Primary invasive breast cancer

Overview 
Theory 
Diagnosis 
Management 
Follow up 
Resources 

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

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

1st line – lumpectomy or total mastectomy (± breast reconstruction)

Back

1st line –

lumpectomy or total mastectomy (± breast reconstruction)

Initial treatment for early-stage breast cancer is usually primary breast surgery (e.g., lumpectomy or total mastectomy).[125][145][210][218]

Decisions on which surgical approach to undertake should be made between the patient and the surgeon following a discussion of benefits and harms.

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 to lumpectomy requiring radiotherapy include: 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.[125]

Relative contraindications to lumpectomy include: 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; and genetic predisposition to breast cancer.[125]

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 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]

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][158][223][224][225][226] 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.[125][228][229]

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]

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.

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][442] Decisions about breast-conserving surgery should be made using similar criteria as for women.[125]

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

Plus – sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND)

Back

Plus –

sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND)

Treatment recommended for ALL patients in selected patient group

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 magnetic resonance imaging, 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 nodes (SLNs) for tumours. It is less invasive than ALND, and leads to fewer complications (e.g., lymphoedema).[240][242]

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]

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][443]

SLNB may be omitted for women with node-negative breast cancer ages ≥70 years with early-stage HR-positive, HER2-negative disease.[256] Guidelines further suggest that omission of SLNB may be considered in select post-menopausal patients ages ≥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 ages <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]

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]

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]

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]

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, and superparamagnetic iron oxide dye is not recommended in pregnancy due to a lack of safety data.[125][158][267][268][269]

The role of SLNB and ALND in men with primary invasive breast cancer follows the same principles as for women.

Consider – neoadjuvant or adjuvant chemotherapy

Back

Consider –

neoadjuvant or adjuvant chemotherapy

Additional treatment recommended for SOME patients in selected patient group

Decisions about chemotherapy should be individualised, taking into account lymph node involvement, tumour size and grade, HR-status, and HER2 expression.

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 smaller tumours (≤1.0 cm) if the tumour is triple-negative or HER2-positive.[125] Adjuvant chemotherapy is not usually recommended for 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. 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]

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

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]

Recommended regimens include: docetaxel plus cyclophosphamide (TC); doxorubicin plus cyclophosphamide (AC) followed or preceded by paclitaxel.[125]

Other regimens that may be considered include: AC; AC followed by docetaxel; epirubicin plus cyclophosphamide (EC); cyclophosphamide plus methotrexate plus fluorouracil (CMF); docetaxel plus doxorubicin plus cyclophosphamide (TAC).[125]

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 combined with trastuzumab); and carboplatin plus paclitaxel, followed by cyclophosphamide plus doxorubicin or epirubicin (as preferred neoadjuvant therapy in triple-negative patients with stage II-III disease, when combined with pembrolizumab).[125]

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] [ ] 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]

For patients with stage II or III triple-negative disease, immunotherapy with pembrolizumab is recommended in combination with neoadjuvant chemotherapy.[212][213][125][263]

docetaxel

and

doxorubicin

and

cyclophosphamide

docetaxel

and

carboplatin

-- AND --

paclitaxel

-- AND --

cyclophosphamide

-- AND --

doxorubicin

epirubicin

paclitaxel

with HER2-positive disease

Consider – neoadjuvant or adjuvant trastuzumab ± pertuzumab

Back

Consider –

neoadjuvant or adjuvant trastuzumab ± pertuzumab

Additional treatment recommended for SOME patients in selected patient group

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

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]

In the adjuvant setting, 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.[125]

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

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]

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 or docetaxel) appears to be safe and is more effective than if given sequentially.[336]

Recommended regimens include: docetaxel plus carboplatin plus trastuzumab plus pertuzumab (TCHP); or docetaxel plus carboplatin plus trastuzumab (TCH). Other regimens that may be considered include: docetaxel plus cyclophosphamide plus trastuzumab; 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]

Patients with low-risk HER2-positive early-stage breast cancer (e.g., node-negative and small tumours <2 cm) 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][342][343][444]

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 a 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 US Food and Drug Administration (FDA) for use in HER2-overexpressing breast cancer.[315] Fixed-dose combinations of pertuzumab, trastuzumab, and hyaluronidase may also be used.

