Breast Cancer (Invasive; Nonmetastatic) Treatment Regimens

Breast Cancer (Invasive; Nonmetastatic) 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.

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.

▶Adjuvant Endocrine Therapy1

REGIMEN

DOSING

Hormone Receptor-Positive Diseasea

Premenopausal at diagnosis

Tamoxifen (with or without Leuprolide or Goserelin) followed by Aromatase Inhibitor2-15

Tamoxifenb 20mg orally once daily for 5 years (Category 1) with or without:

Day 1: Leuprolidec 3.75mg IM of 28-day cycle (Category 1) OR

Day 1: Goserelinc 3.6mg subcutaneous of 28-day cycle (Category 1) followed by (for post-menopausal women): Anastrozoled 1mg orally once daily OR

Exemestaned 25mg orally once daily OR

Letrozoled 2.5mg orally once daily for 5 years (Category 1).

Tamoxifen (with or without Leuprolide or Goserelin)2,6-14,16

Tamoxifenb 20mg orally once daily for 5 years (Category 1), with or without:

Day 1: Leuprolidec 3.75mg IM of 28-day cycle (Category 1) OR

Day 1: Goserelinc 3.6mg subcutaneous of 28-day cycle (Category 1)

Tamoxifen (with or without Leuprolide or Goserelin) followed by consideration of Tamoxifen2,6-14,16

Tamoxifenb 20mg orally once daily for 5 years (Category 1) with or without:

Day 1: Leuprolidec 3.75mg IM of 28-day cycle (Category 1) OR

Day 1: Goserelinc 3.6mg subcutaneous of 28-day cycle (Category 1)

followed by (for pre- or postmenopausal women)

Tamoxifenb 20mg orally once daily for an additional 5 years.

Aromatase inhibitor (with Leuprolide or Goserelin)3-14,17,18

Anastrozoled 1mg orally once daily OR

Exemestaned 25mg orally once daily OR

Letrozoled 2.5mg orally once daily for 5 years (Category 1) AND

Day 1: Leuprolidec 3.75mg IM of 28-day cycle(Category 1) OR

Day 1: Goserelinc 3.6mg SC of 28-day cycle (Category 1).

Postmenopausal at diagnosis

Aromatase inhibitor followed by consideration of an Aromatase Inhibitor3-5,18-23

Anastrozoled 1mg orally once daily OR

Exemestaned 25mg orally once daily OR

Letrozoled 2.5mg orally once daily for 5 years (Category 1) followed by:

Anastrozoled 1mg orally once daily OR

Exemestaned 25mg orally once daily OR

Letrozoled 2.5mg orally once daily for an additional 3-5 years.

Aromatase inhibitor followed by Tamoxifen2-4, 25

Anastrozoled 1mg orally once daily OR

Exemestaned 25mg orally once daily OR

Letrozoled 2.5mg orally once daily for 2 to 3 years (Category 1) followed by:

Tamoxifenb 20mg orally once daily to complete 5 years of endocrine therapy (Category 1).

Tamoxifen followed by an Aromatase Inhibitor2-5,26-42

Tamoxifenb 20mg orally once daily for 2 to 3 years followed by:

Anastrozoled 1mg orally once daily OR

Exemestaned 25mg orally once daily OR

Letrozoled 2.5mg orally once daily to complete 5 years of endocrine therapy (Category 1).

Tamoxifenb 20mg orally once daily for 2 to 3 years followed by:

Anastrozoled 1mg orally once daily OR

Exemestaned 25mg orally once daily OR

Letrozoled 2.5mg orally once daily for up to 5 years of an aromatase inhibitor (Category 2B).

Tamoxifenb 20mg orally once daily for 4 to 6.5 years followed by:

Anastrozoleb 1mg orally once daily OR

Exemestaned 25mg orally once daily OR

Letrozoled 2.5mg orally once daily for 5 years (Category 1).

