Metastatic Breast Cancer: Pharmacologic Management

Breast cancer is the most common type of cancer, with an estimated 300,590 new cases in the United States in 2023. The National Cancer Institute also estimates that breast cancer will account for 43,170 to 43,530 new deaths in 2023.¹ Although the 5-year relative survival rate for individuals diagnosed with localized breast cancer is approximately 63%, it drops significantly to 28% for those with regional disease and to only 6% for those with distant (metastatic) disease.² 

Locally Advanced Breast Cancer

Locally advanced breast cancer is an inoperable disease with spread to nearby lymph nodes but without metastasis to distant sites in the body. Locally advanced breast cancer is categorized as stage IIIB and stage IIIC cancer. In total, locally advanced breast cancer accounts for approximately 5% of newly diagnosed breast cancer cases.³ 

No strict definition of locally advanced breast cancer currently exists, but clinicians may use the American Joint Committee on Cancer (AJCC) staging guidelines, which are generally used to identify tumor size (T), lymph node involvement (N), and metastatic status (M). Stage IIIC locally advanced breast cancer may be defined by metastases to the ipsilateral infraclavicular lymph nodes with or without axillary lymph node involvement; the AJCC also uses this stage to define metastases to the ipsilateral internal mammary lymph nodes.³ 

Locally Advanced or Metastatic Breast Cancer Treatment Recommendations

The National Comprehensive Cancer Network (NCCN) provides treatment recommendations for locally advanced and metastatic (stage IV) breast cancer. Therefore, for this article, treatment details will be provided for both locally advanced and recurrent or metastatic disease.⁴ 

The NCCN recommends that patients with locally advanced and recurrent metastatic disease enroll in clinical trials. In this setting they will be provided with excellent care, constant monitoring, and potential access to experimental therapeutics not otherwise available to them. For patients who cannot participate in a clinical trial, a combination of chemotherapy, endocrine therapy, and immunotherapy is recommended. 

Restaging and biomarker testing — particularly for hormone receptor (HR) status — should be performed in patients with suspected recurrent disease. Specifically, patients with previously unknown HR status or who were originally HR-negative, or those whose tumors did not overexpress HR at the time of diagnosis, should undergo testing. The estrogen receptor (ER) and progesterone receptor (PR) mutations found in the primary tumor may or may not align with those found in the metastatic tumor. Therefore, it is imperative to ensure that the results are not discordant to make accurate treatment decisions. All patients with recurrent or metastatic breast cancer should also be assessed for germline BRCA1/2 mutations. 

HR-Positive, HER2-Negative Disease

Patients who are HR-positive are recommended to undergo first-line endocrine therapy treatment, typically combined with other small molecule inhibitors for maximum efficacy. Postmenopausal patients with recurrent or metastatic disease are recommended to receive combined therapy with an aromatase inhibitor and a cyclin-dependent kinase (CDK) 4/6 inhibitor. Effective combinations for recurrent or metastatic breast cancer previously studied in clinical trials include:

• Letrozole plus palbociclib;
• Letrozole plus ribociclib; and
• Letrozole or anastrozole plus abemaciclib.

Patients may also be given single-agent fulvestrant or combination therapy with fulvestrant and a nonsteroidal aromatase inhibitor. The category 2A preferred treatment recommendation from the NCCN includes nonsteroidal aromatase inhibitors, selective estrogen receptor modulators (SERMs) such as tamoxifen or toremifene, or steroidal aromatase inhibitors such as exemestane. 

Premenopausal patients are recommended to undergo ovarian suppression therapy or ovarian ablation, in addition to the endocrine therapy regimens listed above. Alternatively, they may be treated with tamoxifen or toremifene as single agents. 

Preferred second-line treatments for postmenopausal patients with HR-positive, human epidermal growth factor receptor-2 (HER2)-negative recurrent or metastatic disease recommended by the NCCN include:

• Fulvestrant plus a CDK4/6 inhibitor; 
• Fulvestrant plus alpelisib for patients with PIK3CA mutations;
• Everolimus plus an aromatase inhibitor, fulvestrant, or tamoxifen; and
• Monotherapy with an aromatase inhibitor (steroidal or nonsteroidal), a SERM, or fulvestrant.

HR-Negative, HER2-Positive Disease

Patients who are HR-negative but have tumors that express HER2 are treated with a combination of chemotherapy and HER2-targeted therapy. The NCCN treatment guidelines note that trastuzumab may be substituted for biosimilars approved by the US Food and Drug Administration (FDA) or the FDA-approved subcutaneous injection of trastuzumab and hyaluronidase-oysk. Clinicians are advised to note the changes in dosage when switching from the intravenous (IV) infusion route to the subcutaneous injection. 

In patients whose disease progresses while on a HER2-targeted treatment, an additional line of therapy should be added, and the HER2 treatment should be continued. This is true for patients who were previously treated with trastuzumab in an adjuvant setting. The NCCN believes it is beneficial to continuously suppress the HER2 pathway. Treatments should continue until unacceptable toxicity occurs or the disease progresses. 

