Breast Cancer Management

Evaluation

Staging  

Staging determines the extent of cancer upon diagnosis. It is an important factor in the choice of treatment, and it provides information about the prognosis of the disease. Since asymptomatic metastases are rare, routine staging assessment is for local regional disease.  

Tumor, Nodes, and Metastases (TNM) System  

The TNM system was developed by the American Joint Committee on Cancer and Union Internationale Contre le Cancer. 

Reference: National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: breast cancer. Version 6.2024

Principles of Therapy

Preoperative Systemic Chemotherapy

The advantages of preoperative systemic therapy include the possibility of breast conservation, the possibility of making inoperable tumors operable, the 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 in patients who opt for mastectomy, and allowing time for delayed decision-making for definitive surgery.  

Preoperative systemic therapy is 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 the commencement of surgical treatment.  

Preoperative systemic therapy is 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. It may be considered in patients with operable disease if the 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. It is not applicable in patients with extensive in situ disease with undefined disease extent, with poorly delineated extent of the tumor, or with unpalpable or clinically unassessable tumors.   

The recommended sequence of adjuvant therapies is as follows:

• 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 radiotherapy, except for Capecitabine and Olaparib; Cyclophosphamide/Methotrexate/Fluorouracil (CMF) and radiotherapy may be administered at the same time or CMF may be given before radiotherapy

Preoperative Therapy Options

Chemotherapy

All chemotherapy administration before surgery is preferred. Modalities used in adjuvant therapy may also be used such as endocrine and targeted therapy. This aims to eradicate or control undiscovered distant metastasis. 

The purpose of preoperative chemotherapy is to reduce tumor size which allows complete removal of the tumor with less extensive surgery. It can convert inoperable tumors to viably operable tumors. It can predict how the cancer cells respond to chemotherapeutic drugs.  

It is 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. The indications of preoperative chemotherapy include a tumor size of >2 cm (T2, T3), cancer does not involve the surrounding skin or chest wall, or lymph node enlarged but movable.  

Endocrine Therapy

Endocrine therapy may be considered in patients with strongly hormone receptor-positive tumors. This effectively reduces residual disease and enables breast-conserving surgery in patients with low-rates of local-regional recurrence postop. Tamoxifen (with or without ovarian function suppression for premenopausal women) aromatase inhibitor (preferred for postmenopausal women; administered with ovarian suppression to premenopausal women) may be given in hormone receptor-positive disease. 

HER2-targeted Therapy

HER2-targeted therapy should be considered for HER2-positive patients with clinical node-positive tumors or tumors measuring ≥2 cm (cT2) at presentation. Systemic therapy with Trastuzumab plus Pertuzumab-based therapy is the recommended treatment option for patients with HER2-positive breast cancer who are candidates for neoadjuvant therapy. Patients with HER2-positive tumors should be treated with preoperative chemotherapy incorporating Trastuzumab with or without Pertuzumab for at least 9 weeks. 

Pertuzumab-containing regimen may be considered preoperatively in patients with HER2-positive early breast cancer tumors ≥cT2 or ≥cN1.  

Immunotherapy 

Breast Cancer_Management

Pharmacological therapy

Risk Reduction for Carcinoma in situ  

Tamoxifen  

Tamoxifen competitively binds cytoplasmic ER in the breast, uterus, vagina, anterior pituitary, and tumors containing high levels of ER. The competitive binding protects against the development of breast cancer.  

It decreases breast cancer risk in healthy premenopausal and postmenopausal women ≥35 years old. It is a more effective risk reduction agent for most premenopausal women who want a non-surgical risk reduction therapy but has more toxic effects. It may be considered as adjuvant therapy in ductal carcinoma in situ patients who underwent breast conservation therapy and radiotherapy in ER-positive ductal carcinoma in situ; the benefit of Tamoxifen in ER-negative ductal carcinoma in situ is uncertain. It 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 a Gail Model 5-year breast cancer risk of ≥1.7% or with a history of lobular carcinoma in situ. It is used in ER-positive tumor.  

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

Raloxifene  

Raloxifene may be considered in postmenopausal patients with a history of lobular carcinoma in situ or ≥35 years old with a Gail Model 5-year breast cancer risk of ≥1.7% who have contraindications to Tamoxifen therapy. Its long-term use was shown to be less effective but a safer risk reduction agent compared to Tamoxifen in postmenopausal women, pregnant women, or those planning a pregnancy.  

