Metastatic Breast Cancer

Nicole MacDonald BScPhm ACPROncology Pharmacist

Dr. H. Bliss Murphy Cancer Centre

Disclosures

• I have no conflicts of interest to disclose

• I will receive an honorarium for presenting today from CAPhO

Learning Objectives

• Define metastatic breast cancer and describe the diagnostic criteria and prognostic factors

• Describe the different treatment options for metastatic breast cancer

• Discuss the role of hormone and targeted therapies in metastatic breast cancer

• Describe the role of the pharmacy practitioner in patient education, monitoring, and supportive care in metastatic breast cancer

Breast Cancer in Canada

• Breast cancer is the most common cancer in Canadian women and represents 25% of all new cancer diagnoses in this population

• It is estimated that 1 in 9 Canadian women will develop breast cancer and 1 in 30 will die from the disease

• Breast cancer can also occur in men, with an incident rate of 1.2 out of 100 000 people

• For all new breast cancer diagnoses, 5% will occur at Stage IV (also known as metastatic breast cancer)

Risk Factors

• Age

• Personal or familial history of breast cancer

• Certain genetic mutations or conditions (ex. BRCA)

• Dense breasts

• Reproductive history

• Obese

• Radiation exposure

• Hormonal medications

• Atypical hyperplasia

• Alcohol

** Many women are diagnosed with breast cancer without any identifiable risk factors**

Signs and Symptoms

• While breast cancer may not have any signs or symptoms in its earliest stages, these often appear as the tumor grows large enough to be detected as a lump

• Include:oBreast tendernessoChanges in breast shape or sizeo Inverted nippleoNipple dischargeo Lump in axilla

https://blog.brayola.com/wp-content/uploads/2012/10/signsofbreastcancerposter.jpg

Signs and Symptoms

• If breast cancer metastasizes to other parts of the body, other signs and symptoms may develop in relation to where the cancer has spread

• Can include:

o Bone paino Weight losso Jaundiceo Shortness of breath

o Cougho Headacheo Double visiono Muscle weakness

Diagnosis

• Physical exam, mammogram, ultrasound, biopsy, MRI

• Metastatic symptoms present:• Bone/Brain/Liver/Lung

• Bone scan

• Ultrasound or CT of abdomen

• X-ray or CT of chest

• Bloodwork (chemistry, complete blood count)

Classification

• Stage (0-IV)

• Grade (I-III)

• Lymphovascular invasion

• Receptor status• Hormone

• HER2

• Subtype

• De novo versus recurrent metastatic breast cancer

Stage

• TNM system (Tumor/Nodes/Metastasis)• Tumor = size in cm

• Nodes = number and location

• Metastasis = spread to other organs

• There are 5 stages for breast cancer• Stage 0, I, II, III, and IV

• Generally, the higher the stage number, the more the cancer has spread

• Metastatic breast cancer = Stage IV

Grade

• Describes the level of cell differentiation

• Grade I, II, or III

• Low grade • Well differentiated • Appear more like normal cells• Slow growing and less likely to spread

• High grade• Poorly differentiated• Appear more abnormal• Fast growing and more likely to spread

Lymphovascular Invasion

• Term that describes the spread of cancer cells into the blood vessels (vasculature) and/or lymphatics

• Often abbreviated as LVI

• Presence of LVI is associated with a poorer prognosis

Hormone Receptor Status

• Estrogen and progesterone can stimulate the growth of some breast cancer cells

• Cells that have estrogen receptors (ER) and progesterone receptors (PR) on their surface or inside (in the nucleus or other parts of the cell) use these hormones to grow and divide

• Breast cancers that test positive for hormone receptor status can use endocrine therapy as part of the treatment regime

HER2 Receptor Status

• HER2 stands for human epidermal growth factor receptor 2

• HER2’s function is to control a protein on the surface of cells that that enables growth

• When there are too many copies of the HER2 gene in a cell, this leads to amplification of the HER2 protein, also known as overexpression of HER2

