Breast Cancer (Recurrent or Metastatic) Treatment Regimens

Breast Cancer (Recurrent or Metastatic) Treatment Regimens

Clinical Trials: The NCCN recommends cancer patient participation in clinical trials as the gold standard for treatment.

Cancer therapy selection, dosing, administration, and the management of related adverse events can be a complex process that should be handled by an experienced healthcare team. Clinicians must choose and verify treatment options based on the individual patient; drug dose modifications and supportive care interventions should be administered accordingly. The cancer treatment regimens below may include both U.S. Food and Drug Administration-approved and unapproved indications/regimens. These regimens are only provided to supplement the latest treatment strategies.


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These Guidelines are a work in progress that may be refined as often as new significant data becomes available. The National Comprehensive Cancer Network Guidelines® are a consensus statement of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The NCCN makes no warranties of any kind whatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way.

Note: All recommendations are category 2A unless otherwise indicated.

▶Systemic Therapy for ER- and/or PR-Positive Recurrent or Stage IV (M1) Disease1,a

REGIMEN

DOSING

HER2-Negative and Postmenopausal or Premenopausal Receiving Ovarian Ablation or Suppression2-6,b

Preferred Regimens: First-Line Therapy

Abemaciclib + Anastrozole (Category 1)7-9,c

Days 1-28: Abemaciclib 150mg orally twice daily

Days 1-28: Anastrozole 1mg orally once daily.

Repeat cycle every 4 weeks.

Abemaciclib + Exemestane (Category 1)7,8,10,c

Days 1-28: Abemaciclib 150mg orally twice daily

Days 1-28: Exemestane 25mg orally once daily.

Repeat cycle every 4 weeks.

Abemaciclib + Fulvestrant (Category 1)8,11,12,c

Days 1-28: Abemaciclib 150mg orally twice daily

Day 1 and 15: Fulvestrant 500mg IM.

Administer one 4-week cycle, followed by:

Days 1-28: Abemaciclib 150mg orally twice daily

Day 1: Fulvestrant 500mg IM.

Repeat cycle every 4 weeks.

Abemaciclib + Letrozole (Category 1)7,8,13,c

Days 1-28: Abemaciclib 150mg orally twice daily

Days 1-28: Letrozole 2.5mg orally once daily

Repeat cycle every 4 weeks.

Anastrozole9-12

Days 1-28: Anastrozole 1mg once orally.

Repeat cycle every 4 weeks.

Exemestane10,13-15

Days 1-28: Exemestane 25mg orally once daily.

Repeat cycle every 4 weeks.

Fulvestrant (Category 1)16,17

Days 1,15: Fulvestrant 500mg IM.

Administer for one 28-day cycle, followed by:

Day 1: Fulvestrant 500mg IM.

Repeat cycle every 4 weeks.

Fulvestrant + Anastrozole (Category 1)9,16,18

Days 1,15: Fulvestrant 500mg IM

Days 1-28: Anastrozole 1mg orally.

Administer for one 28-day cycle, followed by:

Day 1: Fulvestrant 500mg IM

Days 1-28: Anastrozole 1mg orally.

Repeat cycle every 4 weeks.

Fulvestrant + Letrozole (Category 1)15,18,19

Days 1,15: Fulvestrant 500mg IM

Days 1-28: Letrozole 2.5mg orally.

Administer for one 28-day cycle, followed by:

Day 1: Fulvestrant 500mg IM

Days 1-28: Letrozole 2.5mg orally.

Repeat cycle every 4 weeks

Letrozole10-19,22

Days 1-28: Letrozole 2.5mg orally once daily.

Repeat cycle every 4 weeks.

Palbociclib + Anastrozole (Category 1)9,23,24,c

Days 1-21: Palbociclib 125mg orally once daily

Days 1-28: Anastrozole 1mg orally once daily.

Repeat cycle every 4 weeks.

Palbociclib + Exemestane (Category 1)13,23,24,c

Days 1-21: Palbociclib 125mg orally once daily

Days 1-28: Exemestane 25mg orally once daily.

Repeat cycle every 4 weeks.

Palbociclib + Fulvestrant (Category 1)15,23,25,c

Days 1-21: Palbociclib 125mg orally once daily

Days 1,15: Fulvestrant 500mg IM daily.

Administer for one 28-day cycle, followed by:

Days 1-21: Palbociclib 125mg orally once daily

Day 1: Fulvestrant 500mg IM.

Repeat cycle every 4 weeks.

Palbociclib + Letrozole (Category 1)19,23,24,c

Days 1-21: Palbociclib 125mg orally once daily

Days 1-28: Letrozole 2.5mg orally once daily.

Repeat cycle every 4 weeks.

Ribociclib + Anastrozole (Category 1)9,26,27,c

Days 1-21: Ribociclib 600mg orally once daily

Days 1-28: Anastrozole 1mg orally once daily.

