Breast Cancer Treatment Protocols

Noninvasive disease

In the United States and other developed nations where screening is performed, most patients present with localized breast cancer that is detected by a screening mammogram; less commonly, patients present with a palpable mass detected by themselves or by a health care provider.[1, 2]

Stage 0 (lobular carcinoma in situ [LCIS])

Management options include the following:

• Surveillance alone (ie, mammography)

• Surveillance plus raloxifene (for postmenopausal women)

• Tamoxifen (for women of any menopausal status)[3, 4]

• Bilateral prophylactic mastectomy (usually in patients who are very concerned about breast cancer risk and have either a strong family history or mammographically dense breasts that impair surveillance)

If LCIS is detected on stereotactic biopsy, wide excision is indicated. In 10-20% of cases, this may reveal invasive cancer or ductal carcinoma in situ (DCIS) that requires additional local or systemic therapy[5]

Surgical excision to negative margins is not indicated; however, LCIS is associated with about a 5% 5-y risk and a 20-30% lifetime risk of developing invasive breast cancer, which may be ipsilateral or contralateral and may be ductal or lobular in origin[6] Pleomorphic LCIS is a LCIS variant that warrants special consideration in that treatment should include excision to negative margins.[7]

Stage 0 (ductal carcinoma in situ [DCIS])

Primary treatment options include the following:

• Lumpectomy without axillary assessment, plus whole-breast radiation therapy (RT); use of radiation boost (photons, brachytherapy, or electron beam) to the tumor bed is recommended, especially in patients age ≥50 y or

• Total mastectomy, with or without sentinel node biopsy (SNB) and with or without breast reconstruction or

• Lumpectomy without lymph node surgery and without radiation therapy (lower-level evidence)

Considerations include the following:

• Although axillary dissection or SNB is often not performed, SNB may be done in some cases if an initial core biopsy showed DCIS, because more extensive sampling may show invasive carcinoma

• In the absence of risk factors for recurrence (eg, palpable mass, larger size, higher grade, close or involved margins, age < 50 y), some patients may not receive RT

• Consider risk-reduction therapy with tamoxifen for 5 years for patients treated with lumpectomy and RT, especially those with estrogen receptor (ER)–positive DCIS

Invasive disease

Stage I, IIA, IIB, or IIIA (T3N1M0)

Treatment for these stages of breast cancer include the following:

• Surgery
• RT in most cases
• Adjuvant chemotherapy, endocrine therapy, or biologic therapy in some cases

Surgical options include the following:

• Lumpectomy to negative margins, plus RT or
• Mastectomy or
• Mastectomy with reconstruction

Axillary assessment is usually performed with SNB. Axillary dissection may be considered in cases of node-positive breast cancer.

RT is used in patients who undergo lumpectomy or, in selected cases, after mastectomy; treatment fields are determined by axillary node status. RT should follow chemotherapy if chemotherapy is indicated.

Patients undergoing lumpectomy with surgical axillary staging

RT recommendations are based on the patient's axillary node status. In patients with ≥4 positive axillary nodes, treatment is as follows:

• Whole-breast radiation therapy (WBRT) with or without boost to the tumor bed
• Comprehensive regional nodal irradiation (RNI) including any portion of the undissected axilla at risk

In patients with 1-3 positive axillary nodes, treatment is as follows:

• All of the following criteria met: cT1-T2 cN0, no preoperative chemotherapy, 1-2 positive sentinel lymph node (SLNs) – WBRT with or without boost to the tumor bed; comprehensive RNI with or without inclusion of axilla
• Not all the above criteria met – WBRT with or without boost, including any portion of undissected axilla at risk; strongly consider RNI

In patients with negative axillary nodes, treatment is as follows:

•  WBRT with or without boost to the tumor bed
• Partial breast irradiation (PBI) may be considered in selected patients

Even without RT, risk of recurrence is extremely low in patients aged 55 and older with low-grade luminal A–type breast cancer (node-negative, grade 1 or 2 tumors < 2 cm) and a Ki67 tumor cell count of 13.25% or less, who receive breast-conserving surgery and endocrine therapy.[8]  

Patients undergoing total mastectomy with surgical axillary staging, with or without reconstruction

RT recommendations are based on the patient's axillary node status, as follows (note that comprehensive RNI may include any portion of undissected axilla at risk):

• Negative axillary nodes, tumor ≤5 cm, and margins ≥1 mm – No RT needed
• Negative axillary nodes, tumor ≤5 cm, and negative margins < 1 mm – Consider RT to the chest wall; for high-risk patients, consider adding comprehensive RNI
• Negative axillary nodes and tumor > 5 cm or positive margins – Consider RT to the chest wall, with or without comprehensive RNI
• 1-3 positive axillary nodes – Consider RT to the chest wall, with or without infraclavicular and supraclavicular nodes; consider RT to internal mammary nodes
• ≥4 positive axillary nodes – RT to the chest wall plus consider comprehensive RNI
• Margins positive – Re-excision to negative margins (preferred); if unable to excise, then strongly consider RT with or without comprehensive RNI

Patients with large, clinical stage IIA, IIB, or IIIA (T3N1M0) tumors

Consider preoperative chemotherapy in patients who have any of the following:

• Inflammatory breast cancer (IBC)
• T3-T4 disease
• Node-positive disease
• ER-negative disease
• HER2-positive disease or triple-negative breast cancer (TNBC), if cT≥2 or cN≥1; may be considered for cT1c, cN0 HER2-positive disease and TNBC
• Tumors that need downsizing for surgery
• Patients in whom definitive surgery may be delayed

If the patient has clinically negative axillary nodes, consider SNB. If the patient has clinically positive axillary nodes, consider a core biopsy or fine-needle aspiration (FNA), then SNB if FNA or core biopsy is negative.

Systemic therapy can be streamlined based on histology, menopause, and hormone receptor/HER2 status.

