Pharmaceutical prospectives of anti-estrogen, m-tor, CDK 4/6 in Breast Cancer

1. Anti-Estrogen, m-tor, CDK 4/6
in Breast Cancer
Noha El Baghdady

2. As refined by Douglas Hanahan and Robert Weinberg in 2011

3. 1- The accelerator => full speed ahead;
signals instruct cells to grow and divide chronically

4. Sustaining Proliferative signaling
Driver mutations that convert
normal cellular genes into
serve to stimulate and sustain
progression of cells through
their growth-and-division
cycles.

5. Hallmark 1: Sustaining proliferative signaling
• In breast cancer, Among the
three hormonal receptors (ER,
PR, AR) and the growth receptor
(HER2), ER plays a determinant
role on differentiating breast
tumors regarding their
proliferation ability
(corresponding to the ‘sustaining
proliferative signaling’).

6. Sustaining Proliferative signaling
• The most prominent of these
signaling channels being growth-
promoting signals transmitted
through the RAS-RAF-MEK-MAPK
pathway.
• one-third of human tumors
expressing a constitutively
activated mutant form of RAS.
• The main members of
the RAS gene family—
KRAS, HRAS, and NRAS

7. 2- The brakes have failed; signals to STOP are disabled

8. Evading growth suppressors
• The most prominent brakes:
1- The direct regulators of the cell
division cycle, embodied in the
retinoblastoma protein (pRb)
2- ‘cyclindependent’ kinase inhibitors
that block progression of an individual
cell through its growth-and-division
cycle.
3- p53 pathways :p53 gene is mutated in
~40% of all human cancers

9. Breast Cancer Subtypes

10. Endocrine Therapy

11. Steelman et al., The therapeutic potential of mTOR inhibitors in breast cancer, Br J Clin Pharmacol (2016) 82
1189–1212

12. Aromatase inhibitors
Factor Anastrozole (Arimidex®) Letrozole (Femara®)
Exemestane (Aromasin®)
MOA
Inhibit cytochrome P450 enzyme(s) responsible for estrogen production through peripheral
aromatization.
Dose
1 mg PO daily; higher doses (10
mg) no better efficacy and more
nausea.
Dose: 2.5 mg PO daily
Dose: 25 mg PO daily.
Toxicities
asthenia, myalgias/arthralgias,
headaches, diarrhea, hot flashes,
mild nausea, vaginal dryness,
possible bone loss with long-term
use.
hot flashes, mild nausea,
headache, fatigue,
arthralgias, possible bone
loss with long-term use.
fatigue, hot flashes, nausea,
dyspnea, anxiety, bone loss,
insomnia, pain at tumor sites,
asthenia.

13. Antiestrogens
Factor Tamoxifen Toremifene (Fareston®) Fulvestrant (Faslodex®)
MOA
Selective estrogen receptor
modulators (SERMs)
Selective estrogen receptor
modulators (SERMs)
Selective Estrogen Receptor
Down-regulators (SERDs)
Dose
20 mg PO daily (available in 10 mg
and 20 mg tabs); Europeans use
up to 40 mg/day.
If more than 20 mg, should be
divided
60 mg PO daily
500 mg IM days 1,15,29 then
once monthly therfore
Toxicities
hot flashes, mild nausea,
thromboembolic events, vaginal
discharge, endometrial
hyperplasia, endometrial cancer
(long-term use), ocular effects
(high doses), induces bone loss in
premenopausal women
hot flashes, mild nausea,
headache, fatigue,
arthralgias, possible bone loss
with long-term use.
Nausea, asthenia, pain,
vasodilation, pharyngitis, back
pain, constipation, vomiting,
abd pain, diarrhea, inj site pain

14. Vasomotor Symptoms
• Hot flashes affect 65%‐85% of breast cancer survivors as a result of
therapy
• Chemotherapy and tamoxifen can cause more frequent and severe
hot flashes than natural menopause
• Hot flashes can result in decreased quality of life
• May effect adherence to endocrine therapy