Repeat cycle every 4 weeks.

Ribociclib + Exemestane (Category 1)13,26,27,c

Days 1-21: Ribociclib 600mg orally once daily

Days 1-28: Exemestane 25mg orally once daily.

Repeat cycle every 4 weeks.

Ribociclib + Fulvestrant (Category 1)16,27,28,c

Days 1-21: Ribociclib 600mg orally once daily

Days 1-15: Fulvestrant 500mg IM.

Administer one 4-week cycle, followed by:

Days 1-21: Ribociclib 600mg orally once daily

Day 1: Fulvestrant 500mg IM.

Repeat cycle every 4 weeks.

Ribociclib + Letrozole (Category 1)19,26,27,c

Day 1-21: Ribociclib 600mg orally once daily

Days 1-28: Letrozole 2.5mg orally once daily.

Repeat cycle every 4 weeks.

Tamoxifen29-31

Day 1-28: Tamoxifen 20mg orally once daily.

Repeat cycle every 4 weeks.

Toremifene32

Days 1-28: Toremifene 60mg orally once daily.

Repeat cycle every 4 weeks.

Preferred Regimens: Second- and Subsequent-Line Therapy

Abemaciclib + Fulvestrant (if CDK4/6 inhibitor not previously used; Category 1)8,16,33,34,c

Days 1-28: Abemaciclib 150mg orally twice daily

Days 1,15: Fulvestrant 500mg IM.

Administer one 4-week cycle, followed by:

Days 1-28: Abemaciclib 150mg orally twice daily

Day 1: Fulvestrant 500mg IM.

Repeat cycle every 4 weeks.

Alpesilib + Fulvestrant (PIK3CA mutation; Category 1)16,35,36,d

Days 1-28: Alpelisib 300mg orally once daily

Days 1,15: Fulvestrant 500mg IM.

Administer for one 4-week cycle, followed by:

Days 1-28: Alpelisib 300mg orally once daily

Day 1: Fulvestrant 500mg IM.

Repeat cycle every 4 weeks.

Anastrozole9-12

Days 1-28: Anastrozole 1mg once orally.

Repeat cycle every 4 weeks.

Everolimus + Exemestane13,37,38,c

Days 1-28: Everolimus 10mg orally once daily

Days 1-28: Exemestane 25mg orally once daily.

Repeat cycle every 4 weeks.

Everolimus + Fulvestrant13,17,37,38,c

Days 1-28: Everolimus 10mg orally once daily

Days 1,15: Fulvestrant 500mg IM.

Administer for one 28-day cycle, followed by:

Days 1-28: Everolimus 10mg orally once daily

Day 1: Fulvestrant 500mg IM.

Repeat cycle every 4 weeks.

Everolimus + Tamoxifen29,37,38,c

Days 1-28: Everolimus 10mg orally once daily

Days 1-28: Tamoxifen 20mg orally once daily.

Repeat cycle every 4 weeks.

Exemestane10,13-15

Days 1-28: Exemestane 25mg orally once daily.

Repeat cycle every 4 weeks.

Fulvestrant16,17

Days 1,15: Fulvestrant 500mg IM.

Administer for one 28-day cycle, followed by:

Day 1: Fulvestrant 500mg IM.

Repeat cycle every 4 weeks.

Letrozole10,19,22

Days 1-28: Letrozole 2.5mg orally once daily.

Repeat cycle every 4 weeks.

Palbociclib + Fulvestrant (if CDK4/6 inhibitor not previously used; Category 1)16,24,25,c

Days 1-21: Palbociclib 125mg orally once daily

Days 1,15: Fulvestrant 500mg IM daily.

Administer for one 28-day cycle, followed by:

Days 1-21: Palbociclib 125mg orally once daily

Day 1: Fulvestrant 500mg IM.

Repeat cycle every 4 weeks.

Ribociclib + Fulvestant (if CDK4/6 inhibitor not previously used; Category 1)16,27,28,c

Days 1-21: Ribociclib 600mg orally once daily

Days 1-15: Fulvestrant 500mg IM.

Administer one 4-week cycle, followed by:

Days 1-21: Ribociclib 600mg orally once daily

Day 1: Fulvestrant 500mg IM.

Repeat cycle every 4 weeks.

Tamoxifen29-31

Day 1-28: Tamoxifen 20mg orally once daily.

Repeat cycle every 4 weeks.

Toremifene32

Days 1-28: Toremifene 60mg orally once daily.

Repeat cycle every 4 weeks.

Useful in Certain Circumstances

Abemaciclib8,34

Days 1-28: Abemaciclib 200mg orally twice daily.

Repeat cycle every 4 weeks.

Ethinyl Estradiol8,39

Days 1-28: Estradiol 10mg orally three times daily.

Repeat cycle every 4 weeks.

Fluoxymesterone40,41

Days 1-28: Fluoxymesterone 10mg orally twice daily.