The NCCN treatment guidelines recommend pertuzumab plus trastuzumab in combination with taxane-based chemotherapy as a first-line treatment for patients with HR-negative, HER2-positive recurrent or metastatic breast cancer. Suggested chemotherapy agents for this combination therapy include docetaxel or paclitaxel. Other options that may be used include:

• Ado-trastuzumab emtansine;
• First-line trastuzumab plus paclitaxel ± carboplatin, vinorelbine, and docetaxel;
• First-line trastuzumab plus capecitabine; and
• Pertuzumab plus trastuzumab.

Second-line treatments for patients with recurrent or metastatic breast cancer include:

• Ado-trastuzumab emtansine;
• Fam-trastuzumab deruxtecan-nxki (recommended for those who have experienced disease progression after receiving at least 2 lines of HER2-targeted therapy);
• Sacituzumab govitecan (for patients who are not candidates for fam-trastuzumab deruxtecan-nxki);
• Lapatinib plus trastuzumab or capecitabine; and
• Neratinib plus capecitabine.

HR-Positive, HER2-Positive Disease

Patients with HER2-positive disease are recommended to receive HER2-targeted therapy. There are several combination treatments that may be used, as these patients have 2 targetable receptors. The NCCN recommends using: 

• HER2-targeted therapy plus chemotherapy;
• Endocrine therapy alone;
• HER2-targeted therapy plus endocrine therapy; or
• Aromatase inhibitor plus lapatinib or trastuzumab.

The latter 2 options are less-toxic approaches and may be used in older patients or those with comorbid conditions that complicate treatment plans. Premenopausal patients who are treated with HER2-targeted therapy plus endocrine therapy are recommended to undergo ovarian suppression or ablation to limit endogenous estrogen production. 

Treatment combinations that have been studied in clinical trials for recurrent or metastatic breast cancer and that are recommended by the NCCN include:

• Trastuzumab plus anastrozole;
• Trastuzumab plus letrozole;
• Lapatinib plus letrozole;
• Lapatinib plus trastuzumab plus an aromatase inhibitor; and
• Trastuzumab plus tamoxifen or fulvestrant (following completion of chemotherapy plus HER2-targeted therapy).

The NCCN also notes that patients who were initially treated with chemotherapy and pertuzumab plus trastuzumab may be treated with endocrine therapy after chemotherapy treatment is stopped. 

Recurrent or Metastatic Breast Cancer with Germline BRCA1/2 Mutations 

The National Cancer Institute estimates that between 5% and 10% of breast cancers harbor BRCA1/2 germline mutations.¹ Patients with HER2-negative disease are more likely to have these mutations than others. The NCCN recommends treatment with the poly(ADP-ribose) polymerase (PARP) inhibitors olaparib or talazoparib for this population based on clinical trial results. 

Although olaparib and talazoparib are approved by the FDA for treating HER2-negative disease, the NCCN recommends that patients with any breast cancer subtype harboring BRCA1/2 germline mutations receive PARP inhibitor therapy. 

Patients with triple-negative breast cancer (TNBC) who are HR-negative and HER2-negative are recommended to receive the preferred treatment of platinum-based chemotherapy (cisplatin or carboplatin). 

Systemic Chemotherapy Recommendations

The NCCN guidelines offer several chemotherapy regimens for recurrent or metastatic breast cancer.⁴ The panel found that there is no survival benefit that outweighs the toxic side effects of combination chemotherapy treatments. Sequential monotherapy is recommended for most patients, as well as more aggressive combination therapy to slow rapid disease progression or provide rapid symptom relief. Patients should be treated until unacceptable toxicity occurs or their disease progresses.

Preferred chemotherapy single agents from the NCCN recommendations include⁴:

• Anthracyclines: Doxorubicin or liposomal doxorubicin;
• Taxanes: Paclitaxel;
• Microtubule inhibitors: Vinorelbine and eribulin;
• Antimetabolites: Gemcitabine and capecitabine; and
• Platinum agents: Carboplatin and cisplatin

Other chemotherapy treatments that may be used include:

• Taxanes: Albumin-bound paclitaxel and docetaxel;
• Anthracyclines: Epirubicin; and
• Single-agent ixabepilone

Chemotherapy combinations that may be useful in some circumstances include:

• Doxorubicin/cyclophosphamide (AC);
• Cyclophosphamide/methotrexate/fluorouracil (CMF);
• Epirubicin/cyclophosphamide (EC);
• Gemcitabine/carboplatin with albumin-bound paclitaxel or paclitaxel; and
• Bevacizumab/paclitaxel

Additional Recommended Therapies

Immunotherapy targeting the programmed death-1/programmed death ligand-1 (PD-1/PD-L1) axis may be useful for treating patients with TNBC with PD-L1 expression in ≥1% of immune cells infiltrating their tumor. Clinical trial results show that atezolizumab with albumin-bound paclitaxel is an effective treatment for patients with advanced TNBC. 

