Approach

The treatment for primary invasive breast cancer is complex and highly individualised, and takes into consideration many different factors, including age, performance status, disease stage, tumour type, tumour biology (e.g., hormone-receptor [HR] status, HER2 status, genetic profile), and prognosis (risk of recurrence).[125][145]​​[169]​​[208][209][210][211]

There are differences in approach for patients with early-stage breast cancer (stages I to IIB [T2 N1 M0]) and those with locally advanced breast cancer (stages IIB [T3 N0 M0] to III, including inflammatory breast cancer).[125]​​[145][208][210]

The goals of treatment are to:

  • Improve survival

  • Reduce the risk of both local and distant recurrence

  • Maintain long-term quality of life

To achieve these goals requires a multi-modal treatment approach that may include one or more of the following:[125][145]​​[208][210]

  • Surgical resection of the primary tumour (e.g., total mastectomy or lumpectomy [breast-conserving surgery])

  • Surgical staging of the axillary lymph nodes (e.g., sentinel lymph node biopsy [SLNB] or axillary lymph node dissection [ALND])

  • Chemotherapy

  • Radiotherapy

  • Targeted therapy (e.g., endocrine therapy for HR-positive disease, HER2-targeted therapy, immunotherapy for triple-negative disease)

Patients are best managed by a multidisciplinary team of breast cancer specialists comprising medical oncologists, surgeons, radiation oncologists, radiologists, pathologists, and nurses.​[145]​​[208][210] Patients should be involved in decision-making and treatment planning throughout the course of treatment.

Genetic counselling is recommended for women at high risk of hereditary breast cancer. The impact of breast cancer treatment on fertility should be discussed with women of reproductive age.[125][145]​​

Early-stage breast cancer (stages I to IIB [T2 N1 M0])

Initial treatment for early-stage breast cancer is usually primary breast surgery (e.g., lumpectomy or total mastectomy) with axillary lymph node surgical staging (e.g., SLNB with or without ALND).[125][145]​​​​[210]

Patients may also receive adjuvant (postoperative) systemic treatment (e.g., chemotherapy and/or targeted therapy) following surgery, depending on disease stage, age, performance status/fitness, HER2 status, HR status, and other prognostic factors.[125][145]​​​[210]​​​[212][213][214][215][216][217]

Certain patients with early-stage breast cancer should be considered for neoadjuvant (preoperative) systemic treatment, including those with large tumours, node-positive disease, or high-risk triple-negative disease or HER2-positive disease.[125]

Radiotherapy is strongly recommended following lumpectomy.[125][145]​​​​[210][Evidence B]​ Radiotherapy may be considered following total mastectomy in certain high-risk patients.[125][145]​​​[210][Evidence B]​ The type and extent of radiotherapy is guided by several factors (e.g., extent of lymph node involvement and tumour resection margins) and individualised to the patient.

Systemic treatments and radiotherapy are the main treatment options for patients unsuitable for surgery.[125][208]

Locally advanced breast cancer (stages IIB [T3 N0 M0] to III)

Initial treatment for locally advanced breast cancer is usually neoadjuvant (preoperative) chemotherapy followed by total mastectomy with ALND (i.e., modified radical mastectomy).[125][208][210]​​ Patients with clinically node-negative locally advanced breast cancer (e.g., T3 N0 M0) may undergo SLNB instead of ALND.[125]​ Targeted treatments may be given in combination with neoadjuvant chemotherapy for certain patients (e.g., HER2-targeted therapy for HER2-positive disease or immunotherapy for triple-negative breast cancer).

Radiotherapy is recommended following mastectomy, particularly for patients at high risk of recurrence.[125][208][210][Evidence B]

Some patients who respond well to neoadjuvant systemic treatment may be considered for lumpectomy plus whole-breast radiotherapy instead of mastectomy.[125][208][210][Evidence A]

Patients with HR-positive disease should also receive endocrine therapy for a minimum of 5 years, which is usually given after surgery.[125][208][210]​​​ HER2-targeted therapy and immunotherapy are continued in the adjuvant setting. Certain patients at high risk of recurrence may be eligible for targeted adjuvant systemic therapy, including kinase inhibitors (abemaciclib or ribociclib) for HR-positive, HER2-negative breast cancer or olaparib (a poly [adenosine diphosphate-ribose] polymerase [PARP] inhibitor) for patients with BRCA-mutations.[125]

Lumpectomy or total mastectomy

Patients with early-stage breast cancer can choose to undergo lumpectomy or total mastectomy.[218]

Lumpectomy followed by whole-breast radiotherapy (or accelerated partial breast irradiation/partial breast irradiation [APBI/PBI] in some low-risk patients) is generally preferred to mastectomy for early-stage breast cancer, depending on the location of the tumour, extent of disease, and the size of the affected breast. However, there are absolute and relative contraindications to lumpectomy requiring radiotherapy.[125]

Absolute contraindications include:[125]

  • Pregnancy, if radiotherapy cannot be given within 12-16 weeks (lumpectomy in the second or third trimester may allow deferral of radiotherapy until after delivery)

  • Diffusely positive pathological margins

  • Homozygous (biallelic inactivation) for ATM mutation

  • Diffuse suspicious or malignant-appearing microcalcifications

  • Widespread disease that cannot be incorporated by local excision of a single region or segment of breast tissue that achieves negative margins with a satisfactory cosmetic result

Relative contraindications include:[125]

  • Prior radiotherapy to the breast or chest wall (knowledge of doses and volumes prescribed is essential)

  • Active connective tissue disease involving the skin (e.g., systemic lupus erythematosus, scleroderma)

  • Positive pathological margins

  • Genetic predisposition to breast cancer

Contraindications to lumpectomy such as widespread disease and diffuse microcalcifications can be evaluated more fully with use of breast magnetic resonance imaging (MRI) and MRI-guided biopsy (which is required if lesions are only seen by MRI). Patients with diffuse microcalcifications should have additional biopsies performed to evaluate the extent of disease. Patients with disease not limited to a single quadrant or who have larger breasts may, in some cases, be feasibly treated with lumpectomy.

