Breast Cancer 2 - Cytotoxic Tx

Question 1

Chemotherapy in Stage I-III
• Many different regimens/ protocols

Answer 1

• Most protocols are combinations of two or more drugs
• Almost always contain an anthracycline or a taxane or both
• May contain cyclophosphamide and/or 5-fluorouracil and/or carboplatin
• Occasionally single agent capecitabine

• All must be:
• Evidence based
• On Provincial Drug Benefit List

• Selection of regimen based on evidence, disease factors (stage, high risk features) and patient factors (age, comorbidities, organ function, fitness)

Question 2

Chemotherapy in Stage IV Breast Cancer

Answer 2

• Some options are similar to
those in Stage I-IIII disease
• Anthracycline +
cyclophosphamide
• Taxane
• Capecitabine

• Nanoparticle Albumin
Bound Paclitaxel (NABpaclitaxel) (reduces toxicity by being bound to albumin)
• Vinorelbine (Vinca Alkaloid)

Question 3

Anthracyclines (Doxorubicin or Epirubicin)

MOA

Answer 3

• MOA:
• Bind directly to DNA via intercalation between base pairs on the DNA helix
and inhibit DNA repair by inhibiting topoisomerase II
• Chelate with iron and bind DNA and cell membranes producing free radicals
that immediately cleave DNA and cell membranes

Doses are different between anthracyclines
• Epirubicin has more rapid elimination than doxorubicin

Both doxorubicin and epirubicin are RED in color
• important to make sure the right drug is chosen

Hepatic clearance
• Dose reduce in hepatic dysfunction

Question 4

Anthracyclines – Adverse Effects

Answer 4

• Myelosuppression (neutropenia, thrombocytopenia)
• Nausea/vomiting
• MEC when alone but HEC if combined with cyclophosphamide
• Mucositis
• Alopecia (hair loss)
• Secondary malignancies (leukemia)

• Cardiotoxicity
• Thought to be due to free radical damage (damage to myocytes can cause HF)
• Acute – sudden onset, not dose related, present as ECG changes
• Chronic – dose related (toxicity is CUMULATIVE) with indolent onset cardiomyopathy
and presents as reduced LVEF or sometimes symptomatic CHF. Onset can be well
after treatment is complete\

• Vesicant (extravasation can cause necrosis of surrounding tissues) if it doesnt stay in vein and goes into tissue

Will stain body fluids (red urine)

Question 5

Cyclophosphamide MOA

Answer 5

• MOA – Alkylating Agent (Nitrogen Mustard type)
• Binds to N on nucleic acids in DNA. Causes DNA breakage and
inhibition of replication.
• Prodrug and requires activation by liver

Question 6

Cyclophosphamide – Adverse Effects

Answer 6

• Hemorrhagic cystitis
• Injury to the urothelium (bladder) by acrolein (metabolite)
• Cumulative and dose related
• good hydration reduces risk
• advise patients to void frequently, dont hold it

• Nausea and/or vomiting
• Dose related (MEC or HEC)
• More AINV when combined with anthracycline (AC combination is HEC regardless of
cyclophosphamide dose)

• Myelosuppression
• Neutropenia, thrombocytopenia, anemia
• Alopecia (Hair loss)
• Fertility suppression

Question 7

Taxanes(Docetaxel or Paclitaxel)
ends in taxel

Answer 7

• MOA: Disruption of microtubular network that is essential for mitotic (for diviision) and interphase cellular functions.

• Hypersensitivity reactions (Hypersenstivie because cannot diluents because these drugs arent very soluble):
• Docetaxel - Polysorbate 80 diluent
• Paclitaxel – Cremophor EL solvent
• Most likely to occur in first 2 cycles and within first few minutes of the infusion.
• Minor: Flushing, rash, chest tightness, dyspnea, drug fever, chills
• Usually symptoms abate within 15 minutes of stopping the infusion
• Can likely rechallenge with supportive care and slower infusion rate
• Severe: bronchospasm, hypotension, generalized rash/erythema, anaphylaxis
• MD to assess – likely cannot rechallenge

• Diluent used to reconstitute the drug contains enough ethanol to cause intoxication (no driving after chemotherapy and watch for ethanol related
drug interactions)

Question 8

Taxanes – Adverse Effects

Answer 8

• Myelosuppression
• Neutropenia (can be severe), anemia
• Hypersensitivity reactions
• Alopecia

• Fluid retention (more common with docetaxel)
• likely due to increased capillary permeability which allows accumulation of proteins in theminterstitial space
• Can be cumulative in incidence and severity
• symptoms are peripheral edema and weight gain
• can lead to pleural effusions, pericardial effusions, ascites, dyspnea at rest