• HER2-positive breast cancer is more aggressive and tend to grow and spread more quickly than HER2-negative breast cancer

Histological Subtypes

https://www.womentowomenhealthcare.com/where-breast-cancer-starts/

• Breast cancer can be broadly categorized into in situ carcinoma and invasive (infiltrating) carcinoma

• Ductal cells

• Lobular cells

• Other (less common)

Molecular Subtypes

http://www.pathophys.org/wp-content/uploads/2012/12/breastcancer-copy/

De novo metastatic breast cancer

• Breast cancer is diagnosed as metastatic from the start

• Previously undiagnosed breast cancer cells have spread to other parts of the body prior to diagnosis

• Common sites include bone, brain, liver, or lungs

Recurrent metastatic breast cancer

• Originally diagnosed and treated as a curative intent

• Recurrence of cancer can occur months or years after initial treatment

• Local recurrence - breast cancer recurs at original cancer site

• Distant recurrence - breast cancer recurs at a different site than the original cancer

• Common sites include bone, brain, liver, or lungs

Recurrent metastatic breast cancer

• For breast cancer patients treated with curative intent, there are several factors that can increase the risk of recurrence:o Lymph node involvement

o Larger tumor size

oPositive or close tumor margins

o Lack of radiation treatment post-lumpectomy

o Younger age

o Inflammatory breast cancer

oCancer cells with certain characteristics

Poor Prognostic Factors

• High grade (III)

• Hormone receptor negative disease

• HER2 over-expression

• Presence of LVI

• Younger age (<35 years)

Polling Question #1

• Which of the following would be considered a favourable prognostic factor?

A. Grade III

B. Hormone receptor positive disease

C. HER2 receptor over-expression

D. Lymphovascular invasion (LVI)

Polling Question #1

• Which of the following would be considered a favourable prognostic factor?

A. Grade III

B. Hormone receptor positive disease

C. HER2 receptor over-expression

D. Lymphovascular invasion (LVI)

Goals of Treatment

• Metastatic breast cancer is not considered curable

• Overall goal of treatment = Palliation

• Specific goals of treatment can include:• Maintain quality of life

• Prevent or slow progression of disease (prolong quantity of life)

• Minimize toxicities related to treatment

Treatment Options

• Treatment options available are based on previous treatments used, patient’s overall presentation, and the receptor status of their present breast cancer• ECOG score

• Patient’s overall physical and mental wellness

• ER/PR receptor status

• HER2 receptor status

Treatment Options

• There are several treatment options available for metastatic breast cancer which can include:• Palliative radiation therapy

• Chemotherapy

• Endocrine therapies

• Targeted therapies

Radiation Therapy

• Use of radiation in metastatic setting differs in comparison to adjuvant treatment

• Goal of radiation therapy is palliation

• Can be used to treat symptoms from sites of metastatic disease, including bone or brain metastases

Chemotherapy

• Chemotherapy is usually recommended as the first-line metastatic cancer treatment for certain patients, including:• ER/PR positive tumors which have become resistant to endocrine therapy

• HER2 positive tumors that are estrogen receptor negative (in combination with HER2 targeted therapy)

• Triple negative tumors (ER/PR negative and HER2 negative)

• Certain cases in which a rapid reduction in the tumor is needed despite sensitivity to endocrine therapies

Chemotherapy

• Chemotherapy treatment for metastatic disease is usually single agent or in combination with a targeted therapy (where indicated)

• This differs from the adjuvant setting in which multiple agents are combined into a treatment regimen and level of aggression of the treatment regimen correlates to the disease’s level of aggression

• Chemotherapy may be given continuously (i.e. no set number of cycles) or a patient may have intermittent treatment to allow for interval breaks

Chemotherapy

• Chemotherapy agents and/or regimens commonly seen in the metastatic setting for breast cancer can include an anthracycline or a taxane (similar to adjuvant setting)

• Chemotherapy agents may be given intravenously (IV) or orally (PO)