The principles of HER2-targeted therapy are the same for women and men with primary invasive breast cancer.[125]

See local specialist protocol for dosing guidelines.

Primary options

trastuzumab

trastuzumab/hyaluronidase

trastuzumab

trastuzumab/hyaluronidase

-- AND --

pertuzumab

pertuzumab/trastuzumab/hyaluronidase

Consider – adjuvant trastuzumab emtansine

Back

Consider –

adjuvant trastuzumab emtansine

Additional treatment recommended for SOME patients in selected patient group

Trastuzumab emtansine is an antibody-drug conjugate of trastuzumab and a cytotoxic microtubule inhibitor. Trastuzumab emtansine can be used for adjuvant treatment in patients with HER2-positive disease 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]

The principles of HER2-targeted therapy are the same for women and men with primary invasive breast cancer.[125]

See local specialist protocol for dosing guidelines.

Primary options

trastuzumab emtansine

Consider – adjuvant neratinib (if HR-positive)

Back

Consider –

adjuvant neratinib (if HR-positive)

Additional treatment recommended for SOME patients in selected patient group

High-risk patients with HR-positive, HER2-positive disease can be considered for extended HER2-targeted therapy with neratinib (an oral irreversible inhibitor of HER1, HER2, and HER4) for 1 year following adjuvant trastuzumab-based therapy.[351][352]

Neratinib has been shown to significantly reduce relapse (5-year invasive disease-free survival rate of 90.2% versus 87.7% for placebo), but is associated with an increased risk of diarrhoea.[352]

The principles of HER2-targeted therapy are the same for women and men with primary invasive breast cancer.[125]

See local specialist protocol for dosing guidelines.

Primary options

neratinib

with hormone receptor-positive disease: pre-menopausal women and men

Consider – adjuvant endocrine therapy ± ovarian function suppression or ablation

Back

Consider –

adjuvant endocrine therapy ± ovarian function suppression or ablation

Additional treatment recommended for SOME patients in selected patient group

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.[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.

Pre-menopausal women with HR-positive breast cancer 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 (e.g., anastrozole, letrozole, or exemestane) 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 tamoxifen for 5 years is recommended for men with HR-positive breast cancer.[125][145][208][430][210] Those at high risk of recurrence may be offered an additional 5 years of tamoxifen treatment.[125][430]

Single-agent adjuvant tamoxifen provides superior outcomes compared with an adjuvant aromatase inhibitor alone in men with HR-positive breast cancer.[441]

Primary options

tamoxifen: 20 mg orally once daily

Secondary options

anastrozole: 1 mg orally once daily

exemestane: 25 mg orally once daily

letrozole: 2.5 mg orally once daily

goserelin: 3.6 mg subcutaneously every 4 weeks

-- AND --

tamoxifen: 20 mg orally once daily

anastrozole: 1 mg orally once daily

exemestane: 25 mg orally once daily

letrozole: 2.5 mg orally once daily

Consider – adjuvant abemaciclib or ribociclib (if HER2-negative)

Back

Consider –

adjuvant abemaciclib or ribociclib (if HER2-negative)

Additional treatment recommended for SOME patients in selected patient group

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 3 tumour of size 2-5 cm. Ribociclib is recommended for 3 years in combination with an aromatase inhibitor (plus ovarian suppression/ablation).[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]

See local specialist protocol for dosing guidelines.

Primary options

abemaciclib

ribociclib

Consider – adjuvant olaparib (if HER2-negative and BRCA-positive)

Back

Consider –

adjuvant olaparib (if HER2-negative and BRCA-positive)

Additional treatment recommended for SOME patients in selected patient group

Olaparib, a poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor 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.[125]

See local specialist protocol for dosing guidelines.

