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Home > For Medical Professionals / Oncology > Breast cancer > Breast Cancer Pharmacology

Breast Cancer Pharmacology

September 26, 2022 - read ≈ 56 min

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Authors

Jonathan Malara, PharmD, BCOP

Clinical Pharmacy – Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Authors

John Patrick Sanchez, PharmD, BCOP

Clinical Pharmacy – Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Content

Breast cancer therapies encompass a wide array of medications from different drug classes depending on the cancer’s receptor status. The chapter below will broadly discuss evidence-based therapies for breast cancer including endocrine agents, targeted agents (both oral and intravenous), immunotherapies, and chemotherapies. Please refer to the National Comprehensive Cancer Network (NCCN) guidelines for the most up to date recommendations or specific citations from this chapter or the guidelines for clinical trial specific information.

Endocrine Therapies

Selective Estrogen Receptor Modulators (SERM)

Tamoxifen can be used in both early stage and metastatic breast cancer as single agent or combination therapy. This is the preferred medication for single agent treatment for pre-menopausal women who are not undergoing ovarian suppression. Tamoxifen may be combined with abemaciclib in the adjuvant setting for early-stage breast cancer, as well as with everolimus in the metastatic setting. Tamoxifen should not be combined with ribociclib due to the increased risk of QTc prolongation that was observed in the Monaleesa-7 study that will be reviewed in the CDK 4/6 inhibitor section.[1] 

Tamoxifen competes with estrogen and is an estrogen receptor antagonist in the breast tissue. It exhibits agonistic effects in other tissues such as the uterus and bone.  Patient’s current medication list should be screened for pertinent drug-drug interactions. Specifically, inhibitors or inducers of cytochrome P450 (CYP) enzyme 2D6 should be noted as tamoxifen relies on this enzyme for pharmacologic activity. Tamoxifen undergoes metabolism to a much more active metabolite (endoxifen) through CYP2D6, so inhibitors may lower efficacy while inducers may increase toxicity. Notable medications that should be avoided are fluoxetine, duloxetine, bupropion, and sertraline.

Generally, if a selective serotonin inhibitor is needed for the treatment of mood disorders, citalopram, escitalopram, and venlafaxine are acceptable choices as they are absent of significant inhibition of CYP2D6 and should not affect clinical efficacy.[2,3,4]

Aromatase Inhibitors (AI)

Aromatase inhibitors prevent the conversion of estrogen in the body by the enzyme, aromatase. They are utilized in both early-stage and metastatic breast cancer as both single agent and combination therapy. They are the adjuvant endocrine therapy of choice in postmenopausal women. Premenopausal patients should receive ovarian suppression therapy, either through medication or bilateral oophorectomy. This may be a consideration for patients who previously received chemotherapy and are younger than age 35 as observed in the SOFT-TEXT study.[5]

There are three aromatase inhibitors for treatment of breast cancer: letrozole, anastrozole, and exemestane. They are generally regarded as equivocal in treatment, though exemestane is considered a third-generation agent with tighter binding affinity and irreversible contact for aromatase compared to the second-generation letrozole and anastrozole. It may be useful to reserve exemestane for later therapies as it can be combined with everolimus for the treatment of metastatic breast cancer following progression on previous aromatase inhibitor therapy.[3,6] 

Selective Estrogen Receptor Downregulator (SERD)

This class of medications works by decreasing the expression of estrogen receptors on the surface of cancer cells. Fulvestrant is the only currently available medication in this class. Oral SERDs are being studied but are not yet available outside of clinical trials. Fulvestrant is indicated for post-menopausal women in the metastatic setting, either as a single agent or in combination with various targeted therapies (CDK inhibitors, mTOR inhibitors, PI3K inhibitors). Premenopausal women receiving this therapy should receive ovarian suppression or undergo bilateral oophorectomy.[7,8]

Endocrine Agent Side Effects and Management

Patients commonly experience menopausal side effects such as hot flashes, night sweats, myalgias, arthralgias, mood swings, and vaginal dryness. Many of these side effects can improve with time, though some patients may not tolerate therapy regardless of aggressive management. Medications such as venlafaxine or oxybutynin may alleviate hot flashes and night sweats.

Myalgias and arthralgias may require medications such as NSAIDS (Non-steroidal anti-inflammatory drugs) or acetaminophen but can also be managed with activities such as exercises, warm baths, and massages. Acupuncture may be beneficial for patients who are refractory to these strategies for the hot flashes, night sweats, myalgias, and arthralgias. Hormone-related side effects(mood swings, weight gain, and vaginal dryness) may be managed through supportive care measures including cognitive behavioral therapy, exercise and diet, and estrogen-free lubrication, respectively. [9]

Each endocrine therapy additionally has their own unique side effect profile. Although rare, Tamoxifen may cause cataracts or fatty liver infiltrates. More rarely, tamoxifen may cause deep vein thrombosis (~2%) or uterine carcinoma. The generally accepted rate of uterine carcinoma risk is an increase of 0.5% for every year that the patient takes tamoxifen. Aromatase inhibitors decrease bone density over time due to their estrogen deprivation effect. Bone density scans are essential monitoring, occurring at least every 2 years, but can be obtained yearly. Bisphosphonates can prevent or treat osteoporosis in patients whose bone densities decrease over time or are significantly low at baseline.

Additionally, aromatase inhibitors can slightly increase the risk of cardiovascular morbidity and mortality, though this is usually only significant in patients with a history of ischemic heart disease. Fulvestrant rarely may cause liver dysfunction, but is generally a well-tolerated medication. Patients may complain of injection site pain or irritation due to the syringe size necessary for administration in the gluteal regions. Patients may place ice packs on the injection site for 10 – 15 minutes for numbing prior to the injections.[4,6-9] See Table 1 for endocrine medication dosing and administration.

Table 1.[4,6-8]

DrugDosingScheduleAdministration
Tamoxifen20 mgOnce dailyWith or without food
Letrozole2.5 mgOnce dailyWith or without food
Anastrozole1 mgOnce dailyWith or without food
Exemestane25 mgOnce dailyWith food
Fulvestrant500 mg as 2 separate 250 mg injectionsLoading Dose: 500 mg once every 2 weeks for 3 doses.

Maintenance Dose: 500 mg once every 4 weeks
One injection into each gluteal region.

Targeted Therapies

Cyclin-Dependent Kinase (CDK) 4/6 Inhibitors

Palbociclib

Palbociclib received approval in the United States as the first-in-class CDK 4/6 inhibitor in 2015. Notable trials include the PALOMA series of trials in the metastatic setting, as well as the PALLAS trial in the adjuvant setting in early-stage breast cancer. The PALOMA studies found benefit in progression free survival when Palbociclib was added to an aromatase inhibitor or fulvestrant in the first line, metastatic setting but mixed results with regard to overall survival. The PALLAS trial did not observe any clinical benefit for patients in the early stage setting.

