Breast%20cancer Treatment

• Advantages of preoperative systemic therapy include possibility of breast conservation, possibility of making inoperable tumors operable, provision of prognostic information especially in patients with triple-negative breast cancer or HER2-positive breast cancer based on treatment response, identification of patients with residual disease at higher risk of relapse to allow additional supplemental adjuvant regimens especially in patients with triple-negative breast cancer or HER2-positive breast cancer, allowing time for genetic testing to be performed, allowing time for breast reconstruction planning inpatients who opt for mastectomy and allowing time for delayed decision-making for definitive surgery
• Preferred for patients with operable locally advanced breast cancer with HER2-positive disease, triple negative breast cancer if ≥T2 or ≥N1, with large primary tumor relative to breast size in favor of breast conservation, node-positive patients likely to be highly responsive to neoadjuvant chemotherapy, or until commencement of surgical treatment 
• Indicated for patients with inoperable locally advanced breast cancer, including inflammatory tumors, those with bulky or matted N2 axillary nodes, N3 regional lymph node nodal disease and/or T4 tumors
• May be considered in patients with operable disease if patient opts for breast-conserving surgery but is not possible due to tumor size, those with tumor subtypes known to be responsive to preoperative systemic therapy, and for patients with T1N0 HER2-positive disease and triple negative breast cancer
• 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 systemic therapy with Trastuzumab + Pertuzumab-based therapy is the recommended treatment option for patients with HER2-positive breast cancer who are candidates for neoadjuvant therapy
• Recommended sequence of adjuvant therapies:
  • Endocrine therapy should be given after chemotherapy administration
  • Adjuvant Olaparib and endocrine therapy may be given at the same time
  • Chemotherapy may be followed by radiation therapy (RT), except for Capecitabine and Olaparib; Cyclophosphamide/Methotrexate/Fluorouracil (CMF) and RT may be administered at the same time or CMF may be given before RT

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 with or without Pertuzumab for at least 9 weeks

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 pre-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
• Low-dose Tamoxifen (5 mg for 3 years) may be considered in patients with undesirable symptoms on standard dose or if unwilling or unable to take the standard dose

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

• 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

• Docetaxel, Carboplatin, Trastuzumab (TCH)
• Docetaxel, Carboplatin, Trastuzumab, Pertuzumab (TCHP)
• 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: If with residual disease after preoperative therapy
• Trastuzumab with or without Pertuzumab: If Ado-trastuzumab emtansine therapy was discontinued due to toxicity or if no residual disease after preoperative therapy was seen or no preoperative therapy was given
  • 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

Conditional Regimens

• Docetaxel plus Cyclophosphamide plus Trastuzumab
• Doxorubicin, Cyclophosphamide (AC) followed by Paclitaxel (T) plus Trastuzumab with or without Pertuzumab
• Neratinib: For adjuvant therapy; to be considered in HR-positive, HER2-positive patients after Trastuzumab-containing regimen with high risk of disease recurrence
• Paclitaxel plus Trastuzumab plus Pertuzumab
• Ado-trastuzumab emtansine (TDM-1): For adjuvant therapy

Other Recommended Regimens

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

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
• Olaparib: For patients with germline BRCA1/2 mutations and
  • Triple-negative breast cancer, if with ≥pathologic T2 or ≥pathologic N1 disease after adjuvant chemotherapy, or residual disease after preoperative chemotherapy
  • ER/PR-positive, HER2-negative tumors, if with ≥4 positive lymph nodes after adjuvant chemotherapy, or residual disease after preoperative therapy and a clinical stage, pathologic stage, ER status, and tumor grade (CPS+EG) score ≥3
• Preoperative Pembrolizumab + Carboplatin + Paclitaxel, followed by preoperative Pembrolizumab + Cyclophosphamide + Doxorubicin or Epirubicin, followed by adjuvant Pembrolizumab: For high-risk triple-negative breast cancer

Conditional Regimens

• Cyclophosphamide, Methotrexate, Fluorouracil (CMF) 
• Dose-dense Doxorubicin, Cyclophosphamide (AC)
• Doxorubicin, Cyclophosphamide (AC) every 3 weeks
• Doxorubicin, Cyclophosphamide (AC) followed by weekly Paclitaxel
• Capecitabine: Maintenance therapy for triple-negative breast cancer chemotherapy after adjuvant chemotherapy

Other Recommended Regimens

• Doxorubicin, Cyclophosphamide (AC) followed by Docetaxel every 3 weeks
• Epirubicin, Cyclophosphamide (EC)
• Docetaxel, Doxorubicin, Cyclophosphamide (TAC)
• For triple-negative breast cancer: Paclitaxel + Carboplatin; Docetaxel + Carboplatin