Re-excision is recommended for patients with a positive margin (‘ink on tumour’; 0 mm) after lumpectomy.[125][219][210]​​​​​ The re-excision rate for positive margins following lumpectomy is 14%.[220]​ Risk of local recurrence may be increased in patients with close margins.[221] ​Therefore, some guidelines recommend consideration of further surgery if there are close margins (e.g., >0 mm and <1 mm or <2 mm), with individualised decisions about further treatment made using shared decision-making.[210][222]

Total mastectomy with ALND (following neoadjuvant systemic treatment) is usually recommended for patients with locally advanced breast cancer, particularly those with inflammatory breast cancer.[125][208] However, some patients who respond well to neoadjuvant systemic treatment may be suitable for lumpectomy with sentinel lymph node sampling followed by whole-breast radiotherapy.

Pregnancy

Evidence suggests that pregnant women with early-stage and locally advanced breast cancer can be safely treated with lumpectomy and neoadjuvant or adjuvant chemotherapy (e.g., anthracyclines or alkylating agents) in the second or third trimester.[125][223][224][225][226][227]​​ Adjuvant HER2-targeted and/or endocrine therapies and radiotherapy are delayed until after delivery.

Breast reconstruction

Should be discussed with all patients before breast surgery. Breast reconstruction can be performed at initial surgery or delayed, but timing should not interfere with appropriate surgical treatment. Likely cosmetic outcome should be evaluated before breast-conserving surgery; oncoplastic techniques can be considered to improve cosmetic results, although there is a lack of evidence for oncological outcomes.​[228][229][125]

Immediate breast reconstruction following mastectomy is not associated with an increased incidence of local recurrence compared with mastectomy alone, so long as surgical removal of the breast cancer is not delayed.[230] However, immediate breast reconstruction is contraindicated in patients with inflammatory breast cancer due to the need for expeditious postoperative radiotherapy.[125]

Skin-sparing mastectomy (with or without sparing of the nipple) can improve cosmesis, and is feasible and effective in women with early-stage breast cancer. No significant difference in local recurrence rates have been found between total mastectomy and skin-sparing mastectomy, but factors such as tumour size and high histological grade may increase the risk of recurrence.[231][232][233]​ Nipple-sparing mastectomy should only be carried out if there is confirmation that the nipple is tumour-free during surgery.

Women with germline BRCA1 or BRCA2 mutations can be treated with breast-conserving therapy.[234] Guidelines recommend discussing the relative risks and benefits of breast-conserving therapy versus ipsilateral therapeutic and contralateral risk-reducing mastectomy. Nipple-sparing mastectomy is appropriate. Considerations include age at diagnosis, which is the strongest predictor of future contralateral breast cancer, comorbidities and life expectancy, family history of breast cancer, overall prognosis from breast and any other cancers, and the patient's ability to undergo screening MRI.[234]

Smoking, obesity, larger breast size, and diabetes may increase complication rates associated with breast reconstruction (e.g., wound healing complications, flap failure); therefore, patients should be fully informed and appropriately assessed.[235][236][237][238]

Breast reconstruction is often followed by autologous fat grafting, which is an elective procedure where fat harvested by liposuction from the abdomen or thighs is injected into the reconstructed breast to improve cosmesis. Autologous fat grafting is not associated with an increased risk of locoregional recurrence.[239] This procedure is associated with risk of development of fat necrosis.

Axillary lymph node surgical staging

Axillary lymph node involvement is an important prognostic factor in patients with breast cancer. Patients should undergo a comprehensive clinical evaluation of the axilla prior to surgery. This may include clinical examination of the axillary region, ultrasound, breast MRI, or US-guided lymph node biopsy of suspicious lymph nodes.

SLNB is a safe and accurate surgical procedure for evaluating axillary nodes in early breast cancer.[240][241][242][243][244][245][246][247]​​ It involves identifying, removing, and examining sentinel lymph node/s (SLNs) for the presence of metastases. It is less invasive than ALND, and leads to fewer complications (e.g., lymphoedema).[240][242]​​ 

Clinically node-negative patients

In patients with early-stage breast cancer who are clinically node-negative or have limited axillary lymph node involvement (≤2 suspicious lymph nodes) on imaging, an SLNB should be performed during surgery.[125][145]​​​​[248][249]​​​ SLNB may be considered in patients with clinically node-negative locally advanced breast cancer (e.g., T3 N0 M0).[125][249]​​​ 

Patients who have a negative SLNB do not require ALND.[125][249]​​​​ ​​ For patients with multiple positive nodes on SLNB, ALND is typically recommended. However, ALND may be avoided in patients who have 1 or 2 positive sentinel lymph nodes, no neoadjuvant chemotherapy, and radiotherapy is planned following surgery.[125][249]​​​​[250][251][252][253][254][255]​​​

SLNB may be omitted for women with node-negative breast cancer aged ≥70 years with early-stage HR-positive, HER2-negative disease.[256]​ Guidelines further suggest that omission of SLNB may be considered in highly select post-menopausal patients aged ≥50 years with HR-positive, HER2-negative disease, tumour ≤2 cm, grade 1-2, and clinically node-negative disease (on preoperative axillary lymph node ultrasound), who undergo breast-conserving surgery and (if aged <65 years) whole-breast radiotherapy.[249][257][258]​​​ SLNB omission may avoid adverse effects, such as reduced arm or shoulder mobility, lymphoedema, and pain.[259]​ 

Decisions about omitting SLNB should be made using shared decision-making.[249]

Clinically node-positive patients

In patients with early-stage breast cancer with clinically suspicious (palpable) lymph nodes or significant axillary lymph node disease (≥3 suspicious lymph nodes) on imaging, a biopsy (fine-needle aspiration [FNA] or core needle biopsy) of the axillary lymph nodes should be performed to confirm nodal involvement.[125] If the biopsy is positive, ALND or neoadjuvant chemotherapy is recommended.[125] If the biopsy is negative, SLNB is recommended to determine whether further axillary surgery is warranted.[125]

