• May be considered in patients with operable disease if patient opts for breast-conserving surgery but is not possible due to tumor size, and those with tumor subtypes known to be responsive to preoperative systemic therapy
• Indicated for patients with locally advanced or inoperable breast cancer, including inflammatory tumors, those with N2 and N3 regional lymph node nodal disease and T4 tumors
• Not applicable in patients with extensive in situ disease with undefined disease extent, with poorly delineated extent of tumor, or with unpalpable or clinically unassessable tumors
• Neoadjuvant chemotherapy aims to eradicate or control undiscovered distant metastasis
• Neoadjuvant endocrine therapy may be considered in patients with strongly hormone receptor-positive tumors
• Neoadjuvant chemotherapy and Trastuzumab-based therapy is the recommended treatment option for patients with HER2-positive breast cancer who are candidates for neoadjuvant therapy

Preoperative Chemotherapy

• All chemotherapy administration before surgery is preferred
  
  • Modalities used in adjuvant therapy may also be used eg endocrine and targeted therapy
• Purpose is to reduce tumor size which allows complete removal of the tumor with less extensive surgery
• Can convert inoperable tumors to viably operable tumors 
• Can predict how the cancer cells respond to chemotherapeutic drugs
• Considered in women with large clinical stage IIA, IIB, and T3N1M0 tumors who meet the criteria for breast-conserving therapy except for tumor size and those who wish to undergo breast-conserving therapy
• Indications:
  
  • Tumor size >2 cm (T2, T3)
  • Cancer does not involve the surrounding skin or chest wall
  • LN enlarged but movable
• Endocrine therapy alone, ie Tamoxifen or aromatase inhibitor (for postmenopausal women; administered with ovarian suppression to premenopausal women) may be given in hormone receptor-positive disease
• Patients with HER2-positive tumors should be treated with preoperative chemotherapy incorporating Trastuzumab for at least 9 weeks

Risk Reduction for Carcinoma In Situ

Tamoxifen

• Competitively binds to cytoplasmic ER in breast, uterus, vagina, anterior pituitary and tumors containing high levels of ER
  • Competitive binding protects against development of breast cancer

• Decreases breast cancer risk in healthy premenopausal and postmenopausal women ≥35 years old
• More effective risk reduction agent for most menopausal women who want a non-surgical risk reduction therapy but has more toxic effects
• May be considered as an adjuvant therapy in DCIS patients who underwent breast conservation therapy and radiation therapy in ER-positive DCIS; benefit of Tamoxifen in ER-negative DCIS is uncertain
  • Reduces the risk of cancer recurrence on the ipsilateral breast

• Studies have shown that Tamoxifen can reduce the risk of invasive breast cancer in premenopausal and postmenopausal patients ≥35 years old with Gail Model 5-year breast cancer risk of ≥1.7% or with history of LCIS
  • Used in ER-positive tumor

• Advised to be taken for 5 years

Raloxifene

• May be considered in postmenopausal patients with history of LCIS or ≥35 years old with Gail Model 5-year breast cancer risk of ≥1.7% who have contraindications to Tamoxifen therapy 
• Long-term use was shown to be less effective but a safer risk reduction agent compared to Tamoxifen in postmenopausal women, in pregnant women or those planning a pregnancy

Aromatase Inhibitors

• Eg Anastrozole, Exemestrane
• Alternative to Tamoxifen in postmenopausal women with DCIS
  • May be of advantage in postmenopausal patients <60 years old or with thromboembolism concerns
• May be considered in postmenopausal patients with history of LCIS or ≥35 years old with Gail Model 5-year breast cancer risk of ≥1.7% who have contraindications to Tamoxifen or Raloxifene therapy

Chemotherapeutic Agents for Invasive Breast Cancer

• Several combination treatment regimens are used for adjuvant chemotherapy
  • Usually includes 4-8 cycles of taxane- and/or anthracycline-based regimen
• Chemotherapy response depends on ER status
• Platinum compounds may be given to BRCA1 patients; cells deficient of BRCA1 are hypersensitive to platinum compounds
• Complete preoperative chemotherapy after surgery if not completed
• Preferred time for initiation of adjuvant systemic therapy is within 3-6 weeks after surgery
• May substitute Paclitaxel or Docetaxel with albumin-bound Paclitaxel if deemed medically necessary (eg hypersensitivity reactions)