In general, those chemotherapy regimens recommended in adjuvant setting may be considered in the preoperative setting[1]

Anti-HER2/neu–directed therapy (eg, trastuzumab, neratinib) is indicated for use in combination with chemotherapy in patients with HER2/neu-positive disease. HER2/neu overexpression occurs in about 15-20% of cases of localized breast cancer, is associated with a higher risk of recurrence, and identifies patients who benefit from adjuvant anti-HER2/neu directed therapy.

Treatment considerations regarding trastuzumab and neratinib include the following:

• Trastuzumab and neratinib are anti-HER2/neu–directed therapies that have been shown to reduce the risk of recurrence.

• In studies of trastuzumab, patients were randomly assigned to receive chemotherapy alone or in combination with trastuzumab.[9]

• Overlapping trastuzumab therapy with taxanes therapy has been suggested to be more effective than a strategy of completing all chemotherapy first and then administering trastuzumab.

• Pertuzumab is indicated for use in combination with trastuzumab and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.

• Trastuzumab cannot be given concurrently with anthracyclines, because of the high risk of cardiac toxicity.

• The FDA has approved four biosimilars of trastuzumab (Herzuma, Ogivri, Ontruzant, Trazimera) to treat HER2-overexpressed breast cancer. The availability of biosimilars will provide additional treatment options for patients in the adjuvant setting.

• The FDA granted accelerated approval to a fixed-dose pertuzumab/trastuzumab/hyaluronidase combination (Phesgo) for subcutaneous (SC) use in combination with IV chemotherapy, for adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence.[10]  Pertuzumab/trastuzumab/hyaluronidase may be substituted anywhere that the combination of IV pertuzumab and IV trastuzumab are given as part of systemic therapy.

• Trastuzumab/hyaluronidase (Herceptin Hylecta) for SC use may be substituted for trastuzumab IV. Do not substitute trastuzumab/hyaluronidase for or with ado-trastuzumab emtansine.

• Neratinib is indicated for extended (ie, 1 year) adjuvant treatment of early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy.[11]

• Diarrhea is a dose-limiting adverse effect of neratinib.

Non-trastuzumab regimens

Regimens are as follows:

• TAC: Docetaxel (Taxotere) 75 mg/m2 IV on day 1 plus doxorubicin (Adriamycin) 50 mg/m2 IV on day 1 plus cyclophosphamide 500 mg/m2 IV on day 1 every 3 wk for six cycles or

• Dose-dense ACP: Doxorubicin 60 mg/m2 IV on day 1 plus cyclophosphamide 600 mg/m2 on day 1 every 2wk for four cycles, followed by paclitaxel 175 mg/m2 on day 1 every 2 wk with colony-stimulating factor support[12]  or

• AC: Doxorubicin 60 mg/m2 IV plus cyclophosphamide 600 mg/m2 IV on day 1 every 3wk for four cycles (comparable to CMF [cyclophosphamide, methotrexate, fluorouracil)[13]  or

• TC: Docetaxel 75 mg/m2 IV on day 1 plus cyclophosphamide 600 mg/m2 IV on day 1 every 3 wk for four cycles

Trastuzumab-containing regimens

The regimens below have been shown to be more effective than non-trastuzumab regimens (with which they were compared).

Paclitaxel plus trastuzumab:

• Consider for low-risk HER2-positive patients who may not be eligible for other standard adjuvant treatments
• Paclitaxel 80 mg/m ² IV weekly for 12 weeks  concurrently with
• Trastuzumab 4 mg/kg with first dose of paclitaxel then 2 mg/kg IV weekly for 1 year or  trastuzumab 6 mg/kg every 3 wk following the completion of paclitaxel, and given for a 1-y total duration of trastuzumab therapy  ^[1]

AC-paclitaxel plus trastuzumab:

• Doxorubicin 60 mg/m ² IV  plus  cyclophosphamide 600 mg/m ² IV on day 1 every 3 wk for four cycles, followed by 
• Paclitaxel 80 mg/m ² IV weekly for 12 weeks  concurrently with
• Trastuzumab 4 mg/kg for the first dose and then 2 mg/kg IV weekly for 1 year or  trastuzumab 6 mg/kg every 3 wk following the completion of paclitaxel, and given for a 1-y total duration of trastuzumab therapy  ^[14]  

Dose-dense ACP:

• Doxorubicin 60 mg/m ² IV  plus  cyclophosphamide 600 mg/m ² every 2wk for four cycles, followed by
• Paclitaxel 175 mg/m ² every 2 wk for four cycles concurrently with
• Trastuzumab 4 mg/kg for the first dose and then 2 mg/kg weekly for 1 year or trastuzumab 6 mg/kg every 3 wk following the completion of paclitaxel, and given for a 1-y total duration of trastuzumab therapy 

AC-docetaxel plus trastuzumab:

• Doxorubicin 60 mg/m ² IV plus  cyclophosphamide 600 mg/m ² IV on day 1 every 3 wk for four cycles, followed by
• Docetaxel 100 mg/m ² every 3 wk for four cycles concurrently with
• Trastuzumab 4 mg/kg IV during week 1 and then 2 mg/kg IV weekly for 11 wk; followed by trastuzumab 6 mg/kg every 3 wk to complete 1 y of trastuzumab ^[15]  

TCH:

• Docetaxel 75 mg/m ² plus  carboplatin AUC 6 IV on day 1 every 3 wk for six cycles (see the  Carboplatin AUC Dose Calculation [Calvert formula] calculator)  plus
• Trastuzumab 4 mg/kg during week 1 and then 2 mg/kg IV weekly for 17 wk; followed by trastuzumab 6 mg/kg every 3 wk to complete 1 y of trastuzumab
• Alternatively, trastuzumab 8 mg/kg IV week 1 followed by trastuzumab 6 mg/kg IV every 3 weeks to complete 1 year of therapy
• This regimen may be more appropriate for patients with contraindications to anthracycline therapy ^[15]  

TCH plus pertuzumab:

• Docetaxel 75 mg/m ²  plus   carboplatin AUC 6 IV on day 1 every 3 wk for six cycles  plus
• Trastuzumab 8 mg/kg IV day 1 plus  pertuzumab 840 mg IV Day 1 followed by trastuzumab 6 mg/kg IV day 1 plus  pertuzumab 420 mg IV day 1 every 3 weeks to complete 1 year of therapy ^[1]  