Primary options

olaparib

Consider – supportive care: bone health

Back

Consider –

supportive care: bone health

Additional treatment recommended for SOME patients in selected patient group

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]

The American Society of Clinical Oncology (ASCO) recommends offering bone-modifying agents to patients with: 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).[416]

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

with hormone receptor-positive disease: post-menopausal women

Consider – neoadjuvant or adjuvant endocrine therapy

Back

Consider –

neoadjuvant or adjuvant endocrine therapy

Additional treatment recommended for SOME patients in selected patient group

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 breast cancer are usually treated with adjuvant aromatase inhibitor therapy (e.g., anastrozole, letrozole, or exemestane), 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]

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]

Primary options

anastrozole: 1 mg orally once daily

exemestane: 25 mg orally once daily

letrozole: 2.5 mg orally once daily

Secondary options

tamoxifen: 20 mg orally once daily

Consider – adjuvant abemaciclib or ribociclib (if HER2-negative)

Back

Consider –

adjuvant abemaciclib or ribociclib (if HER2-negative)

Additional treatment recommended for SOME patients in selected patient group

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. Abemaciclib is recommended for 2 years in combination with endocrine therapy.[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.[125][217][376]

Treatment with abemaciclib or ribociclib is started after completion of surgery, radiotherapy, and/or chemotherapy, concurrently with endocrine therapy.[125]

See local specialist protocol for dosing guidelines.

Primary options

abemaciclib

ribociclib

Consider – adjuvant olaparib (if HER2-negative and BRCA-positive)

Back

Consider –

adjuvant olaparib (if HER2-negative and BRCA-positive)

Additional treatment recommended for SOME patients in selected patient group

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.[125]

See local specialist protocol for dosing guidelines.

Primary options

olaparib

Consider – supportive care: bone health

Back

Consider –

supportive care: bone health

Additional treatment recommended for SOME patients in selected patient group

Bone-modifying agents (e.g., bisphosphonates and 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] [ ]

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]

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

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 CKD 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).

with triple-negative disease

Consider – neoadjuvant and adjuvant pembrolizumab

Back

Consider –

neoadjuvant and adjuvant pembrolizumab

Additional treatment recommended for SOME patients in selected patient group

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]

adjuvant radiotherapy (whole breast or APBI/PBI)

Treatment recommended for ALL patients in selected patient group

Adjuvant 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 regional nodal irradiation (RNI) can further reduce the risk of recurrence in patients with high risk disease.[125][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]

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.

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).

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.

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 regional nodal irradiation 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 typically recommended for whole-breast radiotherapy.[125][390][389][391][392][393] [ ] 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]

The principles of radiotherapy are the same for women and men with primary invasive breast cancer.[125][208]

undergoing mastectomy

Consider – adjuvant radiotherapy (chest wall/reconstructed breast ± comprehensive regional node irradiation)

Back

Consider –

adjuvant radiotherapy (chest wall/reconstructed breast ± comprehensive regional node irradiation)

Additional treatment recommended for SOME patients in selected patient group

Post-mastectomy radiotherapy (irradiation of the chest wall/reconstructed breast and comprehensive regional node irradiation [RNI]) reduces the risk of local recurrence and increases survival rates in patients with node-positive breast cancer.[407][408][409][410][411][406] It may also be beneficial for certain patients with node-negative disease.[411]

For 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 regional nodal irradiation 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]

For patients having mastectomy after neoadjuvant systemic treatment, post-mastectomy radiotherapy is recommended for patients who are node-positive after neoadjuvant therapy.[125][411]

For patients with initial N1 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]

Some guidelines recommend hypofractionated and ultra-hypofractionated regimens for chest-wall radiation, as for whole-breast radiation.[210]

Moderate hypofractionated regimens are preferred for post-mastectomy radiotherapy.[411]