Aromatase Inhibitors  

Example drugs: Anastrozole, Exemestane  

Aromatase inhibitors are used as an alternative to Tamoxifen in postmenopausal women with ductal carcinoma in situ. It may be of advantage in postmenopausal patients <60 years old or with thromboembolism concerns.  

Aromatase inhibitors may be considered in postmenopausal patients with a history of lobular carcinoma in situ or ≥35 years old with a Gail Model 5-year breast cancer risk of ≥1.7% who have contraindications to Tamoxifen or Raloxifene therapy.  

Please see Risk Reduction for Carcinoma in situ under Surgery for further information.    

Systemic Therapy for Invasive Breast Cancer  

Several combination treatment regimens are used for adjuvant chemotherapy. It usually includes 4-12 cycles of taxane- and/or anthracycline-based regimen. Chemotherapy response depends on the ER status. Platinum compounds may be given to BRCA1 patients; cells deficient in BRCA1 are hypersensitive to platinum compounds. One may complete preoperative chemotherapy after surgery if not completed. The preferred time for initiation of adjuvant systemic therapy is within 3-6 weeks after surgery. Systemic adjuvant therapy is administered to reduce cancer recurrence risk in patients with early stage-breast cancer. Paclitaxel or Docetaxel with albumin-bound Paclitaxel may be substituted if deemed medically necessary (eg hypersensitivity reactions).  

Trastuzumab  

Trastuzumab is indicated for patients who are HER2 positive with (non-responsive, incompletely or highly) endocrine-responsive tumors and low-, intermediate- or high-risk categories to decrease disease recurrence. It is also indicated for patients with early breast cancer who are HER2 positive, given after surgery, adjuvant or neoadjuvant chemotherapy, and radiotherapy (if applicable).  

It can help slow cancer growth and may also stimulate the immune system to fight the cells more effectively. It reduces the risk of recurrence by half and improves survival.  

It is given to both premenopausal and postmenopausal patients. It may be given concurrently with a taxane following anthracycline or after completion of all chemotherapy. The accepted standard treatment duration is one year. It is contraindicated in patients with low left ventricular ejection fraction (LVEF) (<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); and Docetaxel, Carboplatin, Trastuzumab, Pertuzumab (TCHP) are preferred adjuvant regimens for HER2-positive disease.  

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 may be considered if with residual disease after preoperative therapy. Trastuzumab with or without Pertuzumab may be considered 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; or Doxorubicin, Cyclophosphamide (AC) followed by Paclitaxel (T) plus Trastuzumab with or without Pertuzumab are considered as conditional regimens for HER2-positive disease.  

Neratinib may be given for adjuvant therapy; to be considered in HR-positive, HER2-positive patients after Trastuzumab-containing regimen with a high risk of disease recurrence.  

Paclitaxel plus Trastuzumab plus Pertuzumab is also a conditional regimen. Ado-trastuzumab emtansine (TDM-1) may be considered for adjuvant therapy.    

Other Recommended Regimens  

Doxorubicin, Cyclophosphamide (AC) followed by Docetaxel plus Trastuzumab with or without Pertuzumab , and Paclitaxel/Carboplatin plus Trastuzumab plus Pertuzumab are other recommended regimens. 

Non-Trastuzumab Combinations (HER2-Negative Disease)  

Preferred Adjuvant Regimens  

CDK4/6 therapy with Abemaciclib in combination with endocrine therapy for patients with ER- and or PR-positive, HER2-negative high-risk breast tumors (≥4 positive axillary lymph nodes or 1-3 positive axillary lymph nodes with grade 3 disease, tumor size ≥5 cm or Ki-67 index ≥20%) for 2 years is one of the preferred adjuvant regimens. Dose-dense Doxorubicin, Cyclophosphamide (AC) followed by Paclitaxel every 2 weeks; or dose-dense Doxorubicin, Cyclophosphamide (AC) followed by weekly Paclitaxel; or Docetaxel, Cyclophosphamide (TC) are considered preferred adjuvant regimens for HER2-negative disease. 

Capecitabine may be considered for triple-negative breast cancer with residual disease after surgery and taxane-/alkylator-/ anthracycline-based chemotherapy.  

Olaparib may be considered 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 of ≥3

Preoperative Pembrolizumab plus Carboplatin plus Paclitaxel, followed by preoperative Pembrolizumab plus Cyclophosphamide plus Doxorubicin or Epirubicin, followed by adjuvant Pembrolizumab may be considered for high-risk triple-negative breast cancer.  

