HCPs: The Pharmacist's Quick Reference - Breast Cancer Therapeutics

Breast Cancer (Therapeutics)

A reference guide to breast cancer therapeutics designed for students of medicine/pharmacy/etc. or professionals for review purposes.

• Non-Modifiable Risk Factors

• Age (increased age, higher risk)

• Family History (1 relative = 2-4x increased risk)

• Personal History of Breast Disease

• Benign Breast Disease

• Radiologically Dense Breasts

• History of ovarian, uterine, or colon cancer

• Personal History of endometrial, ovarian, or colon cancer

• Race

• African Americans have the highest rate of death due to breast cancer

• Modifiable Risk Factors

• Increased education

• Increased socioeconomic status

• Postmenopausal obesity

• Lack of exercise

• High-fat diet

• Alcohol, Smoking

• Radiation to the chest wall

• Chemical exposure

• Organochlorines 

• Hormone-Related Risk Factors

• Early menarche or Late menopause

• Before 12 years old or after 55 years old

• Parity status

• Nulliparity (no children) or 1st pregnancy above the age of 30 

• High Bone Density

• Never breastfed

• Post-menopausal estrogen use 

• Hormonal Contraceptives (unclear)

• Recent use is more significant 

• Genetic Risk Factors

• Most breast cancers have no genetic or familial link

• 5% show strong family history

• Family History suggestive of BRCA

• Multiple cases of early onset breast cancer

• Breast and ovarian cancer in the same patient

• Bilateral (both sides) breast cancer

• Male breast cancer

• Ashkenazi Jewish background

• Prophylactic mastectomies do NOT eliminate the risk of BRCA-related breast cancer completely. 

• Chromosome 17

• BRCA-1

• p53

• Chromosome 13

• BRCA-2

• ASC Screening Guidelines

• All women should be familiar with the benefits, limitations, and potential harms of screening.  Women should know how their breasts normally look and feel so they can report any changes to MD right away.

• Clinical breast exams are no longer recommended

• Some women, because of their family history, a genetic tendency, or certain other factors should be screened with MRIs in addition to mammograms. 

• Ages 40-44

• Women should have the choice to start annual breast cancer screening with mammograms if they wish

• Ages 45-54 

• Mammograms should be done every year 

• Ages 55+

• Switch to mammograms every 2 years, or women can continue yearly if they choose

• Screening should continue as long as a woman is in good health and is expected to live for at least 10 more years.

• Screening for High-Risk Patients

• Women with a known BRCA mutation

• Women untested but have a 1st degree relative with BRCA mutation

• Women with 20-25% lifetime risk of breast cancer based on a specialized estimation model

• Age >30 years old

• ACS suggests mammogram + MRI every year 

• Breast Cancer Prevention

•  Prophylaxis Tx

• If the 5-year calculated risk is greater than 1.66%

• Tamoxifen 20mg PO QD for 5 years OR

• Raloxifene 60mg PO QD 

• These treatments are shown to decrease the 5-year risk by 49%.

• Assess each woman’s individual risk/benefit 

• Evaluate all health risks, including breast cancer risk

• Avoid using the term “high risk” (scary!)

• Diagnosis of Breast Cancer

• History and physical

• Mammogram - bilateral 

• Biopsy

• Before starting Chemotherapy or XRT (External Radiation Therapy)

• Order CBC with differential and LFTs

• Work-up for Metastases…

• CXR and Bone Scan (if skeletal symptoms are present)

• Staging of Breast Cancer

• Stage I: Early Stage

• Cancer has spread to other tissue in a small area

• Stage II: Localized

• Can be IIA or IIB based on size and presence in lymph node 

• Stage III: Regional Spread

• Tumor is larger than 5cm and more lymph nodes are involved across a wider region

• In some cases, there is no tumor at all.  Cancer may have spread to the skin or chest wall

• Stage IV: Distant Spread

• Cancer has spread beyond the breast to other parts of the body

• Poor Prognosis Factors

 (elderly women are less likely to have most of these adverse prognostic factors)

• Larger Tumors 

• More than 3 lymph nodes involved 

• Tumors involving skin or chest wall

• ER- / PR- 

• Aneuploid 

• High S Phase

• Poorly differentiated

• HER-2 / Neu +

• Genetic Alterations 

• p53, EGF, c-erbB2 

• African American and Latino women

• Lower INCIDENCE of breast cancer, but WORSE prognosis

• Adjuvant Therapy (After Surgery) in HR+ Disease

• Small Tumors ( ≤ 1 cm) 