ALND is generally recommended for patients with clinically node-positive locally advanced breast cancer or inflammatory breast cancer.​[260][261][262]​​ Neoadjuvant systemic therapy has been shown to downstage patients with clinically positive axillary lymph nodes, and should be considered in cases when extensive axillary dissection is necessary.[263][264][265]

Axillary staging after neoadjuvant chemotherapy in node-positive breast cancer

Patients who remain clinically node-positive after neoadjuvant chemotherapy should undergo ALND. Those who become clinically node-negative after neoadjuvant chemotherapy are candidates for SLNB. The addition of targeted axillary dissection may reduce the rate of false negatives compared with SLNB alone.[125]

Axillary staging during pregnancy

The use of SLNB during pregnancy is controversial due to possible fetal toxicity associated with radioactive tracers, and possible anaphylaxis (and harm to the fetus) associated with blue dyes.[266]

Use of a radioactive tracer (e.g., technetium [Tc]-99m sulfur colloid or Tc-99m albumin nanocolloid) is deemed to be safe, but use of isosulfan blue, methylene blue , or superparamagnetic iron oxide dye is not recommended in pregnancy due to a lack of safety data.[227][125][267][268]​​[269]

Neoadjuvant (preoperative) systemic therapy

Patients with locally advanced, inoperable, or inflammatory breast cancer are treated initially with neoadjuvant systemic therapy.

Certain patients with early-stage breast cancer should be considered for neoadjuvant (preoperative) systemic treatment, including those with:[125]​​

  • Triple-negative disease or HER2-positive disease with positive nodes and/or large tumours (i.e., >2 cm)

  • Large primary tumour relative to breast size who wish to have breast conservation

  • Clinically node-positive disease likely to become clinically node-negative with neoadjuvant systemic therapy

  • A delay before surgery (e.g., for genetic testing or to consider reconstructive options).

Neoadjuvant treatment may also be considered for triple-negative disease or HER2-positive disease with negative nodes and tumour size >1 cm.

Neoadjuvant chemotherapy

Widely utilised to downsize large and/or inoperable tumours enable lumpectomy or to make them operable, to decrease the need for ALND, and to treat inflammatory breast cancer.[125][208][270][271][272]​​​​ Tumour histology, grade, stage, HR status, and HER2 expression should be used to guide clinical decisions as to whether to use neoadjuvant chemotherapy.[272]

Neoadjuvant chemotherapy is reported to have similar rates of distant recurrence and overall survival compared with adjuvant chemotherapy in patients with early-stage breast cancer, but is associated with higher rates of local recurrence.[273][274][275]​​​ However, developments in treatments and imaging, and accurate staging before therapy, are likely to reduce the risk of local recurrence.[125] Higher rates of recurrence-free survival and successful lumpectomy have been reported with neoadjuvant chemotherapy, compared with adjuvant chemotherapy, in patients with a pathological complete response (i.e., no invasive cancer in breast and axillary lymph nodes).[276][277]​​​​ These effects are most dramatic in triple-negative disease and HER2-positive disease.[273][278][279][280][281]

Tumour response should be routinely assessed by clinical examination and imaging (e.g., mammogram, ultrasound, and/or MRI) during neoadjuvant therapy.[125][150]​​ If there is no response or progression is observed, an alternative neoadjuvant regimen and/or preoperative radiation may be considered. If progression is observed and breast cancer is operable, the patient should be referred for surgery promptly.[125]

Chemotherapy regimens

Usually include an anthracycline and taxane, with the duration of therapy of approximately 4.5 to 5 months. In most cases, assuming clinical response to chemotherapy and acceptable tolerability, patients will receive all chemotherapy in the neoadjuvant setting.

Recommended regimens include:[125]

  • Docetaxel plus cyclophosphamide (TC)

  • Doxorubicin plus cyclophosphamide (AC) followed or preceded by paclitaxel

Other regimens that may be considered include:

  • Doxorubicin plus cyclophosphamide (AC)

  • Doxorubicin plus cyclophosphamide (AC) followed by docetaxel

  • Epirubicin plus cyclophosphamide (EC)

  • Cyclophosphamide plus methotrexate plus fluorouracil (CMF)

  • Docetaxel plus doxorubicin plus cyclophosphamide (TAC)

Recommended regimens for specific patient populations include:

  • Docetaxel plus carboplatin (a preferred regimen in HER2-positive patients, combined with trastuzumab with or without pertuzumab)

  • Paclitaxel (a preferred regimen in low-risk HER2-positive patients when combined with trastuzumab)

  • Carboplatin plus paclitaxel, followed by cyclophosphamide plus doxorubicin or epirubicin (a preferred neoadjuvant therapy in triple-negative patients with stage II-III disease, when combined with pembrolizumab)

Anthracycline-based regimens (e.g., doxorubicin, epirubicin) with a taxane (e.g., docetaxel, paclitaxel), administered concurrently or sequentially, have been shown to reduce the risk of recurrence and improve disease-free survival and overall survival compared with anthracycline-based regimens without a taxane, and compared with non-anthracycline-based regimens.[282][283][284][285][286][287][288][289][290][291][292][293] [ Cochrane Clinical Answers logo ] ​​​​​​ However, anthracyclines incur the risk of cardiotoxicity, which must be weighed against their benefit. The optimal timing for administering a taxane with an anthracycline-based regimen (i.e., concurrently or sequentially) is unclear, but risk of toxicity is lower if given sequentially.​[288][289][294][295][296]​​​​​​ Sequential AC plus paclitaxel chemotherapy may increase the incidence of amenorrhoea, which has been shown to improve outcomes for pre-menopausal women with HR-positive disease.[295]​ Dose-dense chemotherapy schedules have been shown to lower the risk of recurrence.[125][297]