Conditional Regimens  

Cyclophosphamide, Methotrexate, Fluorouracil (CMF); Dose-dense Doxorubicin, Cyclophosphamide (AC); Doxorubicin, Cyclophosphamide (AC) every 3 weeks; or Doxorubicin, Cyclophosphamide (AC) followed by weekly Paclitaxel are considered conditional regimens for HER2-negative disease.  

Capecitabine may be considered as maintenance therapy for triple-negative breast cancer chemotherapy after adjuvant chemotherapy.  

Other Recommended Regimens  

Other recommended regimens include Doxorubicin, Cyclophosphamide (AC) followed by Docetaxel every 3 weeks; Epirubicin, Cyclophosphamide (EC); or Docetaxel, Doxorubicin, Cyclophosphamide (TAC). For triple-negative breast cancer, Paclitaxel plus Carboplatin; Docetaxel plus Carboplatin may be considered.    

Adjuvant Endocrine Therapy  

Adjuvant endocrine therapy is offered to patients with detectable expression of HR (≥1% invasive cancer cells). The minimum duration of therapy is 5 years, but recent data suggest that extending therapy for an additional 5 years reduces the risk of 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 high-risk patients (eg lymph node metastasis, unknown recurrence score, intermediate to high recurrence score).  

Recommended Adjuvant Endocrine Therapy for Premenopausal Women  

For premenopausal women, Tamoxifen for 5 years with or without ovarian suppression or ablation or an aromatase inhibitor for 5 years with ovarian suppression or ablation (may consider continuing aromatase inhibitor treatment for another 3-5 years) is the recommended adjuvant endocrine therapy.  

If the patient becomes amenorrheic while on the 5-year Tamoxifen therapy, an 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 analogue with aromatase inhibitor if Tamoxifen use is contraindicated.  

Recommended Adjuvant Endocrine Therapy for Postmenopausal Women  

For postmenopausal women, the recommended adjuvant endocrine therapy may be any of the following: 

• Aromatase inhibitor for 5 years (or may consider continuing treatment for another 3-5 years) or
• 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  

Example drugs: Anastrozole, Exemestane, Letrozole  

Aromatase inhibitors are considered as 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 a slight decrease in follow-up costs compared to Tamoxifen.  

They all 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  

Tamoxifen is the first-line adjuvant endocrine therapy in both pre- and postmenopausal breast cancer patients.  

Systemic Therapy for Recurrent Unresectable or Metastatic Breast Cancer  

Consider a taxane- or anthracycline-based regimen. Sequential monotherapy rather than concomitant use is recommended. They are considered first-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 a 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  

For HER2-negative disease, a combination regimen may be used for patients with high tumor burden, rapidly progressive disease, and visceral crisis.

HER-2 Negative and HR-Positive with Visceral Crisis or Endocrine-Refractory Disease    

First-line therapy includes systemic therapy (please see list below) for germline BRCA1/2 mutation-negative patients and PARP inhibitors Olaparib and Talazoparib. The latter being a treatment option for HER2-negative, germline BRCA1/2 mutation-positive patients.

Second-line therapy includes Fam-trastuzumab deruxtecan-nxki (for HER2 IHC 1+ or 2+/ISH-negative patients with a history of ≥1 prior line of chemotherapy for metastatic disease and, if the tumor is ER/PR-positive and is refractory to endocrine therapy), 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 canceror or if with contraindications to Fam-trastuzumab deruxtecan-nxki), and systemic chemotherapy (please see list below) for patients with contraindications to Fam-trastuzumab deruxtecan-nxki.

Third-line therapy and beyond includes systemic chemotherapy (please see list below) and targeted agents for biomarker-positive tumors such as Fulvestrant plus Alpelisib, Inavolisib plus Palbociclib plus Fulvestrant, Fulvestrant plus Capivaserib, Elacestrant. 
 
Systemic chemotherapy agents include the following:

• Anthracyclines: Doxorubicin, liposomal Doxorubicin
• Anti-metabolites: Capecitabine, Gemcitabine
• Microtubule inhibitors: Vinorelbine, Eribulin
• Taxanes: Paclitaxel
• Platinum agents: Carboplatin, Cisplatin  
• 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 a history of at least 2 therapies for metastatic breast cancer)  

Combination regimens that are considered useful in certain conditions:

• 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-Negative and HR-Negative (Triple-Negative) Breast Cancer  

First-line therapy includes:

• Pembrolizumab plus albumin-bound Paclitaxel, Paclitaxel or Gemcitabine and Carboplatin: A treatment option for patients with PD-L1-positive triple-negative breast cancer
• Systemic chemotherapy (please see list above)
• PARP inhibitors Olaparib and Talazoparib and platinum agents Carboplatin and Cisplatin: Treatment options for triple-negative, germline BRCA1/2 mutation-positive patients