Repeat cycle every 4 weeks.

Megestrol Acetate 42,43

Days 1-28: Megastrol 40mg orally four times daily.

Repeat cycle every 4 weeks.

HER2-Positive and Postmenopausal or Premenopausal Receiving Ovarian Ablation or Suppressionb,e,f

Anastrozole9,10

Days 1-28: Anastrozole 1mg orally once daily.

Repeat cycle every 4 weeks.

Anastrozole + Lapatinib9,44,45

Days 1-28: Anastrozole 1mg orally once daily

Days 1-28: Lapatinib 1,500mg orally once daily.

Repeat cycle every 4 weeks.

Anastrozole + Lapatinib + Trastuzumab9,44-46

Days 1-28: Anastrozole 1mg orally once daily

Days 1-28: Lapatinib 1,000mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Days 1-28: Anastrozole 1mg orally once daily

Days 1-28: Lapatinib 1,000mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

Anastrozole + Trastuzumab9,46,47

Days 1-21: Anastrozole 1mg orally once daily

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2.

Repeat cycle every 3 weeks.

Exemestane10,13

Days 1-28: Exemestane 25mg orally once daily.

Repeat cycle every 4 weeks.

Exemestane + Lapatinib10,44

Days 1-28: Exemestane 25mg orally once daily

Days 1-28: Lapatinib 1,500mg orally once daily.

Repeat cycle every 4 weeks.

Exemestane + Lapatinib + Trastuzumab10,44,46

Days 1-28: Exemestane 25mg orally once daily

Days 1-28: Lapatinib 1,000mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 4mg/m2 IV over 90 minutes on week 1, then 2mg/m2 IV over 30 minutes starting week 2 cycled weekly.

OR

Days 1-28: Exemestane 25mg orally once daily

Days 1-28: Lapatinib 1,000mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/m2 IV starting with cycle 2 cycled every 3 weeks.

Exemestane + Trastuzumab10,46,47

Days 1-28: Exemestane 25mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV starting week 2 cycled weekly.

OR

Days 1-28: Exemestane 25mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/m2 IV starting with cycle 2 cycled every 3 weeks.

Fulvestrant16.17

Days 1,15: Fulvestrant 500mg IM.

Administer for one 28-day cycle, followed by:

Day 1: Fulvestrant 500mg IM.

Repeat cycle every 4 weeks.

Fulvestrant + Trastuzumab16,46,48,49

Days 1,15: Fulvestrant 500mg IM on cycle 1, followed by:

Day 1: Fulvestrant 500mg IM starting with cycle 2 cycled every 4 weeks, with:

Day 1: Trastuzmab 4mg/kg IV over 90 minutes on week 1, then 2mg/m2 IV starting week 2 cycled weekly.

OR

Days 1,15: Fulvestrant 500mg IM on cycle 1, followed by:

Day 1: Fulvestrant 500mg IM starting with cycle 2 cycled every 4 weeks, with:

Day 1: Trastuzumab 8mg/kg IV 90 minutes on cycle 1, then 6mg/m2 IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

Letrozole19-22,50

Days 1-28: Letrozole 2.5mg orally once daily.

Repeat cycle every 4 weeks.

Letrozole + Lapatinib19,45,51

Days 1-28: Lapatinib 1,500mg orally once daily

Days 1-28: Letrozole 2.5mg orally once daily.

Repeat cycle every 4 weeks.

Letrozole + Lapatinib + Trastuzumab19,44-46

Days 1-28: Letrozole 2.5mg orally once daily

Days 1-28: Lapatinib 1,000mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzmab 4mg/kg IV over 90 minutes on week 1, then 2mg/m2 IV starting week 2 cycled weekly.

OR

Days 1-28: Letrozole 2.5mg orally once daily

Days 1-28: Lapatinib 1,000mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 8mg/kg IV 90 minutes on cycle 1, then 6mg/m2 IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

Letrozole + Trastuzumab19,46,47

Days 1-28: Letrozole 2.5mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting with week 2 cycled weekly.

OR

Days 1-28: Letrozole 2.5mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg over 30 minutes starting with cycle 2 cycled every 3 weeks.

Tamoxifen29,31,52

Day 1-28: Tamoxifen 20mg orally once daily.

Repeat cycle every 4 weeks.

Tamoxifen + Trastuzmab29,46,47

Days 1-28: Tamoxifen 20mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting with week 2 cycled weekly.

OR

Days 1-28: Tamoxifen 20mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg over 30 minutes starting with cycle 2 cycled every 3 weeks.

▶Chemotherapy Regimens For Recurrent or Stage IV (M1) Disease1,a,g,h

HER2-Negative

Preferred Regimens

Capecitabine53,54

Days 1-14: Capecitabine 1,000-1,250mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

Carboplatin (triple-negative breast cancer [TNBC] and germline BRCA1/2 mutation)55

Day 1: Carboplatin AUC 6 IV over 30 minutes.

