Breast Cancer Treatment Protocols

Ductal carcinoma in situ (DCIS)

Primary treatment options include the following:

• Lumpectomy without axillary assessment, plus whole-breast radiation therapy (RT) or

• Total mastectomy, with or without sentinel lymph node biopsy (SLNB) and with or without breast reconstruction

Considerations include the following:

• SLNB is often not performed but may be done in some cases if an initial core biopsy showed DCIS, because more extensive sampling may show invasive carcinoma.

• In the absence of risk factors for recurrence, women with DCIS who have small, low- or intermediate-grade tumors resected with widely negative margins can omit RT.

• Consider risk-reduction therapy with tamoxifen 20 mg PO qDay (in pre- and postmenopausal women) or raloxifene 60 mg PO qDay (in postmenopausal women) for 5 years in patients with estrogen receptor (ER)–positive DCIS.

• Tamoxifen can be given at a lower dose (5 mg daily) in patients with noninvasive breast cancer as shown by the babytam trial. ^[1]

Lobular carcinoma in situ (LCIS)

Management options include the following:

• Surveillance alone (ie, mammography)

• Surveillance plus raloxifene (for postmenopausal women)

• Tamoxifen (for women of any menopausal status) ^{[2, 3]}

If LCIS is detected on stereotactic biopsy, wide excision is indicated. In 10-20% of cases, this may reveal invasive cancer or DCIS that requires additional local or systemic therapy. ^[4]

Surgical excision to negative margins is not indicated; however, patients with LCIS have about a 5% 5-y risk and a 20-30% lifetime risk of developing invasive breast cancer, which may be ipsilateral or contralateral and may be ductal or lobular in origin. ^[5]  

Pleomorphic LCIS is a LCIS variant that warrants special consideration, in that treatment should include excision to negative margins. ^[6]

Consider the following:

• Stage I-II estrogen receptor positive (ER+) disease is usually treated with upfront surgery.
• Locally advanced (stage III) ER+ disease can be treated with neoadjuvant therapy. The goal of neoadjuvant treatment is to induce a tumor response before surgery and enable breast conservation.
• For neoadjuvant treatment, chemotherapy is usually preferred. However, endocrine therapy may be considered in some cases (especially in postmenopausal patients who cannot receive chemotherapy and those with multiple comorbidities)
• Patient who undergo upfront surgery can qualify for adjuvant chemotherapy based on gene expression profiling such as the Oncotype DX, MammaPrint, or Prosigna.
• Almost all patients with ER+ (especially those with ER expression > 10%) breast cancer should be evaluated for adjuvant endocrine therapy
• Patients at high risk for recurrence should be evaluated for adjuvant treatment with CDK4/6 inhibitors.
• Postmenopausal women at high risk for recurrence can be evaluated for adjuvant treatment with a bisphosphonate.

Chemotherapy regimens

Dose-dense doxorubicin (Adriamycin) and cyclophosphamide followed by paclitaxel (AC-P):

• Doxorubicin 60 mg/m ² IV  plus   cyclophosphamide 600 mg/m ² IV every 2 weeks for four cycles, with colony-stimulating factor (CSF) support, followed by 
• Paclitaxel 175 mg/m ² every 2 weeks with CSF support ^[7] or  80 mg/m ² weekly for 12 weeks ^{[8] ​}
• Alternative taxanes (ie, docetaxel, albumin-bound paclitaxel) may be used as substitutes in cases of medical necessity (eg, hypersensitivity reaction).
• Change in administration sequence to paclitaxel followed by doxorubicin/cyclophosphamide is acceptable.

Docetaxel (Taxotere) plus cyclophosphamide (TC):

• Docetaxel 75 mg/m ² IV on Day 1  plus  cyclophosphamide 600 mg/m ² IV on Day 1 every 3 weeks for four cycles  ^[9] ​ 

Neoadjuvant endocrine therapy

Usually reserved for postmenopausal women who are not candidates for chemotherapy but would benefit from neoadjuvant therapy:

• Letrozole 2.5 mg PO daily or
• Anastrozole 1 mg PO daily for 3-6 months or until best treatment response ^[10]

Adjuvant endocrine therapy

Patients with invasive breast cancer that is ER+ or progesterone receptor positive (PR+) should be considered for adjuvant endocrine therapy with tamoxifen or aromatase inhibitors (AIs). Selection considerations are as follows:

• Selection of agents depends on menopausal status and concern about adverse effect profile (eg, thrombosis with tamoxifen, bone loss with AIs).