Second-line therapy includes:

• PARP inhibitors Olaparib and Talazoparib: Treatment option for triple-negative, germline BRCA1/2 mutation-positive patients
• Fam-trastuzumab deruxtecan-nxki: For HER2 IHC 1+ or 2+/ISH-negative patients with a history of ≥1 prior line of chemotherapy for metastatic disease and, if the tumor is ER/PR-positive and is refractory to endocrine therapy
• Sacituzumab govitecan
• Systemic chemotherapy (please see list above)

Third-line therapy includes:

• Targeted agents for biomarker-positive tumors such as Fulvestrant plus Alpelisib, Inavolisib plus Palbociclib plus Fulvestrant, Fulvestrant plus Capivaserib, Elacestrant
• Systemic chemotherapy (please see list above)

HER2-Positive Disease  

For HER2-positive disease, one may substitute Trastuzumab with Trastuzumab plus Hyaluronidase-oysk injection for subcutaneous use. The 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 a history of treatment with intravenous Pertuzumab plus Trastuzumab. 

Preferred Regimens  

The first-line agents for HER2-positive disease are Pertuzumab plus Trastuzumab plus Docetaxel, or Pertuzumab plus Trastuzumab plus Paclitaxel. The second-line agent is Fam-trastuzumab deruxtecan-nxki.  

Other Recommended Regimens Used as Third-line Treatment Option and Beyond

Third-line agents include:

• Ado-trastuzumab emtansine (T-DM1)
• Tucatinib plus Trastuzumab plus Capecitabine is the treatment option for patients with advanced unresectable or metastatic disease, including brain metastases, with a history of ≥1 line of HER2-targeted therapy

Fourth-line agents and beyond:

• Lapatinib plus Capecitabine may be used in patients with HER2-positive tumors who are refractory to therapy with anthracycline, taxane, and Trastuzumab
• Margetuximab-cmkb plus 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 Mutation-specific agents under Pharmacological Therapy: Systemic Therapy for ER/PR-Positive Recurrent Unresectable or Metastatic Disease.


Systemic Therapy for ER/PR-Positive Recurrent Unresectable or Metastatic Disease  

HER2-Positive Postmenopausal Patients or Premenopausal Patients Receiving Ovarian Ablation or 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-Negative Postmenopausal Patients or Premenopausal Patients Receiving Ovarian Ablation or Suppression  

Preferred Regimens - First-line Therapy  

• Aromatase inhibitor plus CDK4/6 inhibitor (eg Abemaciclib, Palbociclib, Ribociclib)
• Fulvestrant plus CDK4/6 inhibitor (eg Abemaciclib, Palbociclib, Ribociclib)

Preferred Regimens - Second-line and Subsequent-line Therapy  

• Everolimus plus endocrine therapy (eg Exemestane, Fulvestrant, Tamoxifen)
• Fulvestrant plus Alpelisib or Inavolisib plus Palbociclib plus Fulvestrant (for PIK3CA activating-mutated tumors)
• Fulvestrant plus Capivasertib (for PIK3CA or AKT1 activating mutated tumors or PTEN alterations after disease progression or recurrence after ≥1 prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor)
• Fulvestrant plus CDK4/6 inhibitor (Abemaciclib, Palbociclib, Ribociclib) if not previously used

Other Recommended Regimens - First-line and/or Subsequent-line Therapy
 

• Selective ER down-regulator
  • Fulvestrant
  • Fulvestrant plus Alpelisib or Inavolisib plus Palbociclib plus Fulvestrant (for PIK3CA activating-mutated tumors)
  • Fulvestrant plus Capivasertib (for PIK3CA or AKT1 activating mutated tumors or PTEN alterations after disease progression or recurrence after ≥1 prior lines of endocrine therapy, including one line containing a CDK4/6 inhibitor)
  • Elacestrant (for ESR1 mutated tumors)
• Selective ER down-regulator (Fulvestrant) plus nonsteroidal aromatase inhibitor (Anastrozole, Letrozole)
• Nonsteroidal aromatase inhibitors: Anastrozole, Letrozole
• Selective ER modulator: Tamoxifen 
• Steroidal aromatase inactivator: Exemestane

Conditional Regimens

First-line therapy

Targeted therapy options for HER2-negative tumors with PIK3CA activating mutations, and disease progression during treatment with adjuvant endocrine therapy or relapse within 12 months of adjuvant endocrine therapy completion includes Fulvestrant plus Alpelisib, Inavolisib plus Palbociclib plus Fulvestrant, Fulvestrant plus Capivaserib Elacestrant.