Repeat cycle every 3 or 4 weeks.

Cisplatin (TNBC and germline BRCA1/2 mutation)56

Day 1: Cisplatin 75mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks.

Doxorubicin57-60

Day 1: Doxorubicin 60-75mg/m2 IV push.

Repeat cycle every 3 weeks.

OR

Day 1: Doxorubicin 20mg/m2 IV push.

Repeat cycle weekly.

Eribulin61,62

Days 1,8: Eribulin 1.4mg/m2 IV push.

Repeat cycle every 3 weeks.

Gemcitabine63

Days 1,8,15: Gemcitabine 800-1,200mg/m2 IV over 30 minutes.

Repeat cycle every 4 weeks.

Liposomal Doxorubicin64,65

Day 1: Liposomal Doxorubicin 40-50mg/m2 IV.

Repeat cycle every 4 weeks.

Paclitaxel66,67

Day 1: Paclitaxel 175mg/m2 IV over 3 hours.

Repeat cycle every 3 weeks.

OR

Day 1: Paclitaxel 80mg/m2 IV over 60 minutes.

Repeat cycle weekly.

Vinorelbine68

Day 1: Vinorelbine 25mg/m2 over 5-10 minutes.

Repeat cycle weekly.

Other Recommended Regimens

Albumin-Bound Paclitaxel69-71

Day 1: Albumin-bound paclitaxel 260mg/m2 IV over 30 minutes.

Repeat cycle every 3 weeks.

OR

Days 1,8,15: Albumin-bound paclitaxel 100mg/m2 IV over 30 minutes.

Repeat cycle every 4 weeks.

OR

Days 1,8,15: Albumin-bound paclitaxel 125mg/m2 IV over 30 minutes.

Repeat cycle every 4 weeks.

Cyclophosphamide72

Days 1-21: Cyclophosphamide 50mg orally once daily.

Repeat cycle every 4 weeks.

Docetaxel73,74

Day 1: Docetaxel 60-100mg/m2 IV over 60 minutes.

Repeat cycle every 3 weeks.

OR

Days 1,8,15,22,29,36: Docetaxel 35mg/m2 IV over 60 minutes.

Repeat cycle every 8 weeks (6 weeks on- followed by 2 weeks off-treatment)

Epirubicin75

Day 1: Epirubicin 60-90 mg/m2 IV push.

Repeat cycle every 3 weeks.

Ixabepilone76,77

Day 1: Ixabepilone 40mg/m2 (max 88mg) IV over 3 hours.

Repeat cycle every 3 weeks.

Useful in Certain Circumstances

AC78

Day 1: Doxorubicin 60mg/m2 IV push

Day 1: Cyclophosphamide 600mg/m2 IV over 30 minutes.

Repeat cycle every 3 weeks.

Carboplatin + Albumin-Bound Paclitaxel69,79

Days 1,8: Albumin-Bound Paclitaxel 125mg/m2 IV over 30 minutes

Days 1,8: Carboplatin AUC 2 IV over 30 minutes.

Repeat cycle every 3 weeks.

Carboplatin + Paclitaxel80,81

Day 1: Paclitaxel 175-200mg/m2 IV over 3 hours, followed by:

Day 1: Carboplatin AUC 6 IV over 30 minutes.

Repeat cycle every 3 weeks.

OR

Days 1,8,15: Paclitaxel 100mg/m2 IV over 60 minutes, followed by:

Days 1,8,15: Carboplatin AUC 2 IV over 30 minutes.

Repeat cycle every 4 weeks.

CMF82-84

Days 1-14: Cyclophosphamide 100mg/m2 orally once daily

Days 1,8: Methotrexate 40mg/m2 IV push

Days 1,8: Fluorouracil 600mg/m2 IV push.

Repeat every 4 weeks.

Docetaxel + Capecitabine85

Day 1: Docetaxel 75 mg/m2 IV over 60 minutes

Days 1-14: Capecitabine 950-1.250mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

EC86,87

Day 1: Epirubicin 100mg/m2 IV push

Day 1: Cyclophosphamide 830mg/m2 IV over 30 minutes.

Repeat cycle every 3 weeks.

Gemcitabine + Carboplatin88

Days 1,8: Gemcitabine 1,000mg/m2 IV over 30 minutes

Days 1,8: Carboplatin AUC 2 IV over 30 minutes.

Repeat cycle every 3 weeks.

GT89-

Day 1: Paclitaxel 175mg/m2 IV over 3 hours, followed by:

Days 1,8: Gemcitabine 1,250mg/m2 IV over 30 minutes.

Repeat cycle every 3 weeks.

Paclitaxel + Bevacizumab90.91

Days 1,8,15: Paclitaxel 90mg/m2 IV over 60 minutes

Days 1,15: Bevacizumab 10mg/kg IV.

Repeat cycle every 4 weeks.