Pembrolizumab and dostarlimab-glxy are also approved for treating patients with inoperable or metastatic cancer with mismatch repair deficiencies or high microsatellite instability who have experienced disease progression on prior therapies and have no alternative treatment options. 

Patients with neurotrophic tropomyosin receptor kinase (NTRK) mutations may be treated with entrectinib or larotrectinib. These are 2 FDA-approved NTRK inhibitors that may be used to treat solid tumors in patients who have acquired this mutation and have no alternative treatment options. 

Recommended Treatments for Bone Metastases

Patients with bone metastases often suffer from a lower quality of life and are more likely to have skeletal complications, including hypercalcemia of malignancy, increased risk of fractures, and spinal cord compression. 

The NCCN recommends treating patients with bone metastases with a bone-modifying agent such as denosumab or bisphosphonates such as pamidronate or zoledronic acid.⁴ These therapies are to be used alongside chemotherapy or endocrine therapy. Studies show that bisphosphonate treatment should be administered on a 3- to 4-week schedule or every 12 weeks. Patients should also supplement with calcium and vitamin D. 

Table 1. Treatment Guidelines for Chemotherapy Regimens/Combination Treatments for Recurrent or Metastatic Breast Cancer

Drug	Dosage	Administration
Bevacizumab/paclitaxel	Bevacizumab 10 mg/kg and paclitaxel 90 mg/m2	IV infusion on days 1, 8, and 15; cycle every 28 d
Capecitabine	1000-1250 mg twice daily	Orally; days 1-14; cycle every 21 d
Carboplatin	AUC 6	IV infusion on day 1; cycle every 21-28 d
Cisplatin	75 mg/m2	IV infusion on day 1; cycle every 21 d
Cyclophosphamide/methotrexate/fluorouracil (CMF)	Cyclophosphamide 100 mg/m2, methotrexate 40 mg/m2, and 5-fluorouracil 600 mg/m2	Cyclophosphamide orally on days 1-14; methotrexate and 5-fluorouracil IV infusion on days 1 and 8; cycle every 28 d
Docetaxel	1: 60-100 mg/m2 2: 35 mg/m2	IV infusion1: Day 1; cycle every 21 d2: Weekly for 6 wk, followed by 2 wk of rest; repeat as needed
Doxorubicin	20 mg/m2 weekly or 60 to 75 mg/m2 every 3 wk	IV infusion
Doxorubicin/cyclophosphamide (AC)	Doxorubicin 60 mg/m2 and cyclophosphamide 600 mg/m2	IV infusion of both drugs on day 1; cycle every 21 d
Epirubicin	60-90 mg/m2	IV infusion on day 1; cycle every 21 d
Epirubicin/cyclophosphamide (EC)	Epirubicin 75 mg/m2 and cyclophosphamide 600 mg/m2	IV infusion of both drugs on day 1; cycle every 21 d
Eribulin	1.4 mg/m2	IV infusion; days 1 and 8; cycle every 21 d
Gemcitabine	800-1200 mg/m2	IV infusion; days 1, 8, and 15; cycle every 28 d
Gemcitabine/carboplatin	Gemcitabine 1000 mg/m2 and carboplatin AUC 2	IV infusion on days 1 and 8; cycle every 21 d
Ixabepilone	40 mg/m2	IV infusion day 1; cycle every 21 d
Liposomal doxorubicin	50 mg/m2 every 4 wk	IV infusion
Nab-paclitaxel	1: 100 mg/m2 or 125 mg/m2 2: 260 mg/m2	IV infusion1: Days 1, 8, and 15; cycle every 28 d2: Cycle every 21 d
Paclitaxel	80 mg/m2 weekly or 175 mg/m2 every 3 wk	IV infusion
Vinorelbine	1: 25 mg/m2 2: 20-35 mg/m2 3: 25-30 mg/m2	IV infusion1: Day 1 every wk2: Days 1 and 8; cycle every 21 d3: Days 1, 8, and 15; cycle every 28 d

AUC = area under the curve; IV = intravenous

From NCCN Treatment Guidelines.⁴

Table 2. Treatment Guidelines for Endocrine Therapy for Recurrent or Metastatic Breast Cancer

Drug	Dosage	Administration
Anastrozole	1 mg once daily	Tablet taken orally with or without food
Elacestrant	345 mg once daily	Tablet taken orally with food daily on days 1-28; take on day 1 of 28-d cycle after initial treatment
Exemestane	25 mg once day	Tablet taken orally after eating
Fulvestrant	500 mg	IM injection into the gluteal area on days 1, 15, and 29; follow up with injections once monthly after the first 3 treatments are complete
Letrozole	2.5 mg once daily	Tablet taken orally with or without food
Tamoxifen	20-40 mg once daily	Oral solution; doses greater than 20 mg should be given twice daily

IM = intramuscular; IV = intravenous.