Tamoxifen followed by consideration of Tamoxifen2,8,16

Tamoxifenb 20mg orally once daily for 4 to 6.5 years followed by:

Tamoxifenb 20mg orally once daily to complete 10 years of endocrine therapy.

Postmenopausal patients with contraindication to aromatase inhibitors or who cannot tolerate or decline aromatase inhibitor

Tamoxifen2,8,16

Tamoxifenb 20mg orally once daily for 5 years (Category 1).

Tamoxifenb 20mg orally once daily for up to 10 years.

▶Preoperative/Adjuvant Chemotherapy1,e-k

HER2-negative Disease

Preferred Regimens

Dose-dense AC followed by Paclitaxel (Category 1)43,k,l

Day 1: Doxorubicin 60mg/m2 IV push

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

Repeat cycle every 14 days for 4 cycles (all cycles are with myeloid growth factor support; refer to NCCN Guidelines for Myeloid Growth Factors), followed by:

Day 1: Paclitaxel 175mg/m2 via 3-hour IV infusion.

Repeat cycle every 14 days for 4 cycles.

All cycles are with myeloid growth factor support.

Dose-dense AC followed by weekly Paclitaxel (Category 1)43,k

Day 1: Doxorubicin 60mg/m2 IV push

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

Repeat cycle every 14 days for 4 cyclesl, followed by:

Day 1: Paclitaxel 80mg/m2 via 1-hour IV infusion weekly for 12 weeks.

TC (Category 1)44,l

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

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

Repeat cycle every 21 days for 4 cycles.

Capecitabine (if triple-negative breast cancer [TNBC] and residual disease after preopera­tive therapy with taxane-, alkylator-, and anthracycline-based chemotherapy. Category 1)45

Days 1-14: Capecitabine 1000-1250mg/m2 orally twice daily every 21 days for 6-8 cycles.

Useful in Certain Circumstances

Dose-dense AC (Category 1)43,l

Day 1: Doxorubicin 60mg/m2 IV push

Day 1: Cyclophosphamide 600mg/m2 IV.

Repeat cycle every 14 days for 4 cycles.

AC followed by weekly Paclitaxel (Category 1)46

Day 1: Doxorubicin 60mg/m2 IV push

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

Repeat cycle every 21 days for 4 cycles, followed by:

Day 1: Paclitaxel 80mg/m2 by 1-hour IV infusion weekly for 12 weeks.

CMF (Category 1)47

Days 1–14: Cyclophosphamide 100mg/m2 orally

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

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

Repeat cycle every 28 days for 6 cycles.

AC (Category 2B)48

Day 1: Doxorubicin 60mg/m2 IV push

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

Repeat cycle every 21 days for 4 cycles.

Other Recommended Regimens

AC followed by Docetaxel (Category 1)49

Day 1: Doxorubicin 60mg/m2 IV push

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

Repeat cycle every 21 days for 4 cycles, followed by:

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

Repeat cycle every 21 days for 4 cycles.

EC (Category 1)50

Day 1: Epirubicin 100mg/m2 IV push

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

Repeat cycle every 21 days for 8 cycles.

TAC (Category 1)51,l

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

Day 1: Doxorubicin 50mg/m2 IV push

Day 1: Cyclophosphamide 500mg/m2 IV over 30 minutes.

Repeat cycle every 21 days for 6 cycles.

HER2-positive Diseasem,n

Preferred Regimenso,p

AC followed by Paclitaxel + Trastuzumab58,59,q,r

Day 1: Doxorubicin 60mg/m2 IV push

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

Repeat cycle every 21 days for 4 cycles, followed by:

Day 1: Paclitaxel 80mg/m2 via 1-hour IV infusion weekly for 12 weeks, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes with first dose of paclitaxel, then 2mg/kg IV over 30 minutes weekly to complete 1 year of trastuzumab therapy.