Trastuzumab

• Indicated for patients who are HER2 positive with (nonresponsive, incompletely or highly) endocrine-responsive tumors and low, intermediate or high-risk categories to decrease disease recurrence
  • Indicated for patients with early breast cancer who are HER2 positive, given after surgery, adjuvant or neoadjuvant chemotherapy, and radiotherapy (if applicable)

• Can help slow cancer growth and may also stimulate the immune system to more effectively fight the cells
  • Reduces risk of recurrence by half and improves survival

• Given to both premenopausal and postmenopausal patients
• May be given concurrently with a taxane following anthracycline or after completion of all chemotherapy
• One year is the accepted standard treatment duration
• Contraindicated in patients with low left ventricular ejection fraction (<50%)
• The antibody-linked Trastuzumab agent, Ado-trastuzumab or Trastuzumab emtansine, is used instead of Trastuzumab if with residual disease after preoperative therapy
• Subcutaneous Trastuzumab plus Hyaluronidase-oysk may be used in place of Trastuzumab

Trastuzumab Combinations (HER2-Positive Disease)

Preferred Adjuvant Regimens:

• Doxorubicin, Cyclophosphamide (AC) followed by Paclitaxel (T) plus Trastuzumab with or without Pertuzumab
• Docetaxel, Carboplatin, Trastuzumab (TCH) with or without Pertuzumab
• Paclitaxel plus Trastuzumab
  • May be considered for HER2-positive patients with low-risk T1N0M0 but with comorbidities not eligible for other adjuvant regimens
• Ado-trastuzumab emtansine

Conditional Regimens:

• Docetaxel plus Cyclophosphamide plus Trastuzumab

Other Adjuvant Regimens:

• Doxorubicin, Cyclophosphamide (AC) followed by Docetaxel plus Trastuzumab with or without Pertuzumab

Non-Trastuzumab Combinations (HER2-Negative Disease)

Preferred Adjuvant Regimens:

• Dose-dense Doxorubicin, Cyclophosphamide (AC) followed by Paclitaxel (T) every 2 weeks
• Dose-dense Doxorubicin, Cyclophosphamide (AC) followed by weekly Paclitaxel
• Docetaxel, Cyclophosphamide (TC)
• Capecitabine: For triple-negative breast cancer with residual disease after surgery and taxane-/alkylator-/anthracycline-based chemotherapy

Conditional Regimens:

• Cyclophosphamide, Methotrexate, Fluorouracil (CMF) 
• Dose-dense Doxorubicin, Cyclophosphamide (AC)
• Doxorubicin, Cyclophosphamide (AC) every 3 weeks
• Doxorubicin, Cyclophosphamide (AC) followed by weekly Paclitaxel

Other Recommended Regimens:

• Doxorubicin, Cyclophosphamide (AC) followed by Docetaxel every 3 weeks
• Epirubicin, Cyclophosphamide (EC)
• Docetaxel, Doxorubicin, Cyclophosphamide (TAC)

Other Treatment Strategies

• Extended adjuvant Neratinib should be considered in HR-positive, HER2-positive patients after treatment with Trastuzumab-containing regimen if at high-risk for disease recurrence

• Offered to patients with detectable expression of HR (>1% invasive cancer cells)
• Minimum duration of therapy is 5 years but recent data suggest that extending therapy for an additional 5 years reduces risk recurrence and improves disease-free survival
  • Discussion should be made with the patient regarding the benefits and risks of extended therapy
• Sequential administration of hormone therapy after chemotherapy is recommended for patients w/ high-risk features (eg lymph node metastasis, unknown recurrence score, intermediate to high recurrence score)

Recommended Adjuvant Endocrine Therapy for Premenopausal Women

• Any of the following:
  • Tamoxifen for 5 years with or without ovarian suppression or ablation or
  • Aromatase inhibitor with ovarian suppression or ablation for 5 years
• If patient becomes amenorrheic while on the 5-year Tamoxifen therapy, assessment of FSH, LH & estradiol levels should be done to confirm menopause
  • Consider continuing aromatase or Tamoxifen therapy for another 5 years once menopause has been confirmed
• Continuation of Tamoxifen therapy for up to 10 years should be considered for patients who remain premenopausal 5 years after initiation of adjuvant endocrine therapy
• Tamoxifen therapy is also recommended for men with breast cancer, and may use a GnRH analog with aromatase inhibitor if Tamoxifen use is contraindicated

