Hormone Therapy Part 1

Episode Notes

• Hypothalamic-pituitary-ovarian axis (HPO axis)

  • Hypothalamus: GnRH > pituitary: FSH, LH > ovary: estrogen, progesterone

  • Progesterone

    • Made by thecal cells in corpus luteum in ovary

    • Also made in high concentrations by placenta in pregnancy

  • Estrogen

    • Converted from androstenedione and testosterone by granulosa cells in ovary

    • Also made by peripheral tissues and brain

• Cellular Signaling

  • Progesterone: multiple mechanisms to promote cellular proliferation and cell survival

    • downstream signaling effects on Cyclin D1 and RANKL, MAPK and AKT, WNT1, and EGFR

  • Estrogen: multiple pathways

    • Direct estrogen/estrogen receptor binding 

    • Estrogen receptor is also a downstream target of the growth-factor pathways

      • PI3K/AKT/mTOR axis and the RAS/RAF/MEK/MAPK axis both feed into estrogen receptor activity

    • Multiple pathways can be reason for single treatment failure

• Mechanism of Action

  • Generally cytostatic, not cytotoxic

    • Thus, not typically used in combo with chemo

    • Stability of disease is a good “response” given above

  • Tend to work best in patients with low-volume, slow-growing, indolent disease

• Progestogens

  • Definitions

    • Progesterone: single naturally occurring hormone in this class

    • Progestin: any synthetic compound engineered to mimic progesterone

    • Progestogen is the class that includes both progesterone and progestins

  • Progestins

    • Derived from either progesterone or testosterone

    • Chemical structure determines cross-reactivity w/ other steroid receptors (i.e. androgen, glucocorticoid, mineralocorticoid, etc.)

  • MOA

    • Not entirely understood

    • Possibles: decreased pituitary gonadotropin output, direct antineoplastic effect on tumor cells, interference with estrogen receptor function

• Selective Estrogen Receptor Modulators (SERMs)

  • Tamoxifen

    • In breast → antagonist by competitive inhibition; in endometrium → partial estrogen agonist

    • Cytostatic

      • Reversible cell-cycle inhibitor

      • Decreases estrogen-mediated protein synthesis → G1 block and slowing of proliferation

    • Risks

      • Raises EMCA risk 2- to 3-fold

        • Rises w/ longer duration of use

        • Seen in all histologic types

      • Raises VTE risk 2-fold

        • Mainly during treatment period

      • Drug-drug interactions

        • Particularly CYP2D6 inhibitors (i.e. paroxetine, fluoxetine)

          • Reduce conversion from tamoxifen to active metabolite endoxifen (decreases drug efficacy)

• Aromatase Inhibitors (AIs)

  • Letrozole, anastrole, exemestane

  • MOA

    • Block conversion of peripheral androgens to estrogens

      • Typically used in postmenopausal patients; if used in premenopausal patients, then need to be combined with ovarian suppression (i.e. GnRH agonist)

    • Used in Gyn cancers off-label

  • Side Effects

    • Accelerated bone loss

      • Get baseline and periodic DEXA, give calcium and vitamin D supplementation, recommend weight-bearing exercise

      • If cross fracture risk thresholds → start bone modifying agent (i.e. bisphosphonate or denosumab)

• Selective Estrogen Receptor Degraders (SERDs)

  • Fulvestrant

    • Dosed intramuscularly, monthly

  • Elacestrant, imlunestrant

    • Newer oral agents

  • MOA

    • Degrade estrogen receptors

    • Pure estrogen receptor antagonist

• GnRH Agonists

  • Leuprolide acetate (Lupron)

  • MOA

    • Pre-menopausal: endocrine-axis suppression

    • Post-menopausal: acts directly on FSH receptor and downregulates it

  • Practical note

    • GnRH agonists are agonists first; will get transient surge in LH and FSH → rise in sex steroids → receptor downregulation/axis shut down over 2-4 weeks

      • May show up as breakthrough or worsening vaginal bleeding

• Practical Applications

  • Uterine Cancer and Pre-Cancer

    • Fertility-sparing / non-surgical mgmt of G1 endometrioid EMCA

      • Oral progestins (megace) → 90% regression rate, 25% recurrence rate

        • Most common dose 80 mg BID or 160 daily

      • LNG-IUD

        • 96% regression rate

        • Minimal systemic uptake

        • Preferred option per NCCN

  • Recurrent or Advanced Uterine Cancer

    • Megace 80 mg BID x 3 weeks alternating with tamoxifen 20 mg BID x 3 weeks

      • Tamoxifen upregulates progesterone receptor expression in the endometrium thereby sensitizing to progestin therapy

      • Fiorica et al. 2004

        • ORR 27%, median OS 14 mo, PFS 2.7 mo

        • Among responders, durable responses exceeding 20 mo

        • 4% w/ serious thromboembolic event

    • Aromatase inhibitors (AIs)

      • Limited use as monotherapy (<10%)

      • In combo w/ mTOR inhibitor, RR increase to 30-50%

      • NCCN lists everolimus/letrozole as preferred hormonal regimen for recurrent endometrial cancer

    • Advanced endometrial stromal sarcoma

      • ER and PR almost universally expressed

      • Surgery = backbone of treatment for operative cases, but hormonal therapy = standard systemic approach for advanced, recurrent, or adjuvant treatment

      • NCCN lists AIs as preferred agents, w/ fulvestrant and progestins as other options

    • Ovarian Cancer

      • HT most useful in low-grade, well-differentiated histologies

        • Low-grade endometrioid, LGSOC

        • 50-90% LGSOC are ER positive (vs ~27% in HGSOC)

          • IHC levels of ER expression don’t cleanly predict benefit

        • Adjuvant hormonal maintenance with letrozole after primary chemotherapy for LGSOC is recommended by the NCCN for advanced stage LGSOC

Image: from Ray-Coquard et al 2023

Figure 1 Combining endocrine and targeted therapies to overcome resistance. Resistance to endocrine therapies is common in hormone-driven cancers. Current strategies to overcome this resistance are focused on inhibiting upstream signaling pathways and CDK4/6. Approved therapies, and those currently in clinical development (italicized), are depicted with mechanisms of action that include targeting estrogens, estrogen receptor (ER), growth signaling pathways, and CDK4/6.

Bibliography

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