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 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 pre-operative 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 especially in ER-positive DCIS; benefit of Tamoxifen in ER-negative DCIS is uncertain
  • Reduces the risk of cancer recurrence on the ipsilateral breast

• May be considered as risk reduction therapy in DCIS patients treated with mastectomy
  • Reduces the development of contralateral 2nd primary breast carcinoma

• Studies have shown that Tamoxifen can reduce the risk of invasive breast cancer in premenopausal and postmenopausal patients
  • Used in ER-positive tumor
  • Aromatase inhibitor may be of advantage in postmenopausal patients <60 year old or with thromboembolism problems

• Advised to be taken for 5 years

Raloxifene

• Long-term use was shown to be less effective but a safer risk reduction agent compared to Tamoxifen in postmenopausal women

Surgery

• Preventive bilateral mastectomy may be an alternative for patients at high risk of developing invasive breast cancer

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

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%)

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 Paclitaxel every week
• Docetaxel, Cyclophosphamide (TC)

Conditional Regimens:

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

Other Recommended Regimens:

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

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

Conditional Regimens:

• Docetaxel plus Cyclophosphamide plus Trastuzumab

Other Adjuvant Regimens:

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

• 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
  • Aromatase inhibitor with ovarian suppression for 5 years
• If patient becomes amenorrheic while on the 5-year Tamoxifen therapy, assessment of FSH, LH & estradiol levels should be done to assure the occurrence of 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

Recommended Adjuvant Endocrine Therapy for Postmenopausal Women

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

• 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

• 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
  • Treatment option for HER2-negative, germline BRCA 1/2-mutation positive patient

Other Recommended Regimens

• Cyclophosphamide, Cisplatin, Carboplatin, 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
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

• Abemaciclib plus aromatase inhibitor
• Abemaciclib plus Fulvestrant
• Estrogen receptor down-regulator (eg Fulvestrant)
• Exemestane plus Everolimus
• Fulvestrant plus Everolimus
• Non-steroidal aromatase inhibitors (eg Anastrozole, Letrozole)
• Palbociclib plus aromatase inhibitor
• Palbociclib plus Fulvestrant
• Ribociclib plus aromatase inhibitor
• Ribociclib plus Tamoxifen
• Serum estrogen receptor modulators (eg Tamoxifen, Toremifene)
• Steroidal aromatase inactivator (eg Exemestane)
• Tamoxifen plus Everolimus

Conditional Regimens

• Abemaciclib
• Ethinyl estradiol
• Fluoxymestrone
• Megestrol acetate 

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
• Includes any of the following:
  • Pertuzumab plus Trastuzumab plus taxane (preferred regimen)
• Ado-Trastuzumab emtansine (T-DM1)
  • Trastuzumab plus chemotherapy

Aromatase Inhibitors

• 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
• 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
• Abemaciclib, Palbociclib, & Ribociclib are highly selective inhibitors of CDK 4/6 kinase activity which are usedto treat hormone receptor-positive, HER2-negative advanced or metastatic breast cancer
• Palbociclib is given with Letrozole in postmenopausal women as initial endocrine-based therapy or with Fulvestrant in women with disease progression after endocrine therapy
• Combination therapy of any CDK4/6 inhibitor with an aromatase inhibitor is a preferred regimen for HER2-negative postmenopausal breast cancer patients
• Ribociclib with Tamoxifen, & Abemaciclib or Palbociclib combined with Fulvestrant are also among the preferred regimens for hormone receptor-positive, HER2-negative postmenopausal breast cancer patients

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 pre-op 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

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

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

Mammalian Target of Rapamycin (mTOR) Pathway Inhibitor

• Inhibits protein in cells that promotes growth and division
• Eg Everolimus
  • Used in addition to 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
  •  Can also be combined with Tamoxifen
  • May also stop angiogenesis which can help limit tumor growth