Recommended Adjuvant Endocrine Therapy for Postmenopausal Women

• Any of the following:
  • Aromatase inhibitor for 5 years or
  • Aromatase inhibitor for 2-3 years followed by Tamoxifen to complete the 5-year treatment duration
  • Tamoxifen for 2-3 years followed by 1 of the following:
    • Aromatase inhibitor to complete the 5-year treatment duration or
    • Aromatase inhibitor for 5 years or
  • Tamoxifen for 4.5-6 years followed by aromatase inhibitor for 5 years or Tamoxifen therapy for additional 5 years to complete the 10-year duration
  • Tamoxifen monotherapy of 5-10 years should only be considered in patients with contraindications to or opposed to aromatase inhibitor therapy

Aromatase Inhibitors

• Adjuvant treatment in postmenopausal patients with ER-positive, stages I and II (tumor size <5 cm) invasive carcinoma
• Based on randomized controlled trials, relative to Tamoxifen, aromatase inhibitors improve clinical outcomes in patients with early ER-positive invasive breast cancer; however, treatment was associated with increased drug costs and slight decrease in follow-up costs compared to Tamoxifen
• Have the same anti-tumor efficacy and toxicity profiles
• Anastrozole is recommended for primary adjuvant therapy
• Exemestane is used as adjuvant therapy following 2-3 years of adjuvant Tamoxifen therapy
• Letrozole is recommended for primary & extended adjuvant therapy following standard Tamoxifen therapy

Tamoxifen

• First-line adjuvant endocrine therapy in both pre- & post-menopausal breast cancer patients

• Consider a taxane- or anthracycline-based regimen
  • Sequential monotherapy rather than concomitant use is recommended
  • Considered as 1st-line agents for patients with HER2-negative metastatic breast cancer who have not yet been on these regimens as adjuvant therapy and for whom treatment with chemotherapy is appropriate
  • If taxane-naive and with history of resistance to anthracycline or with anthracycline maximum cumulative dose or toxicity but is being considered for further chemotherapy, single-agent taxane-based therapy is preferred
• Monotherapy with Capecitabine, Vinorelbine or Eribulin may be considered in patients previously given a taxane- or anthracycline-based therapy without indications for combination regimens

• No evidence states that combination regimens are superior to sequential single agents
• HER2-directed therapy, either as a single agent, combined with chemotherapy or with endocrine therapy, should be proposed early to patients with HER2-positive metastatic breast cancer
  • If without contraindications, further anti-HER2 therapy should be considered in patients with HER2-positive metastatic breast cancer who relapsed following adjuvant or any line metastatic anti-HER2 treatment

HER2-Negative Disease

• Combination regimen composed of sequential single-agent regimens may be used for patients w/ high tumorburden, rapidly progressive disease, & visceral crisis

Preferred Single Agent Regimens

• Anthracyclines: Doxorubicin, liposomal Doxorubicin
• Anti-metabolites: Capecitabine, Gemcitabine
• Microtubule inhibitors: Vinorelbine, Eribulin
• Taxanes: Paclitaxel
• PARP inhibitor: Olaparib, Talazoparib
  • Treatment option for HER2-negative, germline BRCA 1/2-mutation positive patients
• Platinum agents: Carboplatin, Cisplatin
  • Treatment option for triple-negative, germline BRCA1/2-mutation positive patients
• Atezolizumab plus albumin-bound Paclitaxel
  • Treatment option for patients with PD-L1-positive triple-negative breast cancer

Other Recommended Regimens

• Cyclophosphamide, Docetaxel, albumin-bound Paclitaxel, Epirubicin, Ixabepilone

Conditional Combination Regimens:

• Doxorubicin, Cyclophosphamide (AC)
• Epirubicin, Cyclophosphamide (EC)
• Cyclophosphamide, Methotrexate, Fluorouracil (CMF)
• Docetaxel and Capecitabine
• Gemcitabine and Paclitaxel (GT)
• Gemcitabine and Carboplatin
• Paclitaxel and Bevacizumab