The principles of radiotherapy are the same for women and men with primary invasive breast cancer.[125][208]

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

1st line – neoadjuvant chemotherapy

Back

1st line –

neoadjuvant chemotherapy

Patients with locally advanced breast cancer are treated initially with neoadjuvant systemic therapy to downsize large and/or inoperable tumours to enable lumpectomy or to make them operable, or decrease the need for axillary lymph node dissection.[125][208][270][271]

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]

Recommended regimens include: docetaxel plus cyclophosphamide (TC); doxorubicin plus cyclophosphamide (AC) followed or preceded by paclitaxel.[125]

Recommended regimens for specific patient populations include: docetaxel plus carboplatin (a preferred regimen in HER2-positive patients, combined with trastuzumab with or without pertuzumab); and 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).[125]

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 have been reported with 4 cycles of TC compared with AC (without a taxane) in the adjuvant setting.[299][300][301] An anthracycline-based neoadjuvant chemotherapy, with or without a taxane, is standard for patients with inoperable, non-inflammatory, locally advanced disease at presentation.[125] CMF may be used concurrently with radiotherapy.[125][302]

docetaxel

and

doxorubicin

and

cyclophosphamide

docetaxel

and

carboplatin

-- AND --

paclitaxel

-- AND --

cyclophosphamide

-- AND --

doxorubicin

epirubicin

Plus – lumpectomy or total mastectomy (± breast reconstruction)

Back

Plus –

lumpectomy or total mastectomy (± breast reconstruction)

Treatment recommended for ALL patients in selected patient group

Total mastectomy with axillary lymph node dissection (following neoadjuvant systemic treatment) is usually recommended for patients with locally advanced breast cancer, particularly those with inflammatory breast cancer.[125][208] However, certain women who respond well to neoadjuvant systemic treatment may be suitable for lumpectomy plus whole-breast radiotherapy.

Decisions on which surgical approach to undertake should be made between the patient and the surgeon following a discussion of benefits and harms.

Contraindications to lumpectomy such as widespread disease and diffuse microcalcifications can be evaluated more fully with use of breast 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.

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] Adjuvant HER2-targeted and/or endocrine therapies and radiotherapy are delayed until after delivery.

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

Plus – sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND)

Back

Plus –

sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND)

Treatment recommended for ALL patients in selected patient group

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 magnetic resonance imaging, or US-guided lymph node biopsy of suspicious lymph nodes.

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]

Patients with clinically node-negative locally advanced breast cancer (e.g., T3 N0 M0) may undergo SLNB instead of ALND.[125] SLNB involves identifying, removing, and examining SLNs for tumours. It is less invasive than ALND, and leads to fewer complications (e.g., lymphoedema).[240][242] SLNB may be omitted for women with node-negative breast cancer ages ≥70 years with early-stage HR-positive, HER2-negative disease.[256]

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]

with HER2-positive disease

Plus – neoadjuvant and adjuvant trastuzumab ± pertuzumab

Back

Plus –

neoadjuvant and adjuvant trastuzumab ± pertuzumab

Treatment recommended for ALL patients in selected patient group

Neoadjuvant regimens for patients with HER2-positive locally advanced 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); docetaxel plus carboplatin plus trastuzumab (TCH).[125]

Other regimens that may be considered include: docetaxel plus cyclophosphamide plus trastuzumab; AC followed by docetaxel or paclitaxel plus trastuzumab; AC followed by docetaxel or paclitaxel plus trastuzumab plus pertuzumab; paclitaxel plus trastuzumab plus pertuzumab.