Docetaxel/cyclophosphamide plus trastuzumab:

• Docetaxel 75 mg/m ² IV day 1 plus  cyclophosphamide 600 mg/m ² IV Day 1 every 3 weeks for four cycles plus
• Trastuzumab 4 mg/kg during week 1 and then 2 mg/kg IV weekly for 11 wk; followed by trastuzumab 6 mg/kg every 3 wk to complete 1 y of trastuzumab
• Alternatively, trastuzumab 8 mg/kg IV week 1 followed by trastuzumab 6 mg/kg IV every 3 weeks to complete 1 year of therapy  ^[1]  

Paclitaxel, trastuzumab, pertuzumab:

• Paclitaxel 80 mg/m ² IV weekly x 12 cycles plus
• Trastuzumab 8 mg/kg IV day 1 followed by 6 mg/kg IV plus pertuzumab 840 mg IV day 1 followed by 420 mg IV every 3 weeks for four cycles

Neratinib for adjuvant treatment following trastuzumab

Neratinib is indicated for the extended adjuvant treatment of early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy, as follows:

• 120 mg PO daily days 1-7, followed by 160 mg PO daily on days 8-14, followed by 240 mg PO daily on days 15-28 in cycle 1 then
• 240 mg (ie, six 40-mg tablets) PO daily every 28 days for 12 cycles beginning with cycle 2
• Antidiarrheal prophylaxis required when starting therapy

Ado-trastuzumab emtansine (T-DM1) for adjuvant setting only

Ado-trastuzumab emtansine 3.6 mg/kg IV day 1 every 3 weeks for 17 cycles 

Stage I, IIA, IIB, or IIIA (T3N1M0)

Preferred HER2-negative chemotherapy regimens are listed below.

Dose-dense AC followed by P:

• Doxorubicin 60 mg/m ² IV  plus  cyclophosphamide 600 mg/m ² every 2 wk for four cycles; followed by 
• Paclitaxel 175 mg/m ² every 2 wk with colony-stimulating factor (CSF) support (more effective than the 3-wk schedule in ER-negative or progesterone receptor (PR)–negative disease) ^[12] or
• Paclitaxel 80 mg/m ² weekly for 12 weeks with CSF support ^{[16] ​}
• Alternative taxanes (ie, docetaxel, paclitaxel, albumin-bound paclitaxel) may be used as substitutes in cases of medical necessity (eg, hypersensitivity reaction). If substituting weekly paclitaxel and docetaxel, albumin-bound paclitaxel dose should not exceed 125 mg/m ²
• Change in administration sequence to paclitaxel followed by AC is acceptable

TC:

• Docetaxel 75 mg/m ² IV on day 1  plus  cyclophosphamide 600 mg/m ² IV on day 1 every 3 wk for four cycles (more effective than AC) ^[17] ​ 

Preoperative pembrolizumab + chemotherapy followed by adjuvant pembrolizumab (preferred):

• Pembrolizumab 200 mg IV Day 1 plus  paclitaxel 80 mg /m2 IV Days 1, 8, 15 plus  carboplatin AUC 5 IV Day 1 every 3 wk for four cycles followed by
• Pembrolizumab 200 mg IV Day 1 plus doxorubicin 60 mg/m ² IV or epirubicin 90 mg/m 2 IV Day 1  plus  cyclophosphamide 600 mg/m ² every 3 wk for four cycles followed by
• Pembrolizumab 200 mg IV Day 1 every 3 weeks for nine cycles​

Capecitabine monotherapy:

• Capecitabine 1,000-1,250 mg/m2 PO BID on Days 1-14 every 3 weeks for six to eight cycles

Olaparib monotherapy:

• Olaparib 300 mg PO BID every 4 weeks for 1 year

Other recommended HER2-negative chemotherapy regimens are as follows:

• TAC: Docetaxel 75 mg/m ² IV  plus  doxorubicin 50 mg/m ² IV  plus  cyclophosphamide 500 mg/m ² IV on Day 1 every 3 wk for six cycles (more effective than FAC [fluorouracil-doxorubicin-cyclophosphamide]); CSF support recommended ^{[18, 19]}
• ACD: Doxorubicin 60 mg/m ² IV plus cyclophosphamide 600 mg/m ² IV on day 1 every 3 wk for four cycles (comparable to CMF [cyclophosphamide, methotrexate, fluorouracil]) ^[13] followed by docetaxel 100 mg/m ² IV day on 1 for four cycles; change in administration sequence to docetaxel followed by AC is acceptable
• Epirubicin 100mg/m ² IV day1 plus  cyclophosphamide 830 mg/m ² IV day 1 every 3 wk for eight cycles
• Docetaxel 75 mg/m ² IV day 1 plus  doxorubicin 50 mg/m ² IV Day 1 plus  cyclophosphamide 500 mg/m ² IV day 1 every 3 wk for six cycles

• CMF: Cyclophosphamide 100 mg/m2 PO on days 1-14 plus methotrexate 40 mg/m2 IV on days 1 and 8 plus 5-fluorouracil (5-FU) 600 mg/m2 IV on days 1 and 8 every 4 wk for six cycles[20] or

• AC-paclitaxel: Doxorubicin 60 mg/m2 IV plus cyclophosphamide 600 mg/m2 IV on day 1 every 3 wk for four cycles, followed by paclitaxel 80 mg/m2 by 1-h IV infusion weekly for 12 wk (more effective than AC)[16] or

• Capecitabine (maintenance therapy) 650 mg/m ² PO twice daily on days 1-28 every 4 weeks for 1 year

Inclusion of a platinum agent (ie, carboplatin) as neoadjuvant chemotherapy for TNBC remains controversial. It should be considered only in select TNBC patients (eg, for controlling a localized area) and is not recommended for the majority of TNBC patients. Platinum-containing regimens are as follows:

• Paclitaxel 80 mg/m ² IV days 1, 8, and 15 plus carboplatin AUC 5 or 6 day 1 every 3 wk for four cycles
• Paclitaxel 80 mg/m ² IV days 1, 8, and 15 plus carboplatin AUC 1.5-2 days 1, 8, and 15 every 4 wk for six cycles
• For preoperative setting only: Docetaxel 75 mg/m ² IV day 1 plus carboplatin AUC 6 day 1 every 3 weeks x 4-6 weeks 

General considerations

Patients with invasive breast cancer that is estrogen receptor (ER) or progesterone receptor (PR)–positive should be considered for adjuvant endocrine therapy. Options for endocrine therapy in breast cancer patients include the following:

• Tamoxifen
• Aromatase inhibitors (AIs)
• Luteinizing hormone–releasing hormone (LHRH) analogues
• Oophorectomy may produce additional benefit

Selection considerations are as follows:

• Selection of agents depends on menopausal status and concern about side-effect profile (eg, thrombosis with tamoxifen, bone loss with AIs)

• Tamoxifen has been shown to reduce the risk of recurrence by about 40% and the risk of death by about 30%, is effective in both premenopausal and postmenopausal women, and may be used either alone or after chemotherapy[21]

• Acute toxicities of tamoxifen include hot flushes and gynecologic symptoms; long-term toxicities are thrombosis and uterine cancer

• AIs are effective for postmenopausal women, reducing the risk of recurrence by approximately 20% compared with tamoxifen[22, 23, 24, 25]

• Nonsteroidal AIs (anastrozole, letrozole) and steroidal AIs (exemestane) have comparable efficacy and adverse effects

• Acute toxicities of AIs include arthralgias, hot flushes, and gynecologic symptoms; osteoporosis is a long-term adverse effect

Regimens for premenopausal patients

Regimens are as follows:

• Tamoxifen 20 mg PO daily for 5 y[26] or

• Tamoxifen 20 mg PO daily for 2-5 y, followed by an AI for a total of up to 10 y of endocrine therapy; this regimen is typically used for patients who are premenopausal at diagnosis and become postmenopausal during therapy; it has been shown to be more effective than a 5-y course of tamoxifen[27]

• Ovarian suppression with LHRH analogues, added to tamoxifen or an AI, is associated with a modest effect; this approach is being evaluated in ongoing trials

Regimens for postmenopausal patients

Regimens are as follows:

• Tamoxifen 20 mg PO daily for 5 y or

• AIs for 5y, either alone or sequentially after 2-5 y of tamoxifen: anastrozole 1 mg PO daily orletrozole 2.5 mg PO daily orexemestane 25 mg PO daily

Stage III

Considerations are as follows:

• Patients with stage III disease are divided into those who are candidates for operative treatment and those who are not

• Patients with stage IIIA breast cancer are further divided into those with T3N1M0 disease and those with TanyN2M0 disease; for treatment of patients with operable T3N1M0 disease, see Treatment recommendations for localized disease, above

• Therapeutic options for locally advanced disease are similar to those for localized disease but include consideration of preoperative (neoadjuvant) chemotherapy followed by local surgical therapy

• In general, all planned chemotherapy should be given preoperatively to optimize the potential for inducing a pathologic complete response (pCR), which has been shown to be associated with improved outcomes (90% of higher disease-free survival [DFS] rates)

• Preoperative systemic chemotherapy is indicated for all patients with inflammatory breast carcinoma, ipsilateral supraclavicular adenopathy, bulky axillary adenopathy, extension to the skin or chest wall, or a large (>5 cm) primary tumor; patients who do not meet these criteria but would benefit from tumor cytoreduction before surgery to facilitate breast conservation should be considered for such treatment

• Radiopaque clips should be placed in the tumor bed before the start of preoperative therapy, and breast imaging should be repeated after therapy in any such patients for whom breast conservation is being considered

• RT to the breast or chest wall is indicated for any patient who received preoperative systemic chemotherapy

Treatment recommendations for inoperable noninflammatory locally advanced disease (stage IIIA except T3N1M0)

Treatment includes chemotherapy, with or without a taxane. Regimens are as follows:

• TAC: Docetaxel (Taxotere) 75 mg/m2 IV on day 1 plus doxorubicin (Adriamycin) 50 mg/m2 IV on day 1 plus cyclophosphamide 500 mg/m2 IV on day 1 every 3 wk for six cycles or

• Dose-dense AC-P: Doxorubicin 60 mg/m2 IV plus cyclophosphamide 600 mg/m2 every 2wk for four cycles, followed by paclitaxel 175 mg/m2 every 2 wk with colony-stimulating factor (CSF) support (more effective than the 3-wk schedule in ER/PR-negative disease)[12] or

• AC: Doxorubicin 60 mg/m2 IV plus cyclophosphamide 600 mg/m2 IV on day 1 every 3 wk for four cycles (comparable to CMF)[13] or

• TC: Docetaxel 75 mg/m2 IV on day 1 plus cyclophosphamide 600 mg/m2 IV on day 1 every 3 wk for four cycles

Treatment recommendations for HER2/neu+ locally advanced disease

In patients with HER2/neu-positive disease, concurrent trastuzumab with chemotherapy improves the pCR rate. Regimens are listed below.