From NCCN Treatment Guidelines.⁴

From FDA-approved prescribing information.^5-9

Table 3. Treatment Guidelines for Small Molecule Inhibitors for Recurrent or Metastatic Breast Cancer

Drug	Dosage	Administration
Abemaciclib	150 mg twice daily when combined with an aromatase inhibitor, tamoxifen, or fulvestrant	Tablet taken orally with or without food
Alpelisib	300 mg once daily	Two 150-mg tablets taken orally with food
Entrectinib	600 mg once daily	Tablet taken orally with or without food
Everolimus	10 mg once daily	Tablet taken orally with or without food
Lapatinib	1500 mg once daily	Tablet taken orally
Larotrectinib	100 mg once daily	4 capsules taken orally with water
Neratinib	240 mg twice daily on days 1-21 with capecitabine 750 mg/m2 orally twice daily capecitabine days 1-14; treat for 21-d cycles	Administer antidiarrheal prophylaxis for the first 8 wk of treatment
Olaparib	300 mg twice daily	Tablet taken orally with or without food
Palbociclib	125 mg once daily	Capsule taken orally with food for 21 d, then off for 7 d of a 28-d cycle
Ribociclib	600 mg once daily	3 tablets (200 mg each) taken orally with or without food for 21 d, then off for 7 d of a 28-d cycle
Selpercatinib	<50 kg: 120 mg twice daily>50 kg: 160 mg twice daily	Capsule taken orally with or without food
Talazoparib	1 mg once daily	Capsule taken orally with or without food

From NCCN Treatment Guidelines.⁴

From FDA-approved prescribing information.^10-21

Table 4. Treatment Guidelines for Monoclonal Antibody Drugs for Recurrent or Metastatic Breast Cancer

Drug	Dosage	Administration
Ado-trastuzumab	3.6 mg/kg	IV infusion every 3 wk on a 21-d cycle
Denosumab	120 mg	SC injection every 4 wk
Dostarlimab-glxy	Dose 1-4: 500 mgSubsequent doses: 1000 mg	IV infusion over 30 min every 3 wk for doses 1-4; subsequent doses every 6 wk
Fam-trastuzumab-deruxtecan-nxki	5.4 mg/m2	IV infusion on days 1 and 8; cycle every 21 d
Pembrolizumab	200 mg	IV infusion on day 1 of 21-d cycle in combination with chemotherapy
Pertuzumab	840 mg	IV infusion on day 1 of treatment cycle
Pertuzumab, trastuzumab, and hyaluronidase-zzxf	Initial dose: Pertuzumab 1200 mg, trastuzumab 600 mg, and hyaluronidase 30,000 units in a 15-mL injection Maintenance dose: Pertuzumab 600 mg, trastuzumab 600 mg, and hyaluronidase 20,000 units in 10-mL injection	SC injection every 3 wk
Sacituzumab govitcean-hziy	10 mg/kg	IV infusion on days 1 and 8; cycle every 21 d
Trastuzumab	In combination with chemotherapy or a small molecule inhibitor: Initial dosage 4 mg/kg weekly with chemotherapy; subsequent dosages 2 mg/kg every 3 wk Single agent: Initial dose of 8 mg/kg; subsequent dosages at 6 mg/kg every 3 wk	IV infusion
Trastuzumab and hyaluronidase-oysk	Trastuzumab 600 mg with hyaluronidase 10,000 units	SC injection

IV = intravenous; SC = subcutaneous.

From FDA-approved prescribing information.⁴

From NCCN Treatment Guidelines.^22-30

Monitoring Side Effects, Adverse Events, and Drug-Drug Interactions

The charts below detail common side effects, adverse events, and drug-drug interactions to be aware of, as well as special population considerations. The guidelines will assist in personalizing treatment plans. 

Table 5. Side Effect Profiles for Chemotherapy for Recurrent or Metastatic Breast Cancer