• Consider treatment, but generally not required

• HER2 - disease, tumor > 1cm, N0 or N1 - 

• Chemo + Hormone  Therapy

• HER2 + disease, tumor  > 1cm, N0 or N1 - 

• Chemo + Herceptin ± Pertuzumab + Hormone Therapy

• Triple Negative Breast Cancer (TNBC)

• Chemo only 

• HR+ Hormonal Therapy Options

• Premenopausal

• Tamoxifen or Aromatase Inhibitor x5 years 

• ± Ovarian Suppression/Ablation 

• If after 5 years the patient is postmenopausal:

• Tamoxifen or Aromatase Inhibitor x5 years

• If after 5 years the patient is still premenopausal

• Tamoxifen x5 years -OR- no further tx

• Less commonly used Drugs  = Fulvestrant (Qmonthly), Megestrol Acetate (QID), Aminoglutethimide (BID)

• Postmenopausal 

• 1. Aromatase Inhibitor x5-10 years

• Anastrozole or Letrozole are the two preferred 1st line agents for adjuvant & metastatic breast cancer.  They have fewer side effects than SERMs, and are still effective after Tamoxifen or Toremifene failure.

• 2. Aromatase Inhibitor x2-3 years, then Tamoxifen x2-3 years

• Or vice versa 

• Exemestane: a steroidal AI, appears superior to megestrol acetate and tamoxifen.  Used to complete 5 years of adjuvant therapy after 2-3 years of Tamoxifen

• 3. Aromatase Inhibitor x4.5-6 years, then Tamoxifen x5 years

• I believe this also can be done vice versa

• If patient can’t tolerate/refuses to take Aromatase Inhibitor

• Tamoxifen alone

• Less commonly used Drugs  = Fulvestrant (Qmonthly), Megestrol Acetate (QID), Aminoglutethimide (BID)

• Patients with HER-2/Neu Oncogene 

• Expression of these genes is correlated with visceral metastatic disease

• Associated with: shorter DFS, relative resistance to standard Chemotherapy and HRT.

• Trastuzumab (1st Line)

• Binds to extracellular domain of HER-2/Neu

• Synergy with chemotherapy agents

• 2+ or 3+ Expression of HER-2/Neu has the best chance to see a response

• Trastuzumab (Herceptin) as Adjuvant Tx

• If HER-2/Neu 2+ or 3+ give for 52 weeks

• If tumor >1cm or node positive 

• Close Cardiac Monitoring is required

• Baseline, then at 3,6,9 months

• Pertuzumab

• HER-2 receptor antagonist

• 840mg over 60 mins then 420mg over 30-60 mins Q3 weeks

• Black Box Warning: embryo-fetal toxicity (Cat. D)

• Patient must use adequate contraception while taking Pertuzumab + 6 months after d/c (if the woman is of child-bearing age)

• Stages I - III: Adjuvant Chemotherapy 

• AC

• AC = Doxorubicin + Cyclophosphamide

• Given Q2 weeks for 4 cycles, then Q1 week for 12 weeks

• ± Trastuzumab ± Pertuzumab 

• For 1 year

• Monitor CBC, CrCl, LFTs, Cardiac Function, Side Effects

• Stages I - III: General Chemotherapy 

• HR+ but HER2- 

• AC → T → Hormonal Therapy 

• T = Paclitaxel

• These regimens are given sequentially, starting with AC (Doxorubicin + Cyclophosphamide)

• HR+ and HER2+

• AC → T ± Trastuzumab or Pertuzumab → Hormonal Therapy 

• HR- and HER2+

• AC → T ± Trastuzumab or Pertuzumab

• HR- and HER2- (Triple Negative)

• AC → T 

• Predicting the Response to Chemo in HER2- patients

• Scores via 21-gene RT-PCR Assay are approved to determine recurrence score to predict the response to chemo in HER2- patients

• Low (< 18)

• no chemo, only adjuvant endocrine therapy

• Intermediate (18-30) 

• Adjuvant Endocrine Therapy  -OR- 

• Adjuvant Chemo → Endocrine therapy 

• High (>30) 

• Adjuvant Chemo + Endocrine Therapy 

• Treatment of Stage III

• Very poor prognostic group, less than 50% have a 5-year survival

• Local tumor is too large for direct surgical resection

• Use neoadjuvant therapy to shrink tumors prior to surgery

• Chemo → Surgery → Adjuvant Therapy as mentioned above 

• Follow-Up after Adjuvant Therapy if Disease-Free (remission?)