Non-anthracycline-based regimens (e.g., TC and CMF) are less preferred but may offer some advantages over anthracycline-based regimens (e.g., lower risk of toxicity, cytopenias, and leukaemia).[298][299][300]​​​​ Improved disease-free and overall survival has been reported with 4 cycles of TC compared with AC (without a taxane) in the adjuvant setting.[299][300][301]​​​​ However, these two-drug short regimens (4 cycles) are considered less effective than the sequential AC plus paclitaxel regimen or the concurrent three-drug regimen, TAC. CMF may be used concurrently with radiotherapy.[125][302]

Neoadjuvant HER2-targeted therapy

Neoadjuvant therapy for patients with HER2-positive breast cancer should include trastuzumab, and may also include pertuzumab (dual anti-HER2 blockade), combined with neoadjuvant chemotherapy.[125]​​[303]​​​

Patients with high-risk HER2-positive breast cancer (e.g., node-positive and/or tumours ≥2 cm) should be considered for dual anti-HER2 blockade with trastuzumab and pertuzumab in the neoadjuvant setting (combined with chemotherapy).[125]

Recommended regimens include: docetaxel plus carboplatin plus trastuzumab plus pertuzumab (TCHP); or docetaxel plus carboplatin plus trastuzumab (TCH).[125] Paclitaxel plus trastuzumab may be considered for low-risk disease, particularly in patients ineligible for standard regimens.​[125]

Other regimens that may be considered include: docetaxel plus cyclophosphamide plus trastuzumab (TAC); doxorubicin plus cyclophosphamide (AC) followed by docetaxel or paclitaxel plus trastuzumab, with or without pertuzumab; or paclitaxel plus trastuzumab plus pertuzumab.[125]

If an anthracycline-based chemotherapy regimen (e.g., AC plus paclitaxel) is being used, trastuzumab (with or without pertuzumab) should be administered after the anthracycline (e.g., concurrently with a taxane if AC plus paclitaxel is used) to avoid increasing the risk of cardiotoxicity.[125]

Alternative taxanes (e.g., paclitaxel, nanoparticle albumin-bound [nab] paclitaxel) may be substituted, if necessary (e.g., if the patient has a hypersensitivity reaction).[125]

Trastuzumab combined with neoadjuvant chemotherapy has been shown to improve event-free survival (hazard ratio [HR] 0.59, 95% CI 0.38 to 0.90), and response rate, compared with neoadjuvant chemotherapy alone in patients with HER2-positive locally advanced breast cancer.[303]

Dual anti-HER2 blockade combined with neoadjuvant chemotherapy improves response rates compared with: single anti-HER2 blockade (with trastuzumab) combined with neoadjuvant chemotherapy; and trastuzumab emtansine (a HER2-targeted monoclonal antibody and microtubule inhibitor conjugate) plus pertuzumab without neoadjuvant chemotherapy.[304][305][306][307][308][309][310][311][312]​​​​ Risk of cardiovascular adverse effects (e.g., symptomatic left ventricular systolic dysfunction) does not appear to be increased with dual anti-HER2 blockade compared with trastuzumab alone (i.e., single anti-HER2 blockade), even when used with an anthracycline-based chemotherapy regimen.[305][307][308]

Results from one phase 3 study suggest that dual anti-HER2 blockade may avoid the use of anthracycline in the neoadjuvant setting.[313][314]​​ Event-free survival and overall survival were similar for patients receiving neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade at 3-year follow-up.[314]

A fixed-dose formulation of trastuzumab for subcutaneous use (trastuzumab/hyaluronidase) is non-inferior to intravenous trastuzumab and has been approved by the US Food and Drug Administration (FDA) for use in HER2-overexpressing breast cancer.[315] The FDA has also approved a fixed-dose subcutaneous combination of trastuzumab/pertuzumab/hyaluronidase.

Following a complete pathological response, trastuzumab and pertuzumab should be continued in the adjuvant setting to complete 1 year of treatment.[303][306][316][317]​​​​ For those with residual disease following neoadjuvant dual HER2 blockade, trastuzumab emtansine can be used for adjuvant treatment.[318]

Neoadjuvant endocrine therapy

Neoadjuvant endocrine therapy alone may be considered for post-menopausal women with HR-positive, HER2-negative disease. It may be of particular use if chemotherapy is unsuitable (e.g., due to age and/or comorbidities) or in women who have low-risk disease.[125]​​​​[210][272][319][320]​​​​​[321][Evidence C]​ In these patients, use of aromatase inhibitors (e.g., exemestane, letrozole, or anastrozole) is preferred to tamoxifen.[272][320]​​​​​ Response rate and breast conservation rate are reported to be higher with aromatase inhibitors compared with tamoxifen in the neoadjuvant setting.[320]

Neoadjuvant systemic therapy for triple-negative breast cancer

For patients with stage II or III triple-negative disease, immunotherapy with pembrolizumab (an anti-programmed death receptor-1 [anti-PD-1] monoclonal antibody) is recommended in combination with chemotherapy. The preferred regimen is pembrolizumab plus carboplatin plus paclitaxel, followed by pembrolizumab plus cyclophosphamide plus doxorubicin or epirubicin. Following surgery, adjuvant pembrolizumab is continued alone.[125][212][213]

In one phase 3 trial, the percentage of patients with triple-negative breast cancer with a pathological complete response was significantly higher, and event-free survival significantly longer, among those who received pembrolizumab plus neoadjuvant chemotherapy than those who received placebo plus neoadjuvant chemotherapy.[213][263]​

Patients receiving pembrolizumab should be closely monitored for treatment-related adverse effects. Guidelines for monitoring patients on immunotherapy and managing immunotherapy-related toxicity are available.[322][323][324]

For patients with triple-negative disease receiving neoadjuvant chemotherapy, the addition of a platinum agent to chemotherapy regimens may be considered.[125][210][325]​​​ However, the optimal regimen is uncertain.