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Capecitabine	Dysgeusia, abdominal pain, dizziness, fatigue, dyspepsia, skin rash, alopecia, pyrexia, headache, infections, anorexia, neutropenia epistaxis, nausea, vomiting, diarrhea, constipation Warnings: Severe diarrhea, cytopenias, coagulopathy, DPD, hyperbilirubinemia, cardiotoxicity, severe skin reactions, dehydration and renal failure	Anticoagulants; leucovorin; CYP2C9 substrates; phenytoin; allopurinol	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients and those with renal or hepatic insufficiency
Carboplatin	Cough, headache, nausea, musculoskeletal pain, abdominal pain, vomiting, constipation, decreased appetite, diarrhea, fever, rash, back pain, joint pain, fatigue and weakness, upper respiratory tract infection Warnings: Infusion reaction	None indicated	Do not use in pregnant or breastfeeding individuals
Cisplatin	Myelosuppression, nausea, vomiting, infections, pyrexia, peripheral neuropathy Warnings: Ototoxicity, infection reaction, nephrotoxicity, secondary leukemia, ocular toxicity	Nephrotoxic and ototoxic drugs	Do not use in pregnant or breastfeeding individuals; use with caution in patients with renal impairment
Cyclophosphamide	Cytopenias, nausea, vomiting, alopecia, skin rash, abdominal pain, diarrhea, anorexia Warnings: Immunosuppression, myelosuppression, cardiotoxicity, renal and urinary tract toxicity, veno-occlusive liver disease, impaired wound healing, hyponatremia, infertility, secondary malignancies, pulmonary toxicity	ACE inhibitors; G-CSF; GM-CSF; paclitaxel; protease inhibitors; natalizumab; tamoxifen; cyclosporine; thiazide diuretics; anthracyclines; trastuzumab; pentostatin; cytarabine; amiodarone; indomethacin; amphotericin; azathioprine; etanercept; busulfan; metronidazole; coumarins	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients and those with severe renal or hepatic impairment
Docetaxel	Infections, alopecia, myalgia, cytopenias neuropathy, dyspnea, dysgeusia, nail disorders, skin reactions, anorexia Warnings: Hepatic impairment, eye disorders, hypersensitivity, skin and neurologic reactions, colitis	CYP3A4 inhibitors or inducers	Do not use in pregnant or breastfeeding individuals; patients with severe hepatic impairment should not be treated with docetaxel
Doxorubicin	Alopecia, urticaria, pyrexia, chills, asthenia, nausea, vomiting Warnings: Immunosuppression and increased risk of infection, cardiotoxicity, hepatotoxicity, secondary leukemia, injection site reaction	Concomitant use of 6-mercaptopurine, dexrazoxane, or trastuzumab; CYP3A4, CYP2D6, and P-gp inhibitors or inducers	Do not use in pregnant or breastfeeding individuals; reduce dose in patients with severe hepatic impairment
Epirubicin	Infection, pyrexia, cytopenias, hot flashes, alopecia, skin rash and pruritus, amenorrhea  Warnings: Cardiotoxicity, secondary leukemia, tumor lysis syndrome, hematologic toxicity	Paclitaxel; docetaxel; cimetidine; cardiotoxic agents	Do not use in pregnant or breastfeeding individuals; reduce dose in patients with renal or hepatic impairment
Eribulin	Alopecia, nausea, constipation, asthenia, fatigue, anemia Warnings: Neutropenia, prolongation of QT interval, peripheral neuropathy	None indicated	Do not use in pregnant or breastfeeding individuals; reduce dose in patients with mild or moderate hepatic impairment and patients with moderate or severe renal impairment
Fluorouracil	Headache, cytopenias, nausea, vomiting, allergic reaction, skin reactions, vision changes, nail changes, epistaxis, thrombophlebitis Warnings: Cardiotoxicity, severe diarrhea, hyperammonemic encephalopathy, increased risk of reaction in patients with DPD, neurologic toxicity, myelosuppression, mucosal inflammation, hand-foot syndrome (palmar-plantar dysesthesia)	Warfarin; CYP2C9 substrates	Do not use in pregnant or breastfeeding individuals.
Gemcitabine	Cytopenias, vomiting, nausea, dyspnea, skin rashes, proteinuria, elevated liver enzymes Warnings: Pulmonary and hepatic toxicity, myelosuppression, hemolytic uremic syndrome	None indicated	Do not use in pregnant or breastfeeding individuals.
Ixabepilone	Peripheral sensory neuropathy, myalgia, arthralgia, fatigue, asthenia, vomiting, nausea, diarrhea, alopecia, musculoskeletal pain, stomatitis (oral mucositis), mucosal inflammation, constipation, anorexia, nail changes, abdominal pain, hand-foot syndrome Warnings: Peripheral neuropathy, myelosuppression, hypersensitivity, cardiotoxicity	CYP3A4 inhibitors and inducers	Do not use in pregnant or breastfeeding individuals; monitor patient’s hepatic function before and after treatment; lower dose in patients with mild to moderate hepatic impairment; do not treat patients with severe hepatic impairment
Liposomal doxorubicin	Cytopenias, nausea, vomiting, diarrhea, anorexia, rash, stomatitis, asthenia Warnings: Infusion reaction, cardiomyopathy, secondary oral neoplasms, hand-foot syndrome	None indicated	Do not use in pregnant or breastfeeding individuals; reduce dose in patients with hepatic impairment
Methotrexate	Nausea, vomiting, elevated liver enzymes, stomatitis, cytopenias Warnings: Hypersensitivity; serious infections; renal, neurologic, pulmonary, GI, and hepatic toxicity; myelosuppression; skin reactions; TLS; infertility; secondary malignancies	Protein-bound drugs; PPIs; antifolate drugs; penicillin or sulfonamide antibiotics; probenecid; hepatotoxic drugs; mercaptopurine; nephrotoxic drugs	Do not use in pregnant or breastfeeding individuals; reduce dose in patients with renal impairment
Nab-paclitaxel	Sensory neuropathy, alopecia, neutropenia, fatigue, myalgia, asthenia, elevated liver enzymes, nausea, infections, anemia, abnormal ECG Warnings: Severe neuropathy, hypersensitivity, and myelosuppression; sepsis; pneumonitis	CYP2C8 and CYP3A4 inhibitors and inducers	Do not use in pregnant or breastfeeding individuals; treatment is not recommended in patients with moderate to severe hepatic impairment
Paclitaxel	Cytopenias, infections, myalgia, arthralgia, nausea, vomiting, diarrhea, elevated liver enzyme levels Warnings: Bradycardia, hypotension, hypersensitivity	CYP2C8 and CPY3A4 inhibitors and inducers	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients
Vinorelbine	Cytopenias, elevated liver enzymes, injection site reaction, peripheral neuropathy, nausea, vomiting Warnings: Myelosuppression; extravasation; hepatic, neurologic, and pulmonary toxicity; bowel obstruction	CYP3A inhibitors	Do not use in pregnant or breastfeeding individuals; use with caution in patients with hepatic impairment