Palbociclib is dosed at 125 mg, 100 mg, or 75 mg by mouth once daily for 21 days, followed by a 7-day break. This is repeated indefinitely until progression. If further dose reductions are needed at 75 mg, the scheduled can be altered to 14 days of therapy with a 14-day break. Palbociclib is generally the best tolerated CDK 4/6 inhibitor as it is not associated with liver dysfunction, rises in creatinine, or diarrhea that ribociclib or abemaciclib may cause.[10-13]

Ribociclib

Ribociclib received approval in the United States as the second CDK 4/6 inhibitor in 2017. Notable trials include the MONALEESA series of trials in the metastatic setting. These studies found improvements in overall survival for ribociclib when added to aromatase inhibitor or fulvestrant compared to placebo in the first line, metastatic setting. Ribociclib uniquely has data specific for pre-menopausal patients that Palbociclib and abemaciclib do not have.

Ribociclib is dosed at 600 mg, 400 mg, or 200 mg by mouth once daily for 21 days, followed by a 7-day break. This is also repeated indefinitely until progression. Unlike Palbociclib, there are no additional schedule adjustments when at the lowest tablet dose available. Ribociclib carries unique toxicities of QTc prolongation, liver dysfunction, and acute kidney injury. Although this has the best data for improving overall survival, it carries with it more toxicities that may prevent patients from tolerating indefinite therapy.[1,14,15] 

Abemaciclib

Abemaciclib is the last CDK 4/6 inhibitor to receive approval in the United States. Uniquely, abemaciclib has indications for monotherapy in the metastatic setting following prior endocrine therapy and chemotherapy in the metastatic setting based on the MONARCH 1 study and for combination therapy in the curative setting following surgery and chemotherapy based on the MONARCH E study. Abemaciclib also carries the same indications as palbociclib and ribociclib for use in first-line metastatic disease in combination with aromatase inhibitor or fulvestrant based on other MONARCH studies. Abemaciclib has also shown overall survival benefit when used as front-line therapy in the metastatic setting.

Abemaciclib has a different dose schedule than palbociclib or ribociclib. Doses are 50 mg, 100 mg, and 150 mg by mouth twice a day continuously when used in combination with aromatase inhibitor of fulvestrant. When used for the monotherapy indication, the dose may be increased to 200 mg by mouth twice a day. Compared to palbociclib and ribociclib, abemaciclib effects the blood counts at a lower incidence and intensity. Abemaciclib also carries a significant risk of diarrhea, a toxicity that some patients are not able to tolerate even with aggressive supportive care management and dose reduction. Liver dysfunction may also occur. Abemaciclib can cause a transient increase serum creatinine due to inhibition of a transporter in the renal tubule. A nuclear GFR scan can be obtained to assess true kidney function in patients where an increase in creatinine is a concern. Rarely, abemaciclib can cause veno-thromboembolisms that are an indication for discontinuing the medication immediately. The clot should be treated with appropriate anticoagulation. [15-20]

Monitoring, Additional Toxicities and Management:

Complete blood counts should be obtained every 2 weeks for the first 2 months for all CDK 4/6 inhibitors to monitor for hematologic toxicities, most notably neutropenia, though anemia and thrombocytopenia can occur. Ribociclib warrants additional monitoring of liver function tests every 2 weeks for the first two months followed by monthly for the following 4 months. Additional labs include electrolytes and serum creatinine monthly for the first 6 months of therapy. Electrocardiogram should be obtained at baseline, 2 weeks into therapy, and 4 weeks into therapy for ribociclib as well. Abemaciclib monitoring should include liver function tests every 2 weeks for the first two months followed by monthly for an additional 2 months.[13,14,20]

If a patient’s absolute neutrophil count (ANC) is below 1k/mm3, then the therapy should be held and counts rechecked the following week. The patient may continue the same dose if recovered to this threshold. If the patient’s value remains low, the dose should be decreased to allow for appropriate ANC recovery. Patients with liver dysfunction should hold therapy until liver tests return to normal, followed by a dose reduction for tolerability.

One rare class side effect is the development of interstitial lung disease (ILD) or pneumonitis. Generally, discontinuing the medication is warranted with or without steroids for complete recovery of pulmonary function. This can be observed on scans prior to a patient presenting with symptoms such as a persistent dry cough or new or worsening shortness of breath.[13,14,20]

mTOR Inhibitors

Everolimus

Everolimus inhibits mammalian target of rapamycin (mTOR) pathway, a noted form of resistance to endocrine therapy; as such, it is only indicated in hormone receptor positive, HER-2 negative disease. Notably, it should be used as combination therapy with one of the following: tamoxifen, exemestane, or fulvestrant. The patient’s prior treatment history as well as potential contraindications based on past medical history should guide which endocrine therapy is chosen to combine with everolimus.

The most notable trial regarding everolimus is the phase III BOLERO-2 study, which showed an improved median progression free survival of 11 months compared to 4 months when combined with exemestane compared to exemestane alone. The patients in this study had already received prior letrozole or anastrozole. Overall, everolimus should only be used in the second-line metastatic setting and beyond due to the limited clinical benefit when compared to the CDK 4/6 inhibitors. It is, however, a reasonable option if the patient is still sensitive to endocrine therapy and would like to delay the initiation of traditional chemotherapeutic agents.[21,22]

The standard everolimus dose is 10 mg by mouth once daily. There are dose reductions available at 7.5 mg, 5 mg, and 2.5 mg. It carries many side effects along with it, including stomatitis, infections, rash, pneumonitis, hyperglycemia, liver dysfunction, and kidney dysfunction. Specifically, stomatitis may need additional management with the use of a steroid-based mouthwash, as noted by the SWISH trial.[23] If this is unavailable, home recipes for mouthwashes to swish and spit such as a ½ teaspoon of baking soda in 240 mL of water may provide some relief.  The other toxicities require temporary discontinuation followed by dose reduction once toxicity returned to baseline, or, in the case of severe toxicities (permanent pneumonitis) permanent discontinuation of therapy. Additionally, everolimus should be withheld at least one week before and two weeks after any invasive procedure due to impairment of wound healing.[21]

PIK3CA Inhibitors

Alpelisib

Alpelisib is a phosphoinositide 3-kinase inhibitor. This requires the patient to harbor a PIK3CA mutation documented by genetic sequencing of the tumor, and the tumor must be hormone receptor positive and HER-2 negative. Alpelisib is taken by mouth once daily with food and is dosed at 300 mg, 250 mg, and 200 mg. As of now, aleplisib’s use requires combination with fulvestrant, so patients who have already progressed on fulvestrant would not be eligible. Data regarding combination therapy with aromatase inhibitors is being studied. The most notable study is the SOLAR-1 study, which showed an improvement in progression free survival 11 months compared to 6 months with placebo. As of now, alpelisib is recommended second-line therapy and beyond in the metastatic setting and should be used after trial of a CDK 4/6 inhibitor. [24]