AC-paclitaxel plus trastuzumab

• Doxorubicin 60 mg/m ² IV  plus  cyclophosphamide 600 mg/  ² IV on day 1 every 3 wk for 4 cycles, followed by
• Paclitaxel 80 mg/m ² IV weekly for 12 weeks or paclitaxel 175mg/m2 every 3 wk for 4 cycles with:
• Trastuzumab 4 mg/kg IV with first dose of paclitaxel, followed by
• Trastuzumab 2 mg/kg IV weekly to complete 1-y total duration of trastuzumab therapy
• As an alternative, trastuzumab 6 mg/kg IV every 3 wk following the completion of paclitaxel, to complete 1-y total duration of trastuzumab therapy ^[14]

Dose-dense AC–paclitaxel plus trastuzumab

• Doxorubicin 60 mg/m ² IV  plus  cyclophosphamide 600 mg/m ² IV on day 1 every 2 wk for 4 cycles, followed by
• Paclitaxel 175 mg/m ² IV every 2 wk for four cycles, with
• Trastuzumab 4 mg/kg for the first dose and then 2 mg/kg weekly for 1-y total duration
• As an alternative, trastuzumab 6 mg/kg every 3 wk following the completion of paclitaxel, and given to complete 1-y total duration of trastuzumab therapy​ ^[15]

AC-docetaxel plus trastuzumab

• Doxorubicin 60 mg/m ² IV  plus  cyclophosphamide 600 mg/m ² IV on day 1 every 3 wk for four cycles, followed by
• Docetaxel 100 mg/m ² every 3 wk for four cycles, with
• Trastuzumab 4 mg/kg IV during week 1 and then 2 mg/kg IV weekly for 11 wk; followed by trastuzumab 6 mg/kg every 3 wk to complete 1 y of trastuzumab ​ ^[15]

AC-paclitaxel plus trastuzumab and pertuzumab

• Doxorubicin 60 mg/m ² IV  plus  cyclophosphamide 600 mg/m ² IV on day 1 every 3 wk for four cycles, with
• Followed by paclitaxel 80 mg/m ² IV days 1, 8, 15 every 3 wk for four cycles with
• Pertuzumab 840 mg IV followed pertuzumab 420mg IV and trastuzumab 8 mg/kg IV for the first dose and then 6 mg/kg IV every 3 wk for four cycles 
• Then, trastuzumab 6 mg/kg IV every 3 wk to complete 1-yr trastuzumab therapy
• As an alternative, IV trastuzumab and IV pertuzumab may be substituted with Phesgo (pertuzumab/trastuzumab/hyaluronidase); administer a loading dose of 1,200 mg pertuzumab/600 mg trastuzumab SC x 1 dose followed by maintenance dosing of 600 mg pertuzumab/600 mg trastuzumab SC q3wk for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first. Patients who received IV pertuzumab and trastuzumab within 6 weeks since their last dose should skip the loading dose and follow the maintenance dosing schedule. ^[10]

AC-docetaxel plus trastuzumab and pertuzumab

• Doxorubicin 60 mg/m ² IV  plus  cyclophosphamide 600 mg/m ² IV on day 1 every 3 wk for four cycles
• Followed by docetaxel 75-100 mg/  ² every 3 wk for four cycles, with
• Pertuzumab 840 mg IV followed pertuzumab 420 mg IV and trastuzumab 8 mg/kg IV followed by trastuzumab 6 mg/kg every 3 wk for four cycles
• Trastuzumab 6 mg/kg every 3 wk to complete 1 y of trastuzumab therapy
• As an alternative, IV trastuzumab and IV pertuzumab may be substituted with Phesgo (pertuzumab/trastuzumab/hyaluronidase); administer loading dose of 1,200 mg pertuzumab/600 mg trastuzumab SC x 1 dose followed by maintenance dosing of 600 mg pertuzumab/600 mg trastuzumab SC q3wk for a total of 1 year (up to 18 cycles) or until disease recurrence or unmanageable toxicity, whichever occurs first. Patients who received IV pertuzumab and trastuzumab within 6 weeks since their last dose should skip the loading dose and follow the maintenance dosing schedule. ^[10]

TCH plus pertuzumab

• Docetaxel 75 mg/m ²  plus   carboplatin AUC 6 IV every 3 wk for 6 cycles with
• Pertuzumab 840 mg IV followed pertuzumab 420mg IV and  trastuzumab 8 mg/kg IV followed by trastuzumab 6 mg/kg IV every 3 wk for six cycles, followed by
• Trastuzumab 6 mg/kg IV every 3 wk to complete 1-y total duration of trastuzumab therapy
• As an alternative, trastuzumab 8 mg/kg followed by trastuzumab 6 mg/kg every 3 wk to complete 1-y total duration of trastuzumab therapy

Local-only recurrence

Recommended therapy depends on the initial treatment given, as follows[1] :

• Patients whose initial treatment was lumpectomy and radiation therapy (RT) should undergo total mastectomy with axillary lymph node staging if level I/II axillary dissection was not previously done

• Patients whose initial treatment was mastectomy plus level I/II axillary dissection and RT should undergo surgical resection if possible

• Patients whose initial treatment was mastectomy with no prior RT should undergo surgical resection if possible, along with RT if possible to the chest wall and supraclavicular and infraclavicular nodes

Regional-only or local-regional recurrence

Recommendations vary by site of recurrence, as follows:

• For axillary recurrence, treatment is surgical resection if possible, plus RT if possible to the chest wall, supraclavicular and infraclavicular nodes, and axilla

• For supraclavicular recurrence, treatment is RT if possible to the chest wall and supraclavicular and infraclavicular nodes

• For internal mammary node recurrence, treatment is RT if possible to the chest wall, supraclavicular and infraclavicular nodes, and internal mammary nodes

Bone disease

Local irradiation should be considered for patients with localized bony disease that is symptomatic or at risk for producing a catastrophic complication (eg, spinal cord compression or pathologic fracture).

If expected survival is at least 3 mo and renal function is adequate, any of the following may be given (all with calcium and vitamin D supplementation) on a 3-wk to 5-wk schedule in conjunction with chemotherapy or endocrine therapy[1] :

• Denosumab 120 mg SC every 4 wk or
• Zoledronic acid 4 mg IV over 15 min or
• Pamidronate 90 mg IV over 2 h

Original studies continued treatment for up to 2 y; however, there are limited long-term safety data showing that therapy can continue beyond that time. Longer durations of bisphosphonate therapy can potentially provide additional benefits, but this possibility has not been tested in clinical trials.[1, 28, 29]

Systemic disease

Treatments for systemic disease are used to prolong survival and improve quality of life. Considerations in treatment selection are as follows:

• In patients with ER and/or PR expression who have no or minimal disease symptoms and bone-only disease or a low disease burden, endocrine therapy is always preferred to other therapeutic options because of its favorable toxicity profile relative to other alternatives

• Chemotherapy is used in patients with resistance to endocrine therapy or ER/PR-negative disease and a moderate or high disease burden

• Single-agent sequential cytotoxic therapy is preferred; combination cytotoxic therapy is associated with a higher response rate, but it is also more toxic and confers no survival benefit

Endocrine therapy in premenopausal women

Recommended treatment is ovarian suppression plus endocrine therapy with tamoxifen or an AI. Gonadotropin-releasing hormone (GRH) analogues may be used to suppress ovarian estrogen production (as in the following regimens):

• Goserelin 3.6 mg SC depot every 4 wk or

• Leuprolide 7.5 mg IM depot every 4 wk or 22.5 mg IM every 3 mo or 30 mg IM every 4 mo

Treatment considerations are as follows:

• Exercise caution when using GRH analogues in combination with AIs because of inconsistent inhibition of estrogen production.