• Tamoxifen has been shown to reduce the risk of recurrence by about 40% and the risk of death by about 30%, is effective in both premenopausal and postmenopausal women, and may be used either alone or after chemotherapy. ^[11]

• AIs are effective for postmenopausal women, reducing the risk of recurrence by approximately 20% compared with tamoxifen. ^{[12, 13, 14, 15]}

• Nonsteroidal AIs (anastrozole, letrozole) and steroidal AIs (exemestane) have comparable efficacy and adverse effects

Regimens for premenopausal patients:

• Tamoxifen 20 mg PO daily for 5y ^[16]  or

• Tamoxifen 20 mg PO daily for 2-5 y, followed by an AI for a total of up to 10 y of endocrine therapy; this regimen is typically used for patients who are premenopausal at diagnosis and become postmenopausal during therapy; it has been shown to be more effective than a 5y course of tamoxifen ^[17]

• Ovarian function suppression (OFS) with a gonadotropin-releasing hormone (GnRH) agonist (eg, goserelin 3.6 mg SC depot every 28 days [every-3-months therapy not recommended due to ovarian function escape]) added to tamoxifen or an AI, is associated with increased benefit in patients at high risk for recurrence. ^[18]

Regimens for postmenopausal patients:

• Tamoxifen 20 mg PO daily for 5 y or

• AIs for 5y, either alone or sequentially after 2-5 y of tamoxifen: anastrozole 1 mg PO daily or  letrozole 2.5 mg PO daily or  exemestane 25 mg PO daily

Adjuvant CDK4/6 inhibitor therapy

Adjuvant CDK4/6 inhibitors are recommended with patients a high risk for recurrence, as follows:

• Abemaciclib 150 mg PO BID for 2 years, in combination with endocrine therapy ^[19]
• Ribociclib 600 mg PO on Days 1-21 of each 28-day cycle for 3 years, in combination with daily endocrine therapy; although 600 mg is the approved dose, the NATALEE trial reported that a 400-mg dose improves tolerability while maintaining efficacy ^[20]
• Palbociclib 125 mg PO qDay for Days 1-21 of each 28-day cycle, in combination with aromatase inhibitor as initial endocrine-based therapy and in combination with fulvestrant in men or women with disease progression following endocrine therapy ^{[21, 22]}

Adjuvant poly (ADP-ribose) polymerase (PARP) inhibitor therapy

For patients with BRCA1- or BRCA2-mutated breast cancer at high risk for recurrence ^[23] :

• Olaparib 300 mg PO BID every 4 weeks for 1 year

Adjuvant bisphosphonate therapy

Consider in postmenopausal women at high risk for recurrence ^[24] :

• Zoledronic acid 4 mg IV every 6 months for 3 years; q6mo dosing reduces osteonecrosis of the jaw ^[25]  

Any tumor that is T1c and above or node positive should be considered for neoadjuvant therapy. This approach offers several advantages, the most prominent being that the tumor's response to neoadjuvant therapy aids in predicting the likelihood of recurrence. This allows for the tailoring of adjuvant therapy.

Chemoimmunotherapy

Preoperative pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab ^[26] :

• Pembrolizumab 200 mg IV on Day 1 plus  paclitaxel 80 mg/m ² IV on Days 1, 8, and 15 plus  carboplatin area under the curve (AUC) 5 IV (see the Carboplatin AUC Dose Calculation [Calvert] calculator) on Day 1 every 3 weeks for cycles 1-4  followed by
• Pembrolizumab 200 mg IV on Day 1 plus  doxorubicin 60 mg/m ² IV and cyclophosphamide 600 mg/m ² every 3 weeks for cycles 5-8, then   following surgery
• Pembrolizumab 200 mg IV on Day 1 every 3 weeks for nine cycles​ or 400 mg IV every 6 weeks for four cycles

Chemotherapy

Dose-dense doxorubicin (Adriamycin) followed by paclitaxel (AC-P):

• Doxorubicin 60 mg/m ² IV plus  cyclophosphamide 600 mg/m ² every 2 weeks for four cycles with CSF support followed by
• Paclitaxel 80 mg/m ² weekly for 12 weeks ^{[8] ​}
• Alternative taxanes (eg,  docetaxel,  albumin-bound paclitaxel) may be used as substitutes in cases of medical necessity (eg, hypersensitivity reaction).
• Change in administration sequence to paclitaxel followed by doxorubicin/cyclophosphamide is acceptable