15. Options for the Management of Hot
Flashes in Breast Cancer Survivors
Nonpharmacological
• Avoidance of hot flash triggers
• Wearing loose‐fitting clothing
• Exercise

16. Options for the Management of Hot
Flashes in Breast Cancer Survivors
Non hormonal pharmacologic options
• Selective serotonin reuptake inhibitors (SSRIs)
• Selective norepinephrine reuptake inhibitors (SNRIs)
• Gabapentin/pregabalin
• Clonidine

17. Tamoxifen
• Potential drug interactions with CYP2D6 inhibitors.

18. Metabolism
Compared to tamoxifen, endoxifen and 4-hydroxytamoxifen have a 100-fold greater affinity
for the estrogen receptor and 30 to 100-fold potency in suppressing any estrogen-
dependent cell proliferation.

19. Interactions

20. Tamoxifen / CYP2D6 Inhibitors (Strong)
• Citalopram (Cipram®) – (Depram®)
• Venlafaxine (Effexor®)

21. Tamoxifen/Vitamin K Antagonists
• Tamoxifen + warfarin = ↑ warfarin effects
Tamoxifen
• Selective estrogen receptor modulator (SERM)
• Effect for breast cancer prevention & treatment
• Metabolized primarily by CYP 2D6, 3A4
Warfarin
• Oral anticoagulant
• Effective for stroke, DVT/PE prophylaxis
• Narrow therapeutic window (usual INR 2-3)
• Metabolized primarily by CYP 2C9, 3A4

22. Tamoxifen/Vitamin K Antagonists
Tamoxifen + Warfarin (cont’d)
Clinical evidence
• Several case reports
• 65yo woman stabilized on warfarin (x11yrs) .. increased PT time (required 40% dose reduction)
• Woman stabilized on 25mg/d warfarin … subdural hematoma
Mechanism
• Proposed mechanism: plasma protein-binding displacement
• warfarin – 99% bound
• tamoxifen – 99% bound
Management
• Close PT/INR monitoring
• Adjust warfarin dose accordingly

23. Tamoxifen/Vitamin K Antagonists
Vitamin K Antagonists:
International labeling: This combination is not specifically contraindicated in some non-U.S.
labels.
Risk Rating X: Avoid combination
Summary Tamoxifen may increase the serum concentration of Vitamin K Antagonists.
Severity Major Reliability Rating Fair
Patient Management Combined use of tamoxifen with warfarin is contraindicated in U.S.
labeling due to risk of excessive anticoagulant response and resultant increased risk of bleeding.
It is expected that tamoxifen would interact with other coumarin derivatives in a similar manner.

24. Resistance
• Mechanisms of De Novo & Acquired Endocrine Resistance
• De Novo ET Resistance
• The lost/inactivation of ER/ER pathway
• Activation of PI3K/AKT/mTOR pathway
• Activation of the growth factor or HER pathway activation

25. Steelman et al., The therapeutic potential of mTOR inhibitors in breast cancer, Br J Clin Pharmacol (2016) 82
1189–1212
mTOR Inhibitors

26. mTOR Inhibitors
• Everolimus (Afinitor) ----- Breast cancer (BOLERO-2 trial)----- July
2012
• Sirolimus (Rapamune)
• Temsirolimus (Toisel)

27. Everlimus
Administration
• 10 mg PO daily dose With or without food
Adverse events
• Fatigue
• Stomatitis
• Rash
• Anorexia
• Diarrhea
• Less frequent but clinically relevant:
• Hyperglycemia
• Pneumonitis: Rare but potentially fatal

28. Pharmacokinetics
Absorption Distribution Metabolism Elimination
Peak Plasma Time: 1-2 hr
High-fat meals reduced
systemic exposure to Afinitor
10 mg (as measured by AUC)
by 22% and peak plasma
concentration by 54%
High-fat meals reduced
Afinitor Disperz AUC by 12%
and peak plasma
concentration by 60%
Protein
Bound: 74%
CYP3A4 substrate
PgP substrate and
moderate inhibitor
Competitive inhibitor
of CYP3A4 and mixed
inhibitor of CYP2D6
Half Life: 30 hr
Excretion: 80%
feces; 5% urine

29. Interactions
CYP 450
System
Substrate:
Drug is metabolized by the enzyme
system
Inducer:
Drug that will increase the synthesis
of CYP450 enzymes.
Inhibitor
Drug that will decrease the
metabolism of a substrate.

