Preoperative Systemic Therapy
- 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
Pharmacotherapy
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