As an alternative, trastuzumab 6mg/kg IV over 30 minutes every 21 days may be used following the completion of paclitaxel, and given to complete 1 year of trastuzumab treatment.

AC followed by Paclitaxel + Trastuzumab + Pertuzumab58-60,q,r

Day 1: Doxorubicin 60mg/m2 IV push

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

Repeat cycle every 21 days for 4 cycles, followed by:

Day 1: Pertuzumab 840mg IV over 60 minutes for cycle 1, then 420mg IV over 30 minutes for cycles 2-4

Day 1: Trastuzumab 8mg/kg IV over 90 minutes for cycle 1, then 6mg/kg IV over 30 minutes for cycles 2-4, followed by:

Days 1, 8, and 15: Paclitaxel 80mg/m2 IV over 60 minutes.

Repeat cycle every 21 days for 4 cycles, followed by:

Day 1: Trastuzumab 6mg/kg IV over 30 minutes

Day 1: Pertuzumab 420 mg IV over 30 minutes.

Repeat cycle every 21 days to complete 1 year of trastuzumab and pertuzumab therapy.

Dose-dense AC followed by Paclitaxel + Trastuzumab58,61,q,r

Day 1: Doxorubicin 60mg/m2 IV push

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

Repeat cycle every 14 days for 4 cycles, followed by:

Day 1: Paclitaxel 175mg/m2 via 3-hour IV infusion.

Repeat cycle every 14 days for 4 cyclesl, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes with first dose of paclitaxel, then 2mg/kg IV over 30 minutes weekly to complete 1 year of trastuzumab therapy.

As an alternative, trastuzumab 6mg/kg IV over 30 minutes every 21 days may be used following the completion of paclitaxel, and given to complete 1 year of trastuzumab treatment.

Paclitaxel + Trastuzumab58,62,s

Day 1: Paclitaxel 80mg/m2 IV over 60 minutes weekly for 12 weeks

Day 1: Trastuzumab 4mg/kg IV over 90 minutes with first dose of paclitaxel, then 2 mg/kg IV over 30 minutes weekly to complete 12 weeks, followed by:

Day 1: Trastuzumab 6mg/kg IV over 30 minutes.

Repeat cycle every 21 days to complete 1 year of trastuzumab therapy.

OR

Day 1: Paclitaxel 80mg/m2 IV over 60 minutes weekly for 12 weeks

Day 1: Trastuzumab 4mg/kg IV over 90 minutes with first dose of Paclitaxel, then 2mg/kg IV over 30 minutes weekly to complete 12 weeks, followed by:

Day 1: Trastuzumab 2mg/kg IV over 30 minutes weekly to complete 1 year of trastuzumab therapy.

TCH58,63,l,r

Day 1: Trastuzumab 4mg/kg IV over 90 minutes for cycle 1, then 2mg/kg IV over 30 minutes weekly to complete 18 cycles, with:

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

Day 1: Carboplatin AUC 6 IV over 30 minutes.

Repeat cycle every 21 days for 6 cycles, followed by:

Day 1: Trastuzumab 6mg/kg IV over 30 minutes every 21 days to complete 1 year of trastuzumab therapy.

As an alternative, trastuzumab 8mg/m2 IV over 90 minutes may be used on day 1 of cycle 1, then 6mg/kg IV over 30 minutes. Repeat cycle every 21 days to complete 1 year of trastuzumab therapy.

TCH + Pertuzumab58,60,64,l,r

Day 1: Trastuzumab 8mg/kg IV over 90 minutes for cycle 1, then 6mg/kg IV over 30 minutes every 21 days for cycles 2-6

Day 1: Pertuzumab 840mg IV over 60 minutes for cycle 1, then 420 mg IV over 30 minutes every 21 days for cycles 2-6, followed by:

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

Day 1: Carboplatin AUC 6 IV over 30 minutes.