ACE = angiotensin converting enzyme; DPD = dihydropyrimidine dehydrogenase deficiency; ECG = electrocardiogram; G-CSF = granulocyte-colony stimulating factor; GI = gastrointestinal; GM-CSF = granulocyte-macrophage colony-stimulating factor; P-gp = P-glycoprotein; PPIs = proton pump inhibitors; TLS = tumor lysis syndrome.

From FDA-approved prescribing information.^31-46

Table 6. Side Effect Profile for Endocrine Therapy for Recurrent or Metastatic Breast Cancer

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Anastrozole	Fractures, bone pain, headache, dyspnea, arthralgia, cough, insomnia, nausea, hot flashes, vomiting Warnings: Ischemic cardiovascular events, osteoporosis, elevated cholesterol levels	Estrogen-containing treatments; tamoxifen; warfarin; other drugs that inhibitor CYP450	Do not use in pregnant or breastfeeding individuals
Elacestrant	Nausea, musculoskeletal pain, increased cholesterol levels, vomiting, fatigue, elevated liver enzymes, decreased appetite, dyspepsia, hot flashes, constipation, abdominal pain, headache, diarrhea Warnings: Dyslipidemia	Moderate and strong CYP3A4 inhibitors and inducers; P-gp substrates; BCRP substrates	Do not use in pregnant or breastfeeding individuals; avoid use in patients with severe hepatic impairment; reduce dose in patients with moderate hepatic impairment
Exemestane	Hot flashes, arthralgia, fatigue, sweating, insomnia, headache Warnings: Osteoporosis	CYP3A4 inducers	Do not use in pregnant or breastfeeding individuals; do not use in premenopausal women
Fulvestrant	Nausea, injection site reaction, bone pain Warnings: Injection site reaction, risk of bleeding	None indicated	Do not use in pregnant or breastfeeding individuals; reduce dose in patients with moderate hepatic impairment; use has not been studied in patients with severe hepatic impairment
Letrozole	Bone fractures, weight gain, hot flashes, headache, alopecia, depression, back pain, vaginal irritation and bleeding, night sweats, arthralgia, nausea, vomiting, edema Warnings: Elevated cholesterol levels, osteoporosis, severe fatigue and dizziness	Warfarin; tamoxifen; cimetidine	Do not use in pregnant or breastfeeding individuals; reduce dose in patients with hepatic impairment; use with caution in geriatric patients
Tamoxifen	Nausea, weight loss, fluid retention, vaginal discharge, irregular menses, skin changes, hot flashes Warnings: Increased risk of uterine sarcoma, endometrial cancer, and liver cancer; venous thrombosis; eye complications; cytopenias	Concomitant use with letrozole is not recommended; strong inhibitors and inducers of CYP3A4; strong inhibitors of CYP2D6; warfarin	Do not use in pregnant or breastfeeding individuals

BCRP = breast cancer resistant protein; P-gp = P-glycoprotein.

From FDA-approved prescribing information.^5-9

Table 7. Side Effect Profile for Small Molecule Inhibitors for Recurrent or Metastatic Breast Cancer

