Breast Cancer Treatment Protocols 

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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 that is either self-detected or detected by a health care provider. ^{[1, 2]}

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]

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

Treatment for these stages of breast cancer include the following:

Surgical options include the following:

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, as follows:

Four or more positive axillary nodes – Whole-breast RT, with or without boost to the tumor bed; RT to the infraclavicular and supraclavicular areas should also be considered

One to three positive axillary nodes – Whole-breast RT, with or without boost to the tumor bed; RT to the infraclavicular and supraclavicular areas should also be considered, as should RT to internal mammary nodes

Negative axillary nodes – RT to the whole breast, with or without boost to the tumor bed; partial breast irradiation (PBI) may be considered in selected patients

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:

Four or more positive axillary nodes – Postchemotherapy RT to the chest wall plus the infraclavicular and supraclavicular areas; consider RT to internal mammary nodes

One to three positive axillary nodes – Consider postchemotherapy RT to the chest wall, with or without infraclavicular and supraclavicular nodes; consider RT to internal mammary nodes

Negative axillary nodes and tumor >5 cm or positive margins – Consider RT to the chest wall, with or without infraclavicular and supraclavicular nodes; consider RT to internal mammary nodes

Negative axillary nodes, tumor ≤5 cm, and margins <1 mm – Postchemotherapy RT to the chest wall is recommended

Negative axillary nodes, tumor ≤5 cm, and margins ≥1 mm – No RT is needed

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

Preoperative chemotherapy should be considered in these patients if they have any of the following:

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.

Chemotherapy 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 plus  cyclophosphamide 600 mg/m² every 2 wk 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-negative or progesterone receptor (PR)-negative disease) ^[8] or

Dose-dense ACP: Doxorubicin 60 mg/m² IV plus  cyclophosphamide 600 mg/m² every 2 wk for four cycles; followed by paclitaxel 175 mg/m²every 2 wk with colony-stimulating factor (CSF) support ^[9]

AC: Doxorubicin 60 mg/m² IV plus  cyclophosphamide 600 mg/m² IV on day 1 every 3 wk for four cycles (comparable to CMF [cyclophosphamide, methotrexate, fluorouracil]) ^[10] 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

 For HER2-positive tumors, the following neoadjuvant regimen is administered every 3 wk for three to six cycles ^[11] :

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 ^[12]

Overlapping trastuzumab therapy with taxane 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

Neratinib is indicated for extended (ie, 1 year) adjuvant treatment of early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy ^[13]

Diarrhea is a dose-limiting adverse effect of neratinib

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 plus  cyclophosphamide 600 mg/m² every 2wk for four cycles, followed by paclitaxel 175 mg/m² every 2 wk with CSF support ^[8] or

AC: Doxorubicin 60 mg/m² IV plus  cyclophosphamide 600 mg/m² IV on day 1 every 3wk for four cycles (comparable to CMF) ^[10] 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

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

AC-paclitaxel plus trastuzumab: Doxorubicin 60 mg/m² IV plus  cyclophosphamide 600 mg/m² IV on day 1 every 3 wk, followed by paclitaxel 80 mg/m² IV weekly for 12 cycles or  175 mg/m² IV every 3 wk for four cycles given concurrently with trastuzumab 4 mg/kg for the first dose and then 2 mg/kg weekly with each paclitaxel dose; followed by trastuzumab 6 mg/kg every 3 wk for 14 doses, for a 1-y total duration of trastuzumab therapy ^[14] or

AC-docetaxel plus trastuzumab: Doxorubicin 60 mg/m² IV plus  cyclophosphamide 600 mg/m² IV on day 1 every 3 wk for four cycles, followed by docetaxel 100 mg/m² every 3 wk for four cycles given 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] or

TCH: Docetaxel 75 mg/m² plus carboplatin AUC 6 IV on day 1 every 3 wk for six cycles plus  trastuzumab 4 mg/kg during week 1 and then 2 mg/kg weekly for 17 wk; followed by trastuzumab 6 mg/kg every 3 wk to complete 1-y total duration of trastuzumab therapy; this regimen may be more appropriate for patients with contraindications to anthracycline therapy ^[15] (see the Carboplatin AUC Dose Calculation [Calvert formula] calculator)

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

First-generation regimens

First-generation regimens are considered less effective than second- or third-generation regimens but do play a role in selected situations; CMF represents a reasonable alternative for patients who have contraindications to anthracycline (cardiac disease) and/or taxane therapy; AC would be a reasonable consideration for patients with contraindications to taxane therapy (eg, neuropathy). The regimens are as follows:

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 ^[16] or

AC: Doxorubicin (Adriamycin) 60 mg/m² IV plus  cyclophosphamide 600 mg/m² IV on day 1 every 3 wk for four cycles (comparable to CMF) ^[10] or

CMF (PO): Cyclophosphamide 100 mg/m² 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 for six cycles or

CMF (IV): Cyclophosphamide 600 mg/m² IV plus  methotrexate 40 mg/m² IV plus  5-FU 600 mg/m² IV on day 1 every 3 wk for eight cycles