• Nail changes (hyperpigmentation, hyperkeratosis, orange discoloration)
• Lacrimation (tearing/watery eyes)
• Severe fatigue (more common with docetaxel)
• Peripheral neuropathy
• Acute Intoxication (ethanol content)

Question 9

how to reduce frequency of hypersensitvity rxn and flud retention? for docetaxel

Answer 9

• Dexamethasone 8 mg PO BID starting the day before docetaxel
• Must have at least 3 doses prior to infusion
• Can be given IV pre-chemo if the patient forgot to take as directed

• Performs 3 functions:
• Decrease fluid retention (reversal of increased capillary permeability)
• Decrease hypersensitivity reactions (reduces inflammation)
• Lesser extent: anti-emetic (Note: docetaxel is low emetic risk)

Question 10

Carboplatin

Answer 10

• Analog of cisplatin
• similar to bifunctional alkylating agents
• Covalently binds to DNA and disrupts DNA function
• Dosed based on Calvert formula
• Dose (mg) = AUC x (CrCl in mls/min + 25)

• Benefit of carboplatin over cisplatin is that it is less ototoxic and nephrotoxic
• Often used for patients that can’t tolerate cisplatin (example have renal insufficiency)

Question 11

carboplatin
• Side Effects:

Answer 11

Nausea/Vomiting (less than cisplatin)
• Substantially more myelosuppression as compared to cisplatin
• Anemia (70%), Neutropenia (18%), Thrombocytopenia (25%)

Question 12

HER2 Targeted Therapies
• Goal: target the HER2 receptor or signaling pathway
• Approximately 20% of breast cancer has overexpression of HER2 (HER2/neu +)

Answer 12

for your reference only (don’t memorize)

• Trastuzumab (Herceptin®)
• IV infusion every 3 weeks (8 mg/kg loading dose, 6 mg/kg subsequent doses)
• Pertuzumab (Perjeta®)
• IV infusion every 3 weeks (840 mg loading dose, 420 mg maintenance dose)
• Lapatinib (Tykerb®)
• Oral 250 mg tablet taken once daily on empty stomach
• Trastuzumab Emtasine, Kadcyla®
• IV infusion 3.6 mg/kg q3weeks

dosed very differently

Question 13

“HER” Recap

Answer 13

• HER = Human Epidermal
Growth Factor Receptor
• Transmembrane protein
that once activated,
stimulates intracellular
signaling to proliferate
• Activation of HER2 occurs
by dimerization (coupling)
with another HER
receptor
shoots off message to go go go

Question 14

Pertuzumab and Trastuzumab:
Complementary Mechanisms of Action (Synergistic)

Answer 14

Trastuzumab:
• Inhibits ligand-independent HER2 signaling
• Activates ADCC

Pertuzumab:
• Inhibits ligand-dependent HER2 dimerization and signaling
• Activates ADCC
ADCC = antibody-dependent cell-mediated cytotoxicity;

Pertuzumab binds to ocoupling area of HER2, stops HER2 from finding a buddy

lapatinib a small molecule to cross cell membrane and block inside of cancer cell and block HER2 pathway
do not use lapatinib with the pertuz or trastuz

Question 15

HER2+ Targeted Antibody-Drug Conjugate

Answer 15

trastuz to search out the HER2 positive cells and put a bit of chemo on it
DM1 inhibits tubular polymerization and kills cell off

Trastuzumab emtansine
(Kadcyla®)
• HER2 monoclonal antibody
attached to a potent
cytotoxic agent
• “T-DM1” (trastuzumab +
DM1)

Question 16

Anti-HER2 therapies – Adverse Effects

Answer 16

• Cardiotoxicity (trastuzumab)
• decreased left ventricular ejection fraction (LVEF) (>10%), congestive heart failure (2%) , arrhythmias (3%)
hypertension, cardiomyopathy, and cardiac death
• HER2 pathways in heart tissue responsible for maintaining normal growth, repair, and cell survival
• Not dose related and mostly reversible
• Monitor LVEF during anti-HER2 therapy
• ACEi or β-blockers may be used

• Infusion relate reactions
• pertuzumab approx. 15%
• trastuzumab approx. 30%

• Rash
• pertuzumab approx. 10-20%
• trastuzumab approx. 4%

• Diarrhea
• Lapatinib approx. 40-60% VERY BAD
• pertuzumab approx. 50%
• NOTE: Note: Trastuzumab emtansine (Kadcyla®) has a chemotherapy component and therefore
has adverse effects similar to chemo agents aswell

Question 17

Hormonal Manipulation

Answer 17

• Goal: deprive estrogen for cancer cells that rely on it for growth/proliferation
• Approximately 70% of breast cancer is hormone receptor positive (ER+ and/or PR+)
• Remember: HR+ breast cancer can occur in women and men