Subsequent-line Therapy

The following are conditional regimens for HER2-Negative postmenopausal or premenopausal patients receiving ovarian ablation or abrasion:

• Abemaciclib
• Ethinyl estradiol
• Megestrol acetate
• Targeted therapy options: Fulvestrant plus Alpelisib, Inavolisib plus Palbociclib plus Fulvestrant, Fulvestrant plus Capivaserib, Elacestrant

HER2-Targeted Therapy  

The treatment options for ER/PR-positive, HER2-positive patients, should be offered once the diagnosis is confirmed. This 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
• Abemaciclib plus Trastuzumab and Fulvestrant
• Pertuzumab if not previously used

Aromatase Inhibitors  

Example drugs: Anastrozole, Letrozole  

Aromatase inhibitors are used in postmenopausal patients. They are the preferred first-line therapy for recurrent disease in postmenopausal women who have received previous anti-estrogen therapy and are within one year of antiestrogen exposure. They are 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 one year.  

Endocrine Therapy plus Ovarian Ablation or Suppression or Selective ER Modulators  

Tamoxifen is a standard therapy. Monotherapy with Tamoxifen may be considered in HER2-negative premenopausal women who decline ovarian ablation or suppression. Endocrine therapy plus ovarian ablation or suppression or selective ER modulators are 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  

Example drugs: Abemaciclib, Palbociclib, Ribociclib  

Highly selective inhibitors of CDK4/6 kinase activity 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 first-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 first-line treatment option, together with ovarian suppression, in patients 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  

Example drug: Everolimus  

This class of drugs inhibits protein in cells that promotes growth and division. Everolimus is 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 nonsteroidal aromatase inhibitor. It may also stop angiogenesis which can help limit tumor growth.  

Monoclonal Antibodies  

Bevacizumab  

Bevacizumab may be used to treat advanced or metastatic breast cancer which is commonly used in combination with Paclitaxel. It prevents angiogenesis.  

Dostarlimab  

Dostarlimab is indicated for patients with microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) unresectable or metastatic tumors that have progressed on or following prior treatment and without satisfactory alternative treatment options.

Margetuximab  

Margetuximab is 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  

Pembrolizumab is approved for use in patients with any subtype of breast cancer with unresectable or metastatic, MSI-H or dMMR solid tumors with disease progression after first-line therapy or when no alternative therapy options are available.  

Pertuzumab  

Pertuzumab is a HER dimerisation inhibitor preventing HER2 heterodimerisation with other HER receptors thereby inhibiting HER signaling pathway activation. It is 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. It is 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 treatment if with confirmed clinically significant decline in left ventricular function.  

Trastuzumab  

Trastuzumab is indicated for high-risk, HER2-positive tumor. It is added in preoperative chemotherapy regimens in patients with HER2-positive tumors. It may be used to treat metastatic breast cancer, with or without chemotherapy. It may be given as monotherapy to patients with HER2-overexpressing tumors who have received at least 2 regimens of chemotherapy for metastatic disease.  

Trastuzumab 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 the preferred options for patients with recurrent or metastatic breast cancer (any subtype) with BRCA1 and BRCA2 germline mutation, respectively. Inavolisib plus Palbociclib plus Fulvestrant combination therapy is recommended for patients with HR-positive, HER2-negative recurrent unresectable stage IV breast cancer with PIK3CA activating mutations.

Alpelisib plus 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.  

Capivaserib plus Fulvestrant combination therapy is recommended for patients with ER- and/or PR-positive, HER2-negative recurrent unresectable or stage IV breast cancer with PIK3CA or AKT1 activating mutations or PTEN alterations after disease progression or recurrence after ≥1 previous lines of endocrine therapy including 1 line containing CD4/6 inhibitor.

Pembrolizumab plus 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 while TRK inhibitor Repotrectinib is indicated for any subtype of breast cancer with NTRK gene fusions and are locally advanced or metastatic or where surgical resection will likely result in severe morbidity and with disease progression following treatment or no satisfactory alternative treatments.

Elacestrant is indicated for postmenopausal women with ER-positive, HER2-negative recurrent unresectable, or stage IV breast cancer with ESR1 mutation after progression with 1 or 2 previous lines of endocrine therapy including 1 line containing a CDK4/6 inhibitor.  