Significant toxicities that may force discontinuation include hyperglycemia, rash, and diarrhea. Other toxicities include fatigue, stomatitis, nausea and vomiting, and alopecia. For hyperglycemia, patients may be initiated on metformin when blood glucose reaches 160 mg/dL. Additional antihyperglycemic medications such as SGLT2 inhibitors, insulin sensitizers (thiazolidinediones, dipeptidyl peptidase-4 inhibitors) and GLP-1 agonists may be used as necessary. Up to two-thirds of patients experience hyperglycemia, therefore glucose management is imperative and endocrinologists should be utilized when necessary. Patients may experience diarrhea within the first two months of therapy. Supportive care measures such as loperamide, increased fluids, and temporary withholding of alpelisib should be utilized. For rashes, patients may initiate prophylactic antihistamines (loratadine or cetirizine) to lessen the intensity and pruritus. If rashes progress to a severe cutaneous adverse reaction (SCAR) such as Stevens-Johnson syndrome (SJS), erythema multiforme, toxic epidermal necrolysis, or significant skin changes covering greater than 30% of the patient’s body, then the medication must be discontinued.[24,25]

PARP Inhibitors

Olaparib

Olaparib is an oral poly (ADP-ribose) polymerase enzyme (PARP) inhibitor that is used in a variety of solid tumors.  PARP inhibitors induce cell death via double stranded DNA breaks in BRCA 1/2 (breast cancer gene 1 or 2) deficient tumor cells, necessitating patients to express a germline BRCA mutation.  BRCA mutations exist in roughly 5% of breast cancer patients and can be assessed with an appropriate assay.[26]

Olaparib has demonstrated efficacy in patients with both early stage and metastatic cancer.[26,27]  It comes as a tablet with a standard dose of 300 mg by mouth twice daily.  Capsules are potentially available, but have different dosing and have not been evaluated in breast cancer.  Olaparib is metabolized via CYP3A4, but does not have any recommended hepatic dose adjustments.  Providers should reduce the dose from 300 mg to 200 mg twice daily in patients with reduced creatinine clearance (31-50 mL/min).

Toxicities for Olaparib can include pancytopenia, nausea/vomiting, fatigue, and pneumonitis.  Patients should be monitored monthly for myelosuppression and be counseled to take an anti-emetic prior to each scheduled dose.  PARP inhibitors carry a rare risk for secondary malignancy, primarily myelodysplastic syndrome/acute myeloid leukemia that can present at a median timepoint of 2 years.[26,27,28]

Talazoparib

Talazoparib is the other PAPR inhibitor used in breast cancer. Is it only indicated for metastatic breast cancer for patients who express a germline BRCA mutation. It is a tablet that is dosed 1 mg by mouth once daily. Dose reductions are recommended for creatinine clearance less than 60 mL/min but none are recommended for hepatic impairment.  It is a substrate of p-glycoprotein, an efflux pump that can be inhibited by other medications, hence drug-drug interactions should be assessed. Toxicities from talazoparib include myelosuppresion, most commonly anemia, nausea/vomiting, fatigue, and diarrhea. Increased blood sugar, decreased liver function, and decreased calcium were seen in the metastatic clinical trial.

PARPs are also associated with a small risk of developing a secondary leukemia as mentioned previously with olaparib. Talazoparib has a single center study assessing its use in neoadjuvant BRCA positive patients but has not been formally studied in a large clinical trial setting.[29,30]

HER-2 Targeting Therapies

Trastuzumab

Trastuzumab is a monoclonal antibody that targets the Human epidermal growth factor receptor 2 (HER-2neu).[31]  The antibody binds to subdomain 4 of the HER-2 receptor and inhibits HER receptor dimerization with other HER family receptors (including EGFR/HER-1, HER-3, and HER-4). It promotes antibody-dependent cellular cytotoxicity and blocks HER2 signaling which inhibits downstream signaling pathways such as PI3K-Akt-mTOR or RAS-RAF-MAPK.[32]  Trastuzumab can also increase cellular apoptosis by means of chemotherapy sensitization or angiogenesis inhibition.[2]

Trastuzumab can be administered weekly or once every 3 weeks with an initial loading dose, followed by maintenance dosing.  The interval selected often coincides with other combined treatments.  When administered weekly, trastuzumab is given as a 4 mg/kg loading dose followed by 2 mg/kg maintenance.  If administered every three weeks, dosing is 8 mg/kg loading dose followed by 6 mg/kg thereafter.[31]

Regardless of schedule, trastuzumab loading doses should be administered over 90 minutes and maintenance doses over 30 minutes (if initial dose is tolerated without hypersensitivity reaction).  Trastuzumab has a half-life of roughly 28 days at steady state (which takes ~ 4 doses), does not undergo any metabolism, and is broken down through regular protein degradation.  Per the package insert, trastuzumab requires reloading after a one-week dose delay.  In clinical practice, providers should determine if this is appropriate.  Theoretically, the long half-life of steady state trastuzumab should maintain therapeutic levels long after a dose is missed.  Given the pharmacokinetics of trastuzumab, patients could go 6-8 weeks without needing to be reloaded.  If administered in combination with chemotherapy on the same day, trastuzumab should be administered prior to chemotherapy.[31]

There are additional products and routes of administration available for trastuzumab, known as biosimilars.  Unlike generic formulations of oral drugs, biosimilars are required to undergo clinical trial evaluation for efficacy and safety equivalency.  Trastuzumab can also be administered subcutaneously with a separate product called trastuzumab-hyaluronidase.  This product does not have a loading dose and is administered at 600 mg/10,000 units subcutaneously every 3 weeks.[33]

Trastuzumab can be used in combination with many chemotherapy agents, such as microtubule inhibitors (paclitaxel, docetaxel, eribulin, vinorelbine), antimetabolites (capecitabine, gemcitabine), other anti-HER2 therapies (pertuzumab, tucatinib, lapatinib), or as a single agent.[2] 

Trastuzumab should not be used concurrently with anthracycline chemotherapy due to increased risk of cardiotoxicity.  Patients should be monitored for cardiotoxicity via echocardiogram (ECHO) or multigated acquisition scan (MUGA) every 3 months while receiving trastuzumab therapy.  Rates of cardiotoxicity are relatively low (~2%) when used appropriately, but can occur at any point during therapy.[34]  Conditions for withholding trastuzumab therapy include a left ventricular ejection fraction decrease (LVEF) of greater than 16% from pre-treatment values or an LVEF below institutional limits combined with an absolute decrease of > 10%.  Treatment should be held for a minimum of four weeks and then reassessed for LVEF recovery.[31]

Trastuzumab has several significant safety considerations.  There are black box warnings for hypersensitivity reactions, cardiotoxicity, pneumonitis, and embryo-fetal toxicity.[31]  Hypersensitivity reactions are most likely to occur during the first or second administration and can vary in presentation.  Patients can experience traditional symptoms such as chest pain, shortness of breath, arthralgias, and hypotension.  If symptoms are reported, treatment should be paused and managed with acute remedies, such as steroids and antihistamines.  Upon resolution of symptoms, patients can be rechallenged at half-rate.  Embryo-fetal toxicity is a major concern for any patient who is currently pregnant or breastfeeding and any anti-HER2 therapy should be avoided in these situations.