Remember: In ER/PR positive breast cancer, the pathology could also reveal HER2 positive OR HER2 negative
• Examples: ER/PR+ & HER2/neu+ OR ER/PR+ & HER2/neu-

Question 18

Tamoxifen

Answer 18

• Dose = tamoxifen 20 mg po daily
• Adjuvant setting X 5-10 years used for adjuvant setting usually
• Occasionally used in metastatic setting - duration assessed based on tolerance and disease

MOA:
• “SERM”: mixed agonist (estrogenic) and antagonist (antiestrogenic) activity depending on the tissue
When it comes to breaset cancer tissue, it is an estrogen blocker
• For breast cancer that is ER+ and/or PR+ , tamoxifen competitively binds to estrogen
receptors producing a nuclear complex that reduces DNA synthesis (antiestrogen effect)
• Blocks estrogen receptors in the breast and breast cancer cells
• Estrogen agonist on endometrium, bone, and lipids

• Tamoxifen (as compared to no endocrine therapy) reduces the risk of breast cancer recurrence by about 40% and mortality by 1/3 over 15 years

Question 19

Tamoxifen – Adverse Effects

Doesn’t change CV risk, brings down LDL AND HDL
Good for bones as agonist for some

Answer 19

• Hot flashes, menopausal symptoms (very common, up to 80%) blockeing some estrogen recepotrs
• Depression (approximately 10%)
• If pre-menopausal, amenorrhea can occur
• Decreased libido, vaginal dryness
• Arthralgia/Myalgias (up to 30%) for 5-10 yrs
• Tumour pain/tumour flare (if metastatic setting)

• Serious Risks:
• DVT/PE (black box warning) 2-5%
• Patients require teaching of the signs/symptoms of blood clots
• Uterine cancers (black box warning) (eg. endometrial adenocarcinoma), agonist in endometrium
• Promptly report any pelvic pain or abnormal vaginal bleeding

Question 20

Tamoxifen Metabolism

Answer 20

• Tamoxifen is sort of a prodrug
• Tamoxifen is metabolized to Ndesmethyltamoxifen (NDM-TAM) (90%) and 4-
Hydroxytamoxifen (4-OH-TAM) (10%)
• NDM-TAM is then metabolized primarily by
CYP2D6 to endoxifen
• Endoxifen’s anti-estrogen potency is 30-100
times higher than tamoxifen
• CYP 2D6 metabolism is important for
endoxifen concentration

Question 21

Tamoxifen
• Drug Interactions

Answer 21

• Strong inhibitors of 2D6 can impact endoxifen concentrations
• Examples of strong inhibitors are several antidepressants such as fluoxetine, paroxetine,
bupropion
• Venlafaxine is NOT a 2D6 inhibitor (use for antidepressant)
• Warfarin
• Anticoagulant effect is increased through unknown mechanism (More frequent INR testing might be needed)
More frequent INR testing might be needed until stable
Drug can caus e blood clots , someone might be on warfarin
Take them off of tamoxifen if they got a clot from it

• Pharmacogenomics
• 2D6 polymorphisms can potentially impact tamoxifen exposure

A lot of potency coming from endoxifen
Debate if CYP2D6 should be avoided - avoid if poss

Question 22

Aromatase Inhibitors

Answer 22

• Anastrozole 1 mg po daily (Arimidex®, generics)
• Letrozole 2.5 mg po daily (Femara®,generics)
• Exemestane 25 mg po daily (Aromasin®, generics)
• In postmenopausal women, the principal source of estrogen is through conversion of androstenedione, produced by the adrenal gland, into estrone and estradiol
• This conversion is catalyzed by the enzyme aromatase and occurs mainly in adipose tissue
• Aromatase inhibitors significantly reduce estrogen levels in postmenopausal women

Blocks aromatase enzyme
Post menopausal - majority of estrogen not coming from ovaries, converted from androstenedione to test or oestrone to estradiol
Enyme converts testos to estradiol in adipose tissue
NOT FOR PREMENOPAUSAL
- see next slide

Question 23

Aromatase Inhibitors – Place in Therapy

Answer 23

• Postmenopausal women
• Premenopausal women with INDUCED menopause
• Oopherectomy
• Medication induced ovarian suppression (goserelin or leuprolide)
• GnRH agonist - creates constant, artificially high levels of FSH/LH → eventually get down-regulation
of GnRH receptors and inhibition of LH secretion → less estrogen production

• Adjuvant Setting
• Administered for up to 5 years or for up to 5 years after tamoxifen (10 years of endocrine therapy total

