Breast cancer pharmacology

1. Breast Cancer
and Palliative
Care – Case
Study
• GROUP BC3
• EMILY ANDERSON, ALISON DAVIES, ELLEN
PAPE, LOUIS PEARCE, MAISIE REVILL

2. Mrs. JP Background Information
70-year-old active lady, first diagnosed with ER+ Breast Cancer 8 years ago.
Tumour Surgically Removed
Prescribed Tamoxifen
After 5 years of Tamoxifen, was prescribed Letrozole instead for a
further 2 years

3. ER+ Breast Cancer
 ER+ Breast Cancers express oestrogen receptors on their cell surface, with around 80% of
breast cancers falling within this category.
 During surgery or a biopsy, the cancerous cells are tested for oestrogen or progesterone
receptors.
 The binding of oestrogen to the receptor stimulates the cancer to grow. Endocrine therapy is
normally considered in combination with surgery.
(Lumachi et al., 2015)

4. Mechanisms of Oestrogen Receptors
Estrogen enters the cell and Binds to ERa, interacting with Heat shock Protein (HSP)
This interaction causes HSP to dissociate, allowing the conformational change of Era
Phosphorylation and dimerization occurs whereby a functional complex of two subunits is formed, leading to the
activation of Activating Function 1 (AF1) and 2
Ligand-activate binds to the estrogen response element (ERE) upstream of the estrogen-dependent genes
Various co-activators and other transcription factors are recruited to the site leading to the transcription of many
estrogen sensitive growth-promoting genes.
Causing further cell division
(Ring & Dowsett, 2004)

5. Tamoxifen – Partial ER Blocker
Tamoxifen is a selective estrogen receptor modulator (SERM) and
is a partial agonist, directly competing with oestrogen for the
oestrogen receptors.
 Tamoxifen binds to ERa causing dissociation of HSP90 and
allowing dimerization of the ER.
 Helix 12 is prevented from sealing the binding pocket.
 Complex translocates to the nucleus, binding to ERE.
 Helix 12 repositioning prevents the binding of co-activators,
leading to the prevention of AF-2 transcription
 AF-1 remains active so recruits co-activators to the ERE,
promoting RNA polymerase-mediated transcription
 Reduced cancer cell division
(Ali et al., 2016)

6. Letrozole –
Aromatase Inhibitor
Letrozole- Lowers the amount of oestrogen in the
body
Steroidal C- 19 androgen is converted into C-
18 oestrogen by the enzyme aromatase
Letrozole competitively binds to the heme of
aromatase, preventing the conversion of androgens
into oestrogens.
Adverse effects of Letrozole can be hepatitis of the
liver
(Breast International Group, 2005)(Mukhjeree et al, 2022), (Badawy et al., 2021) (Ellis et al., 2001) (Mouridsen et al., 2003)

7. Tamoxifen vs Letrozole
A clinical trial by The Breast International Group compared the
two:
Double blind trial on postmenopausal women, 8028 patients
participated
Disease-free survival was greater in the letrozole group than
the tamoxifen group
Letrozole - 84% Disease free survival, 5-year estimates
Tamoxifen – 81.4% Disease free survival, 5-year estimates
Letrozole was associated with more reported adverse effects
e.g.
Hypercholesterolaemia, Letrozole-43.6% vs Tamoxifen-19.2%
Letrozole – More effective in post-menopausal women than
Tamoxifen
(The Breast International Group, 2005)

8. Why Change to Letrozole?
Mrs. JP changed to Letrozole after 5 years of Tamoxifen treatment
Clinical trials held by Cancer Research only show a 2% reduction in returning cases of
breast cancer in women who took Tamoxifen for 5 years compared to 10 years.
The benefits of another 5 years of treatment must be weighed up against the side effects and
possible resistance development to Tamoxifen
Possible mechanisms of resistance:
Alterations is co-regulatory proteins
Pharmacologic Tolerance
Loss of ERα expression/function
(Gray et al, 2013) (Ring & Dowsett, 2004)

9. Mrs JP's Routine Check-up ...
Cancer progression revealed to be possible metastatic
disease.
Admitted to hospital for scans where liver metastases
is confirmed.
A course of Epirubicin 100mg/m^2 every 3-4 weeks