Pertuzumab

Pertuzumab is a monoclonal antibody that works similarly to trastuzumab, but binds to subdomain two of HER-2, providing more steric inhibition.  It is used in combination with trastuzumab to provide more complete inhibition and improved efficacy.  It has similar downstream inhibition to trastuzumab.  Of note, pertuzumab has not demonstrated single agent effectiveness and should not be administered as monotherapy.  Pertuzumab is administered as a flat dose once every 3 weeks with a loading dose of 840 mg IV over 60 minutes.  Maintenance doses are 420 mg IV and can be given over 30 minutes if tolerated.  Pertuzumab’s half-life is roughly 18 days and undergoes conventional protein degradation.  Pertuzumab should be reloaded if the interval between doses is greater than 6 weeks.[35]

Trastuzumab and pertuzumab are available as a combination product that is administered subcutaneously, referred to as Phesgo©.  This agent is administered once every three weeks as a flat dose, 1200 mg/600 mg/30,000 units once as a load, and then 600 mg/600 mg/20,000 units thereafter as maintenance.  If patients were previously receiving intravenous pertuzumab and trastuzumab, they do not require a loading dose of Phesgo© for continued therapy.[36]

Pertuzumab has a similar toxicity profile to trastuzumab.  It is associated with hypersensitivity reactions, cardiotoxicity, pneumonitis, and embryo-fetal toxicity.  Patients can also experience significant diarrhea when receiving pertuzumab therapy, which should respond well to traditional management strategies of hydration and antidiarrheal agents.[35]

Ado-trastuzuman emtansine (T-DM1)

Ado-trastuzumab emtansine is an antibody drug conjugate (ADC) that combines the targeted effect of trastuzumab with an anti-microtubule chemotherapy, emtansine (DM1).  Upon trastuzumab attaching to the extracellular HER2 receptor, the drug is internalized and lysed, allowing emtansine to exert antineoplastic effects.  Ado-trastuzumab emtansine comprises a linker to keep the DM1 molecule attached to trastuzumab, ensuring cellular delivery and minimizing systemic toxicity.  Once in the intracellular space, DM1 is released via lysosome degradation.  Emtansine works similarly to vinca alkaloids by inhibiting microtubule assembly.  Ado-trastuzumab emtansine is administered once every three weeks and does not require a loading dose.  It is not interchangeable with any other trastuzumab based products.  It is dosed at 3.6 mg/kg intravenously over 90 minutes for the first dose; infusion time can be reduced to thirty minutes for subsequent doses if prior infusions were well tolerated.  Ado-trastuzumab emtansine is dose adjusted based upon hepatic function and treatment setting.  See Table 2 for details. [37]

Table 2

Hepatic adjustments – Adjuvant
BaselineMild to moderate (Child Pugh A or B): Use with caution
Severe impairment (Child Pugh C): Has not been studied
Hepatotoxicity during treatmentTransaminases:
Grade 2 AST: Withhold until Grade 1 or less, then resume at same dose level
Grade 3 AST: Withhold until returns to Grade 2 then resume with one dose level reduction
Grade 2-3 ALT: Withhold until Grade 1 or less, then resume with one dose level reduction
Grade 4: Permanently discontinue
Bilirubin:
Total bili >1 to <2x ULN : Withhold until returns to <1x ULN then resume w one dose level reduction Total bili >2x ULN: Discontinue treatment
Hepatic adjustments – Metastatic
BaselineMild to moderate (Child Pugh A or B): Use with caution
Severe impairment (Child Pugh C): Has not been studied
Hepatotoxicity during treatmentTransaminases:
Grade 2: Continue at same dose level
Grade 3: Withhold until returns to Grade 2 then resume w one dose level reduction
Grade 4: Permanently discontinue
Bilirubin:
Grade 2-3: Withhold until returns to Grade 1 then resume w one dose level reduction
Grade 4: Permanently discontinue
Concomitant ALT/AST >3x ULN and bilirubin >2x ULN: Permanently discontinue

Ado-trastuzumab emtansine exhibits additional toxicities compared to trastuzumab due to the chemotherapy moiety.  Patients should still be monitored with ECHOs for cardiotoxicity every 3 months and should be aware of possible hypersensitivity reactions.  Patients with previous hypersensitivity to trastuzumab are at an increased risk to experience a reaction to T-DM1.  Additional toxicities include hepatoxicity, neutropenia, thrombocytopenia, and anemia, diarrhea, and mucositis.  Black-box warnings exist for the hepatoxicity and embryo-fetal toxicity.  Patients should be monitored for hepatic function and a CBC with differential every treatment cycle to ensure safe administration.[37,38,39,40]

Fam-trastuzumab deruxtecan-nxki (T-Dxd)

Fam-trastuzumab deruxtecan-nxki is an antibody drug conjugate that combines trastuzumab with a novel topoisomerase I inhibitor called deruxtecan.  Like T-DM1, T-Dxd binds to subdomain IV of the HER2 receptor and, upon internalization, releases a cytotoxic compound.  Deruxtecan exerts an effect by causing single stranded DNA breaks which lead to apoptosis. T-Dxd is administered once every three weeks at 5.4 mg/kg as an intravenous infusion.  The initial treatment is given over 90 minutes and subsequent doses can be administered over 30 minutes if well tolerated.  There are no hepatic or renal dose adjustments recommended for T-Dxd as it has not been studied in extremely impaired patients.