HER2-Positivei

Preferred Regimens

Pertuzumab + Trastuzumab + Docetaxel (Category 1)46,92-94,j

Day 1: Pertuzumab 840mg IV over 60 minutes on cycle 1, then 420mg IV over 30 minutes starting with cycle 2

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2, followed by:

Day 1: Docetaxel 75mg/kg IV over 60 minutes on cycle 1, then 75-100mg/m2 over 60 minutes starting with cycle 2.

Repeat cycle every 3 weeks.

Pertuzumab + Trastuzumab + Paclitaxel46,92,95

Day 1: Pertuzumab 840mg IV over 60 minutes on cycle 1, then 420mg IV over 30 minutes starting with cycle 2

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2

Days 1,8,15: Paclitaxel 80mg/kg IV over 60 minutes.

Repeat cycle every 3 weeks.

OR

Day 1: Pertuzumab 840mg IV over 60 minutes on cycle 1, then 420mg IV over 30 minutes starting with cycle 2

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on cycle 1, followed by:

Days 8,15: Trastuzumab 2mg/kg IV over 30 minutes on cycle 1, followed by:

Days 1,8,15: Trastuzumab 2mg/kg IV over 30 minutes starting with cycle 2

Days 1,8,15: Paclitaxel 80mg/kg IV over 60 minutes.

Repeat cycle every 3 weeks.

OR

Day 1: Pertuzumab 840mg IV over 60 minutes on cycle 1, then 420mg IV over 30 minutes starting with cycle 2

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2

Day 1: Paclitaxel 175mg/m2 IV over 3 hours.

Repeat cycle every 3 weeks.

OR

Day 1: Pertuzumab 840mg IV over 60 minutes on cycle 1, then 420mg IV over 30 minutes starting with cycle 2

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on cycle 1, followed by:

Days 8,15: Trastuzumab 2mg/kg IV over 30 minutes on cycle 1, followed by:

Days 1,8,15: Trastuzumab 2mg/kg IV over 30 minutes starting with cycle 2

Day 1: Paclitaxel 175mg/m2 IV over 3 hours.

Repeat cycle every 3 weeks.

Other Recommended Regimens

Ado-Trastuzumab Emtansine (T-DM1; Category 1)96-98

Day 1: Ado-trastuzumab emtansine 3.6mg/kg IV over 90 minutes on cycle 1, followed by:

Day 1: Ado-trastuzumab emtansine 3.6mg/kg over 30 minutes beginning with cycle 2.

Repeat cycle every 3 weeks.

Fam-Trastuzumab Deruxtecan-nxki99,100,k

Day 1: Fam-Trastuzumab Deruxtecan-nxki 5.4mg/kg IV.

Repeat cycle every 3 weeks.

Lapatinib + Capecitabine48,54,101

Days 1-21: Lapatinib 1,250mg orally once daily

Days 1-14: Capecitabine 1,000mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

Neratinib + Capecitabine102,103

Days 1-21: Neratinbi 240mg orally

Days 1-14: Capecitabine 750mg/m2 orally twice daily.

Repeat cycle every 3 weeks.

Trastuzumab + Albumin-bound Paclitaxel46,69-71,104,j

Day 1: Albumin-bound Paclitaxel 260mg/m2 IV over 30 minutes cycled every 3 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Day 1: Albumin-bound Paclitaxel 260mg/m2 IV over 30 minutes.

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

OR

Days 1,8,15: Albumin-bound Paclitaxel 100 or 125mg/m2 cycled every 4 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 30 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Days 1,8,15: Albumin-bound Paclitaxel 100 or 125 mg/m2 IV over 30 minutes cycled every 4 weeks, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes of cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

Trastuzumab + Capecitabine46,54,105,106

Days 1-14: Capecitabine 1,000-1.250mg/m2 orally twice daily cycled every 3 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled every week.

OR

Days 1-14: Capecitabine 1,000-1,250mg/m2 orally twice daily

Day 1: Trastuzumab 8mg/kg IV over 90 minutes, then 6mg/kg IV over 30 minutes cycled every 3 weeks.

Trastuzumab + Carboplatin46,55,104,j

Day 1: Carboplatin AUC 6 IV over 30 minutes cycled every 3 or 4 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Day 1: Carboplatin AUC 6 IV over 30 minutes cycled every 3 or 4 weeks, with:

Day 1: Tratuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV starting with cycle 2 cycled every 3 weeks.

Trastuzumab + Cisplatin46,56,104,j

Day 1: Cisplatin 75mg/m2 IV over 60 minutes cycled every 3 weeks, with:

Day 1: Trastuzumab 4mg/kg IV 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Day 1: Cisplatin 75mg/m2 IV over 60 minutes.

Day 1: Trastuzumab 8mg/kg IV over 90 minutes, then 6mg/kg IV over 30 minutes cycled every 3 weeks.