Selpercatinib is indicated for adult patients with locally advanced or metastatic solid RET gene fusion-positive tumors with progression on or after previous systemic therapy or without satisfactory alternative therapy options.  

Neratinib with or without Fulvestrant and Neratinib with or without Trastuzumab/Fulvestrant may be considered for patients with positive for HER2 activating mutations.

Poly (ADP-ribose) Polymerase (PARP) Inhibitors

Example drugs: Olaparib, Talazoparib

They are the preferred options for HER2-negative patients with recurrent or metastatic breast cancer (any subtype) with BRCA1 and BRCA2 germline mutation. Olaparib may be considered for patients positive for germline PALB2 mutations.

Selective ER Down-Regulator  

Example drug: Fulvestrant  

Fulvestrant is the recommended regimen for postmenopausal, HER2-negative patients with recurrent or metastatic breast cancer when given in combination with Palbociclib, Abemaciclib, or Everolimus. It may also be considered in postmenopausal, HER2-positive patients with recurrent or metastatic breast cancer. It is given with or without Trastuzumab.  

Selective ER Modulators  

Example drug: Tamoxifen  

Tamoxifen is the 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.  

Tropomyosin Receptor Kinase (TRK) Inhibitors

Example drugs: Entrectinib, Larotrectinib, Repotrectinib

Tropomyosin receptor kinase (TRK) inhibitors Entrectinib and Larotrectinib 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 while TRK inhibitor Repotrectinib is indicated for any subtype of breast cancer with NTRK gene fusions and are locally advanced or metastatic or where surgical resection will likely result in severe morbidity and with disease progression following treatment or no satisfactory alternative treatments. 


Tyrosine Kinase Inhibitors  

Example drugs: Lapatinib, Neratinib, Selpercatinib

Tyrosine kinase inhibitors are combined with an aromatase inhibitor, Capecitabine, or Trastuzumab as a treatment option for HER2-positive patients with recurrent or metastatic disease. The 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 of prior HER2-targeted treatment. Selpercatinib is indicated for patients with locally advanced or metastatic solid RET gene fusion-positive tumors with progression on or after previous systemic therapy or without satisfactory alternative therapy options. 

Other Agents  

Bisphosphonates and Denosumab  

Bisphosphonates and Denosumab are given in addition to endocrine therapy or chemotherapy if bone metastasis is present. They may be considered in postmenopausal women receiving adjuvant aromatase inhibitor therapy. Ibandronic acid, Pamidronate, or Zoledronic acid (with calcium citrate and vitamin D) helps strengthen bones, decrease the risk of fractures, and bone pains, and prevents 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. 

Surgery

Risk Reduction for Carcinoma in situ  

Risk-reducing mastectomy (RRM or prophylactic bilateral mastectomy) and/or bilateral salpingo-oophorectomy may be an alternative for patients at high risk of developing invasive breast cancer.  

Primary Treatment for Ductal Carcinoma in situ (DCIS) and Encapsulated or Solitary Papillary Carcinoma (SPC)  

Patients with breast cancer in one area with positive margins after complete surgical excision are advised to undergo either total mastectomy, breast-conserving surgery, or excision of margin.

Breast-Conserving Surgery  

There is a higher recurrence rate when done alone, without radiation therapy (RT), endocrine therapy, or chemotherapy, especially in high-risk patients.  

Whole breast radiotherapy (WBRT) may be offered to patients who are treated with breast-conserving surgery. Several trials support the findings that breast-conserving surgery with whole breast radiotherapy reduces recurrence rates in ductal carcinoma in situ by about 50-70% and invasive disease in the ipsilateral breast. Accelerated partial breast irradiation (APBI) or partial breast irradiation (PBI) may be considered in patients with ductal carcinoma in situ measuring ≤2.5 cm with a negative margin width of ≥3 mm.    

A sentinel node biopsy may be done. Mammogram is advised post-lumpectomy to ensure complete removal of the tumor.  

Total Mastectomy  

Total mastectomy is associated with near-total avoidance of recurrence in 3-20 years. It is recommended in widespread ductal carcinoma in situ with involvement of ≥2 areas and when there is persistent marginal involvement even after repeat surgery. It may not require post-op radiation unless the carcinoma is at the margin of the mastectomy. Sentinel lymph node biopsy should be done at the time of definitive surgery since mastectomy alters the feasibility of this procedure.  

Invasive Breast Cancer  

Breast-conserving Surgery  

Breast-conserving surgery is the local treatment of choice for most invasive breast cancer.  It involves the selective removal of the breast mass and a margin of normal surrounding tissues.