Docetaxel (Taxotere) plus cyclophosphamide (TC):

• Docetaxel 75 mg/m ² IV on Day 1  plus  cyclophosphamide 600 mg/m ² IV on Day 1 every 3 weeks for four cycles ^[9] ​

Adjuvant capecitabine monotherapy (for TNBC only)

Can be considered in patients with TNBC who received neoadjuvant chemotherapy and had residual disease at the time of surgery ^[27] :

• Capecitabine 1000-1250 mg/m ² PO BID on Days 1-14 every 3 weeks for 6-8 cycles

PARP inhibitors

Adjuvant olaparib monotherapy (for patients with BRCA1- or BRCA2-mutated breast cancer) ^[23] :

• Olaparib 300 mg PO BID every 4 weeks for 1 year

Neoadjuvant talazoparib (for patients with BRCA1- or BRCA2-mutated breast cancer) ^[28]

Can be considered as an alternative to neoadjuvant chemotherapy in these patients:

• Talazoparib 1 mg PO once daily for 24 weeks

Any tumor that is T2 and above or node positive should be considered for neoadjuvant therapy. This approach offers several advantages, the most prominent being that the tumor's response to neoadjuvant therapy aids in predicting the likelihood of recurrence. This allows for the tailoring of adjuvant therapy.

Trastuzumab-containing regimens

Paclitaxel plus trastuzumab:

• Consider for low-risk HER2-positive patients who may not be eligible for other standard adjuvant treatments
• Paclitaxel 80 mg/m ² IV weekly for 12 weeks  concurrently with
• Trastuzumab 4 mg/kg IV with first dose of paclitaxel, then  2 mg/kg IV weekly for 1 year or  trastuzumab 6 mg/kg every 3 weeks following the completion of paclitaxel therapy, and given for a 1-year total duration of trastuzumab therapy ^[29]

Dose-dense doxorubicin (Adriamycin) followed by paclitaxel (AC-P):

• Doxorubicin 60 mg/m ² IV  plus   cyclophosphamide 600 mg/m ² IV on Day 1 every 2 weeks for four cycles with colony-stimulating factor (CSF) support, followed by 
• Paclitaxel  80 mg/m ² IV weekly for 12 weeks  concurrently with
• Trastuzumab 4 mg/kg IV with first dose of paclitaxel  then  2 mg/kg IV weekly for 1 year  or  trastuzumab 6 mg/kg every 3 weeks following the completion of paclitaxel, and given for a 1-year total duration of trastuzumab therapy ^[30]  

AC-docetaxel plus trastuzumab:

• Doxorubicin 60 mg/m ² IV plus  cyclophosphamide 600 mg/m ² IV on Day 1 every 2 weeks for four cycles with CSF support, followed by
• Docetaxel 100 mg/m ² IV every 3 weeks for four cycles concurrently with
• Trastuzumab 4 mg/kg IV with first dose of paclitaxel then 2 mg/kg IV weekly for 1 year  or  trastuzumab 6 mg/kg every 3 weeks following the completion of paclitaxel, and given for a 1-year total duration of trastuzumab therapy ^[31]  

Docetaxel (Taxotere)/carboplatin/trastuzumab (Herceptin)(TCH):

• Docetaxel 75 mg/m ² IV plus  carboplatin AUC 6 IV on Day 1 every 3 weeks for six cycles (see the  Carboplatin AUC Dose Calculation [Calvert formula] calculator)  plus
• Trastuzumab 4 mg/kg IV during week 1 and then  2 mg/kg IV weekly for 17 weeks; followed by trastuzumab 6 mg/kg every 3 weeks to complete 1 year of trastuzumab
• Alternatively, trastuzumab 8 mg/kg IV week 1, then 6 mg/kg IV every 3 weeks to complete 1 year of therapy
• This regimen may be more appropriate for patients with contraindications to anthracycline therapy ^[31]  

TCH plus pertuzumab:

• Docetaxel 75 mg/m ² IV plus  carboplatin AUC 6 IV on Day 1 every 3 weeks for six cycles  plus
• Trastuzumab 8 mg/kg IV on Day 1, then  trastuzumab 6 mg/kg IV Day 1 every 3 weeks to complete 1 year of therapy  plus
• Pertuzumab 840 mg IV on Day 1, then  420 mg IV Day 1 every 3 weeks to complete 1 year of therapy ^[29]  