Trastuzumab + Cyclophosphamide46,72,104

Days 1-21: Cyclophosphamide 50mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Days 1-21: Cyclophosphamide 50mg orally once daily cycled every 4 weeks, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

Trastuzumab + Docetaxel46,107,108,j

Day 1: Docetaxel 80-100mg/m2 IV over 60 minutes cycled every 3 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/m2 IV over 30 minutes starting week 2 cycled weekly.

OR

Day 1: Docetaxel 80-100 mg/m2 IV over 60 minutes.

Day 1: Trastuzumab 8mg/kg IV over 90 minutes with cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

OR

Days 1,8,15: Docetaxel 35mg/m2 IV over 60 minutes cycled every 4 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Days 1,8,15: Docetaxel 35mg/m2 IV over 60 minutes cycled every 4 weeks, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2

cycled every 3 weeks.

Trastuzumab + Eribulin46,61,62,104,j

Days 1,8: Eribulin 1.4mg/m2 IV push cycled every 3 weeks, with:

Day 1: Trastuzumab 4mg/m2 IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Days 1,8: Eribulin 1.4mg/m2 IV push.

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

Trastuzumab + Gemcitabine46,63,104,j

Days 1,8,15: Gemcitabine 800-1,200mg/m2 IV over 30 minutes cycled every 4 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Days 1,8,15: Gemcitabine 800-1,200mg/m2 IV over 30 minutes cycled every 4 weeks, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

Trastuzumab + Ixabepilone46,76,77,104,j

Day 1: Ixabepilone 40mg/m2 (maximum 88mg) IV over 3 hours cycled every 3 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Day 1: Ixabepilone 40mg/m2 (maximum 88mg) IV over 3 hours cycled every 3 weeks, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

Trastuzumab + Lapatinib (without cytotoxic therapy)45,46,109

Days 1-21: Lapatinib 1,000mg orally once daily cycled every 3 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Days 1-21: Lapatinib 1,000mg orally once daily, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

Trastuzumab + Paclitaxel46,104,110,111,j

Day 1: Paclitaxel 80-90mg/m2 IV over 60 minutes

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Day 1: Paclitaxel 80-90mg/m2 IV over 60 minutes cycled weekly, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6 mg/kg IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

OR

Day 1: Paclitaxel 175mg/m2 IV over 3 hours cycled every 3 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes on week 1, then 2mg/kg IV over 30 minutes starting week 2 cycled weekly.

OR

Day 1: Paclitaxel 175mg/m2 IV over 3 hours

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

Trastuzumab + Paclitaxel + Carboplatin46,111-113

Day 1: Paclitaxel 175mg/m2 IV over 3 hours, followed by:

Day 1: Carboplatin AUC 6 IV over 30 minutes cycled every 3 weeks, with:

Day 1: Trastuzumab 4mg/kg IV on week 1, then 2mg/kg over 30 minutes starting with week 2 cycled weekly.

OR

Day 1: Paclitaxel 175mg/m2 IV over 3 hours, followed by:

Day 1: Carboplatin AUC 6 IV over 30 minutes, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV starting with cycle 2 cycled every 3 weeks.

OR

Days 1,8,15: Paclitaxel 80mg/m2 IV over 60 minutes, followed by:

Days 1,8,15: Carboplatin AUC 2 IV over 30 minutes cycled every 4 weeks, with:

Day 1: Trastuzumab 4mg/kg IV on week 1, then 2mg/kg over 30 minutes starting with week 2 cycled weekly.

OR

Days 1,8,15: Paclitaxel 80mg/m2 IV over 60 minutes, followed by:

Days 1,8,15: Carboplatin AUC 2 IV over 30 minutes cycled every 4 weeks, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV starting with cycle 2 cycled every 3 weeks.

Trastuzumab + Vinorelbine46,114,j

Day 1: Vinorelbine 25mg/m2 IV over 5-10 minutes, with:

Day 1: Trastuzumab 4mg/kg over 90 minutes on week 1, then 2mg/kg over 30 minutes starting with week 2 cycled weekly.

OR

Day 1: Vinorelbine 25mg/m2 IV over 5-10 minutes cycled weekly, with:

Day 1: Trastuzumab 8mg/kg IV over 90 minutes on cycle 1, then 6mg/kg IV over 30 minutes starting with cycle 2 cycled every 3 weeks.

▶Additional Targeted Therapies and Associated Biomarker Testing for Recurrent or Stage IV (M1) Disease1,a

Preferred Regimens

Atezolizumab + Albumin-Bound Paclitaxel (PD-L1 expression 1% or higher on tumor-infiltrating immune cells)69,115,116

Days 1,15: Atezolizumab 840mg IV over 60 minutes, followed by:

Days 1,8,15: Albumin-bound Paclitaxel 100mg/m2 IV.

Repeat cycle every 4 weeks.

Olaparib (germline BRCA1/2 mutation; Category 1)117,118,l

Days 1-28: Olaparib 300mg orally twice daily.