Second-generation regimens

Second-generation regimens have been shown to be more effective than other regimens with which they were compared, which in some studies included first-generation regimens such as CMF. Some of these regimens may be appropriate for patients who desire less prolonged regimens. There is geographic variation in the use of these regimens: DC and AC-P are more commonly used in the United States, and epirubicin-containing regimens are more commonly used in Europe. The regimens are as follows:

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 (more effective than CMF) ^[17] or

CEF: Cyclophosphamide 75 mg/m² PO on days 1-14 plus epirubicin 60 mg/m² on days 1 and 8 plus  5-FU 500 mg/m² IV on days 1 and 8 every 4 wk for six cycles (more toxic than other alternatives in this category; with cotrimoxazole support) or

Dose-dense AC-P: Doxorubicin 60 mg/m² IV on day 1 plus  cyclophosphamide 600 mg/m² IV on day 1 every 2 wk for four cycles, followed by paclitaxel 175 mg/m² by 3-h IV infusion on day 1 every 2 wk for four cycles with colony-stimulating factor (CSF) support (more effective than the 3-wk schedule in ER/PR-negative disease) ^[8] 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 (more effective than AC) ^[18]

Third-generation regimens

Third-generation regimens have been shown to be more effective than some second-generation regimens and include both taxanes and anthracyclines. The regimens are as follows:

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) ^[9] or

TAC: Docetaxel 75 mg/m² IV plus  doxorubicin 500 mg/m² IV plus  cyclophosphamide 500 mg/m² IV on day 1 every 3 wk for six cycles (more effective than FAC; CSF support recommended) ^{[19, 20]} or

FEC-docetaxel: 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, followed by docetaxel 100 mg/m² IV every 3 wk for three cycles (more effective than six cycles of FEC) ^[21] or

FEC-paclitaxel: 5-FU 600 mg/m² IV plus  epirubicin 90 mg/m² IV plus  cyclophosphamide 600 mg/m² IV on day 1 every 3 wk for four cycles, followed by 3 wk of no treatment; followed by paclitaxel 100 mg/m² IV weekly for eight cycles (more effective than six cycles of FEC) ^[22]

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:

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 ^[23]

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 ^{[24, 25, 26, 27]}

Nonsteroidal AIs (anastrozole, letrozole) and steroidal AIs (exemestane) exhibit comparable efficacy and side effects

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

Regimens are as follows:

Tamoxifen 20 mg PO daily for 5 y ^[28] 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 ^[29]

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 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 or letrozole 2.5 mg PO daily or exemestane 25 mg PO daily

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 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) ^[8] 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) ^[10] 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

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

AC-paclitaxel plus trastuzumab

Dose-dense AC–paclitaxel plus trastuzumab

AC-docetaxel plus trastuzumab

AC-paclitaxel plus trastuzumab and pertuzumab

AC-docetaxel plus trastuzumab and pertuzumab

TCH plus pertuzumab

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

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

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] :

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, 30, 31]}

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

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 does not necessitate 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) or estradiol (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

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 relapse or have progressive disease on tamoxifen may be switched to an AI

Patients who 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 ^{[32, 33, 34]}

Optionally, consider the androgenic agent fluoxymesterone 10 mg PO BID ^[35] or  the progestational agent megestrol acetate 40 mg PO QID ^[36] or  estradiol 2 mg PO BID ^[37]

Systemic chemotherapy should be reserved for patients with hormone-insensitive disease or for patients with symptomatic hormone-sensitive disease who have failed all hormone therapy options 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

Regimens are as follows:

Regimens are as follows:

Regimens are as follows:

Regimens are as follows:

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 (Taxotere) 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

First-line cytotoxic therapy should always be given in combination with trastuzumab. ^{[39, 40]} 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.

Regimens are as follows:

Regimens are as follows:

PCH: Carboplatin AUC 6 IV on day 1 plus  paclitaxel 175 mg/m² IV on day 1 every 3 wk or

Weekly TCH: 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

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) ^[41]

Regimens are as follows:

Capecitabine 1000 mg/m² PO BID on days 1-14 plus lapatinib 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 ^{[38, 42]} 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 ^[43]

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

Bevacizumab seems to be effective only when used in combination with chemotherapy and as first-line therapy and is most effective when used with weekly paclitaxel. ^{[44, 45, 46]} It is not effective when used beyond second-line therapy with capecitabine ^[47]

Olaparib inhibits poly (ADP-ribose) polymerase (PARP) enzymes. It is the first PARP inhibitor approved for breast cancer and the first time a phase 3 randomized trial in breast cancer has shown PARP inhibitors are superior to single-agent chemotherapy regarding PFS for patients with HER2-negative metastatic breast cancer who have a BRCA mutation. ^[71] (REF) The regimen is as follows:

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 hormone receptor (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). ^[48]

In postmenopausal women with ER-positive, HER2-negative advanced breast cancer, initial endocrine-based therapy for metastatic disease may include the following ^[49] :

Palbociclib was also approved for hormone receptor (HR)–positive, HER2-negative advanced breast cancer in combination with fulvestrant in women (regardless of menopausal status) who have disease progression following endocrine therapy. ^{[50, 51]} The regimen is as follows:

Another option in postmenopausal women with HR+/HER- advanced or metastatic breast cancer is the following ^[52] :

An option for women with HR+/HER2- advanced or metastatic breast cancer with disease progression following endocrine therapy is as follows ^{[53, 54]} :

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. ^{[55, 42]}

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 ^[56] ; 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

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

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

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.