• Oral chemotherapy agents that may be seen in metastatic breast cancer include capecitabine or etoposide

Adverse Effects

• Chemotherapy agents can cause a variety of adverse effects that can affect a patient’s quality of life or ability to proceed with treatment

• Adverse effects that may occur with chemotherapy can include:• Fatigue

• Hair loss

• Nausea/Vomiting

• Bone marrow suppression

• Bowel changes

• Peripheral neuropathy

Adverse Effects

• Patients may be given supportive medications to help prevent to manage toxicities that can occur with their treatment

• These can include:• Anti-emetics (metoclopramide, prochlorperazine, dimenhydrinate)

• Corticosteroids (dexamethasone)

• Hypersensitivity medications (dexamethasone, ranitidine, diphenhydramine)

• The dosing regimen of these medications can changes based on the chemotherapy agent or regimen used

Endocrine Therapy

• Endocrine therapy can be used in breast cancer that is hormone receptor positive (ER/PR positive) and acts to remove or block hormones and stop or slow down the growth of cancer cells

• These agents are not given concurrently with chemotherapy, but may be given alongside targeted therapies

• Unlike in the adjuvant setting where these agents have a pre-specified duration of therapy, these agents are used in the metastatic setting until they are no longer tolerated or there is disease progression

Endocrine Therapy

• Endocrine agents used in metastatic breast cancer include:

Agent Mechanism of Action

Tamoxifen Selective estrogen receptor modulator (SERM)

Megestrol Synthetic progestin

Fulvestrant Estrogen receptor antagonist

Letrozole Aromatase inhibitor (AI)

Exemestane Aromatase inhibitor (AI)

Anastrozole Aromatase inhibitor (AI)

Tamoxifen

• Selective estrogen receptor modulator (SERM)• Antagonistic action at the estrogen receptor in the breast• Agonistic action at the estrogen receptors in bone, lipids, endometrium

• Used in adjuvant or metastatic premenopausal or postmenopausal patients• Dosed as 20mg PO once daily• Contraindicated with moderate or strong CYP 2D6 inhibitors (ex. paroxetine

or fluoxetine)• Adverse effects:

• Increased risk of VTE• Increased risk of endometrial cancer• Increased risk of hyperlipidemia• Hot flashes• Increase in vaginal discharge

Tamoxifen

https://www.sciencedirect.com/topics/medicine-and-dentistry/tamoxifen-citrate

Megestrol

• Synthetic progestin• Has antiestrogenic properties which disrupt the estrogen receptor cycle

• Used in metastatic breast cancer patients

• Dosed as 160mg PO once daily

• Adverse effects:• Increased risk of VTE

• Adrenal suppression

• Fluid retention

• Glucose intolerance

Fulvestrant

• Estrogen receptor antagonist• Reduces the number of estrogen receptors on breast cancer cells

• Used in postmenopausal metastatic breast cancer patients

• Dosed at 500mg IM into the buttocks every four weeks, after a loading dose of 500mg IM of days 1, 15, 29 in the first cycle

• Adverse effects:• Injection site reaction• Fatigue• GI upset (nausea, diarrhea, abdominal pain)• Hot flashes• Elevated LFTs (liver function tests)

Aromatase Inhibitors

• Block aromatase, an enzyme that the body uses to make estrogen in areas of the body other than the ovaries (such as fat tissue and the adrenal glands

• Used in postmenopausal metastatic breast cancer patients• Can be used with LHRH analogues to medically induce menopause in

premenopausal women

• Letrozole: 2.5mg PO once daily

• Anastrozole: 1mg PO once daily

• Exemestane: 25mg PO once daily

Aromatase Inhibitors

• Adverse effects:• Increased risk of osteoporosis due to bone mineral density loss - patients are

also prescribed calcium and vitamin D to reduce osteoporosis risk

• Hot flashes

• Vaginal dryness

• Muscle or joint pain

• Fatigue

Hot flashes

• Can occur with endocrine therapy agents and can be quite debilitating

• Can be treated with lifestyle modifications or medications

• Lifestyle modifications:• Exercise• Avoidance of triggers (spicy foods, caffeine, stressful situations)• Wearing multiple clothing layers to adjust to body temperature

• Medications:• SNRIs: venlafaxine, desvenlafaxine• SSRIs: paroxetine, citalopram, escitalopram, sertraline• Gabapentin• Clonidine

Polling Question #2

• Which of the following would be the best option to use for hot flashes in a patient on tamoxifen?