The purpose is to provide a pathologically negative margin of resection. A negative margin should be reported as ink is not touching invasive cancer or ductal carcinoma in situ, and ≥2 mm (for in situ disease) is preferred. Image-detectable markers are placed during a core biopsy for tumor bed demarcation for surgical management post-chemotherapy. In cases where there is a positive margin, the option is to re-excise or perform mastectomy to achieve a negative margin.  

Radiation is usually done after breast-conserving surgery. The survival rates are similar to mastectomy alone for stage I or II treated with breast-conserving surgery and radiotherapy and in patients with ductal carcinoma in situ treated with breast-conserving surgery and radiotherapy.

Absolute contraindications for breast-conserving surgery requiring radiotherapy include inflammatory breast cancer or invasive breast cancer with extensive skin or dermal lymphatic involvement, patients with gestational breast cancer who cannot receive radiotherapy within 12-16 weeks, inability to clear multiple positive pathologic margins after one or more re-excision attempts, suspicious or malignant-appearing microcalcifications that are disseminated throughout the breast, multicentric disease (with any of the following: >2 lesions involving >2 quadrants by evaluation with MRI, any individual lesion measuring ≥5 cm, age ≤40 years, BRCA mutation carrier, cN2-cN3, inability to achieve negative margins multicentric pure DCIS, recipient of neoadjuvant chemotherapy or endocrine therapy, triple negative [ER-, PR-, and HER2-negative] breast cancer, other reasons with contraindication to adjuvant WBRT plus boost), and homozygous (biallelic inactivation) for ATM mutation.  

Relative contraindications for breast-conserving surgery requiring radiotherapy include prior chest wall or breast radiation therapy with known prescribed doses and volumes, active connective tissue disease with skin involvement (eg scleroderma, lupus), women with known or suspected genetic predisposition to breast cancer (with increased risk for ipsilateral breast recurrence or contralateral breast cancer with breast-conserving therapy, can be considered for prophylactic bilateral mastectomy, known or suspected Li-Fraumeni syndrome), and pathologic p53 mutation.
 
Partial or segmental mastectomy or quadrantectomy is the removal of up to one-quarter of the breast.  

Breast Cancer_Management 2

Radiation Therapy

Radiation therapy involves treatment with high-energy rays or particles that destroy cancer cells. It is also used to treat cancer that has metastasized to other organs. It can be given as external beam radiation therapy (EBRT) or brachytherapy.  

Whole Breast Radiotherapy (WBRT)  

Whole breast radiotherapy targets the entire breast tissue. It is recommended for patients with ductal carcinoma in situ who had breast-conserving surgery and for post-lumpectomy patients to decrease the chance of ipsilateral breast tumor recurrence.  

The recommended dose is 45-50.4 Gy in 25-28 fractions or 40-42.5 Gy in 15-16 fractions with or without boost to tumor bed at 10-16 Gy in 4-8 fractions to be given 5 days per week. Boost radiotherapy to tumor bed at 10-16 Gy in 4-8 fractions further reduces the risk for disease relapse, especially in patients at high risk for local recurrence (<50 years old, with grade 3 tumors, with vascular invasion or extensive intraductal component, and radical tumor excision).     

Ultrafractionated whole breast radiotherapy of 28.5 Gy delivered once a week in 5 fractions may be considered in >50-year-old patients with pTis/T1/T2/N0 after breast conservation surgery. An alternative dose of 26 Gy given in 5 daily fractions over 1 week may be an option.  

Post-mastectomy Radiotherapy  

Post-mastectomy radiotherapy targets the ipsilateral chest wall and mastectomy scar and may also drain indicated sites. The recommended dose is 45-50.4 Gy in 25 to 28 fractions to the chest wall with or without scar boost at 1.8-2 Gy per fraction. The total dose is approximately 60-66 Gy, to be given 5 days per week.  

Regional Nodal Radiation  

Regional nodal radiation targets supraclavicular, infraclavicular, and axillary nodes. It is recommended for patients with lymph node involvement and patients without lymph node involvement but with high-risk features. Undissected portions of the axilla should be included in post-lumpectomy patients with positive axillary nodes, and in post-mastectomy patients; not required in post-lumpectomy patients with clinical T1-T2, N0 tumor, not given preoperative chemotherapy, 1-2 positive sentinel lymph node/s, and planned whole breast radiotherapy.    

CT-based planning is recommended with regional nodal radiation. The recommended dose is 45-50.4 Gy in 25-28 fractions to the regional nodal fields, to be given 5 days per week.  