Alternative taxanes (e.g., paclitaxel, nanoparticle albumin-bound [nab] paclitaxel) may be substituted, if necessary.[125]

AC followed by TC with anti-HER2 blockade is an option for high-risk patients, but this has been associated with increased risk of cardiotoxicity, due to overlapping toxicities of anthracycline and trastuzumab.[446]

Neoadjuvant 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 has demonstrated improved response rates compared with trastuzumab plus neoadjuvant chemotherapy, and compared with trastuzumab emtansine 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) do not appear to be increased with dual anti-HER2 blockade compared with trastuzumab (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 FDA for use in HER2-overexpressing breast cancer.[315]

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]

The principles of HER2-targeted therapy are the same for women and men with primary invasive breast cancer.[125]

See local specialist protocol for dosing guidelines.

Primary options

trastuzumab

trastuzumab/hyaluronidase

trastuzumab

trastuzumab/hyaluronidase

-- AND --

pertuzumab

pertuzumab/trastuzumab/hyaluronidase

Consider – adjuvant trastuzumab emtansine

Back

Consider –

adjuvant trastuzumab emtansine

Additional treatment recommended for SOME patients in selected patient group

In one study, adjuvant trastuzumab emtansine reduced the risk of recurrence or death by approximately 50% compared with trastuzumab alone in HER2-positive patients with early breast cancer who had residual invasive disease following neoadjuvant trastuzumab-based treatment.[318] Reports of fatigue, thrombocytopenia, and peripheral neuropathy were increased with trastuzumab emtansine.[318]

The principles of HER2-targeted therapy are the same for women and men with primary invasive breast cancer.[125]

See local specialist protocol for dosing guidelines.

Primary options

trastuzumab emtansine

Consider – adjuvant neratinib (if HR-positive)

Back

Consider –

adjuvant neratinib (if HR-positive)

Additional treatment recommended for SOME patients in selected patient group

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]

The principles of HER2-targeted therapy are the same for women and men with primary invasive breast cancer.[125]

See local specialist protocol for dosing guidelines.

Primary options

neratinib

with hormone receptor-positive disease: pre-menopausal women and men

Plus – adjuvant endocrine therapy ± ovarian function suppression or ablation

Back

Plus –

adjuvant endocrine therapy ± ovarian function suppression or ablation

Treatment recommended for ALL patients in selected patient group

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

Pre-menopausal women with HR-positive breast cancer 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 (e.g., anastrozole, letrozole, or exemestane) 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 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 treatment may consider continuing it for a further 3-5 years.[125]

Single-agent adjuvant tamoxifen provides superior outcomes compared with an adjuvant aromatase inhibitor alone in men with HR-positive breast cancer.[441]

Primary options

tamoxifen: 20 mg orally once daily

Secondary options

anastrozole: 1 mg orally once daily

exemestane: 25 mg orally once daily

letrozole: 2.5 mg orally once daily

goserelin: 3.6 mg subcutaneously every 4 weeks

-- AND --

tamoxifen: 20 mg orally once daily

anastrozole: 1 mg orally once daily

exemestane: 25 mg orally once daily

letrozole: 2.5 mg orally once daily

Plus – supportive care: bone health

Back

Plus –

supportive care: bone health

Treatment recommended for ALL patients in selected patient group

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 DXA).[416][417]

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

Consider – adjuvant abemaciclib or ribociclib (if HER2-negative)

Back

Consider –

adjuvant abemaciclib or ribociclib (if HER2-negative)

Additional treatment recommended for SOME patients in selected patient group

See local specialist protocol for dosing guidelines.

Primary options

abemaciclib

ribociclib

Consider – adjuvant olaparib (if HER2-negative and BRCA-positive)

Back

Consider –

adjuvant olaparib (if HER2-negative and BRCA-positive)

Additional treatment recommended for SOME patients in selected patient group

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.[125]

See local specialist protocol for dosing guidelines.

Primary options

olaparib

with hormone receptor-positive disease: post-menopausal women

Plus – neoadjuvant or adjuvant endocrine therapy

Back

Plus –

neoadjuvant or adjuvant endocrine therapy

Treatment recommended for ALL patients in selected patient group

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

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]

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 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]

Primary options

anastrozole: 1 mg orally once daily

exemestane: 25 mg orally once daily

letrozole: 2.5 mg orally once daily

Secondary options

tamoxifen: 20 mg orally once daily

Additional treatment recommended for SOME patients in selected patient group

See local specialist protocol for dosing guidelines.