Adjuvant chemotherapy

Decisions about chemotherapy should be individualised, taking into account lymph node involvement, tumour size and grade, HR-status, and HER2 expression. Chemotherapy regimens used in the adjuvant setting are the same as those used in the neoadjuvant setting, and the same considerations apply regarding sequencing and toxicity.[125][145]​​​[294][297][298]​​​[326]​​[327][328]

Adjuvant chemotherapy is typically recommended for patients at risk of recurrence (e.g., large tumours or node-positive disease).[125] It may be considered for patients with smaler tumours (≤1.0 cm) if the tumour is triple-negative or HER2-positive.[125] Adjuvant chemotherapy is not usually recommended for node-negative patients with tumours ≤0.5 cm, although it may be considered for those with HER2-positive disease.[125]

Additional risk assessment with a gene expression assay is recommended for patients with HR-positive, HER2-negative disease with tumour size >0.5 cm, or with 1-3 positive nodes, or with micrometastases, to help guide decisions on the use of adjuvant chemotherapy.[125] The 21-gene Oncotype Dx® assay is preferred because it is validated for predicting the benefit of chemotherapy. Other assays (e.g., Breast Cancer Index, MammaPrint®, Prosigna®, EndoPredict®) may be considered to help assess the risk of recurrence.[125][165][166][167][168][169][170][171][329]​​ Several clinical trials (MINDACT, TAILORx, and Plan B) have identified groups of patients who can safely avoid adjuvant chemotherapy.[172][330][331][332]

Adjuvant capecitabine may be used in patients with triple-negative breast cancer who have residual disease after neoadjuvant systemic therapy. Capecitabine may also be used as maintenance therapy after adjuvant chemotherapy for triple-negative disease.[125][333]​ Capecitabine is given after completion of adjuvant radiotherapy.

Dose-intense chemotherapy, where drugs are given at shorter intervals or sequentially at full dose (instead of concurrently at lower doses), reduces the 10-year risk of breast cancer recurrence, breast cancer mortality, and all-cause mortality.[334]

Adjuvant HER2-targeted therapy

Adjuvant trastuzumab (combined with adjuvant chemotherapy) is recommended for patients with HER2-positive early-stage breast cancer who are node-negative and have HR-positive tumours >0.5 cm or HR-negative tumours >1.0 cm.[125][209][335][336][337][338][339]​​ For patients with smaller tumours, adjuvant trastuzumab should be considered, although benefits are less certain.[209]

Dual anti-HER2 blockade with trastuzumab plus pertuzumab (combined with adjuvant chemotherapy) is recommended for patients with HER2-positive early-stage breast cancer who are node-positive and may be considered for node-negative tumours >2 cm in size. Dual anti-HER2 blockade has been found to improve response rate and disease-free survival rate with minimal additional toxicity compared with trastuzumab alone.[125][304]​​[312][340][341]

The sequencing and timing of adjuvant HER2-targeted therapy in combination with chemotherapy in the adjuvant setting follows the same principles as in the neoadjuvant setting. If an anthracycline-based chemotherapy regimen (e.g., AC plus paclitaxel) is being used, trastuzumab should be administered after the anthracycline (e.g., concurrently with a taxane if AC plus paclitaxel is used) to avoid increasing the risk of cardiotoxicity.​​ Trastuzumab can be administered concurrently with non-anthracycline-based chemotherapy regimens (e.g., docetaxel plus carboplatin).[209][335][336]

Disease-free survival and overall survival rates are similar when trastuzumab is added to an anthracycline-based regimen or a non-anthracycline-based regimen, but the risk of cardiotoxicity and leukaemia is lower when added to a non-anthracycline-based regimen.[335][337]​​​ Trastuzumab given concurrently with a taxane (e.g., paclitaxel, docetaxel) appears to be safe and is more effective than if given sequentially.[336]

​Patients with low-risk HER2-positive early-stage breast cancer (e.g., node-negative and small tumours) may be considered for adjuvant trastuzumab plus weekly paclitaxel (i.e., without an anthracycline), particularly if tolerability of chemotherapy is a concern due to age and/or comorbidities.[209][339][342][343]​​

HER2-targeted therapy should continue for 1 year. This provides optimal long-term benefits compared with continuing for a shorter (≤6 months) or longer (2 years) duration.[209][316][317][344][345][346][347][348][349]

Biosimilars of trastuzumab have been approved for the treatment of breast cancer, which offer similar efficacy, similar safety profile, and equivalent immunogenicity to the original product, without the added cost.[350]

A fixed-dose formulation of trastuzumab for subcutaneous use (trastuzumab/hyaluronidase) is non-inferior to intravenous trastuzumab and has been approved by the FDA for use in HER2-overexpressing breast cancer.[315] The FDA has also approved a fixed-dose subcutaneous combination of trastuzumab/pertuzumab/hyaluronidase.

Extended HER2-targeted therapy for high-risk patients

High-risk patients with HR-positive, HER2-positive disease can be considered for extended HER2-targeted therapy with neratinib for 1 year following initial adjuvant trastuzumab-based HER2-targeted therapy.[351][352]​​ Neratinib has been shown to significantly reduce relapse (5-year invasive disease-free survival rate of 90.2% vs. 87.7% for placebo), but it is associated with an increased risk of diarrhoea.[352]

Adjuvant HER2-targeted therapy for residual disease

Trastuzumab emtansine is an antibody-drug conjugate of trastuzumab and a cytotoxic microtubule inhibitor. It can be used for adjuvant treatment of HER2-positive patients with early breast cancer who have residual invasive disease at the time of surgery following neoadjuvant trastuzumab-based treatment.[318][353]​​​ Trastuzumab emtansine reduced the risk of recurrence or death by approximately 50% compared with trastuzumab alone in these patients.[318] Reports of fatigue, thrombocytopenia, and peripheral neuropathy were increased with trastuzumab emtansine.[318]

Adjuvant endocrine therapy for HR-positive disease

Endocrine therapy is recommended for most patients with HR-positive breast cancer (e.g., those who are node-positive, or node-negative with tumours >0.5 cm), which is usually given in the adjuvant setting (i.e., following surgery and chemotherapy if given).[125][145]​​​​[208][210]

Adjuvant endocrine therapy may be considered for patients who are node-negative with tumours ≤0.5 cm (i.e., low risk), based on a discussion with the patient about the risks and benefits.[125]

The type of endocrine therapy used in the adjuvant setting is determined by menopausal status at diagnosis.