• 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 with 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 for 5 years with ovarian suppression or ablation
    • May consider continuing aromatase inhibitor treatment for another 3-5 years
• If patient becomes amenorrheic while on the 5-year Tamoxifen therapy, assessment of FSH, LH and estradiol levels should be done to confirm menopause
  • Aromatase inhibitor therapy should be started to be given for 5 years 
  • Consider continuing Tamoxifen therapy for another 5 years to complete 10 years
• 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
    • May consider continuing treatment for another 3-5 years 
  • Aromatase inhibitor for 2-3 years followed by Tamoxifen to complete the 5-year treatment duration or
  • Tamoxifen for 2-3 years followed by 1 of the following: or
    • Aromatase inhibitor to complete the 5-year treatment duration
    • Aromatase inhibitor for 5 years
  • 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 or
  • Tamoxifen monotherapy of 5-10 years should only be considered in patients with contraindications to or opposed to aromatase inhibitor therapy

Aromatase Inhibitors

• Eg Anastrozole, Exemestane, Letrozole 
• 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 and extended adjuvant therapy following standard Tamoxifen therapy

Tamoxifen

• 1st-line adjuvant endocrine therapy in both pre- and postmenopausal 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 (neo)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
• Metronomic chemotherapy may be considered in patients with advanced breast cancer not needing immediate tumor response

HER2-Negative Disease

• Combination regimen may be used for patients with high tumor burden, rapidly progressive disease, and visceral crisis

Preferred Single-Agent Regimens

• Anthracyclines: Doxorubicin, liposomal Doxorubicin
• Anti-metabolites: Capecitabine, Gemcitabine
• Fam-trastuzumab deruxtecan-nxki: For HER2 IHC 1+ or 2+/ISH-negative patients with history of ≥1 prior line of chemotherapy for metastatic disease and, if tumor is ER/PR-positive and are refractory to endocrine therapy
• 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
• Pembrolizumab plus albumin-bound Paclitaxel, Paclitaxel or Gemcitabine and Carboplatin: Treatment option for patients with PD-L1-positive triple-negative breast cancer
• Sacituzumab govitecan-hziy: For patients with triple-negative breast cancer who received ≥2 previous therapies with ≥1 line for metastatic disease or ER/PR-positive/HER2-negative breast cancer after previous treatment including endocrine therapy, a CDK4/6 inhibitor and ≥2 lines of chemotherapy including taxane for advanced breast cancer

Other Recommended Regimens

• Cyclophosphamide, Docetaxel, albumin-bound Paclitaxel, Epirubicin, Ixabepilone (for patients with triple-negative breast cancer with history of at least 2 therapies for metastatic breast cancer)

Useful in Certain Conditions (Eg High Tumor Burden, Rapidly Progressing Disease, Visceral Crisis)

• Doxorubicin, Cyclophosphamide (AC)
• Epirubicin, Cyclophosphamide (EC)
• Carboplatin and Paclitaxel or albumin-bound Paclitaxel
• Cyclophosphamide, Methotrexate, Fluorouracil (CMF)
• Docetaxel and Capecitabine
• Gemcitabine and Paclitaxel (GT)
• Gemcitabine and Carboplatin

HER2-Positive Disease

• May substitute Trastuzumab with Trastuzumab plus Hyaluronidase-oysk injection for subcutaneous use
• 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
• Pertuzumab, Trastuzumab, and Hyaluronidase-zzxf injection for subcutaneous use may be used as substitute agents in patients with history of treatment with IV Pertuzumab + Trastuzumab

Preferred Regimens

• First-line agents: Pertuzumab plus Trastuzumab plus Docetaxel, or Pertuzumab plus Trastuzumab plus Paclitaxel
• Second-line agent: Ado-trastuzumab emtansine (T-DM1), Fam-trastuzumab deruxtecan-nxki

Other Recommended Regimens

• Regimens used as 3rd-line treatment option and beyond
• Tucatinib plus Trastuzumab plus Capecitabine: Treatment option for patients with advanced unresectable or metastatic disease, including brain metastases, with history of ≥1 line of HER2-targeted therapy
• Lapatinib plus Capecitabine: May be used in patients with HER2-positive tumors who are refractory to therapy with anthracycline, taxane and Trastuzumab
• Margetuximab-cmbk + chemotherapy (eg Capecitabine, Eribulin, Gemcitabine, Vinorelbine)
• Neratinib plus Capecitabine: May be used in patients with HER2-positive tumors who are refractory to therapy with anthracycline, taxane and Trastuzumab
• 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 [eg mutation-specific agents (please see Systemic Therapy for Recurrent Unresectable or Metastatic Disease section)]

HER2-negative Postmenopausal Patients or Premenopausal Patients Receiving Ovarian Ablation/Suppression