Repeat cycle every 21 days for 6 cycles, followed by:

Day 1: Trastuzumab 6mg/kg IV over 30 minutes every 21 days to complete 1 year of trastuzumab therapy

Day 1: Pertuzumab 420mg IV over 30 minutes every 21 days to complete 1 year of pertuzumab therapy.

Useful in Certain Circumstances

Docetaxel + Cyclophosphamide + trastuzumab58,65,r

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

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

Repeat cycle every 21 days for 4 cycles, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes week 1, then 2mg/kg IV over 30 minutes weekly for 11 weeks, then 6mg/kg every 21 days to complete 1 year of trastuzumab therapy OR

Day 1: Trastuzumab 8mg/kg IV over 90 minutes cycle 1, then 6mg/kg IV over 30 minutes every 21 days to complete 1 year of trastuzumab therapy.

Other Recommended Regimens

AC followed by Docetaxel + Trastuzumab58,62,66,q,r

Day 1: Doxorubicin 60mg/m2 IV push

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

Repeat cycle every 21 days for 4 cycles, followed by:

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

Repeat cycle every 21 days for 4 cycles, with:

Day 1: Trastuzumab 4mg/kg IV over 90 minutes week 1, then 2mg/kg IV weekly for 11 weeks, followed by:

Day 1: Trastuzumab 6mg/kg IV over 30 minutes beginning week 13.

Repeat cycle every 21 days to complete 1 year of trastuzumab therapy.

AC followed by Docetaxel + Trastuzumab + Pertuzumab58,60,67,q,r

Day 1: Doxorubicin 60mg/m2 IV push

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

Repeat cycle every 21 days for 4 cycles, followed by:

Day 1: Pertuzumab 840mg IV over 60 minutes for cycle 1, then 420mg IV over 30 minutes for cycles 2-4

Day 1: Trastuzumab 8mg/kg IV over 90 minutes for cycle 1, then 6mg/kg IV over 30 minutes for cycles 2-4 followed by

Day 1: Docetaxel 75mg/m2 IV over 60 minutes for cycle 1, then 100mg/m2 IV over 60 minutes for cycles 2-4 (if tolerated).

Repeat cycle every 21 days for 4 cycles, followed by:

Day 1: Trastuzumab 6mg/kg IV over 30 minutes and Pertuzumab 420 mg IV over 30 minutes (beginning with week 13) every 21 days to complete 1 year of trastuzumab and pertuzumab therapy.

Weekly Paclitaxel + Carboplatin68

Days 1, 8, 15: Paclitaxel 80mg/m2 IV

Day 1: Carboplatin AUC 6.

Repeat cycle every 21 days to complete 1 year of trastuzumab therapy.

Docetaxel + Carboplatin69

Day 1: Docetaxel 75mg/m2 IV

Day 1: Carboplatin AUC 6

Repeat cycle every 21 days for 6 cycles.

a  If patient is not postmenopausal, sequential evaluation of hormonal status is recommended to consider an alternative endocrine agent.

b  Some SSRIs like fluoxetine and paroxetine decrease the formation of impact its efficacy. Caution is advised about coadministration of these drugs with tamoxifen. However, citalopram and venlafaxine appear to have minimal impact on tamoxifen metabolism. At this time, based on current data the panel recommends against CYP2D6 gene testing for women being considered for tamoxifen therapy. Coadministration of strong inhibitors of CYP2D6 should be used with caution.

c  A balanced discussion of the risk and benefits associated with ovarian suppression therapy is critical. Aromatase inhibitor or tamoxifen for 5 years plus ovarian suppression should be considered, based on SOFT and TEXT clinical trial outcomes, for premenopausal women at higher risk of recurrence (ie, young age, high-grade tumor, lymph node involvement).

d  The three selective aromatase inhibitors (ie, anastrozole, letrozole, exemestane) have shown similar anti-tumor efficacy and toxicity profiles in randomized studies in the adjuvant and preoperative settings. The optimal duration of aromatase inhibitors in adjuvant therapy is uncertain.