A. Venlafaxine

B. Paroxetine

C. Fluoxetine

D. None of these are a good option for this patient

Polling Question #2

• Which of the following would be the best option to use for hot flashes in a patient on tamoxifen?

A. Venlafaxine

B. Paroxetine

C. Fluoxetine

D. None of these are a good option for this patient

Targeted Therapy

• Targeted therapies are available for those with HER2 positive breast cancers and ER/PR positive breast cancers

• May be used alone or in combination with other treatments

• Unlike traditional chemotherapy, these agents directly target cancer cells or signaling pathways that contribute cell growth

• This results in targeted therapies often having fewer toxicities in comparison to traditional chemotherapy

Targeted Therapy: HER2 positive

• Trastuzumab:• Monoclonal antibody (MAB) that is given IV every 3 weeks alone or with chemotherapy• Requires monitoring of cardiac function as may cause heart failure

• Trastuzumab-emtansine Kadcyla®:• Trastuzumab that is combined with a potent chemotherapy agent (emtansine)• Given IV every 3 weeks as a single agent (dosing is different than for trastuzumab alone)• Requires monitoring of cardiac function as may cause heart failure

• Pertuzumab:• Monoclonal antibody (MAB) that is given IV every 3 weeks with trastuzumab +/-

chemotherapy• Requires monitoring of cardiac function as may cause heart failure

• Lapatinib:• Oral small molecule kinase inhibitor with capecitabine or letrozole• Taken once daily on an empty stomach• Known for acne-like rash and diarrhea

Targeted Therapy: HER2 Positive

Wong DJ, Hurvitz SA. Recent advances in the development of anti-HER2 antibodies and antibody-drug conjugates. Ann Transl Med 2014;2(12):122. doi: 10.3978/j.issn.2305-5839.2014.08.13

©2009 by AME Publishing Company

Targeted Therapy: ER/PR Positive

• Everolimus• mTOR kinase inhibitor and immunosuppressive agent• Used in postmenopausal ER/PR positive patients• Cannot be used in patients on concomitant immunosuppressive therapies

• Everolimus is given concurrently with exemestane• Everolimus 10mg PO once daily on an empty stomach• Exemestane 25mg PO once daily with or without food

• Stomatitis: possible toxicity with everolimus• Patients can use an alcohol-free dexamethasone mouth wash to lower risk• 0.1mg/mL suspension use 10 mLs four times a day (swish around mouth for a

minimum of 2 minutes, do not swallow)• Avoid eating or drinking for one hour after use

Targeted Therapy: ER/PR Positive

• CDK 4/6 inhibitors• Palbociclib

• Ribociclib

• Abemaciclib

• Cyclin-dependent kinases (CDKs) are proteins that control the cell cycle

• CDK 4/6 inhibitors selectively block these two kinases to block cell cycle progression

• CDK 4/6 inhibitors are given concurrently with an endocrine agent

CDK 4/6 Inhibitors

Endocrine-Related Cancer 26, 1; 10.1530/ERC-18-0317

Palbociclib

• Taken once daily with food for 21 out of 28 days each cycle

• Dose levels: 125mg, 100mg, 75mg

• Used concurrently with endocrine agents:• Letrozole• Anastrozole• Exemestane• Fulvestrant• +/- LHRH agonist (used in peri or premenopausal patients)

• Drug interactions:• Major substrate of CYP 3A4

Palbociclib

• Adverse effects:• Neutropenia • Thrombocytopenia• Fatigue• Increased infection risk• GI upset