Docetaxel/cyclophosphamide plus trastuzumab:

• Docetaxel 75 mg/m ² IV on Day 1 plus   cyclophosphamide 600 mg/m ² IV Day 1 every 3 weeks for four cycles plus
• Trastuzumab 4 mg/kg during week 1, then  2 mg/kg IV weekly for 11 weeks; followed by trastuzumab 6 mg/kg every 3 weeks to complete 1 year of trastuzumab
• Alternatively, trastuzumab 8 mg/kg IV week 1, then  6 mg/kg IV every 3 weeks to complete 1 year of therapy ^[29]  

Paclitaxel/trastuzumab/pertuzumab:

• Paclitaxel 80 mg/m ² IV weekly for 12 cycles plus
• Trastuzumab 8 mg/kg IV on Day 1,  then  by 6 mg/kg IV every 3 weeks for four cycles  plus
• Pertuzumab 840 mg IV on Day 1,  then by 420 mg IV every 3 weeks for four cycles

Neratinib for adjuvant treatment following trastuzumab

Neratinib is indicated for the extended adjuvant treatment of early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy ^[32] , as follows:

• Neratinib 120 mg PO daily on Days 1-7, then  160 mg PO daily on Days 8-14, then  by 240 mg PO daily on Days 15-28 in cycle 1 followed by
• Neratinib 240 mg (ie, six 40-mg tablets) PO daily continuously for 1 year
• Antidiarrheal prophylaxis required when starting therapy ^[33]

Ado-trastuzumab emtansine (T-DM1) for adjuvant setting only

Ado-trastuzumab emtansine is approved as an adjuvant treatment for HER2-positive early breast cancer when the patient has received neoadjuvant treatment including a taxane and trastuzumab and there is residual disease in the tissue removed during surgery. ^[34]

• Ado-trastuzumab emtansine 3.6 mg/kg IV on Day 1 every 3 weeks for 14 cycles

Considerations

See the list below:

• The US Food and Drug Administration (FDA) has approved several biosimilars of  trastuzumab (Herzuma, Kanjinti, Ogivri, Ontruzant, Trazimera) to treat HER2-overexpressed breast cancer. The availability of biosimilars provides additional treatment options for patients in the adjuvant setting.
• The FDA granted accelerated approval to a fixed-dose  pertuzumab/trastuzumab/hyaluronidase combination (Phesgo) for subcutaneous (SC) use in combination with IV chemotherapy, for adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence. ^[35]  Pertuzumab/trastuzumab/hyaluronidase may be substituted anywhere that the combination of IV pertuzumab and IV trastuzumab are given as part of systemic therapy.
• Trastuzumab/hyaluronidase (Herceptin Hylecta) for SC use may be substituted for trastuzumab IV.

First-line treatment of endocrine-sensitive disease

In postmenopausal women with estrogen receptor (ER)-positive, HER2-negative advanced breast cancer, initial endocrine-based therapy for metastatic disease may include the following:

• Ribociclib 600 mg PO once daily for Days 1-21 of a 28-day cycle plus  endocrine therapy (aromatase inhibitor or fulvestrant) ^[36]
• Palbociclib 125 mg PO once daily on Days 1-21 of each 28-day cycle with food plus  endocrine therapy ^[37]
• Abemaciclib 150 mg BID plus  endocrine therapy; continue for 2 years, or until disease recurrence or unacceptable toxicity ^[38]

In premenopausal women with ER-positive, HER2-negative advanced breast cancer, the treatment of choice is as follows ^[39] :

• Ribociclib 600 mg PO once daily on Days 1-21 of a 28-day cycle plus
• Tamoxifen 20 mg PO daily or  a nonsteroidal aromatase inhibitor ( letrozole 2.5 mg PO daily or anastrozole 1 mg PO daily) plus
• Goserelin 3.6 mg SC on Day 1 of every 28-day cycle

Second-line treatment and beyond of endocrine-sensitive disease

See the list below:

• Alpelisib 300 mg PO daily  plus   fulvestrant 500 mg IM on Days 1, 15, and 29, and once monthly thereafter, in tumors with confirmed PIK3CA mutation ^[40]
• Everolimus 10 mg PO daily  plus fulvestrant 500 mg IM on Days 1, 15, and 29, and once monthly thereafter
• Everolimus 10 mg PO daily  plus   exemestane 25 mg PO daily ^[41]
• Elacestrant 345 mg PO daily in tumors with confirmed  ERS1 mutations  ^[42]