Fam-trastuzumab deruxtecaan-nxki can cause several key toxicities. T-Dxd is a moderately emetogenic drug, requiring several pre-medications to manage.  Patients can experience myelosuppression, primarily neutropenia, fatigue, alopecia, diarrhea and hypokalemia.  This agent has a black-box warning for potential embryo-fetal toxicity and interstitial lung disease (ILD).  In the initial T-Dxd phase 3 trial, roughly 15 percent of patients experienced varying grades of ILD or pneumonitis, including some deaths.  Typical onset is about 2.8 months from the start of treatment.  Patients should receive baseline pulmonary function tests and be regularly assessed for symptoms of ILD.[40,41]

Margetuximab

Margetuximab is a monoclonal antibody that binds to subdomain IV of the HER2 receptor.  It functions similarly to trastuzumab but has a modified Fc binding region that promotes antibody dependent cellular cytotoxicity and natural killer cell activation.  It is used in combination with a variety of chemotherapy agents in the third line or later setting in metastatic breast cancer management.  Margetuximab can be utilized with capecitabine, eribulin, gemcitabine, or vinorelbine.[4]  Margetuximab is dosed at 15 mg/kg IV once every 3 weeks with no loading dose.  Like other anti-HER2 therapies, it has a longer initial administration to limit infusion related reactions.  The first dose should be given over 120 minutes with subsequent doses over 30 minutes.  Administration sequence with margetuximab is opposite other anti-HER2 agents and should be given after chemotherapy is complete.  Margetuximab shares similar toxicities to other HER2 targeted agents including hypersensitivity reaction, cardiotoxicity, diarrhea, and embryo-fetal toxicity.[42, 43]

Tucatinib

Tucatinib is an oral tyrosine kinase inhibitor that is highly selective for the HER2 kinase domain, inhibiting HER2 phosphorylation and dimerization.  It is supplied as both 150 mg and 50 mg tablets and dosed as 300 mg by mouth twice daily of a 21-day cycle.

Tucatinib is only currently approved for use in combination with capecitabine and trastuzumab.  It is particularly useful as it has demonstrated benefit in patients with brain metastases.  Tucatinib is metabolized through the liver via CYP2C8 and CYP3A4.  It is recommended to avoid strong inducers and inhibitors of these enzymes.  Dose adjustments for tucatinib are based upon Child-Pugh scoring.  Class C scores should have an initial dose reduction to 200 mg by mouth twice daily.[44]

Tucatinib toxicity is highlighted by two significant issues – diarrhea and hepatotoxicity.  Patients should be monitored for liver dysfunction every 3 weeks while on treatment.  Patients require one level of dose reduction if transaminases are >5X the upper limit of normal or bilirubin is >3X the upper limit of normal.[44,45]

Neratinib

Neratinib is an oral tyrosine kinase inhibitor that bind to EGFR, HER3, and HER4 receptors.  It works to block downstream signaling pathways.  Neratinib is typically administered as a single agent in the curative setting following the completion of one year of trastuzumab treatment.  It is supplied as 60 mg tablets and is dosed as 240 mg by mouth daily with or without food.

Neratinib is metabolized via the liver by CYP3A4, strong inducers and inhibitors should be avoided.  Proton pump inhibitors can also reduce neratinib levels and should be avoided in combination.  Neratinib causes significant diarrhea and has been shown to be best tolerated by titrating the dose over several weeks.  The trial by Barcenas et al., demonstrated that a titration schedule combined with prophylactic loperamide can increase tolerance and prevent dose delays, reductions, and discontinuation of the therapy.  Patients should start by taking 120 mg of neratinib daily for one week and then increase to 160 mg daily the second week.  Week three and beyond can be increased to 240 mg.[46,47]

Lapatinib

Lapatinib is an oral tyrosine kinase inhibitor that acts intracellularly at EGFR and HER2.  It is administered in combination with a variety of several other agents.  Lapatinib is supplied as 250 mg tablets and should be taken without food daily.  See table 3 for dosing recommendations dependent on the paired agent.

Lapatinib is hepatically metabolized via CYP3A4 and should avoid concurrent strong CYP3A4 inhibitors and inducers.  Patients with Child-Pugh class C liver impairment should be dose reduced by one tablet (250 mg).  Lapatinib can cause significant hepatoxicity, a black-box warning, which should be monitored every 6 weeks.  Patients can develop acneiform rash which can be managed with topical antibiotics.[48]

Table 3 49,50,51

Combination agentLapatinib dose
Letrozole1500 mg
Capecitabine1250 mg
Trastuzumab1000 mg

Immunotherapy

Pembrolizumab

Pembrolizumab is an immunotherapy which harnesses the body’s own immune system to seek out cancer cells. It inhibits programmed-cell death 1 receptor (PD-1), preventing the tumor from inhibiting T-cells and allowing the body to utilize its full arsenal of T-cell mediated immunity.

In breast cancer, Pembrolizumab has shown activity in combination with chemotherapy in the early stage and metastatic triple negative breast cancer settings. In the early stage setting, PD-1 activity testing on the tumor is not required; however, Pembrolizumab should only be used in patients whose tumors are at least 2 cm large or who have positive lymph nodes.

In the metastatic setting, Pembrolizumab with chemotherapy should only be used in patients whose combined positive score (CPS) is greater than 10, a measurement that should be evaluated by apathologist on biopsy specimens. Additionally, it has evidence for use as monotherapy in the metastatic setting in patients who have microsatellite instability (MSI-H), are deficient in mismatch repair proteins (dMMR), or have a high tumor mutation burden (TMB, which is defined as 10 mutations per 100 base pairs) in the metastatic setting, regardless of receptor status.[52-56]

Pembrolizumab is traditionally dosed at 200 mg every 3 weeks; this can be extended to 400 mg every 6 weeks if clinically appropriate. Pre-medications are not usually required and administration time is only 30 minutes for both doses. There are no specific dose adjustments for renal or hepatic dysfunction, nor are there dose adjustments for toxicity.

The main modality of managing toxicity is through temporary discontinuation of pembrolizumab with either usual supportive care or initiation of corticosteroid therapy. Due to the nature of pembrolizumab’s mechanism of action, inflammation of organs and organ systems throughout the body are possible, though some are rarer than others are. Generally, the most common side effects are rash, fatigue, arthralgias, and myalgias. Varying levels of colitis may be present, though it can be difficult to discern whether diarrhea is due to the chemotherapy or pembrolizumab. Normal supportive care measures such as loperamide or diphenoxylate-atropine are able to control chemotherapy-associated diarrhea. Immunotherapy-induced colitis generally requires treatment escalation with corticosteroids.  Thyroiditis is a somewhat common side effect, though this can be managed with initiation of levothyroxine and monitoring of thyroid stimulating hormone and free thyroxine levels.

Other rarer side effects include pneumonitis, optic neuritis, hypophisitis, hepatitis, nephritis, myocarditis, myositis, and pancreatitis, among others. Pertinent consults to specialized practitioners of each organ or organ system should be made for assistance in management, in addition to holding immunotherapy and initiation of steroids.[52,57]

Trop-2 Inhibitors

Sacituzumab govitecan-hziy

Sacituzumab govitecan-hziy is a novel antibody drug conjugate that targets the trophoblast cell surface antigen-2 (Trop-2) receptor, which has demonstrated overexpression in several solid tumors, including breast cancer.  It has demonstrated notable anti-cancer activity in triple negative breast cancer and more recently in  estrogen-receptor positive subtypes.  This ADC combines a monoclonal antibody with a linked topoisomerase I inhibitor, govitecan, which causes single stranded DNA breaks.  Govitecan is the active metabolite (SN-38) of irinotecan that is released in the tumor microenvironment, both intra- and extracellularly.  Sacituzumab is administered at a dose of 10 mg/kg on Days 1 and 8 of a 21 day cycle.  The first dose should be administered over 3 hours due to a high rate of hypersensitivity reaction.