Screening and improved adjuvant therapy have led to reduced breast cancer mortality in the United States, highlighting the importance of appropriate detection and management of the disease. ^[57]

Targeted ultrasonography and contrast-enhanced bilateral breast magnetic resonance imaging (MRI) may be indicated in selected cases. ^[58]

MRI should be performed only if the appropriate resources and expertise are available and if the capability of performing MRI may be useful for evaluating the following patients:

Patients who are being considered for breast-conserving surgery but who may not be adequately imaged by other modalities (eg, mammographically dense breasts)

Patients who are at high risk for having extensive and/or occult ipsilateral and/or contralateral disease (eg, multicentric disease, BRCA mutation carrier)

Patients who have had neoadjuvant chemotherapy

Patients in whom a primary tumor cannot be detected by other modalities (eg, patients presenting with axillary node metastases without a breast primary)

All patients should undergo testing of the primary tumor for ER, PR, and HER2/neu expression by immunohistochemistry (IHC); testing should be done again if there is disease recurrence because of discordance biomarker testing between the primary tumor and recurrent disease. ^[59]  (This shouldnt be in screening section)

A tumor is defined as ER positive and/or PR positive if ≥1% of tumor cells exhibit staining; a positive finding predicts benefit from endocrine therapy. ^[60]

A tumor is defined as exhibiting HER2/neu overexpression if ≥ 30% of tumor cells exhibit strong staining on IHC or if gene amplification is identified by fluorescent in situ hybridization (FISH); both findings predict benefit from HER2/neu-directed therapy. ^[61]

Some prognostic multiparameter gene expression assays have been shown to provide prognostic information, including the Mammaprint and Oncotype DX assays; Oncotype DX assays have also been shown to predict benefit from adjuvant chemotherapy in ER-positive node-negative disease and in postmenopausal women with ER-positive, axillary node-positive disease. ^[62] These markers may be used to assist in making more informed treatment decisions regarding chemotherapy, particularly in low-risk patients with ER-positive, HER2/neu-negative disease. ^{[63, 64]}

Considerations are as follows:

Imaging may be indicated if there are signs, symptoms, or laboratory abnormalities suggesting distant metastases

Bone scan and CT of the chest/abdomen/pelvis are recommended for patients with clinical or pathologic stage IIIA-C disease

Functional imaging with fluorodeoxyglucose (¹⁸ F) positron emission tomography (FDG-PET) may offer improved diagnostic accuracy over CT alone, especially for detecting recurrent disease, ^[65] but FDG-PET is not sensitive enough to replace SNB. ^{[66, 67]}

Considerations are as follows:

A complete blood count and liver function tests (including alkaline phosphatase) are indicated in patients with localized and advanced disease

For monitoring patients with metastatic disease during active therapy, CA 27.29 or CA 15-3 can be used in conjunction with diagnostic imaging, history, and physical examination ^[64]

Circulating tumor cells (CTCs) may be measured with an approved assay in metastatic breast cancer and have been shown to provide prognostic information, ^[68] although there is currently no evidence that such information is useful in guiding therapy so as to yield improved outcomes ^[64]

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 renal insufficiency), the prognosis for the comorbidity must be considered in the context of the cancer; the Charlson index is commonly used for this purpose. ^[69]

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Joseph A Sparano, MD Professor, Department of Medicine (Oncology), Professor, Department of Obstetrics and Gynecology and Women’s Health, Albert Einstein College of Medicine; Associate Chairman for Clinical Research, Department of Oncology, Montefiore Medical Center; Associate Director for Clinical Research, Albert Einstein Cancer Center

Joseph A Sparano, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology

Disclosure: Nothing to disclose.

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

Christopher D Braden, DO Hematologist/Oncologist, Chancellor Center for Oncology at Deaconess Hospital; Medical Director, Deaconess Hospital Outpatient Infusion Centers; Chairman, Deaconess Hospital Cancer Committee

Christopher D Braden, DO is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology

Disclosure: Nothing to disclose.

John V Kiluk, MD, FACS Associate Professor, Department of Oncologic Sciences, Department of Surgery (Joint Appointment), University of South Florida Morsani College of Medicine; Clinical Director, Breast Surgical Oncology, Associate Member, Comprehensive Breast Program, Department of Women’s Oncology, H Lee Moffitt Cancer Center and Research Institute

John V Kiluk, MD, FACS is a member of the following medical societies: American College of Surgeons, American Society of Breast Surgeons, Moretz Surgical Society, Society of Surgical Oncology, Southeastern Surgical Congress

Disclosure: Nothing to disclose.

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