module 16: hormone and targeted cancer therapies

only works on hormone-dependant tumors

- estrogen/progesterone dependent (ex: anti estrogens, aromatase inhibitors)

- testosterone dependent (ex: GnRH modulators, androgen antagonists, CYP17 inhibitors)

often used as adjuvant to surgery and radiation

- post-op: decrease risk of recurrence and kill some metastasized cells.

- pre-op: decrease size of tumor

- overall decrease recurrence rate and prolong life

estrogen receptor modulators

aromatase inhibitors

cyclin dependent kinase 4/6 inhibitors

anti-estrogen drug

- blocks the action of estrogen at breast tissue + other locations -> cancer cell proliferation is prevented

breast cancer therapy

- prodrug -> CYP2D6 activation (CYP2D6 inhibitors interactions !!!)

- long half-life -> single daily dose

- recurrence decline after 5 years = 47%

breast cancer prophylaxis

- decreased breast cancer development by 44% in 4 years

- endometrial cancer development INCREASE

- appropriate only for high risk individuals

adverse effects

- endometrial cancer

- thrombosis + cardiovascular events

- menopause Sx: hot flashes, fluid retention, vaginal discharge...

- very powerful teratogen

aromatase inhibitor

- inhibits the action of the aromatase enzyme which is responsible from for converting testosterone into estrogen

- reduce quantity of estrogen synthesis

1st choice for ER positive breast cancer in post menopausal women

- super high efficacy, so risk of osteoporosis is so high that it cannot be initiated before menopause

- no risk of endometrial cancer or cardiovascular events

adverse effects

- bone pain: use acetaminophen to manage

- bone loss: use vit D to manage

CDK 4/6 inhibitors

- always have to be combined with letrozole (aromatase inhibitor) to be sufficiently active

reserved for types of breast cancer that are resistant to other treatments

adverse effects: SUPER toxic

- bone marrow suppression

- neutropenia

- QT prolongation

- hepatotoxicity

anti-HER2 agent

- monoclonal antibody that inhibits action of HER2

- HER2 is a receptor that promotes cell growth and it is predominantly expressed on breast cancer cells

only for HER2 positive breast cancer patients

adverse effects

- cardiotoxicity: HER2 receptors are also on heart tissue

- hypersensitivity: fatal flu like syndrome that develops within 1st dose

dual mechanism of action

- trastuzumab: inhibits action of HER2

- emtansine: cytotoxic, inhibits microtubule formation

because some cancer cells become resistant to Trastuzumab by absorbing the antibodies inside and degrading it so that it was to stop inhibiting the HER2, but if you add cytotoxic agent this doesn't happen

for HER2 breast cancer patients resistant to Trastuzumab + Paclitaxel

adverse effects:

- same as Trastuzumab

- hepatotoxicity

- neurotoxicity

- teratogen

drugs given to minimize toxicity associated with treatment, not meant to treat the cancer

- doxorubicin and cyclophosphamide or paclitaxel are very common for breast cancer

objective is to block testosterone production from 3 synthesis sites

- testes

- adrenal glands

- prostate tumors

physical castration only removes testes production

anti-testosterone agent: GnRH agonist

- initial testosterone flare up followed by chemical castration (amount increases after the admin but then quickly decreases and goes down to 0)

- only decreases testosterone production at the testes

indication

- advanced prostate carcinoma

toxicity management

- androgen receptor blocker -> minimize flare and adrenal/prostate synthesis

- zolendronate or denosumab or Vit D -> mitigate skeletal related events

anti-testosterone agent: GnRH antagonist

- immediately inhibits testosterone levels

- no flare

- safety+efficacy same as Leuprolide

- half life = 53 days (this is HUGE)

anti-testosterone: androgen receptor blocker

- inhibits adrenal + prostatic testosteron

- adjuvant to chemical/surgical castration

- decreased Leuprolide flare

toxicity

- same as GnRH agonists

- hepatotoxicity

- teratogen

discontinue after flare risk period

- no further advantage + increases toxicity

anti-testosterone: CYP17 inhibitor

- blocks de novo testosterone synthesis

- usually combined with prednisone

indication

- metastatic castration-resistant prostate cancer

- increases survival around 4 months

toxicity

- glucocorticoid deficiency

- hyperaldosteronism -> leads to hypokalemia + HTN

- hepatotoxicity -> do LFT every 2 weeks

- teratogen

- hepatic enzyme interactions -> metabolized by CYP3A4, inhibits CYP2D6

immunotherapy agent

- unique to each patient

- moderate efficacy + high cost

- slight survival improvement over chemo

- no change in tumor progression

dosage

- 3 doses, 2 weeks apart

use

- minimally symptomatic metastatic castration resistant prostate cancer

toxicity management

- NSAIDs + anti-histamine pre-treatment to decrease infusion reactions