• Physical Exam

• Annual:

• Mammography

• IF taking a SERM: Pelvic exam

• If taking AI: Monitor Bone Health and CV Risk

• DEXA scan

• Lipid Panel 

• Treatment of Stage IV (Metastatic)

• No longer curable, but some women may survive 5+ years with therapy

• Hormonal Therapy

• used if ER/PR +, unknown or cannot tolerate chemotherapy, or visceral crisis

• Chemotherapy 

•  1st Line option if the patient has a life-threatening disease, is very symptomatic, or is hormone refractory

• Can also be used in a neoadjuvant (BEFORE surgery) setting

• Denosumab or IV Bisphosphonates

• If the patient has bone disease, to prevent fractures and pain

• Goal of Treatment = to maintain the QOL while controlling symptoms and prolonging survival 

• Treatment of Metastatic HR+, HER2- Breast Cancer

• If patient had Endocrine Therapy within the past year

• Premenopausal 

• Ovarian Ablation/Suppression + Different Endocrine Tx

• Postmenopausal

• Different Endocrine Tx ± CDK4/6 or mTOR inhibitor 

• If the patient DID NOT have Endocrine Therapy within the past year

• Premenopausal

• Same as above

• Postmenopausal

• Aromatase Inhibitor + CDK4/6 (preferred)

• Visceral Crisis - use Chemotherapy

• Treatment of Metastatic HR+ HER2+ Breast Cancer

• TAXANE + TRASTUZUMAB + PERTUZUMAB

• Always the preferred option for +/+ 

• Regardless of HR status, treat with HER2 therapy

• Hormonal Options or Chemo alone are reserved for Refractory/Intolerant Patients

• HER2 Alternatives

• Kadcyla (ado-Trastuzumab Emtansine) 

• HER2 antibody + microtubule inhibitor 

• 3.6 mg/kg IV Q3 weeks over 90 minutes for 1st infusion, then over 30 mins if tolerated

• Ab is humanized anti-HER2 IgG1, Trastuzumab.  Small molecule cytotoxin, DM1, is a microtubule inhibitor 

• Upon binding to sub-domain IV of the HER2 receptor, Kadcyla undergoes receptor-mediated internalization → lysosomal degradation → intracellular release of DM1-containing cytotoxic catabilites.  Binding of DM1 to tubulin disrupts microtubule networks in the cell, which results in CELL CYCLE ARREST (M) and apoptosis.  Also works on HER2 in other ways, but I don’t care enough to type it.

• Warnings: hepatotoxicity, LVEF dysfunction, embryo fetal toxicity (Category D), do not sub for Herceptin, ILD, infusion-related rxns, thrombocytopenia, PN, extravasation

• ADRs: fatigue, musculoskeletal pain, headache, thrombocytopenia, increased transaminases (LFTs) & constipation

• Trastuzumab + Chemo 

• Lapatinib or Other HER2 Therapies:

• Inhibits intracellular TK or HER2 & EGFR → inhibits tumor growth

• Not the preferred tx option

• The patient must overexpress HER2

• Used in combo with Capecitabine 

• Lapatinib 1250 mg PO w/o food QD continuously + Capecitabine 2000 mg/m2 divided into 2 doses Q12h with food for days 1-14 of 21 day schedule

• Adjust dose for cardiac toxicity, hepatic impairment, or other severe toxicity

• Absorption increases with food, metabolized through CYP3A4

• ADRs: NVD, rash, hand-foot-syndrome, reversible cardiotoxicity, ILD, QT prolongation 

• Patient Counseling

• clearly explain the regimen

• Take Lapatinib 1 hour before or after a meal, but Capecitabine with food or within 30 minutes of a meal

• Avoid grapefruit juice, St. John’s Wort

• Teach patient how to manage diarrhea, rash, and to report major side effects

• Stage IV Hormonal Therapy

• Aromatase Inhibitors are 1st line

• Restart if they worked in the past, and they haven’t used an AI within 12 months

• If taking AI and Relapse:

• Switch to SERM

• Hormone withdrawal may induce a short-term response

• Greatest response to HRT is seen in postmenopausal, ER+/PR+ non-visceral disease

• Visceral Disease and Not Responding:

• Can use Chemotherapy 

• Stage IV Chemotherapy

• Optimal agents and sequencing are unclear

• Elderly Patients

• are more likely to have hematological toxicity, mucositis, and cardiotoxicity with Anthracyclines 

• Avoid Taxanes if there is significant residual neuropathy 

• May not tolerate lots of bone marrow suppression, Vinca Alkaloids are a good choice

• If HER2+ 

• Add anti-HER2 drugs to chemo 

• Chemotherapy drugs are often chosen based on SE profile, patient concomitant diseases, and efficacy.

• Anthracyclines

• Only start if the patient can receive a sufficient dose

• Usually not much benefit after 3 cycles of chemo - go to BSC