10. Epirubicin (EPI)
Epirubicin- chemotherapeutic agent belonging to a group of
anthracyclines.
Mechanism of action:
EPI forms a complex with DNA via intercalation between the base pairs
The inhibition of topoisomerase II activity and DNA helicase activity
directly interferes with transcription.
Results in the inhibition of mRNA formation, subsequently leading to
the suppression of nucleic acid and protein synthesis
EPI inhibits DNA helicase activity, whilst inducing reactive oxygen
species formation, triggering apoptosis.
(Liu et al , 2021) (Luiz et al., 2023) (Gao et al., 2020) (Liu et al., 2017) (McClendon & Osheroff, 2007) (Pfizer, n.d.) (Gl & D, 1993) (Wang
et al., 2023)

11. Monitoring whilst on Chemotherapy
Close monitoring is needed for Mrs. JP whilst going through chemotherapy.
 To see if the treatment is working – blood tests to see if there are lowered blood cell counts,
which leads to infection, and physical examinations.
Detecting these side effects early can allow adjustments to be made to manage issues that arise.
 Epirubicin, an anthracycline, has adverse effects on the heart - cardiac monitoring, ECGs and
heart function tests are completed.
ECGs can detect abnormalities within the heart can that can cause heart failure. The abnormality will usually present
with a reduced left ventricular ejection fraction (LVEF).
Mrs. JP's well-being is also important.
Giving her a chance to provide an opportunity to discuss any concerns.
(Wang et al., 2023) (Neftel et al., 2023)

12. Mrs. JP contacts the doctors...
Mrs JP had her first dose of Epirubicin.
She starts passing red urine, the area around the injection site is sore
and "angry" looking.
At the clinic, new blood tests are taken.
The Doctors decide to discontinue Epirubicin and start her
on Trastuzumab and Paclitaxel

13. Discontinuation of Epirubicin
Intravenous administration
May cause severe irritation and damage due to leakage into surrounding tissue
 Extravasation of Epirubicin can result in severe local tissue injury and necrosis requiring wide
excision of the affected area and skin grafting.
In this case the drug is immediately terminated, and ice is applied to the affected area.
(Mt et al., 2023)

14. Trastuzumab Testing
Trastuzumab affects heart function, significantly decreasing left ventricular ejection
fraction (LVEF).
 An ECG and heart scan are done before hand as Trastuzumab can lead to cardiac related
side effects and cardiotoxicity.
Blood tests are used to assess for liver and kidney function.
Kidney – Measure the levels of waste product (creatine) in the blood.
 Liver – Measuring the chemical levels of the blood. Serum Albumin, Bilirubin, Alanine
Transaminase (ALT) and Aspartate Transaminase (AST) are all substances that are measured
to check the functioning level of the liver.
(Woreta & Alqahtani, 2014), (Ishizuna et al., 2014) (Karaye & Sani, 2008), (Maximiano et al., 2016)

15. Paclitaxel
 Broad spectrum anti cancer agents -
Chemotherapy drug.
Paclitaxel binds to microtubules and causes
kinetic suppression of microtubule dynamics,
stopping mitosis.
Consequent arrest at the mitotic stage of the
cell cycle is considered the cause of paclitaxel-
induced cytotoxicity.
Only administered Intravenously
(Zuo et al, 2021)(Wang et al., 2000)(Škubník et al., 2021)

16. How Trastuzumab and Paclitaxel work in
combination?
Trastuzumab – is a monoclonal antibody, which is used for a type
of targeted therapy.
Trastuzumab targets the G0/G1 phase of the cell cycle.
It inhibits the growth of the cell as it reduces signaling mediated by
HER2 through PI3K and MAPK pathways. This promotes apoptosis and
cell cycle arrest.
Trastuzumab works by attaching HER2 proteins onto the surface the
HER2 positive cancer cells and blocks signals that allow the cancer cells
to grow.
Paclitaxel targets Mitosis of the cell cycle
It inhibits the microtubules that make up the mitotic
spindle, kinetically suppressing them so they cannot divide.
(Zuo et al, 2021) (Lee et al., 2002) (Sardesai et al., 2020) (Shu et al., 2020)

17. Human Epidermal Growth Factor
receptor (HER)2
v20-25% of invasive breast cancers exhibits overexpression of the human epidermal
growth factor receptor (HER2) tyrosine kinase receptor.
v10-30% of all HER2 breast cancer are also ER positive breast cancers, the aggressive
condition of Mrs. JP's cancer suggests that she also has HER2 positive proteins.
vThe combination enhances the efficacy of killing the HER2 positive cancer cells through
the different mechanisms, resulting in tumour cell death, compared to using either drug
alone.
(Nahta & Esteva, 2006)

18. Mrs. JP after Trastuzumab and Paclitaxel...
Mrs. JP’s condition deteriorates
She loses weight (60kg down to 45kg)
Liver tests due to abdominal pain
Chemotherapy stopped
Oral Morphine prescribed (Zomorph® m/r capsules 60mg twice a day)