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Abemaciclib	Cytopenia, decreased appetite, abdominal pain, headache, fatigue, infections, alopecia Warnings: Neutropenia, severe diarrhea, venous thrombosis, hepatotoxicity, ILD	Moderate or strong CYP3A inhibitors and inducers	Do not use in pregnant or breastfeeding individuals
Alpelisib	Abdominal pain, stomatitis, peripheral edema, fatigue, pyrexia, nausea, vomiting, constipation, diarrhea, infections, mucosal dryness and inflammation, decreased appetite, weight loss, headache, dysgeusia, skin reactions, alopecia Warnings: Hypersensitivity, severe diarrhea or colitis, pneumonitis, hyperglycemia, severe skin reactions	CYP3A4 inducers; BCRP inhibitors; CYP2C9 substrates (warfarin)	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients
Entrectinib	Constipation, diarrhea, nausea, dyspnea, fatigue, dysgeusia, edema, cognitive impairment, dizziness, cough, weight gain, arthralgia, pyrexia, vomiting Warnings: CNS effects, CHF, hepatotoxicity, bone fractures, hyperuricemia, vision problems, prolonged QT interval	Moderate or strong CYP3A inhibitors or inducers; drugs that prolong QT interval	Do not use in pregnant or breastfeeding individuals
Everolimus	Decreased appetite, fatigue, rash, diarrhea, infections Warnings: Infections, pneumonitis, stomatitis, angioedema with ACE inhibitor use, hypersensitivity reaction, impaired wound healing, myelosuppression, impaired wound healing, renal failure	Strong CYP3A4 and P-gp inhibitors and inducers; avoid concomitant ACE inhibitor use	Do not use in pregnant or breastfeeding individuals; reduce dose in patients with hepatic impairment
Lapatinib	Skin rash, hand-foot syndrome, nausea, fatigue, vomiting Warnings: Hepatotoxicity, severe diarrhea, decreased left ventricular ejection fraction, ILD, prolonged QT interval, severe skin reactions	CYP3A4, CYP2C8, and P-gp inhibitors (paclitaxel, digoxin, midazolam); CYP3A4 inhibitors or inducers (carbamazepine, ketoconazole); PPIs	Do not use in pregnant or breastfeeding individuals; monitor and adjust dose accordingly in patients with moderate to severe renal impairment
Larotrectinib	Cytopenia, musculoskeletal pain, dizziness, fatigue, pyrexia, elevated liver enzyme levels, nausea, vomiting, diarrhea, constipation Warnings: Hepatotoxicity,skeletal fractures, CNS effects	Moderate or strong CYP3A4 inhibitors and inducers; sensitive CYP3A4 substrates	Do not use in pregnant or breastfeeding individuals
Neratinib	Abdominal pain, decreased appetite, fatigue, skin rash, infections, stomatitis, dyspepsia, elevated liver enzymes, weight loss, muscle spasms Warnings: Severe diarrhea, hepatotoxicity	Moderate or strong CYP3A4 inhibitors and inducers; P-gp inhibitors; avoid PPIs while taking neratinib	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients
Olaparib	Cytopenias, fatigue, nausea, vomiting Warning: Risk of developing MDS/AML, pneumonitis, venous thrombosis	Other myelosuppressive agents; moderate or strong CYP3A inhibitors and inducers	Do not use in pregnant or breastfeeding individuals
Palbociclib	Cytopenias, fatigue, stomatitis, skin reactions, decreased appetite, dysgeusia, pyrexia, vomiting, constipation, diarrhea, nausea Warnings: ILD, neutropenia	Strong CYP3A inhibitors and inducers; midazolam	Do not use in pregnant or breastfeeding individuals; reduce dose in patients with severe hepatic impairment
Ribociclib	Cytopenias, diarrhea, elevated liver enzyme levels, infections, nausea, headache, fatigue, cough, skin rash, alopecia, hypoglycemia, back pain, constipation, vomiting Warnings: Severe skin reactions, ILD, neutropenia, hepatobiliary toxicity, prolonged QT interval	Tamoxifen; strong CYP3A inhibitors and inducers; CYP3A4 substrates; drugs that cause prolonged QT interval	Do not use in pregnant or breastfeeding individuals; reduce dose in patients with moderate to severe hepatic and severe renal impairment
Selpercatinib	Edema, headache, nausea, vomiting, dry mouth, rash, abdominal pain, hypertension, constipation, cytopenia, elevated liver enzyme levels, diarrhea Warnings: ILD, hepatotoxicity, hypertension, prolonged QT interval, impaired wound healing, hypersensitivity, hemorrhage, hypothyroidism, TLS	Drugs affecting gastric pH; moderate or strong CYP3A inhibitors and inducers; CYP2C8, CYP3A, and P-gp substrates; drugs that prolong QT interval	Do not use in pregnant or breastfeeding individuals; reduce dose in patients with severe hepatic impairment
Talazoparib	Cytopenias, constipation, diarrhea, headache, decreased appetite, vomiting, fatigue, alopecia, nausea Warning: Risk of developing MDS/AML, myelosuppression	P-gp inhibitors; BCRP inhibitors	Do not use in pregnant or breastfeeding individuals; monitor and adjust dose accordingly in patients with moderate to severe renal impairment

ACE = angiotensin-converting enzyme; AML = acute myeloid leukemia; BCRP = breast cancer-resistant protein; CHF = congestive heart failure; CNS = central nervous system; ILD = Interstitial lung disease; MDS = myelodysplastic syndrome; P-gp = P-glycoprotein; PPIs = proton pump inhibitors; TLS = tumor lysis syndrome.