• Oophorectomy is preferred because it induces permanent menopause and obviates repeated injections.

• Tamoxifen or AIs are used in the same doses and schedules commonly employed for adjuvant therapy.

• Selected patients who have had prolonged response or periods of stability on AIs may be switched to one of the following: progestational agents (megestrol acetate 40 mg PO QID) or androgens (fluoxymesterone 10-40 mg PO in divided doses) orestradiol (10 mg PO TID).

• In patients whose menopausal status is uncertain (eg, because of hysterectomy or chemotherapy-induced amenorrhea), confirmation of menopausal status may require documentation of an elevated serum follicle-stimulating hormone (FSH) level and a low estradiol level.

Endocrine therapy in postmenopausal women

Treatment with a single endocrine agent is usually continued until disease progression. Considerations are as follows:

• AIs have been shown to be more effective than tamoxifen for adjuvant therapy and metastatic disease.

• Patients who experience relapse or have progressive disease on tamoxifen may be switched to an AI.

• Patients who experience relapse or progress while receiving a nonsteroidal AI (eg, anastrozole or letrozole) may be changed to a steroidal AI (eg, exemestane) or a selective ER-downregulator (eg, fulvestrant).

• Fulvestrant regimen is 500 mg IM on days on days 1, 15, 29 and once monthly thereafter or in combination with palbociclib 125 mg PO once daily days 1-21.[30, 31, 32]

• Optionally, consider the androgenic agent fluoxymesterone 10 mg PO BID[33] or the progestational agent megestrol acetate 40 mg PO QID[34]  or estradiol 2 mg PO BID.[35]

• Systemic chemotherapy should be reserved for patients with hormone-insensitive disease or for patients with symptomatic hormone-sensitive disease in whom all hormone therapy options have failed or who are moderately to severely symptomatic and in urgent need of symptom palliation.

• The options for cytotoxic-containing chemotherapy include single-agent therapy and combination cytotoxic therapy.

Preferred single-agent anthracycline regimens

Regimens are as follows:

• Doxorubicin 60-75 mg/m ² on day 1 every 3 wk or  20 mg/m ² IV weekly or
• Epirubicin 60-90 mg/m ² IV on day 1 every 3 wk or
• Pegylated liposomal-encapsulated doxorubicin 50 mg/m ² IV on day 1 every 4 wk

Preferred single-agent taxane regimens

Regimens are as follows:

• Paclitaxel 175 mg/m ² IV on day 1 every 3 wk or  80 mg/m ² IV weekly or
• Docetaxel 60-100 mg/m ² IV on day 1 every 3 wk or  40 mg/m ² IV weekly for 6 wk followed by a 2-wk rest and then repeated or
• Albumin-bound paclitaxel 100 or 150 mg/m ² IV on days 1, 8, and 15 every 4 wk or  260 mg/m ² IV every 3 wk

Preferred single-agent antimetabolite regimens

Regimens are as follows:

• Capecitabine 1000-1250 mg/m ² PO BID on days 1-14 every 3 wk ^[36] or
• Gemcitabine 800-1200 mg/m ² IV on days 1, 8, and 15 every 4 wk

Preferred single-agent microtubule inhibitor regimens

Regimens are as follows:

• Vinorelbine 25 mg/m ² IV weekly or
• Eribulin 1.4 mg/m ² IV on days 1 and 8 every 3 wk

Preferred chemotherapy combinations

Regimens are as follows:

• CAF: Cyclophosphamide 100 mg/m2 IV on day 1 plus doxorubicin (Adriamycin) 30 mg/m2 IV on days 1 and 8 plus 5-fluorouracil (5-FU) 500 mg/m2 IV on days 1 and 8 every 4 wk for six cycles or

• FAC: 5-FU 500 mg/m2 IV on days 1 and 8 or days 1 and 4 plus doxorubicin 50 mg/m2 IV on day 1 plus cyclophosphamide 500 mg/m2 IV on day 1 every 3 wk for six cycles or

• FEC: 5-FU 500 mg/m2 IV plus epirubicin 100 mg/m2 IV plus cyclophosphamide 500 mg/m2 IV on day 1 every 3 wk for three cycles or

• AC: Doxorubicin 60 mg/m2 IV plus cyclophosphamide 600 mg/m2 IV on day 1 every 3 wk for four cycles or

• EC: Epirubicin 100 mg/m2 IV on day 1 plus cyclophosphamide 830 mg/m2 IV on day 1 every 3 wk for eight cycles or

• AT: Doxorubicin 50 mg/m2 IV plus paclitaxel 125-200 mg/m2 every 3 wk or

• AT: Doxorubicin 50 mg/m2 IV plus docetaxel 75 mg/m2 IV every 3 wk or

• CMF: Cyclophosphamide 100 mg/m2 IV PO on days 1-14 plus methotrexate 40 mg/m2 IV on days 1 and 8 plus 5-FU 600 mg/m2 IV on days 1 and 8 every 4 wk or

• Docetaxel/capecitabine: Docetaxel 75 mg/m2 IV on day 1 plus capecitabine 950 mg/m2 PO BID on days 1-14 every 3 wk or

• GT: Paclitaxel (Taxol) 175 mg/m2 on day 1 plus gemcitabine 1250 mg/m2 IV on days 1 and 8 (following paclitaxel on day 1) every 3 wk

General considerations

First-line cytotoxic therapy should always be given in combination with trastuzumab.[37, 38] Trastuzumab regimens are 4 mg/kg IV on day 1 followed by 2 mg/kg IV weekly or 8 mg/kg IV on day 1 followed by 6 mg/kg every 3 wk. In patients who have progression after initial therapy, anti-HER2 therapy should be continued by either continuing trastuzumab and changing cytotoxic therapy or switching to lapatinib plus capecitabine.