Patients should be pre-medicated with antihistamines (H1 and H2 blockers) and acetaminophen, with or without corticosteroids, to limit the incidence and severity of a reaction.  There are no recommended dose adjustments for renal or hepatic function, but consideration can be given to UGT1A1 polymorphism genotyping, which can suggest increased irinotecan-related toxicity.  It is not a commonly performed test but can be considered if a patient exhibits excessive toxicity (prolonged neutropenia, unresolved diarrhea).  Patients with elevated bilirubin or liver function tests may require closer monitoring as that could suggest decreased UGT1A1 activity.  It is recommended to avoid concurrent use of sacituzumab and known UGT1A1 inhibitors or inducers (Table 4).

Common toxicities can include nausea/vomiting, fatigue, alopecia, decreased electrolytes (magnesium, potassium, phosphorus), and mucositis.  There are black box warnings for neutropenia and diarrhea.  Irinotecan-associated diarrhea may require different supportive care management for early onset (within 24 hours) or late onset (>24 hours) symptoms.  Early onset diarrhea is primarily driven by a cholinergic response and can be associated with abdominal cramping, skin flushing, and salivation.  Anti-cholinergic agents, such as atropine (in combination with diphenoxylate) can manage and alleviate symptoms.  Late onset diarrhea due to SN-38 is multi-factorial, but primarily caused by direct mucosa damage.  Loperamide is the standard of care option for managing delayed diarrhea.  Routine monitoring for sacituzumab includes a complete blood count and metabolic panel for liver and electrolyte monitoring. [58,59,60]

Table 4

UGT1A1 InducersUGT1A1 Inhibitors
Phenytoin Phenobarbital Rifampin LamotriginePropofol Erlotinib Sorafenib

Chemotherapy

Anthracyclines

Anthracyclines have exceptional activity against breast cancer are used in both the curative and metastatic setting. Doxorubicin and epirubicin are usually combined with cyclophosphamide to improve cure rates in the early stage setting while liposomal doxorubicin is an agent available to use as monotherapy in the metastatic setting. Anthracyclines are considered cell-cycle non-specific chemotherapies; they work by intercalating between DNA base pairs and inhibiting both topoisomerase II and DNA helicase, causing apoptosis at all stages of the cellular reproductive cycle.[61-63]

Doxorubicin is dosed at 60 mg/m2 over 15 minutes and scheduled every 2 or 3 weeks. When scheduled at every 2 weeks in combination with cyclophosphamide, the regimen is described as “Dose-Dense AC”, which requires growth factor support to maintain optimal scheduling. Dose-dense is typically the favored schedule, but patients, specifically elderly patients or patients with prior neutropenic or febrile neutropenia episodes may require the dosing interval to be extended to every 3 weeks. Central line access is a must for doxorubicin to avoid extravasation, though peripheral lines may be used in emergent situations. Doxorubicin is metabolized through the liver via CYP2D6 and 3A4.

It is also a substrate of p-glycoprotein.Dose adjustments should be made for patients with elevated transaminases or bilirubin. The liposomal doxorubicin differs in many ways, most notably in its starting dose (40 mg/m2) and dosing interval (every 4 weeks). Additionally, the infusion time for the first infusion is recommended to be run at 1 mg/minute; this can be shortened to 60 minutes if the patient does not experience an infusion-related reaction. Liposomal doxorubicin should also be dose adjusted for elevated bilirubin. Epirubicin is also combined with cyclophosphamide in the curative setting. It is dosed at 100 mg/m2 over 15 minutes and is only scheduled once every 3 weeks. Unlike doxorubicin, epirubicin does not undergo liver metabolism via cytochrome P450 enzymes, nor is it a p-glycoprotein substrate. Doses should still be adjusted for elevated bilirubin or transaminases due to potential for direct liver damage from the epirubicin itself.[2,61-63]

Anthracyclines as a class are known to cause delayed type I cardiomyopathies. The risk in curative breast cancer regimens with the doses above is generally accepted to be in between 1 – 2%. These can present as early as within the 1st year after exposure or years after in the form of heart failure. Rarely, anthracyclines can cause acute arrhythmias or cardiotoxicity, usually in patients with underlying cardiac disease. Baseline ECHOs or MUGAs are required prior to initiation to measure LVEF.[64]

Patients who develop cardiotoxicity should be followed by a cardiologist and initiated on cardioprotective medications such as angiotensin converting enzyme (ACE) inhibitors and appropriate beta blockers to prevent further cardiac remodeling. As noted, before central access is preferred for all anthracyclines, though liposomal doxorubicin may be given safely through a peripheral vein. Anthracyclines are a nauseating medicine, with liposomal doxorubicin being a moderately emetogenic and doxorubicin and epirubicin being highly emetogenic when combined with cyclosphosphamide. Appropriate pre-medications, usually consisting of a serotonin receptor antagonist, a neurokinin-1 inhibitor, and corticosteroid, are required to help prevent both acute and delayed nausea and vomiting.[65]

Due to their DNA intercalation, anthracyclines are associated with a small risk of secondary malignancies (0.25 – 1%)[66], specifically secondary myelodysplastic syndromes and leukemias, due to a specific chromosomal translocation). Bone marrow suppression can cause leukopenia, anemia, thrombocytopenia, and neutropenia that may force dose or schedule modification. Liposomal doxorubicin may additionally cause hand-foot syndrome (sloughing, cracking, reddening or hands or feet) that will require frequent moisturization (alcohol and scent-free) to help mitigate.[2,61-63]

Taxanes

Taxane chemotherapy serves as one of the two backbone categories for treating breast cancer.  There are three agents primarily utilized – paclitaxel, docetaxel, or nab-paclitaxel.  All three are utilized as single agents or in combination with other treatments.  Paclitaxel is an anti-microtubule agent that is derived from the Pacific yew tree and works to inhibit microtubule disassembly by stabilizing the existing microtubules in metaphase.  It can be administered weekly or every 3 weeks with similar results, but different toxicity profiles.