• Monitoring:• Bloodwork (CBC, renal and liver function, electrolytes) at baseline and before

each cycle• Day 14 of first two cycles – bloodwork (CBC) assessed

Ribociclib

• Taken once daily with or without food for 21 out of 28 days each cycle• Dose levels: 600mg, 400mg, 200mg• Used concurrently with endocrine agents:

• Letrozole• Anastrozole• Exemestane• Fulvestrant• Tamoxifen – recent study

• Drug interactions:• Major substrate of CYP 3A4• Moderate inhibitor of CYP 3A4• QT prolonging agents

Ribociclib

• Adverse effects:• Neutropenia • QT prolongation• Thrombocytopenia• Hepatotoxicity• Fatigue• Increased infection risk• GI upset

• Monitoring:• Bloodwork (CBC, renal and liver function, electrolytes) and EKG at baseline and

before each cycle (EKG before cycle 1 and 2 only)• Day 14 of first two cycles – bloodwork (CBC) and EKG assessed (cycle 1 only)

Abemaciclib

• Taken twice daily with or without food continuously each cycle

• Dose levels: 200mg (single agent), 150mg, 100mg, 50mg

• Can be used as a single agent or concurrent with endocrine agents

• Concurrent endocrine agents:• Letrozole

• Anastrozole

• Fulvestrant

• Drug interactions:• Major substrate of CYP 3A4

Abemaciclib

• Adverse effects:• Diarrhea• Elevated serum creatinine• Elevated LFTs• Neutropenia/Thrombocytopenia• Fatigue• Increased infection risk• Nausea

• Monitoring:• Bloodwork (CBC, renal and liver function, electrolytes) at baseline and before each

cycle• Day 14 of first two cycles – bloodwork (CBC and liver function) assessed• Monitor closely for onset of diarrhea – treat with loperamide

CDK 4/6 Inhibitors

Drug Dose levels Frequency Duration Administration

Palbociclib 125mg100mg75mg

Once daily Taken 21 days out of every 28 days cycle

WITH food

Ribociclib 600mg400mg200mg

Once daily Taken 21 days out of every 28 days cycle

WITH or WITHOUT food

Abemaciclib 200mg (single agent)150mg100mg50mg

Twice daily Taken continuously WITH or WITHOUT food

Polling Question #3

• A patient with ER/PR positive metastatic breast cancer is going to start treatment with a CDK 4/6 inhibitor and letrozole. She is on citalopram 40mg PO once daily at home, a drug known to prolong the QT interval. Which CDK 4/6 inhibitor would her citalopram be most likely to interact with?

A. Palbociclib

B. Ribociclib

C. Abemaciclib

D. It does not interact with any of the CDK 4/6 inhibitors

Polling Question #3

• A patient with ER/PR positive metastatic breast cancer is going to start treatment with a CDK 4/6 inhibitor and letrozole. She is on citalopram 40mg PO once daily at home, a drug known to prolong the QT interval. Which CDK 4/6 inhibitor would her citalopram be most likely to interact with?

A. Palbociclib

B. Ribociclib

C. Abemaciclib

D. It does not interact with any of the CDK 4/6 inhibitors

Polling Question #4

• Which adverse effect is more significant with Abemaciclib in comparison with the other CDK 4/6 inhibitors?

A. Fatigue

B. Torsades de Pointe

C. Neutropenia

D. Diarrhea

Polling Question #4

• Which adverse effect is more significant with Abemaciclib in comparison with the other CDK 4/6 inhibitors?