Adjuvant endocrine therapy for pre-menopausal women with HR-positive disease

Pre-menopausal women with HR-positive disease are usually treated with adjuvant tamoxifen (following surgery and chemotherapy if given).[354][355]​​​​ For certain patients at high-risk of recurrence (e.g., young women with a high-grade tumour and positive nodes), tamoxifen or an aromatase inhibitor may be given in combination with ovarian suppression (e.g., goserelin) or ablation by surgical oophorectomy.[125][145]​​​[356]​​

Combining adjuvant endocrine therapy with ovarian suppression or ablation has been shown to improve rates of disease-free survival and reduce mortality in pre-menopausal women with HR-positive disease.[357][358][359][360]​​​​​ The decision to use ovarian suppression or ablation should take into account tumour and patient characteristics, and expected adverse effects, and be based on a discussion of the risks and benefits of treatment.[361]

Endocrine therapy is continued for at least 5 years. After 5 years of treatment with tamoxifen, some high-risk patients may consider continuing treatment with tamoxifen for a further 5 years, switch to an aromatase inhibitor for 5 years (if post-menopausal), or stop endocrine treatment (if pre-menopausal).[362][363]​​​​ Toxicity (including the rate of endometrial cancer) may be increased with extended tamoxifen treatment.[364]​ Those taking an aromatase inhibitor as initial endocrine therapy may consider continuing it for a further 3-5 years.[125]

Adjuvant endocrine therapy for post-menopausal women with HR-positive disease

Endocrine therapy is recommended for most patients with HR-positive breast cancer (e.g., those who are node-positive, or node-negative with tumours >0.5 cm), which is usually given in the adjuvant setting (i.e., following surgery and chemotherapy if given).[125][145]​​​[208][210]

Adjuvant endocrine therapy may be considered for patients who are node-negative with tumours ≤0.5 cm (i.e., low risk), based on a discussion with the patient about the risks and benefits.[125]

The type of endocrine therapy used in the adjuvant setting is determined by menopausal status at diagnosis.

Post-menopausal women with HR-positive disease are usually treated with adjuvant aromatase inhibitor therapy, which can be given for 5 years or for 2-3 years followed by tamoxifen (to complete 5 years of endocrine therapy). Alternatively, an aromatase inhibitor may be given after 2 or 3 years of tamoxifen (to complete 5 years of endocrine therapy).[125][145]​​ Adjuvant aromatase inhibitors have been shown to improve disease-free survival by 18% to 21% compared with adjuvant tamoxifen.[365][366][367][368]​​​​ The improved efficacy of aromatase inhibitors compared with tamoxifen is maintained over the long term.[369]

High-risk post-menopausal women with HR-positive disease (e.g., node-positive) may be considered for extended adjuvant endocrine therapy for up to 10 years to reduce the risk of recurrence.[370][371][372]​​​​​ The optimal duration is unknown; extended regimens reduce the risk of recurrence, particularly in higher-stage cancers, but risk of adverse effects is higher.[371][373][374]​​​​​

Tamoxifen may be be considered in post-menopausal women for 5 years (or up to 10 years if high risk) if aromatase inhibitors are declined or contraindicated.[125]​​

Adjuvant abemaciclib and ribociclib for HR-positive, HER2-negative disease

In HR-positive, HER2-negative patients, abemaciclib or ribociclib (cyclin-dependent kinase 4 and 6 [CDK 4/6] inhibitors), given in combination with endocrine therapy, lead to a significant improvement in invasive disease-free survival compared with endocrine therapy alone.[375][376]​​ Benefit has been shown to continue beyond completion of treatment with abemaciclib (5-year follow-up).[377]​ Either abemaciclib or ribociclib may be considered for patients with HR-positive, HER2-negative early breast cancer at high risk of recurrence.

  • Abemaciclib may be considered for patients who have: ≥4 positive axillary lymph nodes; or 1-3 positive axillary lymph nodes with tumour size ≥5 cm and/or histological grade 3 disease. Abemaciclib is recommended for 2 years in combination with endocrine therapy (plus ovarian suppression/ablation if indicated).[125][217][375]​​

  • Ribociclib may be considered for patients who have any lymph node involvement, or tumour size >5 cm, or grade 2 or grade 3 tumour of size 2-5 cm. Ribociclib is recommended for 3 years in combination with an aromatase inhibitor (plus ovarian suppression/ablation if pre-menopausal).[125][217]​​[376]​​

Treatment with abemaciclib or ribociclib is started after completion of surgery, radiotherapy, and/or chemotherapy, concurrently with endocrine therapy (with or without ovarian suppression/ablation).[125]

Adjuvant olaparib for HER2-negative, BRCA-positive disease

Olaparib can be offered to patients with HER2-negative breast cancer with high risk of recurrence and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants.[214][215][216]​ One year of adjuvant olaparib should be offered after completion of radiotherapy. 