• Metastatic/Palliative Setting
• Duration based on patient tolerance and disease
• If HER2 negative, often given in combination with CDK4/6 inhibitor (stay tuned)
• The efficacy of the different AIs considered to be generally similar

Question 24

Aromatase Inhibitors (AIs) – Adverse Effects

Answer 24

• Common:
• Arthralgia/myalgias (up to 35%)
Evidence says exercise helps, but may never fully go away
• Hot flashes (menopausal symptoms)
• Peripheral edema
• Vaginal dryness

• Monitoring:
• Bone loss (osteoporosis or fractures), blocking estrogen formation everywhere
• Hypercholesterolemia

Question 25

Fulvestrant

Answer 25

• Estrogen receptor antagonist with NO partial agonist effects
• Competitive binding with estrogen receptors with affinity comparable to estradiol

Place in therapy:
• Metastatic disease mostly
• ER/PR positive
• More evidence in HER2 negative
• Postmenopausal or Premenopausal with ovarian suppression

Administration
• IM injection into buttocks
• Initial: 500 mg IM q 14 days X 3 doses (ie DAY 1, 15,29)
• Maintenance 500 mg IM every 28 days therafter (ie monthly)
• Supplied as TWO 250 mg/5mL pre-filled syringes
• administer contents of syringe intogluteal muscle of
each buttock to provide 500 mg dose

Question 26

Fulvestrant – Adverse Effects

Answer 26

• Injection site reactions (pain, discomfort, neuralgia)
• Up to 27%
• Be mindful of injection site and proximity to sciatic nerve and large blood vessels
• Hypersensitivity reactions
• Can occur quickly or up to several days later
• Estimated at > 10%
• Can be localized pruritus or can be more severe including uticaria or even angioedema
• Hot flashes/vasodilation (up to 18%)
• Headache
• Up to 15%
• Hepatotoxicity
• Elevated ALT/AST (up to 40%) -MONITOR PARAMETER
• Hepatic failure (1%)
• Bleeding or hematoma at injection site (IM) if on anticoagulants or have severe thrombocytopenia (hihger risk of clot with cancer)

Question 27

CDK4/6 Inhibitors

Since it is newer, would give to a pt who has tried 1st 2nd 3rd line tx and didnt work

Answer 27

• CDK 4/6 process:
• Is downstream from estrogen receptorsignaling
• Facilitates phosphorylation of retinoblastoma
(Rb) protein allowing progression from G1 to S
phase in the cell cycle
• Is overactive in cancer cells so there is
uncontrolled cell cycle progression

Indication:
• First line in metastatic breast cancer that is ER/PR positive and HER2 negative in combination
with aromatase inhibitor
• Can be combined with fulvestrant as well, more commonly in second line setting
• NOTE – when combined with tamoxifen, there is a higher risk of QTc prolongation

• Examples of CDK 4/6 inhibitors:
• Palbociclib
• Ribociclib
• CDK 4/6 inhibitors block a signaling process that is downstream from the estrogen receptor.
• SYNERGISM with Anti-estrogen therapies!

Question 28

CDK4/6 Inhibitor – Adverse Effects

Answer 28

• Bone Marrow Suppression
• Anemia
• Neutropenia
• Thrombocytopenia
• Fatigue
• Infections
• Pulmonary Embolism (1-5%)
• CYP 3A4 substrate – watch for drug interactions (no grapefruit!)
• QTc prolongation (for ribociclib, severe prolongation can occur in up to 12%) DONT combine with tamoxifen

Question 29

Triple Negative Breast Cancer

not tested

Answer 29

Pembrolizumab

• Immune Checkpoint Inhibitor
• Stage II and Stage III TRIPLE NEGATIVE breast cancer
• Keynote 522 trial
• Neoadjuvant with “CT (carboplatin + paclitaxel) followed by “AC” (anthracycline + cyclophosphamide)

• THIS IS NEW DATA – it won’t be testable just want you to have it on your radar as
practice may change.
• NOTE - Also sometimes used in metastatic setting with chemotherapy

Question 30

Natural Health Products and Breast Cancer

Answer 30

• Multivitamin may be useful
• Vitamin D 1000 U daily is recommended for bone health (if serum calcium level is not elevated)
• NHP (especially antioxidants) are typically not recommended during chemotherapy
• NHP for menopausal symptoms (hot flashes) are generally not recommended
• Concern that products containing phytoestrogens may encourage the growth of hormone positive breast cancers
• Common examples: black cohosh, evening primrose oil, flaxseed, ginseng, red clover, soy supplements (estrogen like provid fuel to cancer)
• Good reference: http://www.bccancer.bc.ca/patient-and-public-infosite/Documents/NHPandBreastCancer2008.pdf
• Dietary restrictions are not typically necessary