Repeat cycle every 4 weeks.

Talazoparib (germline BRCA1/2 mutation) (Category 1)119,120

Days 1-28: Talazoparib 1mg orally once daily.

Repeat cycle every 4 weeks.

Preferred Regimens: Second-Line Therapy

Alpesilib + Fulvestrant (for Hormone-receptor positive, HER2-negative disease; PIK3CA mutation; Category 1)16,35,36,d

Days 1-28: Alpelisib 300mg orally once daily

Days 1,15: Fulvestrant 500mg IM.

Administer for one 4-week cycle, followed by:

Days 1-28: Alpelisib 300mg orally once daily

Day 1: Fulvestrant 500mg IM.

Repeat cycle every 4 weeks.

Useful Under Certain Circumstances

Entrectinib (NTRK gene fusion)121,122,m

Days 1-28: Entrectinib 600mg orally once daily.

Repeat cycle every 4 weeks.

Larotrectinib (NTRK gene fusion)123,124,m

Days 1-28: Larotrectinib 100mg orally twice daily.

Repeat cycle every 4 weeks.

Pembrolizumab (MSI-H/dMMR)125-127,n

Day 1: Pembrolizumab 200mg IV over 30 minutes.

Repeat cycle every 3 weeks.

a. The selection, dosing, and administration of anti-cancer agents and the management of associated toxicities are complex. Modifications of drug and schedule and initiation of supportive care interventions are often necessary because of expected toxicities and individual patient variability, prior treatment, and comorbidity. The optimal delivery of anti-cancer agents therefore requires a health care delivery team experienced in the use of anti-cancer agents and the management of associated toxicities in patients with cancer.

b. Ovarian suppression for premenopausal women with hormone receptor-positive disease: Day 1: Goserelin 3.6mg subcutaneous every 4 weeks until endocrine therapy is completed or no longer required or Day 1: Leuprolide 3.75mg IM every 4 weeks until endocrine therapy is completed or no longer required.

c. If there is disease progression while on CDK4/6 inhibitor therapy, there are no data to support an additional line of therapy with another CDK4/6-containing regimen. Likewise, if there is disease progression while on an everolimus-containing regimen, there are no data to support an additional line of therapy with another everolimus-containing regimen.

d. Indicated after progression on prior endocrine therapy and prior chemotherapy in the metastatic setting.

e. Trastuzumab and hyaluronidase-oysk injection (Day 1: Trastuzumab and hyaluronidase-oysk 600mg subcutaneous over 2-5 minutes every 3 weeks) for subcutaneous use may be substituted for trastuzumab.128,129 Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine or fam-trastuzumab deruxtecan-nxki. An FDA-approved biosimilar is an appropriate substitute for trastuzumab.

f. If treatment was initiated with chemotherapy and trastuzumab + pertuzumab, and the chemotherapy was stopped, endocrine therapy may be added to the trastuzumab + pertuzumab.

g. Albumin-bound paclitaxel may be substituted for paclitaxel or docetaxel due to medical necessity (ie, hypersensitivity reaction). If substituted for weekly paclitaxel or docetaxel, then the weekly dose of nab-paclitaxel shown not exceed 125mg/m2.

h. Sequential single agents are preferred, but chemotherapy combinations may be used in select patients with high tumor burden, rapidly progressive disease, and visceral crisis.

i. Trastuzumab given in combination with an anthracycline is associated with significant cardiac toxicity. Concurrent use of trastuzumab and pertuzumab with an anthracycline should be avoided.

j. Patients previously treated with chemotherapy plus trastuzumab in the absence of pertuzumab in the metastatic setting may be considered for one line of therapy including both trastuzumab and pertuzumab in combination with or without cytotoxic therapy (such as vinorelbine or taxane). Further research is needed to determine the ideal sequencing strategy for anti-HER2 therapy.

k. Fam-Trastuzumab Deruxtecan-nxki is indicated following two or more lines of prior HER2-targeted therapy in the metastatic setting. This agent is contraindicated for patients with pneumonitis or interstitial lung disease (ILD).

l.  There is also a capsule formulation available. However, do not substitute the capsules for the tablets on a mg-per-mg basis due to differences in dosing and bioavailability

m. Larotrectinib and entrectinib are indicted for the treatment of solid tumors that have an NTRK gene fusion without a known acquired resistance mutation and have no satisfactory alternative treatments or that have progressed following treatment.

n. Pembrolizumab is indicated for the treatment of patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options.

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100. Modi S, Saura C, Yamashita T, et al. Trastuzumab deruxtecan in previously treated HER2-positive breast cancer. N Engl J Med. 2020;382:610-621.

101. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2- positive advanced breast cancer. N Engl J Med. 2006;355:2733-2743.