19. Pharmacology of
Opioids

20. Opioid Analgesics- Pharmacokinetics
Absorption
 Majority of opioids are absorbed through the intestine when taken orally
 Some opioids (i.e. Fentanyl) -low bioavailability and rapid first pass metabolism- taken in other routes such
as intranasal, transdermal or intravenous
Distribution
 Distributed through the body through different proteins- morphine and fentanyl by P-glycoprotein (P-gp),
allows movement across BBB
Metabolism - liver
 Phase 1 metabolism: Cytochrome P450 pathway- mainly CYP3A4 (Fentanyl and Oxycodone) and CYP2D6
(Codeine, Tramadol)
 Phase 2 metabolism: Conjugation/both- glucuronidation
Excretion
 Metabolites excreted via the kidneys in urine
(Smith, 2009) (Reeves et al., 2022) (Lugo & Kern, 2002) (Ofoegbu & Ettienne, 2021) (Pathan & Williams, 2012)

21. Opioid Analgesics- Mechanism of Action
Opioids bind to mu (µ), kappa (κ) and delta (δ) opioid receptors which are g-protein coupled
receptors. Once activated, a portion of the g-protein diffuses into the cell and inhibits the production of
cyclic AMP.
This blocks the release of pain neurotransmitters such as glutamate and substance P on the
presynaptic neuron
On the post-synaptic neuron, activated opioid receptors directly block sodium channels to stop
sodium ions from moving into the cell and open potassium channels to allow potassium ions to move
out
This hyperpolarizes the cell, so a larger action potential is required to produce a response
(Drewes et al., 2013) (Trescot et al., 2008) (Cohen et al., 2023)

22. Suitability of Morphine

23. Mrs. JP’s Liver Function Tests
Levels of serum Alanine Transaminase, Aspartate
Transaminase and Bilirubin.
Levels of serum Albumin
Abdominal pain and yellow eyes (Jaundice)
Suggest Mrs. JP has liver damage
Causes of liver damage:
Metastasis
Paclitaxel
Careful considerations will need to be taken when
choosing the suitable pain relief, as this will alter the
metabolism of the drug prescribed.
(Akuyam et al., 2011)

24. Morphine
Pros
First choice medication for severe cancer
pain
Morphine is recommended in patients with
hepatic impairment
Metabolic pathway is primarily
glucuronidation – safer for hepatic impaired
patients
Low doses of Morphine can be used in opioid
naïve patients
Cons
Has clinically relevant active metabolites
Not recommended for patient with reduced
renal function
Can cause nausea, confusion and
constipation
(Viera et al, 2019) (Afsharimani et al, 2011) (Harris et al, 2014)

25. Fentanyl: A Suitable Alternative to
Oral Morphine?
Pros
Does not have any clinically relevant active
metabolites
Safe for patients with renal impairment
Safe for patients with hepatic impairment
Less side effects – Less constipation, nausea
etc..
Cons
Variability in pharmacokinetics when
administered transdermal
Extremely potent
Not recommended for opioid naïve patients
(Viera et al, 2019) (Gelot and Nakhla, 2014) (Harris et al, 2014)

26. Morphine or Fentanyl?
Clinical trial by Claxton et al findings:
Morphine produced better quality of analgesia
Morphine was associated with more side effects
Fentanyl can be used to acute pain, but oral Morphine should be given as a supplement to
Fentanyl
Morphine is believed to be suitable for Mrs. JP in her current condition
Considerations:
Morphine is not safe for patients with renal impairment
Due to Mrs. JP’s age she may have renal impairment
Estimated glomerular filtration rate and urine albumin-creatinine ratio tests should be done
(Claxton et al, 1997)

27. Palliative Care for Mrs. JP
(Cherny et al, 2021)

28. Pain Management and Controlling
Distressing Symptoms
Pain Management
Severe abdominal pain
Manged with opioids such as morphine
Controlling Symptoms e.g.
Fatigue
Constipation
Nausea
Dyspnoea
(Cherny et al, 2021)

29. Psychological Care
Anxiety
Anxiolytic pharmacotherapy
- In conjunction with psychotherapy or cognitive behavioural therapy
(CBT)
Depression
Can be iatrogenic
Antidepressants (SSRIs)
- Psychotherapy and CBT also
Psychological care for both the patient and the family
(Cherny et al, 2021)

30. Other Palliative Care Considerations
Comfort and Mobility
Spiritual support
Communication: with the family and the patient
End of life planning
(Cherny et al, 2021)

31. Thank you
For Your Attention