Treatment of endocrine-refractory disease

Antibody-drug conjugates (ADCs) are recommended for treatment of endocrine-refractory disease. However, ADCs are currently indicated for second-line use after at least one prior line of chemotherapy. Recommended single-agent regimens include any of the following:

• Capecitabine fixed dose 1500 mg PO BID 7 days on, 7 days off ^[43]
• Albumin-bound paclitaxel  260 mg/m ² every 3 weeks or  (off-label) 100 mg/m ² IV on Days 1, 8, and 15 every 4 weeks ^[44]  
• Olaparib 300 mg PO BID or  talazoparib 1 mg PO daily, in patients with  BRCA1 or BRCA2 mutations

Patients whose cancer progresses on first-line treatment should be offered an ADC. There is currently no consensus on which ADC to use first and whether these agents can be used sequentially. However, there is a growing consensus that in patients with HER2-low disease (defined as HER2 expression by immunohistochemistry 1+ or 2+ with non-amplification by in-situ hybridization), trastuzumab deruxtecan should be used first:

• Trastuzumab deruxtecan 5.4 mg/kg IV every 3 weeks, in patients with HER2-low or HER2-positive disease ^[45]  

In patients with triple-negative or hormone receptor–positive, HER2-negative disease ^[46] :

• Sacituzumab govitecan 10 mg/kg IV on Days 1 and 8 of every 21-day cycle

Patients whose cancer progresses on ADC therapy should be encouraged to seek clinical trial options. Otherwise, they can be treated with single-agent chemotherapy. Options include capecitabine and albumin-bound paclitaxe or any of the following:

• Paclitaxel 80 mg/m ² IV weekly
• Docetaxel 60-100 mg/m ² IV every 3 weeks for at least 6 cycles or  (off-label dose) 40 mg/m ² IV weekly for 6 weeks followed by a 2-week rest and then repeat  ^[47]
• Eribulin 1.4 mg/m ² IV on Days 1 and 8 every 3 weeks
• Gemcitabine 1,250 mg/m ² IV on Days 1 and 8 in combination with paclitaxel of a 21-day cycle or  (off-label) 800-1200 mg/m ² IV on Days 1, 8, and 15 of a 28-day cycle ^[48]
• Vinorelbine (off-label) 25 mg/m ² IV weekly ^[49]  
• Pegylated liposomal-encapsulated doxorubicin (off-label) 50 mg/m ² IV on Day 1 every 4 weeks ^[50]  

First-line therapy for advanced triple-negative breast cancer (TNBC) that is programmed death–ligand 1(PD-L1) positive (combined positive score [CPS] ≥10⁹), regardless of BRCA mutation status ^[51] :

• Pembrolizumab 200 mg IV every 3 weeks plus
• Albumin-bound paclitaxel 100 mg/m ² IV on Days 1, 8, and 15 of every 28-day cycle or
• Paclitaxel 90 mg/m ² IV on Days 1, 8, and 15 of every 28-day cycle or
• Gemcitabine 1000 mg/m ² IV plus carboplatin AUC 2 IV on Days 1 and 8 of every 21-day cycle

First-line therapy for PD-L1–negative, BRCA1 or BRCA2 wild-type TNBC:

• Albumin-bound paclitaxel 100 mg/m ² IV on Days 1, 8, and 15 of every 28-day cycle or
• Gemcitabine 1000 mg/m ² IV plus carboplatin AUC 2 IV on Days 1 and 8 of every 21-day cycle

First-line therapy for PD-L1–negative, BRCA1- or BRCA2-mutated TNBC: 

• Olaparib  300 mg PO BID or
• Talazoparib 1 mg PO daily

Second-line therapy for advanced TNBC:

• Sacituzumab govitecan 10 mg/kg IV on Days 1 and 8 of every 21-day cycle ^[52]

Third-line therapy and beyond for advanced TNBC is with any of the following:

• Paclitaxel 80 mg/m ² IV weekly
• Docetaxel 60-100 mg/m ² IV every 3 weeks for at least 6 cycles or (off-label) 40 mg/m ² IV weekly for 6 weeks followed by a 2-week rest and then repeat ^[47]
• Eribulin 1.4 mg/m ² IV on Days 1 and 8 every 3 weeks
• Gemcitabine 1,250 mg/m ² IV on Days 1 and 8 in combination with paclitaxel of a 21-day cycle or  (off-label) 800-1200 mg/m ² IV on Days 1, 8, and 15 of a 28-day cycle ^[48]
• Vinorelbine (off-label) 25 mg/m ² IV weekly ^[49]  
• Pegylated liposomal-encapsulated doxorubicin (off-label) 50 mg/m ² IV on Day 1 every 4 weeks ^[50]
• Capecitabine fixed dose 1500 mg PO BID 7 days on, 7 days off ^[43]   

First-line therapy for HER+ metastatic breast cancer ^[53] :

• Docetaxel 75 mg/m ² IV every 3 weeks plus
• Trastuzumab 8 mg/kg IV on Day 1, then 6 mg/kg every 3 weeks plus
• Pertuzumab 840 mg IV on Day 1, then 420 mg IV every 3 weeks

Second-line therapy for HER+ metastatic breast cancer:

• Trastuzumab deruxtecan 5.4 mg/kg IV every 3 weeks ^[54]

Second-line therapy for HER+ metastatic breast cancer, including brain metastasis ^[55] :

• Tucatinib 300 mg PO daily plus
• Capecitabine 1000 mg/m ² PO BID on Days 1-14 plus
• Trastuzumab 8 mg/kg IV on Day 1 followed by 6 mg/kg every 3 weeks ^[55]

Third-line therapy and beyond for HER+ metastatic breast cancer can be with any of the following:

• Ado-trastuzumab 3.6 mg/kg IV every 3 weeks ^[56]
• Neratinib 240 mg PO once daily plus capecitabine 750 mg/m ² PO BID on Days 1-14 ^[57]

• Lapatinib 1250 mg PO in days 1-21 every 3 weeks plus capecitabine 1000 mg/m² PO BID on days 1-14

• Margetuximab 15 mg/kg IV every 3 weeks plus chemotherapy ^[58]

• Trastuzumab 4 mg/kg IV on Day 1, then  2 mg/kg IV weekly or  8 mg/kg IV on Day 1, followed by 6 mg/kg every 3 weeks, in combination with single-agent chemotherapy

Any of the following chemotherapy regimens may be used in combination with margetuximab or trastuzumab ^[58] :

• Capecitabine 1000 mg/m ² PO BID on Days 1-14
• Eribulin 1.4 mg/m ² IV on Days 1 and 8 every 3 weeks
• Gemcitabine 1000 mg/m ² IV on days 1 and 8 every 3 weeks
• Vinorelbine (off-label) 25 mg/m ² on Days 1 and 8 every 3 weeks ^[49]

Considerations

See the list below:

• The FDA has approved several biosimilars of  trastuzumab (Herzuma, Kanjinti, Ogivri, Ontruzant, Trazimera) to treat HER2-overexpressed breast cancer. The availability of biosimilars provides additional treatment options for patients in the adjuvant setting.
• The FDA granted accelerated approval to a fixed-dose  pertuzumab/trastuzumab/hyaluronidase combination (Phesgo) for subcutaneous (SC) use in combination with IV chemotherapy, for adjuvant treatment of patients with HER2-positive early breast cancer at high risk of recurrence. ^[35]  Pertuzumab/trastuzumab/hyaluronidase may be substituted anywhere that the combination of IV pertuzumab and IV trastuzumab are given as part of systemic therapy.
• Trastuzumab/hyaluronidase (Herceptin Hylecta) for SC use may be substituted for trastuzumab IV.

Surgical options include the following:

• Lumpectomy to negative margins (no tumor at ink for invasive disease, 2 mm for DCIS)
• Mastectomy with or without reconstruction reconstruction
• Axillary assessment is usually performed with sentinel lymph node biopsy (SLNB). Axillary dissection may be considered in cases of node-positive breast cancer.
• Although axillary dissection had been the standard of care for patients with a positive SLNB, studies have indicated comparable local and systemic control rates without axillary dissection for patients who also receive radiation and systemic chemotherapy. ^{[59, 60]}

Radiation therapy (RT) is used in patients who undergo lumpectomy or, in selected cases, after mastectomy; treatment fields are determined by axillary node status. RT should follow chemotherapy if chemotherapy is indicated.