From FDA-approved prescribing information.^10-21

Table 8. Side Effect Profile for Monoclonal Antibodies for Recurrent or Metastatic Breast Cancer

Drug	Most Common Adverse Events	Drug-Drug Interactions	Special Population Considerations
Ado-trastuzumab emtansine	Headache, nausea, constipation, epistaxis, fatigue, musculoskeletal pain, elevated transaminase levels Warnings: Thrombocytopenia, neurotoxicity, hemorrhage, infusion reaction and hypersensitivity, pulmonary toxicity, left ventricular dysfunction	Strong CYP3A4 inhibitors	Do not use in pregnant or breastfeeding individuals; use with caution in patients with severe renal and hepatic impairment
Bevacizumab	Proteinuria, infection, headache, fatigue Warnings: GI perforation, ovarian failure, hypertension, renal injury, infusion reaction, hemorrhage, venous thrombosis, CHF	None indicated	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients
Denosumab	Arthralgia, back pain Warnings: Hypocalcemia, hypersensitivity, bone fractures, musculoskeletal pain, serious infections, skin reactions	None indicated	Do not use in pregnant or breastfeeding individuals
Dostarlimab-glxy	Headache, proteinuria, infection, fatigue Warnings: Infusion reaction, CHF, venous thrombosis, GI perforation, hypertension, renal injury, ovarian failure, hemorrhage	None indicated	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients
Fam-trastuzumab-deruxtecan-nxki	Stomatitis, decreased appetite, abdominal pain, weight loss, nausea, vomiting, constipation, diarrhea, infection, headache, cough, dizziness, alopecia, peripheral neuropathy, anemia Warnings: Neutropenia, left ventricle dysfunction, ILD	None indicated	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients; monitor patients with hepatic and renal impairment
Pembrolizumab	Decreased appetite, headache, pyrexia, fatigue, stomatitis, abdominal pain, peripheral neuropathy, insomnia, skin rash, alopecia, myalgia, cough, arthralgia  Warnings: Severe immune-related reactions, infusion reactions	None indicated	Do not use in pregnant or breastfeeding individuals
Pertuzumab	Alopecia, nausea, vomiting, diarrhea, peripheral neuropathy, neutropenia Warnings: Infusion reaction, left ventricular dysfunction, hypersensitivity	None indicated	Do not use in pregnant or breastfeeding individuals
Pertuzumab, trastuzumab, and hyaluronidase-zzxf	Alopecia, nail complications, stomatitis, skin reactions, cytopenia, asthenia, abdominal pain, hemorrhoids, fatigue, headache, peripheral edema, myalgia, peripheral neuropathy, dysgeusia, back pain, arthralgia, hot flashes, decreased appetite, dyspnea, cough, infections, epistaxis Warnings: Cardiomyopathy, pulmonary toxicity, neutropenia, administration-related reaction and hypersensitivity	Avoid anthracycline-based regimens for up to 7 mo after discontinuing treatment to reduce risk of cardiac dysfunction	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients to reduce risk of cardiac dysfunction
Sacituzumab govitcean-hziy	Cytopenias; nausea; diarrhea; constipation; alopecia; fatigue; hyperglycemia; vomiting; decreased appetite; elevated liver enzymes; decreased potassium, sodium, and magnesium Warnings: Diarrhea, neutropenia, infusion reaction and hypersensitivity, nausea and vomiting, increased risk of reaction in patients with UGT1A1 deficiency	UGT1A1 inhibitors and inducers	Do not use in pregnant or breastfeeding individuals
Trastuzumab	Myalgia, rash, fatigue, pyrexia, cough, infections, dyspnea, low blood cell count, headache, nausea, vomiting, constipation, diarrhea Warnings: Cardiomyopathy, pulmonary toxicity, infusion reaction, neutropenia	Avoid anthracycline-based regimens for up to 7 mo after discontinuing treatment to reduce risk of cardiac dysfunction	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients to reduce risk of cardiac dysfunction
Trastuzumab/hyaluronidase	Asthenia, alopecia, myalgia, fatigue, dyspnea, cough, rash, pyrexia, leukopenia, peripheral sensory neuropathy, hot flashes, leukopenia, decreased appetite, nausea, diarrhea, mucosal inflammation	Avoid anthracycline-based regimens for up to 7 mo after discontinuing treatment to reduce risk of cardiac dysfunction	Do not use in pregnant or breastfeeding individuals; use with caution in geriatric patients to reduce risk of cardiac dysfunction

CHF = congestive heart failure; GI = gastrointestinal; ILD = interstitial lung disease; UGT1A1 = uridine diphosphate-glucuronosyltransferase 1A1.

From FDA-approved prescribing information.^22-30

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Author Bio

Emily Wagner, MS, earned a Bachelor of Science in biotechnology from the Rochester Institute of Technology in 2018 and a Master of Science in biomedical sciences with a focus in pharmacology from the University of Colorado Anschutz Medical Campus in 2020. During her thesis work, she studied non-small cell lung cancer and how the immune system plays a role in response to different treatments. Emily currently lives in Colorado where she enjoys the mountains, spending time with her dog, baking, and reading a good book.