HER2-Positive Disease

• May substitute Trastuzumab with Trastuzumab plus Hyaluronidase-oysk
• Combination of Trastuzumab and Pertuzumab with or without cytotoxic therapy may be considered in HER2-positive patients with recurrent or metastatic disease if without previous history of Pertuzumab treatment
• Combination of Lapatinib and Capecitabine may be used in patients with HER2-positive tumors who are refractory to therapy with anthracycline, taxane and Trastuzumab
  • Study has shown that the combination was associated with 51% risk reduction of cancer progression

Preferred Regimens

• Pertuzumab plus Trastuzumab plus Docetaxel
• Pertuzumab plus Trastuzumab plus Paclitaxel

Other Recommended Regimens

• Ado-trastuzumab emtansine (T-DM1)
• Lapatinib plus Capecitabine
• Trastuzumab plus Capecitabine
• Trastuzumab plus Docetaxel
• Trastuzumab plus Lapatinib (without cytotoxic therapy)
• Trastuzumab plus Paclitaxel with or without Carboplatin
• Trastuzumab plus Vinorelbine
• Trastuzumab plus other agents

Systemic Therapy for Recurrent or Metastatic Disease

HER2-Negative Postmenopausal Patients

Preferred Regimens

• Aromatase inhibitor plus CDK4/6 inhibitor (Abemaciclib, Palbociclib, Ribociclib)
• Estrogen receptor down-regulator (eg Fulvestrant)
• Exemestane plus Everolimus
• Fulvestrant plus Alpelisib (for PIK3CA-mutated tumors)
• Fulvestrant plus CDK4/6 inhibitor (Abemaciclib, Palbociclib, Ribociclib)
• Fulvestrant plus Everolimus
• Non-steroidal aromatase inhibitors (eg Anastrozole, Letrozole)
• Serum estrogen receptor modulators (eg Tamoxifen, Toremifene)
• Steroidal aromatase inactivator (eg Exemestane)
• Tamoxifen plus Everolimus

Conditional Regimens

• Abemaciclib
• Ethinyl estradiol
• Fluoxymesterone
• Megestrol acetate 
• Ribociclib plus Tamoxifen

HER2-Positive Postmenopausal Patients

• Aromatase inhibitor with or without Trastuzumab
• Aromatase inhibitor with or without Lapatinib
• Aromatase inhibitor with or without Lapatinib plus Trastuzumab
• Fulvestrant with or without Trastuzumab
• Tamoxifen with or without Trastuzumab

HER2-Targeted Therapy

• Treatment option for ER/PR-positive, HER2-positive patients, should be offered once diagnosis is confirmed
• Includes any of the following:
  • Pertuzumab plus Trastuzumab plus taxane (preferred regimen)
  • Ado-Trastuzumab emtansine (T-DM1)
  • Trastuzumab plus chemotherapy

Aromatase Inhibitors

• Eg Anastrozole, Letrozole 
• Used in postmenopausal patients
• Preferred 1st-line therapy for recurrent disease in postmenopausal women who have received previous antiestrogen therapy and are within 1 year of antiestrogen exposure
• Used in postmenopausal patients with ER- and/or PR-positive, HER2-negative or positive recurrent or stage IV breast cancer with no prior endocrine therapy within 1 year 

Endocrine Therapy plus Ovarian Ablation or Suppression or Selective ER Modulators

• Tamoxifen is a standard
  • Monotherapy with Tamoxifen may be considered in HER2-negative premenopausal women who declines ovarian ablation/suppression
• Used in premenopausal patients with ER- and/or PR-positive, HER2-negative or positive recurrent or stage IV breast cancer with or without prior endocrine therapy within 1 year

CDK4/6 Inhibitors

• Eg Abemaciclib, Palbociclib, Ribociclib
• Highly selective inhibitors of CDK 4/6 kinase activity which are used to treat hormone receptor-positive, HER2-negative advanced or metastatic breast cancer
• Combination therapy of any CDK4/6 inhibitor with an aromatase inhibitor or Fulvestrant is a preferred 1st-line regimen option for hormone-receptor positive, HER2-negative postmenopausal patients or premenopausal patients receiving ovarian suppression or ablation with an LHRH agonist
• Abemaciclib or Palbociclib combined with Fulvestrant is among the preferred regimens for hormone receptor-positive, HER2-negative postmenopausal breast cancer patients
• Ribociclib with Tamoxifen may be considered as 1st-line treatment option, together with ovarian suppression, inpatients with hormone-receptor positive, HER2-negative metastatic breast cancer
• Abemaciclib may be considered in the presence of disease progression despite endocrine therapy and chemotherapy for metastatic disease