102. Neratinib (Nerlynx) [package insert]. Los Angeles, CA: Puma Biotechnology, Inc.; 2020.

103. Saura C, Oliveira M. Feng Y-H, et al. Neratinib + capecitabine versus lapatinib + capecitabine in patients with HER2+ metastatic breast cancer previously treated with ≥2 HER2-directed regimens: Findings from the multinational, randomized, phase III NALA trial. J Clin Oncol. 2019;37(15_suppl): Abstract 1002.

104. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344:783-792.

105. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2-positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 Study. J Clin Oncol. 2009;27:1999-2006.

106. Bartsch R, Wenzel C, Altorjai G, et al. Capecitabine and trastuzumab in heavily pretreated metastatic breast cancer. J Clin Oncol. 2007;25:3853-3858.

107. Marty M, Cognetti F, Maraninchi D, et al. Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. J Clin Oncol. 2005;23: 4265-4274.

108. Esteva FJ, Valero V, Booser D, et al. Phase II study of weekly docetaxel and trastuzumab for patients with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2002;20:1800-1808.

109. Blackwell KL, Burstein HJ, Storniolo AM, et al. Randomized study of Lapatinib alone or in combination with trastuzumab in women with ErbB2-positive, trastuzumab-­refractory metastatic breast cancer. J Clin Oncol. 2010;28:1124-1130.

110. Seidman AD, Fornier MN, Esteva FJ, et al. Weekly trastuzumab and paclitaxel therapy for metastatic breast cancer with analysis of efficacy by HER2 immunophenotype and gene amplification. J Clin Oncol. 2001;19:2587-2595.

111. Leyland-Jones B, Gelmon K, Ayoub JP, et al. Pharmacokinetics, safety, and efficacy of trastuzumab administered every three weeks in combination with paclitaxel. J Clin Oncol. 2003;21:3965-3971.

112. Perez EA. Carboplatin in combination therapy for metastatic breast cancer. Oncologist. 2004;9:518-527.

113. Robert N, Leyland-Jones B, Asmar L, et al. Randomized phase III study of trastuzumab, paclitaxel, and carboplatin compared with trastuzumab and paclitaxel in women with HER-2-overexpressing metastatic breast cancer. J Clin Oncol. 2006;24:2786-2792.

114. Burstein HJ, Keshaviah A, Baron AD, et al. Trastuzumab plus vinorelbine or taxane chemotherapy for HER2-overexpressing metastatic breast cancer: the trastuzumab and vinorelbine or taxane study. Cancer. 2007;110:965-972.

115. Schmid P, Adams S, Rugo HS, et al. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. N Engl J Med. 2018;379:2108-2121.

116. Atezolizumab (Tecentriq) [package insert]. South San Francisco, CA: Genentech, Inc.; 2019.

117. Olaparib [Lynparza) [package insert]. Wilmington, DE: AstraZeneca Pharmaceuticals LP; 2019.

118. Robson M, Im SA, Senkus E, et al. Olaparib for metastatic breast cancer in patients with a germline BRCA mutation. N Engl J Med. 2017;377:523-533.

119. Litton JK, Rugo HS, Ettl J, et al. Talazoparib in patients with advanced breast cancer and a germline BRCA mutation. N Engl J Med. 2018;379:753-763.

120. Talazoparib (Talzenna) [package insert]. New York, NY: Pfizer Labs; 2020.

121. Entrectinib (Rozlytrek) [package insert]. South San Francisco, CA: Genentech, Inc.; 2019

122. Drilon A, Siena S, Ou S, et al. Safety and antitumor activity of the multitargeted pan-TRK, ROS1, and ALK inhibitor entrectinib: Combined results from two phase I trials (ALKA-372-001 and STARTRK-1). Cancer Discov. 2017;7:400-409.

123. Larotrectinib (Vitrakvi) [package insert]. Whippany, NJ: Bayer HealthCare Pharmaceuticals, Inc.; 2019.

124. Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion- positive cancers in adults and children. N Engl J Med. 2018;378:731-739.

125. Le DT, Uram JN, Wang H, et al. PD-1 blockage in tumors with mismatch-repair deficiency. N Engl J Med. 2015;372:2509-2520.

126. Pembrolizumab (Keytruda) [package insert]. Whitehorse Station, NJ: Merck & Co. Inc.; 2020.

127. Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts responses of solid tumors to PD-1 blockage. Science. 2017;357:409-413.

128. Gligorov J, Ataseven B, Verrill M, et al. Safety and tolerability of subcutaneous trastuzumab for the adjuvant treatment of human epidermal growth factor receptor 2-positive early breast cancer: SafeHer phase III study’s primary analysis of 2573 patients. Eur J Cancer. 2017;82:237-246.

129. Trastuzumab hyaluronidase-oysk (Herceptin Hylecta) [package insert]. South San Francesco, CA: Genentech, Inc. 2019.

(Revised 5/2020; NCCN Breast Cancer Guidelines v3.2020) © 2020 by Haymarket Media, Inc.