Olaparib can be given at the same time as adjuvant endocrine therapy. The optimal sequence of therapy is not known for patients eligible for both adjuvant olaparib and abemaciclib or ribociclib, or for patients with triple-negative disease eligible for both adjuvant olaparib and capecitabine.[125]

Radiotherapy post-lumpectomy

Radiation planning and delivery should be individualised. CT-based treatment planning is preferred, and techniques to reduce radiation exposure of normal tissues and organs should be used.[125]

Whole-breast radiotherapy is strongly recommended for most patients following lumpectomy (and chemotherapy if given) as it reduces the risk of local recurrence and breast cancer mortality.[125][145]​​​​​​​[378][379][380][381]​​​​​ Boost radiotherapy and RNI therapy can further reduce the risk of recurrence in patients with high-risk disease.[145][382][383][384][385]​​​​​ For highly selected low-risk patients, APBI/PBI may be an alternative option to whole-breast radiotherapy, with the benefit of sparing healthy breast tissue, and reducing treatment time and some treatment-related adverse effects (e.g., acute skin toxicity).[125][145][210]​​​​​​[386][387]​​​​​​​ Radiotherapy is given after completion of adjuvant chemotherapy (except capecitabine and olaparib, which are given after radiotherapy, and CMF, which can be given concurrently).[125] Radiotherapy can be given concurrently with adjuvant trastuzumab in HER2-positive patients.[388]​​​​​​​​​

Consideration may be given to omitting radiotherapy in highly selected older patients (e.g., aged ≥65 years, HR-positive, HER-negative, small tumour size) who are planning endocrine therapy.[125][145][210]

Radiotherapy post-lumpectomy: negative axillary nodes

Whole-breast radiotherapy, with or without boost to the tumour bed, is recommended for most patients with negative axillary nodes.[125]

  • Comprehensive RNI can be considered alongside whole-breast radiotherapy for patients with high-risk features (e.g., central/medial tumours; tumour size >5 cm; or tumour size ≥2 cm plus grade 3, HR-negative, or extensive lymphovascular invasion).

  • Hypofractionated regimens (with fewer, higher dose fractions over a shorter period) are typically recommended for whole-breast radiotherapy.[125][389][390][391][392][393] [ Cochrane Clinical Answers logo ] ​ Hypofractionated radiotherapy reduces the risk of breast oedema, telangiectasia, and acute skin​​ radiation toxicity compared with conventional regimens.[394]​ Ultra-hypofractionated regimens may be considered for select patients with early-stage, node-negative disease aged >50 years after breast-conserving surgery (particularly those who are not having a boost).[125]​ Ultra-hypofractionated regimens have shown similar results when compared with hypofractionated regimens.[210][395][396]

APBI/PBI may be used as an alternative to whole-breast radiation in highly select, low-risk patients with negative axillary nodes:

  • Criteria for APBI/PBI include all of the following: BRCA negative, age ≥40 years, grade 1 to 2 invasive ductal carcinoma, tumour size ≤2 cm, negative margins ≥2 mm, HR-positive disease, and no lymphovascular invasion.[387] Guidelines suggest that APBI/PBI may also be considered with caution in some patients with grade 3 disease, or HR-negative disease, or tumour size >2-3 cm; however, there may be an increased risk of recurrence, especially when more than one of these factors are present.​[387]

  • APBI/PBI using external beam radiotherapy (EBRT) techniques (3-D conformal radiotherapy or intensity modulated radiotherapy) or multi-catheter brachytherapy has similar recurrence rates to whole-breast radiotherapy in low-risk patients.[397][398][399][400][401]​​​​​​​​​[402][403]​​ EBRT once daily or on alternate days is associated with improved cosmesis and reduced acute and late toxicities compared with whole-breast radiotherapy.[397]​​​​[399][404]​ Twice-daily regimens are associated with worse late toxicity and cosmesis.[386][398]​​ Multi-catheter brachytherapy has shown similar late toxicity outcomes to whole-breast radiotherapy, with improved cosmesis.​[400][402][405] No studies have directly compared APBI/PBI techniques and regimens.​

Radiotherapy post-lumpectomy: positive axillary nodes

Whole-breast radiotherapy, with or without tumour boost, is recommended for patients with positive axillary nodes.

  • In addition, comprehensive RNI, including undissected axilla at risk, is recommended for those with ≥4 positive nodes. RNI, with or without undissected axilla, may be considered for those with 1-3 positive nodes. Decisions about including the internal mammary nodes in RNI should be individualised, taking into account the risks, including cardiac and lung toxicity.[125]

  • Hypofractionated regimens (with fewer, higher dose fractions over a shorter period) are recommended for whole-breast radiotherapy.[125][390][389][391][392][393] [ Cochrane Clinical Answers logo ] Hypofractionated radiotherapy reduces the risk of breast oedema, telangiectasia, and acute skin radiation toxicity compared with conventional regimens.[394]

Radiotherapy post-mastectomy

Post-mastectomy radiotherapy (irradiation of the chest wall/reconstructed breast and comprehensive RNI) reduces the risk of local recurrence and increases survival rates in patients with node-positive breast cancer.​[406]​​[407][408][409]​​​​​​[410][411]​​​ It may also be beneficial for certain patients with node-negative disease.[411] Moderate hypofractionated regimens are preferred for post-mastectomy radiotherapy. A radiation boost to the chest wall/scar can be considered if residual disease is suspected in patients with positive margins and for patients with tumours involving the skin or chest wall (T4).[411]

Patients having mastectomy as initial treatment

Post-mastectomy radiotherapy is recommended for node-positive patients, and should be considered for node-negative patients with tumours >5 cm.[125][145]​​​​​​[208]​​​[411][412]​​​​​​ Chest wall irradiation can be considered in node-negative patients with tumours ≤5 cm and negative surgical margins that are ≤1 mm (and RNI also considered if they have additional high-risk features). Node-negative patients with margins ≥1 mm may be considered for radiotherapy only if they have multiple high-risk features (e.g., central/medial tumours, or tumours ≥2 cm and grade 3, ER-negative, or lymphovascular invasion).[125]

For patients with positive surgical margins, radiotherapy to the chest wall/reconstructed breast should be considered if re-excision is not possible.[125][411]

Patients having mastectomy after neoadjuvant systemic treatment

Post-mastectomy radiotherapy is recommended for patients with initial (pre-treatment) T4 or N2-3 tumours, regardless of response to neoadjuvant therapy, and for patients who are node-positive after neoadjuvant therapy.[125][411]