Mammalian Target of Rapamycin (mTOR) Pathway Inhibitor

• Inhibits protein in cells that promotes growth and division
• Eg Everolimus
  • Used in addition to an aromatase inhibitor, Exemestane, Fulvestrant, or Tamoxifen in postmenopausal women with hormone receptor-positive, HER2-negative advanced breast cancer that had progressed or recurred during treatment with a non-steroidal aromatase inhibitor
  • May also stop angiogenesis which can help limit tumor growth

Monoclonal Antibody Therapy
Bevacizumab

• May be used to treat metastatic breast cancer which is commonly used in combination with Paclitaxel
• Prevents angiogenesis

Pertuzumab

• A human epidermal growth factor receptor (HER) dimerisation inhibitor preventing HER2 heterodimerisation with other HER receptors thereby inhibiting HER signalling pathway activation
• Used in combination with Trastuzumab, a taxane, chemotherapeutic agents & HER2-targeted therapy in the treatment of HER2-positive premenopausal or postmenopausal patients with recurrent or metastatic disease, regardless if with history of endocrine therapy in the past 12 months
  • Also used for the treatment of locally advanced, inflammatory or early stage HER2-positive breast cancer

• LVEF assessment should be done at baseline and during treatment; discontinue if with confirmed clinically significant decline in LV function

Trastuzumab

• Indicated for high-risk, HER2-positive tumor
  • Added in preoperative chemotherapy regimens in patients with HER2-positive tumors

• May be used to treat metastatic breast cancer, with or without chemotherapy
  • May be given as monotherapy to patients with HER2-overexpressing tumors who have received at least 2 regimens of chemotherapy for metastatic disease

• May be used as adjuvant therapy along with chemotherapy in cancer recurrence risk reduction and as neoadjuvant therapy with chemotherapy to reduce the tumor size prior to surgical operation
• Combination with an anthracycline is related to significant cardiac toxicity, except as part of the neoadjuvant Trastuzumab with Paclitaxel followed by CEF regimen
• Ado-trastuzumab/Trastuzumab emtansine/T-DM1 is preferred over Trastuzumab for patients with disease progression after Trastuzumab-based treatment
• Subcutaneous Trastuzumab plus Hyaluronidase-oysk may be used in place of Trastuzumab

Selective ER Down-Regulator

• Eg Fulvestrant
• Recommended regimen for postmenopausal, HER2-negative patients with recurrent or metastatic breast cancer when given in combination with Palbociclib, Abemaciclib, or Everolimus
• May also be considered in postmenopausal, HER2-positive patients with recurrent or metastatic breast cancer
  • Given with or without Trastuzumab

Selective ER Modulators

• Eg Tamoxifen, Toremifene
• Preferred regimen for postmenopausal, HER2-negative patients with recurrent or metastatic breast cancer
• Tamoxifen with or without Trastuzumab is an alternative option for postmenopausal, HER2-positive patients with recurrent or metastatic disease

Tyrosine Kinase Inhibitors

• Eg Lapatinib
• Combined with an aromatose inhibitor, Capecitabine, or Trastuzumab as a treatment option for HER2-positive patients with recurrent or metastatic disease
  • Combination with Trastuzumab may be considered in patients with disease progression after Trastuzumab-based therapy

Other Agents

Bisphosphonates and Denosumab

• Given in addition to endocrine therapy or chemotherapy if bone metastasis is present
• Ibandronic acid, Pamidronate or Zoledronic acid (with calcium citrate and vit D)
  • Help strengthen bones and decrease the risk of fractures and bone pains

• Zoledronic acid may be more effective than Pamidronic acid in lytic breast metastasis
• A randomized trial had shown Denosumab to have slightly better tolerability and efficacy when compared to Zoledronic acid