e  Retrospective evidence suggests that anthracycline-based chemotherapy regimens may be superior to nonanthracycline-based regimens in patients with HER2-positive tumors.

f  Randomized clinical trials demonstrate that the addition of a taxane to anthracycline-based chemotherapy provides an improved outcome.

g  CMF and radiation therapy may be given concurrently, or the CMF may be given first. All other chemotherapy regimens should be given prior to radiotherapy.

h  Chemotherapy and endocrine therapy used as adjuvant therapy should be given sequentially with endocrine therapy following chemotherapy.

i   Nab-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 should not exceed 125mg/m2.

j   Consider scalp cooling to reduce incidence of chemotherapy-induced alopecia for patients receiving neoadjuvant/adjuvant chemotherapy. Results may be less effective with anthracycline- containing regimens.

k  It would be acceptable to change the administration sequence to paclitaxel followed by dose-dense AC.

l   All cycles are with myeloid growth factor.

m Trastuzumab and hyaluronidase-oysk injection for subcutaneous use may be substituted for trastuzumab.52,53 It has different dosing and administration instructions compared to intravenous trastuzumab. Do not substitute trastuzumab and hyaluronidase-oysk for or with ado-trastuzumab emtansine. (Trastuzumab and hyaluronidase-oysk 600mg subcutaneous over 2-5 minutes. Cycle length is regimen specific. Trastuzumab and hyalruonidase-oysk is administered as a substitute for intravenous trastuzumab on the days that intravenous trastuzumab is administered as per the regimen. This agent dose not require a loading dose. No dose adjustments for patient body weight or for different concomitant chemotherapy are required). An FDA-approved biosimilar is an appropriate substitute for trastuzumab.

n  Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use may be substituted anywhere that the combination of intravenous pertuzumab and intravenous trastuzumab are given as part of systemic therapy. Pertuzumab, trastuzumab, and hyaluronidase-zzxf injection for subcutaneous use has different dosing and administration instructions compared to the intravenous product.

o  If no residual disease after preoperative therapy or no preoperative therapy: Complete up to one year of HER2-targeted therapy with trastuzumab (Category 1) +/- pertuzumab. Consider extended neratinib (Neratinib 240mg orally once daily for 1 year) following adjuvant trastuzumab-containing therapy for patients with hormone receptor-positive, HER2-positive disease with a perceived high risk of recurrence.54,55 The benefit or toxicities associated with extended neratinib in patients who have received pertuzumab or ado-trastuzumab emtansine is unknown.

p  If residual disease after preoperative therapy: Ado-trastuzumab emtansine alone (Category 1; Ado-trastuzumab emtansine 3.6mg/kg IV every 21 days for 14 cycles. If ado-trastuzumab emtansine discontinued for toxicity, then trastuzumab (Category 1) +/- pertuzumab to complete one year of therapy.56,57 Consider ex­tended neratinib (Neratinib 240mg orally once daily for 1 year) following adjuvant trastuzumab-containing therapy for patients with hormone receptor-posi­tive, HER2-positive disease with a perceived high risk of recurrence.54,55 The benefit or toxicities associated with extended neratinib in patients who have received pertuzumab or ado-trastu­zumab emtansine is unknown.

q  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.

r   Evaluate left ventricular ejection fraction (LVEF) before and during treatment. The optimal frequency of LVEF assessment during adjuvant trastuzumab therapy is not known, The FDA label recommends LVEF measurements prior to initiation of trastuzumab and every 3 months during therapy.

s  Paclitaxel + trastuzumab may be considered for patients with low-risk, T1, N0, M0, HER2-positive disease, particularly those not eligible for other standard adjuvant regimens due to comorbidities.

References

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(Revised 8/20; NCCN Breast Cancer Guidelines v5.2020) © 2020 by Haymarket Media, Inc.

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Breast Cancer Treatment Regimens