Preferred first-line single agents with trastuzumab

Regimens are as follows:

• Paclitaxel 175 mg/m ² IV on day 1 every 3 wk or
• Paclitaxel 80-90 mg/m ² IV weekly or
• Docetaxel 80-100 mg/m ² IV on day 1 every 3 wk or
• Docetaxel 35 mg/m ² IV weekly or
• Vinorelbine 25 mg/m ² IV weekly or
• Capecitabine 1000-1250 mg/m ² PO BID on days 1-14 every 3 wk

Preferred combination chemotherapy with trastuzumab

Regimens are as follows:

• PCH: Carboplatin AUC 6 IV on day 1 plus paclitaxel 175 mg/m2 IV on day 1 every 3 wk plus trastuzumab (Herceptin) or

• Weekly PCH: Paclitaxel 80 mg/m2 IV on days 1, 8, and 15 plus carboplatin AUC 2 IV on days 1,8, and 15 every 4 wk plus trastuzumab

• Pertuzumab/trastuzumab/docetaxel: pertuzumab 840 mg IV plus trastuzumab 8 mg/kg IV plus docetaxel 75 mg/m2 IV on day 1, then pertuzumab 420 mg plus trastuzumab 6 mg/kg plus docetaxel 75 mg/m2 q3 wk (may increase docetaxel to 100 mg/m2 if initial dose well tolerated)[39]

• As an alternative, IV trastuzumab and IV pertuzumab may be substituted with Phesgo (pertuzumab/trastuzumab/hyaluronidase)  administer loading dose of 1,200 mg pertuzumab/600 mg trastuzumab SC x 1 dose followed by 600 mg pertuzumab/600 mg trastuzumab SC q3Weeks; continue until disease recurrence or unmanageable toxicity, whichever occurs first
• Patients who received IV pertuzumab and trastuzumab within 6 weeks since their last dose should skip the loading dose and administer the maintenance dose of 600 mg pertuzumab/600 mg trastuzumab and every 3 weeks for subsequent administrations ^[10]

   

Preferred agents for trastuzumab-exposed patients

Regimens are as follows:

• Capecitabine 1000 mg/m2 PO BID on days 1-14 pluslapatinib 1250 mg PO on days 1-21 every 3 wk or

• Trastuzumab 4 mg/kg IV on day 1 followed by 2 mg/kg IV weekly or 8 mg/kg IV on day 1 followed by 6 mg/kg every 3 wk plus other first-line agents or

• Trastuzumab 4 mg/kg IV on day 1 followed by 2 mg/kg IV weekly or 8 mg/kg IV on day 1 followed by 6 mg/kg every 3 wk plus capecitabine 2500 mg/m² on days 1-14 every 3 wk[36, 40] or

• Trastuzumab 4 mg/kg IV on day 1 followed by 2 mg/kg IV weekly or 8 mg/kg IV on day 1 followed by 6 mg/kg every 3 wk plus lapatinib 1000 mg PO daily or

• Ado-trastuzumab: 3.6 mg/kg IV infusion q3 wk as a single agent in patients who previously received trastuzumab and a taxane, either separately or in combination[41]

• Trastuzumab deruxtecan: 5.4 mg/kg IV q3 wk as a single agent for unresectable or metastatic HER2-positive breast cancer in adults who have received 2 or more prior anti-HER2-based regimens in the metastatic setting[42]  

• Trastuzumab 8 mg/kg IV on day 1 followed by 6 mg/kg every 3 wk plus capecitabine 1000 mg/m2 on days 1-14 every 3 wk plus tucatinib 300 mg PO BID[43]

General considerations

For patients with HER2/neu-negative disease, options include the following:[1]

• Single-agent cytotoxic therapy
• Olaparib
• Combination cytotoxic therapy
• Endocrine-based therapy

Olaparib inhibits poly (ADP-ribose) polymerase (PARP) enzymes. It is the first PARP inhibitor approved for breast cancer, based on the first phase 3 randomized trial to show superior PFS with PARP inhibitors than with single-agent chemotherapy in patients with HER2-negative metastatic breast cancer who have a BRCA mutation.[44]  The regimen is as follows:

• Olaparib: 300 mg (two 150-mg tablets) PO BID
• Use tablets for breast cancer indication; do not substitute olaparib capsules for olaparib tablets on a mg-to-mg basis due to differences in the dosing and bioavailability of each formulation

In postmenopausal women with estrogen receptor (ER)–positive, HER2-negative advanced breast cancer, initial endocrine-based therapy for metastatic disease may include the following[45] :

• Palbociclib (Ibrance) 125 mg PO once daily with food for 21 days followed by 7 days off therapy to comprise a complete cycle of 28 days, plus
• Letrozole 2.5 mg/day PO continuously throughout the 28-day cycle

Ribociclib was approved for hormone receptor (HR)–positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women in combination with fulvestrant as initial endocrine-based therapy or following disease progression on endocrine therapy[46]

• Ribociclib (Kisqali), 600 mg/day PO for days 1-21 of a 28-day cycle, plus
• Fulvestrant (Faslodex) 500 mg IM on days 1, 15, 29, and once monthly thereafter 

Palbociclib and abemaciclib are also approved for HR-positive, HER2-negative advanced breast cancer in combination with fulvestrant in women (regardless of menopausal status) who have disease progression following endocrine therapy.[47, 48, 49, 50] The regimens are as follows:

• Palbociclib, 125 mg PO once daily with food for 21 days followed by 7 days off therapy, plus
• Fulvestrant 500 mg IM on days 1, 15, 29, and once monthly thereafter  or 
• Abemaciclib (Verzenio) 150 mg PO BID with or without food, plus
• Fulvestrant: 500 mg IM on Days 1, 15, and 29, and then once monthly thereafter  

Another option for first-line treatment in postmenopausal women with HR+/HER- advanced or metastatic breast cancer is the following[51, 52] :

• Ribociclib (Kisqali), 600 mg/day PO for days 1-21 of a 28-day cycle, plus
• Letrozole 2.5 mg/day PO continuously throughout the cycle

The US Food and Drug Administration (FDA) has approved everolimus (Afinitor) 10 mg/day in combination with exemestane 25 mg/day for postmenopausal women with advanced HR-positive, HER2-negative breast cancer. The drug combination is intended to be used in women with recurrent or progressive breast cancer after failure of treatment with either letrozole (Femara) or anastrozole (Arimidex).[53]

Alpelisib plus fulvestrant is indicated for treatment of men and postmenopausal women with HR+/HER2-, PIK3CA-mutated, advanced or metastatic breast cancer following progression on or after an endocrine-based regimen.[54]  The regimen is as follows:

• Alpelisib 300 mg PO daily  plus fulvestrant 500 mg IM on Days 1, 15, 29, and once monthly thereafter

Atezolizumab in combination with nab-paclitaxel is approved for patients with unresectable locally advanced or metastatic triple-negative (ER-, PR-, and HER2-negative) breast cancer whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells of any intensity covering ≥11% of the tumor area), as defined by an FDA-approved test.[55]  The regimen is as follows: 

• Nab-paclitaxel 100 mg/m ² IV on days 1, 8, and 15, plus
• Atezolizumab 840 mg IV on days 1 and 15 of a 28-day cycle

Sacituzumab govitecan is indicated for metastatic triple-negative breast cancer in patients who have received at least two prior therapies for metastatic disease.[56]  The regimen is as follows: 

• Sacituzumab govitecan 10 mg/kg IV on Days 1 and 8 of every 21-day cycle
• Continue until disease progression or unacceptable toxicity 

Elacestrant is indicated for men or postmenopausal women with ER+/HER2-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least 1 line of endocrine therapy[57]   

• Elacestrant 345 mg PO qDay with food
• Continue until disease progression or unacceptable toxicity 

General considerations

See the list below:

• Primary surgery usually includes either a mastectomy (with or without reconstruction) or lumpectomy with wide excision to cancer-free margins of excision (No tumor at ink for invasive disease, 2mm for DCIS).

• Patients with invasive disease also receive axillary surgery with sentinel node biopsy (SNB). Axillary dissection may be considered in patients with a positive SNB or positive node identied preoperatively with fine-needle aspiration/core biopsy. 

• SNB involves identification of ≥1 lymph nodes in the draining lymph node basin by injecting, into the breast, isosulfan blue dye that may be visualized, technetium-labeled sulfur colloid that may be detected by a handheld probe, or both; the success rate in identifying sentinel nodes varies by experience but is usually 90-95% in experienced hands and is associated with a false negative rate ≤5-10%.

• Although axillary dissection had been the standard of care for patients with a positive SNB, studies have indicated comparable local and systemic control rates without axillary dissection for patients who also receive radiation and systemic chemotherapy.[58, 40]

Hereditary breast cancer

See the list below:

• Approximately 5% of all breast cancers are attributable to a heritable mutation, including BRCA1/2 or other less common genetic mutations[59] ; factors associated with a higher likelihood of having a mutation include diagnosis before the age of 50y (especially before 40y), bilateral disease, family history in ≥2 first-degree relatives, family history of ovarian cancer, or Ashkenazi Jewish descent

• Algorithms are available to estimate the likelihood of an individual with breast cancer harboring a mutation, including those from Myriad Genetics, Inc. (www.myriad.com), BCRAPRO (www.stat.duke.edu/~gp/brcapro.html), and other models; it is recommended that testing begin with a family member diagnosed with breast cancer rather than with unaffected individuals

• High-risk patients should be provided with information on genetic testing (http://www.cancer.gov/cancertopics/pdq/genetics/breast-and-ovarian/HealthProfessional) and should be referred for genetic counseling

Breast cancer in the elderly

Infirm elderly patients who are not suitable candidates for surgery may be managed with endocrine therapy alone if the tumor is ER/PR positive

Ipsilateral breast, chest wall, or locoregional recurrence

See the list below:

• Patients with localized recurrence should undergo a thorough evaluation for metastatic disease, including a careful history and physical examination, bone scan, and computed tomography (CT) of the chest and abdomen; clinically unsuspected metastases are not uncommon; the tumor should be resected with an attempt to establish adequate tumor-free margins, whenever feasible

• RT should also be administered to the chest wall and regional lymphatics, although this may be problematic for those who have previously undergone chest wall irradiation in the adjuvant setting

• Systemic therapy should also be considered in order to decrease the likelihood of subsequent recurrence

Oligometastatic disease

See the list below:

• Surgery may be able to achieve prolonged disease control in selected patients with oligometastatic disease, especially those with solitary lung metastases.

• Patients with single cerebral metastases may benefit from surgical resection, even if there are other sites of systemic metastases.

• Resection of bone metastases is generally reserved for patients with, or at high risk for, pathologic fracture and is generally followed by local irradiation.

• Resection or ablation of liver metastases may also be indicated in some cases.

Certain comorbidities may pose relative or absolute contraindications to specific therapies, including cardiac disease (anthracycline) and neuropathy (taxanes).

Adjustment of prognosis for comorbidity is more complex and is influenced by its severity, time since onset, age of the individual, and other comorbidities.

For patients with significant comorbidities characterized by organ system dysfunction (eg, congestive heart failure, chronic obstructive pulmonary disease, cirrhosis, or chronic kidney disease), the prognosis for the comorbidity must be considered in the context of the cancer; the Charlson index is commonly used for this purpose.[60]