Preferred Regimens - 1st-line Therapy

• Aromatase inhibitor plus CDK4/6 inhibitor (eg Abemaciclib, Palbociclib, Ribociclib)
• Estrogen receptor (ER) down-regulator (eg Fulvestrant) with or without non-steroidal aromatase inhibitor (eg Anastrozole, Letrozole)
• Fulvestrant plus CDK4/6 inhibitor (eg Abemaciclib, Palbociclib, Ribociclib)

Preferred Regimens - 2nd-line and Subsequent-line Therapy

• Everolimus plus endocrine therapy (eg Exemestane, Fulvestrant, Tamoxifen)
• Fulvestrant plus Alpelisib (for PIK3CA-mutated tumors)
• Fulvestrant plus CDK4/6 inhibitor (Abemaciclib, Palbociclib, Ribociclib) if not previously used

Other Recommended Regimens - 1st- and Subsequent-line Therapy

• Selective ER down-regulator (eg Fulvestrant)
• Non-steroidal aromatase inhibitors (eg Anastrozole, Letrozole)
• Selective ER modulators (eg Tamoxifen)
• Steroidal aromatase inactivator (eg Exemestane) 

Conditional Regimens

• Abemaciclib
• Ethinyl estradiol
• Megestrol acetate 

HER2-positive Postmenopausal Patients or Premenopausal Patients Receiving Ovarian Ablation/Suppression

• 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 (eg Docetaxel, Paclitaxel) (preferred regimen)
  • Ado-trastuzumab emtansine (T-DM1)
  • Capecitabine plus Trastuzumab or Lapatinib
  • Fam-trastuzumab deruxtecan-nxki (preferred regimen)
  • Trastuzumab plus chemotherapy (eg Carboplatin, Docetaxel, Paclitaxel, Vinorelbine, Lapatinib)
  • Tucatinib with Trastuzumab and Capecitabine
  • Neratinib plus Capecitabine
  • Margetuximab-cmkb with 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 Antibodies

Bevacizumab

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

Margetuximab

• Approved for use in patients with metastatic HER2-positive breast cancer previously given ≥2 anti-HER2 regimen, with at least 1 regimen for metastatic disease

Pembrolizumab

• Approved for use in patients with any subtype of breast cancer with unresectable or metastatic, microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors with disease progression after 1st-line therapy or when no alternative therapy options are available

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 and 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

• Left ventricular ejection fraction (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

Mutation-specific Therapies

• PARP inhibitors Olaparib and Talazoparib are preferred options for patients with recurrent or metastatic breast cancer (any subtype) with BRCA1 and BRCA2 germline mutation, respectively
• Alpelisib + Fulvestrant combination therapy is recommended for patients with ER- and/or PR-positive, HER2-negative recurrent or stage IV breast cancer with PIK3CA activating mutation
• Atezolizumab + albumin-bound Paclitaxel combination therapy is recommended for ER- and/or PR-negative, HER2-negative recurrent or stage IV breast cancer with PD-L1 expression with ≥1% threshold for positivity on tumor-infiltrating immune cells
• Pembrolizumab + albumin-bound Paclitaxel, Paclitaxel or Gemcitabine and Carboplatin combination therapy are recommended for ER- and/or PR-negative, HER2-negative recurrent or stage IV breast cancer with PD-L1 expression with ≥1% threshold for positivity combined positive score of ≥10
• Pembrolizumab and Dostarlimab-gxly are indicated for patients with MSI-H/dMMR unresectable or metastatic tumors that have progressed on or following prior treatment and without satisfactory alternative treatment options 
• For patients with unresectable or metastatic tumor mutational burden-high (TMB-H) [≥10 mutations/megabase (mut/Mb)] solid tumors that have progressed following prior treatment and without satisfactory alternative treatment options, Pembrolizumab may be considered
• Tropomyosin receptor kinase (TRK) inhibitors Larotrectinib and Entrectinib are recommended agents for patients with any subtype of breast cancer with neurotrophic tropomyosin receptor kinase (NTRK) gene fusions without a known acquired resistance mutation, no satisfactory alternative treatments or with disease progression following treatment

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
• 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, Neratinib
• Combined with an aromatase inhibitor, Capecitabine, or Trastuzumab as a treatment option for HER2-positive patients with recurrent or metastatic disease
• Combination of Lapatinib and Trastuzumab or Capecitabine may be considered in patients with disease progression after Trastuzumab-based therapy
• Neratinib/Capecitabine combination is an option for patients with ≥2 lines of prior HER2-targeted treatment

Other Agents

Bisphosphonates and Denosumab

• Given in addition to endocrine therapy or chemotherapy if bone metastasis is present
• May be considered in postmenopausal women receiving adjuvant aromatase inhibitor therapy
• Ibandronic acid, Pamidronate or Zoledronic acid (with calcium citrate and vitamin D)
  • Help strengthen bones and decrease the risk of fractures and bone pains and prevent hypercalcemia of malignancy

• 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