If administered weekly, paclitaxel is dosed at 80 mg/m2 over 60 minutes, for a maximum of 12 weeks in early stage breast cancer.  If metastatic, patients can continue treatment indefinitely and providers may opt for a 2 week on 1 week off schedule to help prolong tolerance.  When administered every three weeks, paclitaxel is given at 175 mg/m2 IV over 3 hours every 21-days or can be every 14-days with growth factor support.  Paclitaxel is metabolized through the liver via CYP2C8 and -3A4.  Dose adjustments are based upon hepatic function, but recommendations are specific to the every 3 week schedule.[67,68]

Paclitaxel weekly schedules should be monitored closely in settings of liver dysfunction.  Nab-paclitaxel combines traditional paclitaxel and suspends it in albumin-bound nanoparticles rather than cremophor.  It is indicated for breast cancer use at 260 mg/m2 once every three weeks, but in clinical practice it is more commonly dosed at 100 mg/m2 on days 1, 8, and 15 of a 28-day cycle.  Nab-paclitaxel is also hepatically metabolized and does not have any recommended reductions for weekly dosing.[69]

Docetaxel is a semi-synthetic analogue of paclitaxel that is used in many areas of breast cancer care.  It can be used in combination with other chemotherapy agents, targeted HER-2 therapy, or as a single agent.  It is administered at 75 mg/m2 over 60 minutes once every 3 weeks.  Docetaxel is hepatically metabolized via CYP3A4.  Per the manufacturer, it is recommended to avoid use of docetaxel if total bilirubin or transaminases are greater than 1.5 times the upper limit of normal.  Retrospective review of docetaxel use in patients with hepatic dysfunction does provide some guidance to appropriate dose reductions (Table 5).[70,71]

Table 5

Dose levelParametersDocetaxel (mg/m2)
Group ITBili normal and ALT/AST 1.5-2.5 x ULN and alkaline phosphatase (Alk Ph) ≥ 2.5 x ULN75
Group IITBili normal and ALT/AST 2.5-5 x ULN and/or Alk Ph ≥ 2.5 x ULN in the absence of bone mets50
Group IIITBili 1.5-3 x ULN and ALT/AST 1.5-2.5 x ULN and/or Alk Ph ≥ 2.5 x ULN50
Group IVTBili 1.5-3 x ULN and ALT/AST 2.5-5 x ULN and/or Alk Ph ≥ 2.5 x ULN25
Group VTBili > 3 x ULN and any ALT/AST/Alk Ph or ALT/AST > 5 x ULN and any TBili or Alk Ph12

Taxanes as a class can cause a variety of issues.  Known toxicities include alopecia (full body hair loss), myelosuppression, diarrhea, arthralgias and myalgias, rash or nail changes, peripheral neuropathy, fatigue, and mouth sores.  Patients receiving paclitaxel can have slightly different toxicity profiles depending on the schedule of treatment.  Those who receive weekly paclitaxel are more likely to experience peripheral neuropathy, nail changes, and mouth sores due to the increased exposure.  Every 3-week schedules cause more neutropenia and nausea or vomiting.  Patients receiving either schedule are likely to experience arthralgias or myalgias that persist for up to 48 hours.  Peripheral neuropathy is a cumulative toxicity and needs to be assessed regularly to ensure that it does not disrupt activities of daily living or become a permanent effect.  Medications such as venlafaxine or gabapentin can help address neuropathic pain, but dose reductions and treatment breaks are the most effective way to navigate the numbness or tingling.[67] 

Nab-paclitaxel has similar toxicities and incidence to that of paclitaxel, but is not associated with hypersensitivity reactions due to the omission of cremophor.[68] Docetaxel is more commonly associated with neutropenia, with estimated rates of febrile neutropenia greater than 20%.  Because of this, all patients receiving docetaxel should be considered candidates for growth factor support.  Patients receiving docetaxel may also experience greater rates of peripheral edema or chemical conjunctivitis.  Edema is typically a cumulative toxicity that occurs more commonly beyond 400 mg/m2 in a lifetime.  Diuretics can be prescribed to alleviate it.  Docetaxel induced conjunctivitis can be managed with artificial tear drops and warm compresses to clear tear ducts which may be clogged.[70]

Hypersensitivity reactions can occur and require pre-medication.  Most patients do not have a true allergy to paclitaxel, but rather are allergic to a castor oil solubilizing ingredient called cremophor.  Higher doses of paclitaxel contain more cremophor, which increases the risk of reaction and requires greater levels of pre-medication.  If paclitaxel is administered weekly, patients start with dexamethasone 10 mg IV with the first three treatments and then 4 mg IV for the remaining treatments.  If being treated with every 3-week doses of paclitaxel, patients should be pre-medicated with 20 mg IV of dexamethasone, H1RA, and H2RA agents.  Symptoms of hypersensitivity reaction can include skin flushing, itching, chills, myalgias, shortness of breath, or chest pain.  If patients experience a reaction the infusion should be stopped and managed with additional supportive care medications such as hydrocortisone and diphenhydramine.  Adjustments for future cycles could include decreased infusion rates or adding pre-medications if the classes mentioned above were not already included.  Patients with anaphylactic reactions should not be rechallenged.

Patients receiving docetaxel can also experience hypersensitivity reactions, due to polysorbate 80.  Prophylaxis is similar – patients should be premedicated with dexamethasone.  Different approaches can be taken to the dosing schedule.  Patients can receive a one-time dose of dexamethasone 20 mg IV prior to each docetaxel infusion, or could receive oral dexamethasone to take leading up to treatment.  If the latter, patients should receive 8 mg orally twice daily for three days (the day before chemotherapy, the day of, and the day after) with a potential added benefit of limiting docetaxel-induced peripheral edema.  Docetaxel reactions present similarly to paclitaxel and patients with anaphylactic presentation should not be rechallenged.

Nab-paclitaxel does not contain either cremophor or polysorbate 80 and can be considered an option in patients who had a previous reaction to either taxane.  Thought should be given to using nab-paclitaxel if the patient previously experienced an anaphylactic reaction as that could be a true taxane allergy.

Cyclophosphamide

Cyclophosphamide is an alkylating agent that is metabolized by CYP3A4 to active metabolites. These metabolites cross-link DNA strand and decrease DNA synthesis as a cell-cycle non-specific agent. Cyclophosphamide is typically used in the curative setting in combination with an anthracycline at a dose of 600 mg/m2 administered over 30 minutes every 2 to 3 weeks.

It can, however, also be combined with methotrexate and 5-Fluorouracil in a rarely used regimen called CMF that utilizes either IV dosing (600 mg/m2 on day 1 every 21 days) or oral dosing (100 mg/m2/day on days 1 through 14 every 28 days). The metastatic regimen of 50 mg by mouth daily for 21 days every 28 days, is typically reserved for poor performing patients and is not a preferred regimen.

There are both renal adjustments at a creatinine clearance of less than 30 mL/min and hepatic dose adjustments for elevated bilirubin (3.1 – 5 mg/dL) and transaminases (greater than 3 times the upper limit of normal). Many of cyclophosphamide specific toxicities, including cyclophosphamide induced cardiomyopathy, sinusoidal obstruction syndrome, hyponatremia, pneumonitis and pulmonary fibrosis, and hemorrhagic cystitis, are not observed in breast cancer regimens due to the much lower dose given in comparison to patients receiving cyclophosphamide for other indications such as lymphoma, leukemia, or stem cell transplants.