For patients with initial T1-3N1 or T3N0 tumours, who have node-negative disease after neoadjuvant systemic therapy, post-mastectomy radiotherapy should be considered; age, presence of lymphovascular invasion, and residual cancer burden should be taken into account.[125][413]​​ Omission of radiotherapy may be considered in certain patients with a complete pathological response (tumour and lymph nodes); treatment teams are encouraged to discuss omission for these patients, taking into account that this approach is based on 5-year follow-up.[411]

Post-mastectomy radiotherapy is not routinely recommended for patients with initial T1-2N0 breast cancer who are node-negative after neoadjuvant systemic therapy.[125][411]

​For patients with positive surgical margins, post-mastectomy radiotherapy is recommended if re-excision is not possible.[411]

Supportive care: bone health

Breast cancer can negatively impact bone health.[414] Incidence of vertebral fracture is reported to be approximately 5 times greater in women with non-metastatic breast cancer (from the time of first diagnosis) than in the general population.[414] Use of aromatase inhibitors further reduces bone mineral density.[415]

Risk factors for osteoporosis should also be taken into account, including: post-menopausal status, increasing age, current cigarette smoking, excess alcohol intake, prior non-traumatic fractures in adulthood, impaired mobility, increased falls risk, hypogonadism, long-term glucocorticoid exposure, parental hip fracture, and low body weight. Patients with non-metastatic cancer and one or more of these risk factors should be offered bone mineral density testing.[416]

Patients receiving an aromatase inhibitor or ovarian function suppression agent should have an adequate intake of calcium and vitamin D, and undergo regular assessment of bone mineral density (e.g., with dual energy x‑ray absorptiometry [DXA]).[416][417]

Bone-modifying agents (e.g., bisphosphonates, denosumab) can be considered for preventing bone loss and reducing the risk of bone fracture in post-menopausal women with HR-positive breast cancer who are receiving adjuvant aromatase inhibitor therapy.[125][417][418][419][420][421][422] [ Cochrane Clinical Answers logo ]

Adjuvant bisphosphonate therapy should be discussed with all post-menopausal patients (natural or therapy-induced) with primary breast cancer, irrespective of HR status and HER2 status, who are candidates to receive adjuvant systemic therapy.[125][417][420][421][423][424][425] Early use is recommended.[417]

ASCO recommends offering bone-modifying agents to patients with:[416]

  • Osteoporosis confirmed on DXA scan

  • A 10-year probability of ≥20% for major osteoporotic fracture (based on the US-adapted FRAX tool), or

  • A 10-year probability of ≥3% for hip fracture (based on the US-adapted FRAX tool).

Clinicians should actively encourage patients to stop smoking, limit alcohol consumption, and engage in a range of exercise types.

In January 2024, the FDA warned of an increased risk of severe hypocalcaemia in patients with advanced chronic kidney disease who are receiving denosumab (Prolia® 60 mg/mL approved for treatment to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer).[426] Two safety studies showed a significant increase in the risk of severe hypocalcaemia in patients treated with denosumab compared with those treated with bisphosphonates, with the highest risk reported in patients with advanced kidney disease, particularly those on dialysis. Severe hypocalcaemia was more common in those with mineral and bone disorder. Before prescribing denosumab, healthcare professionals should assess kidney function and calcium levels, and consider other treatment options for patients at risk. During treatment, frequent blood calcium monitoring and prompt management of severe hypocalcaemia are essential.​ The FDA has not issued a warning with respect to the brand of denosumab approved specifically for the prevention of skeletal-related adverse events in malignancy (Xgeva® 120 mg/1.7 mL).

Recurrent disease

Recurrence rates of approximately 1% to 2% per year occur in patients treated with lumpectomy. Those at increased risk of recurrence include younger patients, those with positive surgical margins, those with an extensive intraductal component, and those who do not undergo radiotherapy. These recurrences tend to occur within 3-5 years after completion of therapy and occur most commonly in the same quadrant as the initial lesion. In patients treated with mastectomy, 90% of local recurrences occur within the first 5 years. Prompt recognition of tumour recurrence is the goal of close follow-up imaging.[427]

Treatment of locoregional recurrence is individualised and requires the coordination of a multidisciplinary team to determine the optimal role and timing of local therapy (surgery and radiotherapy) and systemic therapy.

Considerations for local therapy include the determination of whether the recurrence occurred within a previously irradiated site, the presence or absence of distant metastases, and the number of sites experiencing recurrent disease. Other considerations include the ability to achieve negative margins and whether the patient will need systemic therapy before resection.[428]

Systemic therapy following recurrence should take account of prior treatment. For completely resected isolated locoregional recurrences of breast cancer, adjuvant chemotherapy should be considered.[429]

Male breast cancer

Due to the rarity of male breast cancer (<1%), most treatment recommendations are based on retrospective studies and extrapolation from studies in female breast cancer.[430][431][432]

Men with primary invasive breast cancer are usually offered total mastectomy.[125] Radical mastectomy does not appear to improve risk of recurrence or survival compared with total mastectomy; however, it may be considered for those with disease involving the pectoralis major muscle or Rotter's nodes.[433]​​ Breast-conserving surgery is increasingly performed in men (often older patients) and studies suggest that outcomes are similar to mastectomy.[432][434]​​[435][436]​​​ Decisions about breast-conserving surgery should be made using similar criteria as for women.[125]

The role of SLNB and ALND in men with primary invasive breast cancer follows the same principles as for women. The effectiveness of SLNB appears to be similar for men and women with clinically node-negative disease.[437][438][439][440]

Chemotherapy (combined with HER2-targeted therapy, if HER2-positive) is recommended for men with breast cancer, following the same principles as for women with breast cancer.[125][438]

Adjuvant tamoxifen for 5 years is recommended for men with HR-positive breast cancer.[125][145]​​​​[208][210][430]​​​​​ Those at high risk of recurrence may be offered an additional 5 years of tamoxifen treatment.[430][125] Single-agent adjuvant tamoxifen provides superior outcomes compared with an adjuvant aromatase inhibitor alone in men with HR-positive breast cancer.[441]

Use of radiotherapy for men with breast cancer follows the same principles as for women with breast cancer.[125]​​[208]

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