Patients undergoing lumpectomy with surgical axillary staging

RT recommendations are based on the patient's axillary node status. In patients with ≥4 positive axillary nodes, treatment is as follows:

• Whole-breast radiation therapy (WBRT) with or without boost to the tumor bed
• Comprehensive regional nodal irradiation (RNI) including any portion of the undissected axilla at risk

In patients with 1-3 positive axillary nodes, treatment is as follows:

• All of the following criteria met: cT1-T2 cN0, no preoperative chemotherapy, 1-2 positive sentinel lymph node (SLNs) – WBRT with or without boost to the tumor bed; comprehensive RNI with or without inclusion of axilla
• Not all the above criteria met – WBRT with or without boost, including any portion of undissected axilla at risk; strongly consider RNI

In patients with negative axillary nodes, treatment is as follows:

•  WBRT with or without boost to the tumor bed
• Partial breast irradiation (PBI) may be considered in selected patients

Even without RT, risk of recurrence is extremely low in patients aged 55 and older with low-grade luminal A–type breast cancer (node-negative, grade 1 or 2 tumors < 2 cm) and a Ki67 tumor cell count of 13.25% or less, who receive breast-conserving surgery and endocrine therapy. ^[61]  

Patients undergoing total mastectomy with surgical axillary staging, with or without reconstruction

RT recommendations are based on the patient's axillary node status, as follows (note that comprehensive RNI may include any portion of undissected axilla at risk):

• Negative axillary nodes, tumor ≤5 cm, and margins ≥1 mm – No RT needed
• Negative axillary nodes, tumor ≤5 cm, and negative margins < 1 mm – Consider RT to the chest wall; for high-risk patients, consider adding comprehensive RNI
• Negative axillary nodes and tumor > 5 cm or positive margins – Consider RT to the chest wall, with or without comprehensive RNI
• 1-3 positive axillary nodes – Consider RT to the chest wall, with or without infraclavicular and supraclavicular nodes; consider RT to internal mammary nodes
• ≥4 positive axillary nodes – RT to the chest wall plus consider comprehensive RNI
• Margins positive – Re-excision to negative margins (preferred); if unable to excise, then strongly consider RT with or without comprehensive RNI

Invasive Lobular Carcinoma

Invasive lobular carcinoma (ILC) is the second most common histologic subtype of breast cancer after invasive ductal carcinoma (IDC), accounting for 10-15% of all breast cancer cases. ^[62]

The majority of ILCs are ER-positive and HER2-negative and exhibit distinct clinicopathologic and molecular characteristics compared with IDC. Those features impact the response of ILCs to systemic therapy:

• Early-stage ILC tends to be less responsive than IDC to neoadjuvant chemotherapy. ^[63] However, ILC tends to respond well to neoadjuvant endocrine therapy. ^[64] In the adjuvant setting, ILC patients treated with a nonsteroidal aromatase inhibitors ( anastrozole or letrozole) had better long-term outcomes than those treated with tamoxifen. ^{[65, 66]} . 
• Metastatic endocrine-sensitive ILC tends to respond well to endocrine therapy in combination with targeted therapy (eg, a CDK4/6 inhibitor, everolimus, alpelisib). ^[67] Once ILC becomes endocrine refractory, capecitabine might be the preferred agent of choice. ^[68] Data are lacking on whether antibody-drug conjugates are effective in ILC. 

Oligometastatic disease

See the list below:

• Surgery and/or radiation therapy may be able to achieve prolonged disease control in selected patients with oligometastatic disease.

• Management of oligometastatic disease should be overseen by a multidisciplinary team.

Patient age and comorbidities must be taken into account when planning breast cancer treatment. In patients age ≥ 65 years with stage I-III breast cancer for whom neoadjuvant or adjuvant chemotherapy is planned, tools such as the Cancer and Aging Research Group (CARG) score should be used to determine the risk of grade 3-5 chemotherapy toxicity. ^[69]

Considerations regarding comorbidities include the following:

• Certain comorbidities may pose relative or absolute contraindications to specific therapies, including cardiac disease (anthracyclines) and neuropathy (taxanes).
• Adjustment of prognosis for comorbidity is more complex and is influenced by its severity and duration, patient age, and presence of other comorbidities.
• For patients with significant comorbidities characterized by organ system dysfunction (eg, congestive heart failure, chronic obstructive pulmonary disease, cirrhosis, chronic kidney disease), the prognosis for the comorbidity must be considered in the context of the cancer; the Charlson index is commonly used for this purpose. ^[70]