receptor-Positive Advanced Breast Cancer: A phase 3 trial comparing everolimus and exemestane.

Tolerability

Comparison of adverse events between Anastrozole and Fulvestrant:

Actual New Therapies

Strategies include:

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

Summary

• Endocrine therapy is established in adjuvant and advanced settings.
• ER is the best predictor of response.
• Pharmacological manipulation is favored over ablative procedures.
• Ongoing studies are optimizing treatment strategies.