However, patients still experience bone marrow suppression and are at risk for secondary malignancies, specifically due to incomplete or full deletions of chromosome 5 or 7.[72,73]

Carboplatin

Carboplatin is a platinum agent that covalently binds to DNA and produces interstrand DNA cross-links. Carboplatin is used in both the early stage and metastatic settings, usually as part of a combination chemotherapy, though single agent chemotherapy may be an option in patients who harbor a BRCA mutation. Carboplatin is combined with docetaxel, trastuzumab, and sometimes pertuzumab in the HER-2 positive curative setting. It is also combined with paclitaxel and pembrolizumab in the early stage triple negative setting studied in the Keynote-522. It can be used in the metastatic setting in combination with gemcitabine, with or without pembrolizumab, in triple negative breast cancers. It is dosed based on an area under the curve (AUC) measurement that adjusts the dose based on the patients creatinine clearance using the Calvert equation. It can be given either weekly or every 3 weeks depending on the regimen.

Generally, weekly AUC dosing ranges between an AUC of 1 – 2, whereas every 3 week AUC dosing ranges between an AUC of 4 – 6. The Calvert equation inherently adjusts for kidney dysfunction, and there are no specific hepatic impairment dose adjustments recommended. Carboplatin is generally administered over 30 minutes and requires pre-medications for nausea prevention. An AUC of 4 or greater is considered highly emetogenic and an AUC of less than 4 is considered moderately emetogenic.

One consideration for weekly dosing of carboplatin is the risk of hypersensitivity reactions as there are typically 12 weekly doses of carboplatin planned for a curative course of chemotherapy. Carboplatin can also cause electrolyte wasting, most commonly with potassium and magnesium but can also include calcium, sodium, and phosphorus. To help prevent acute kidney injury, patients should increase fluid intake to at least 2 liters per day. Rarely, carboplatin can cause tinnitus which may become irreversible if not identified early on.

If carboplatin is not available, cisplatin can also be used though it is generally seen as more toxic and difficult to use in breast cancer.[53,74-76]

Capecitabine

Capecitabine is the prodrug and oral form of 5-fluoropyrimidine. It acts as an antimetabolite that inhibits thymidylate synthetase and blocks methylation of deoxyurdylic acid to thymidylic acid; as such, it is specific to the G1 and S phase of the cell cycle when DNA replication is being conducted.

Capecitabine is used in the adjuvant setting in triple negative breast cancer if residual disease is present following neoadjuvant chemotherapy. It is also commonly used in the metastatic setting for all subtypes of breast cancer, though it must be combined with a HER-2 targeting agent for HER-2 positive breast cancer. Labelled dosing is 2500 mg/m2/day; most patients should be initiated at 2000 mg/m2/day as the 2500 mg/m2/day dose is poorly tolerated by most patients due to the decreased presence of dihydropyrimidine dehydrogenase which helps metabolize 5-fluorouracil. The dose is divided into morning and evening doses that are taken within 30 minutes after a meal. Patients should take tablets for 14 days followed by 7 days of rest for a 21-day cycle.

Patients who are taking proton-pump inhibitors should be counseled regarding a drug-drug interaction that decreases capecitabine absorption; discontinuing the proton-pump inhibitor should be considered in a curative patient to optimize outcomes, but patients with metastatic breast cancer may have other gastrointestinal issues where the benefit of acid suppression therapy may outweigh the risk.[77,78]

The most common side effect is hand-foot syndrome; patients should moisturize their hands and feet at least 3 – 4 times per day to prevent redness, cracking, and skin drying/peeling from occurring. There are other therapies that have not been as well studied and therefore are not usually recommended up front for treating or preventing hand-foot syndrome.[79]

Diarrhea and mouth sores are other common adverse effects that may occur during therapy. One rare side effect is the ability of capecitabine to cause coronary artery vasospasms. These are generally reversible, but they are not distinguishable from an acute myocardial infarction without an EKG, so patients should be counseled to go to the emergency center for assessment should they experience sudden chest pain.[80]

Eribulin

Eribulin is a halichondrin B analog anti-microtubule agent.  It works to prevent the creation of microtubules in the G2 and M phases of mitosis, similar to vinka alkaloids.  It is administered as undiluted drug at 1.4 mg/m2 IV over 2-5 minutes on days 1 and 8 every 21 days.  It has negligible metabolism, but does have dose reductions in patients with either renal or hepatic impairment.

Hepatic adjustments are based upon Child-Pugh class. Renal dose adjustments are required for patients with a creatinine clearance of 15-49 mL/min.  Eribulin can cause toxicities similar to other microtubule inhibitors, such as myelosuppression, peripheral neuropathy, fatigue, diarrhea/constipation, and in rare cases can cause QT prolongation.  A baseline EKG can be considered in patients with a history of cardiac issues.[81]

Ixabepilone

Ixabepilone is an epithilone B analog anti-microtubule agent.  It acts as a microtubule inhibitor that binds to the Beta-tubulin subunit of the microtubule, stabilizing it and preventing breakdown in the M phase.  It is dosed at 40 mg/m2 IV over 3 hours once every 3 weeks.  Ixabepilone is formulated with cremophor (about 1/10 the amount seen in paclitaxel) so hypersensitivity reactions are possible and standard pre-medications should include an H1RA and H2RA. It should both be mixed in lactated ringers and flushed after administration.

Ixabepilone is hepatically metabolized through CYP3A4 and should be dose reduced for AST and/or ALT greater than 2.5 times the upper limit of normal or bilirubin greater than 1.5 times the upper limit of normal.  Common toxicities of ixabepilone include myelosuppression (primarily neutropenia), fatigue, peripheral neuropathy, and diarrhea.  Ixabepilone was previously used in combination with capecitabine, but had an increased risk of neutropenic-related deaths and it is no longer recommended to be used together.[82]

Vinorelbine

Vinorelbine is a vinka alkaloid agent that binds to tubulin and prevents microtubule formation.  It is dosed at 30 mg/m2 IV over 10 minutes weekly until disease progression.  It is hepatically metabolized via CYP3A4 and should be dose reduced in patients with hepatic impairment.  It is recommended to dose reduce vinorelbine if the bilirubin is greater than 2 mg/dL.  Toxicities of vinorelbine include neutropenia, diarrhea/constipation, and peripheral neuropathy.[83]

Gemcitabine

Gemcitabine is a pyrimidine analog antimetabolite that inhibits DNA synthesis via inhibition of DNA polymerase and ribonucleotide reductase.  It is dosed at 1000 mg/m2 IV over 30 minutes once weekly.  It can be used in combination with carboplatin or administered as a single agent.  Gemcitabine can be used safely in patients with hepatic impairment and can be used as preferred agent in patients with extremely elevated bilirubin values.  Toxicities associated with gemcitabine include neutropenia, thrombocytopenia, edema, fatigue, and flu-like symptoms.  Patients who experience chills, aches, or low-grade fevers within 24 hours of a gemcitabine infusion can be instructed to utilize acetaminophen to resolve the symptoms.[84]

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