30. Interactions

31. Drug Interactions
Grabowsky, J. A. (2013). Drug Interactions and the Pharmacist: Focus on Everolimus. Annals of Pharmacotherapy, 47(7–8), 1055–1063.

32. CDk4/6 Kinases

33. CDk4/6 Kinases
• Cyclin D1 gene is amplified in up to 20% breast cancers
• The protein product is overexpressed in over 50% breast cancers
• CDK 1---- G2 to M checkpoint
• CDK 2/4/6- G1 to S checkpoint
• It has been thought that CDK 4/6 inhibitors may have broad
antitumor activity
CDK 4/6 may be able to put the breaks on cancer cell division

34. CDk4/6 Kinases

35. Palbociclib (Ibrance®)

36. CDk4/6 inhibitors
• Palbociclib (Ibrance)--- PALOMA-1,2,3 trials--- February 2015
• Ribociclib (Kisquali) ---- MONALEESA-2,7 trial ---- March 2017
• Abemaciclib (Verzonio) ---- MONARCH 1,2,3 -- -- September 2017

37. Main differences in PK, PD, dosing, and toxicity
between the three CDKi
Factor Palbociclib Ribociclib Abemaciclib (Verzenio ®)
PK
Tmax 4.2–5.5 hours
T1/2 25.9–26.7 hours
Tmax 4 hours
T1/2 24–36 hours
Tmax 4–6 hours
T1/2 17–38 hours
(Crosses blood: brain barrier)
PD
Reduced Rb phosphorylation in
paired tumour biopsies, along with
reduced fluorothymidine-PET
uptake
Reduced Rb
phosphorylation and Ki67
expression in paired
tumour biopsies
Reduced Rb phosphorylation
and TOPO Iiα expression in
paired tumour and skin biopsies
Dosing
125 mg daily (3 weeks, 1-week drug
holiday) or 200 mg daily (2 weeks,1-
week drug holiday) with
food.
600 mg daily (3 weeks, 1-
week drug holiday)
with or
without food.
200 mg twice daily (continuous
dosing) with or without food
when used as a monotherapy
and 150 mg twice daily
continuously in combination
with endocrine treatment.

38. Drug Interactions
Factor Palbociclib Ribociclib Abemaciclib
Strong CYP3A inhibitor
(e.g. itraconazole)
Should be avoided
If use required with
strong inhibitor, reduce
palbociclib dose to 75
mg
Should be avoided
If use required with
strong inhibitor,
reduce the dose to
400 mg
Modify therapy/ monitor closely
• If use required, If the patient Started
with 200 mg or 150 mg BID ↓to 100
mg BID
• In patients who reduced dose to 100
mg BID … ↓50 mg BID
If Strong CYP 3A inhibitor DC, ↑ the
dose after 3-5 T1/2 of the inhibitor
moderate CYP3A
inhibitors (e.g.
verapamil)
Should be avoided
/monitor
increase plasma
palbociclib by ∼40%
Monitor Monitor

39. Factor Palbociclib Ribociclib Abemaciclib
Strong CYP3A inducers
(e.g. phenytoin,
clarithromycin)
decrease plasma
exposure by ∼ 85% 
should be avoided
Should be avoided Should be avoided
Moderate CYP3A
inducers (e.g. modafinil,
diltiazem)
Should be avoided
Weak CYP3A inhibitors
(e.g. fluoxetine) had an insignificant DDI
Drug Interactions

40. • Tamoxifen # Cyp 2D6
• Everolimus # Cyp 3A4 / pgp Substrate
• CDK 4/6 Inhibitors # Cyp 3A4

41. THANK YOU !