A. Fatigue

B. Torsades de Pointe

C. Neutropenia

D. Diarrhea

Prevention of skeletal related events

• Metastatic breast cancer commonly metastasizes to the bone

• Patients with metastatic breast cancer often receive systemic therapy to prevent the occurrence of skeletal related events secondary to metastatic breast cancer

• Agents can include:• zoledronic acid

• denosumab

• pamidronate

Prevention of skeletal related events

• Important to monitor bloodwork prior to administration of bone antiresorptive agents• Calcium and albumin (corrected calcium)

• Renal function

• Patients should also undergo regular dental assessment to monitor for development of osteonecrosis of the jaw (ONJ)

Pharmacy Practitioner Role

• Pharmacy practitioners can play an important role in education, monitoring, and supportive care management

• Patients receiving treatment for metastatic breast cancer can experience many adverse effects related to their treatment which pharmacy practitioners can help prevent or manage

• Patients may also identify drug-related questions involving their treatment, supportive medications, or natural health products that require pharmacy consultation

• Pharmacy practitioners are involved in patient care during hospital admissions, in outpatient cancer clinics, and in community pharmacies

Pharmacy Practitioner Role

• Pharmacy practitioners that encounter metastatic breast cancer patients can ensure treatment regimen will be safe• Identify treatment protocol and supportive medications selected for patient

• Complete patient medication history of home medications, allergies, natural products, over-the-counter products

• Conduct a drug interaction check of all identified medications

Pharmacy Practitioner Role

• Pharmacy practitioners that encounter metastatic breast cancer patients can provide important education regarding their treatment• Review treatment protocol for possible adverse effects or toxicities

• Assess supportive medications for appropriateness for toxicity risk

• Counsel patient on possible adverse effects or toxicities

• Provide prevention and management tips

• Suggest reputable resources for additional information

• Enlist aid of a drug access navigator for coverage assistance where applicable

Pharmacy Practitioner Role

• Pharmacy practitioners that encounter metastatic breast cancer patients can provide monitoring throughout treatment• Assess for adverse effects or toxicities during patient rounds, through a call-

back system, or at next cycle medication fill

• Assess medication adherence• Correct dose (number of tablets)

• Dosing frequency (once daily, twice daily)

• Administration (with or without food, do not chew or crush)

• Use open ended questions during assessments

• Look for adjustments or switches that can be made to supportive medications

Pharmacy Practitioner Role: Natural Products

• Many patients are interested in using natural products while on treatment for either their overall health benefit or to specifically help with chemotherapy toxicities

• Some patients are also interested in taking them as they feel they can contribute to helping delay or slow progression of disease

• Natural products can interact with treatments via metabolic or execratory interactions, or via their own mechanisms of action

• It is important to counsel patients on checking with their pharmacy team before starting any natural products

Pharmacy Practitioner Role: Natural Products

When assessing the safety of a natural product for a patient on a cancer treatment, consider the following to look out for:

• CYP enzyme interactions – does the natural product slow/increase removal or formation of the drug?

• Hormonal effects – does the natural product contain hormones and is contraindicated in a patient with hormone sensitive cancer (Ex. black cohosh, evening primose oil, flaxseed)?

• Antioxidant – is the patient on a chemotherapy agent that uses oxidation as part of its mechanism of action (ex. anthracyclines)?

• Anticoagulative/antiplatelet effect – Will the natural product increase a chemotherapy patient’s risk of bleeding?

• Mimic adverse effect – is the natural product known to mimic a toxicity caused by treatment that could result in a delay or dose reduction (ex. diarrhea, neutropenia, neuropathy)?

Helpful Resources

• Canadian Cancer Society • Good resource to direct patients to for information presented in a patient-friendly

language

• BC Cancer Agency Natural Products and Breast Cancer• Good summary of natural products that contain hormones for patients with

hormone sensitive breast cancer to avoid

• Natural Medicines and MSKCC “About Herbs”• Great resources for assessing natural product drug interactions, toxicities, or

mechanisms of action

• BC Cancer Agency and Cancer Care Ontario• Great websites for regimen or drug monograph information as well as patient

handouts

Summary

• Metastatic breast cancer patients have several treatment options available to them depending upon their presentation and receptor status

• All treatment options can cause potential adverse effects or toxicities that need to be monitored for and managed accordingly

• Pharmacy practitioners have an important role to play in providing education, monitoring, and supportive care management to these patients both in hospital and community practice

Questions?