Accelerated Partial-breast Irradiation (APBI)  

Accelerated partial-beam irradiation is the treatment option in patients with a low-risk for local recurrence prior to chemotherapy, especially if with a history of adjuvant endocrine therapy.

It is recommended in low-risk, BRCA-negative patients if any 1 of the following is present:

• ≥50 years old with invasive ductal carcinoma ≤2 cm (T1) with negative margin widths of ≥2 mm, no lymphovascular involvement, and ER-positive
• Low or intermediate nuclear grade ductal carcinoma in situ detected during screening measuring ≤2.5 cm with negative margin widths of ≥3 mm 

It may also be considered in patients with ductal carcinoma in situ. The recommended dose is 30 Gy given in 5 daily fractions via external beam radiotherapy is the preferred regimen; 34 Gy in 10 fractions given twice per day with brachytherapy, 40 Gy given in 15 fractions via external beam radiotherapy, or 38.5 Gy fractions twice per day via external beam radiotherapy.  

Radiotherapy for Invasive Breast Cancer Stage I, IIA, IIB, IIIA (T3N1M0)  

Post-mastectomy Radiotherapy  

Radiotherapy to the chest wall, infraclavicular region, supraclavicular area, and internal mammary nodes, and to any area of involved axillary nodes is recommended for patients with ≥4 positive axillary nodes.  

Radiotherapy to the chest wall, infraclavicular region, supraclavicular area, and internal mammary nodes, and to any area of involved axillary nodes should be strongly considered in patients with 1-3 positive axillary nodes.  

Radiotherapy to the chest wall, with or without coverage of the infraclavicular region, supraclavicular area, and internal mammary nodes, and any area of involved axillary nodes may be considered in patients without any involved axillary nodes but with a tumor of >5 cm in size, and those with positive margins if re-excision is not feasible.  

Radiotherapy to the chest wall, with or without regional nodal radiation in patients with central or medial tumors, tumor ≥2 cm in size with <10 axillary nodes removed, and with a grade 3, ER-negative or lymphovascular invasion should be considered in patients without axillary node involvement, tumor of ≤5 cm and negative margins but <1 mm.  

Post-mastectomy radiotherapy is commonly done after chemotherapy except in patients with negative axillary nodes, tumors with ≤5 cm in size, and margins of ≥1 mm.    

Post-lumpectomy Radiotherapy  

Radiotherapy to the whole breast with or without boost to the tumor bed, supraclavicular and infraclavicular areas, and internal mammary nodes, and within the area of involved axillary nodes is recommended for patients with ≥4 positive axillary nodes.  

Radiotherapy to the whole breast with or without boost to the tumor bed is recommended for patients with 1-3 positive axillary nodes, with consideration for supraclavicular, infraclavicular, and internal mammary node radiotherapy, and to any area of involved axillary nodes. This is recommended as locoregional treatment in patients with unmet requirements for the ACOSOG Z0011 criteria. A boost to the tumor bed should be considered in patients with high-risk features (eg high-grade disease, <50 years of age).  

Radiotherapy to the whole chest with or without boost to the tumor bed is recommended in patients negative for axillary node involvement. It may consider regional nodal radiation in patients with tumors of >2 cm in size or in tumors located near or at the center with other high-risk features.  

It is commonly done after chemotherapy and may be omitted in patients ≥70 years of age with ER-positive, cN0, T1 tumors who received adjuvant endocrine therapy.  

Radiotherapy for Invasive Breast Cancer Stage IIIA (except T3N1M0), IIIB, IIIC  

Adjuvant radiotherapy to the chest wall, infraclavicular region, supraclavicular area, and internal mammary nodes, and to any area of involved axillary nodes should be considered in post-mastectomy patients at risk of invasive disease and axillary lymph node involvement and indicated if with node involvement.  

Whole breast radiotherapy with or without boost to the tumor bed instead of chest wall radiotherapy is recommended for post-lumpectomy patients. Radiotherapy to the infraclavicular region, supraclavicular area, and internal mammary nodes and to any area of involved axillary nodes should be considered in post-lumpectomy patients at risk of invasive disease and axillary lymph node involvement and should be done if positive for node involvement.  

For patients with inoperable tumor upon initial diagnosis with positive response to preoperative systemic therapy and subsequently underwent surgery, adjuvant radiotherapy to the whole breast or chest wall, infraclavicular region, supraclavicular area, internal mammary nodes, and to any area of involved axillary nodes is recommended.