Primary options

pembrolizumab

Consider – adjuvant capecitabine

Back

Consider –

adjuvant capecitabine

Additional treatment recommended for SOME patients in selected patient group

Adjuvant capecitabine may be used in patients with triple-negative breast cancer who have residual disease after neoadjuvant therapy with taxanes, alkylating agents, or anthracyclines.[125][333] Capecitabine is given after completion of adjuvant radiotherapy.

See local specialist protocol for dosing guidelines.

Primary options

capecitabine

Consider – adjuvant olaparib (if BRCA-positive)

Back

Consider –

adjuvant olaparib (if BRCA-positive)

Additional treatment recommended for SOME patients in selected patient group

The optimal sequence of therapy is not known for triple-negative patients eligible for both adjuvant olaparib and capecitabine.[125]

See local specialist protocol for dosing guidelines.

Primary options

olaparib

undergoing lumpectomy

Plus – adjuvant radiotherapy (whole breast)

Back

Plus –

adjuvant radiotherapy (whole breast)

Treatment recommended for ALL patients in selected patient group

Adjuvant whole-breast radiotherapy is strongly recommended 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 regional nodal irradiation can further reduce the risk of recurrence in patients with high-risk disease.[125][145][382][383][384][385]

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.

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 typically recommended for whole-breast radiotherapy.[125][389][390][391][392][393] [ ] Hypofractionated radiotherapy reduces the risk of breast oedema, telangiectasia, and acute skin radiation toxicity compared with conventional regimens.[394]

The principles of radiotherapy are the same for women and men with primary invasive breast cancer.[125]

undergoing mastectomy

Consider – adjuvant radiotherapy (chest wall/reconstructed breast ± comprehensive regional node irradiation)

Back

Consider –

adjuvant radiotherapy (chest wall/reconstructed breast ± comprehensive regional node irradiation)

Additional treatment recommended for SOME patients in selected patient group

Post-mastectomy radiotherapy (irradiation of the chest wall/reconstructed breast and comprehensive regional node irradiation [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]

For patients having mastectomy after neoadjuvant systemic treatment, post-mastectomy radiotherapy is recommended for patients with initial (pretreatment) 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]

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

The principles of radiotherapy are the same for women and men with primary invasive breast cancer.[125]

ONGOING

disease recurrence

1st line – individualised treatment

Back

1st line –

individualised treatment

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 involved by 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]

Use of this content is subject to our disclaimer

Primary invasive breast cancer

Treatment algorithm

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

lumpectomy or total mastectomy (± breast reconstruction)

sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND)

neoadjuvant or adjuvant chemotherapy

Primary options

TC

AC plus paclitaxel

Secondary options

AC

AC plus docetaxel

EC

CMF

TAC

neoadjuvant or adjuvant trastuzumab ± pertuzumab

Primary options

adjuvant trastuzumab emtansine

Primary options

adjuvant neratinib (if HR-positive)

Primary options

adjuvant endocrine therapy ± ovarian function suppression or ablation

Primary options

Secondary options

adjuvant abemaciclib or ribociclib (if HER2-negative)

Primary options

adjuvant olaparib (if HER2-negative and BRCA-positive)

Primary options

supportive care: bone health

neoadjuvant or adjuvant endocrine therapy

Primary options

Secondary options

adjuvant abemaciclib or ribociclib (if HER2-negative)

Primary options

adjuvant olaparib (if HER2-negative and BRCA-positive)

Primary options

supportive care: bone health

neoadjuvant and adjuvant pembrolizumab

Primary options

adjuvant capecitabine

Primary options

adjuvant olaparib (if BRCA-positive)

Primary options

adjuvant radiotherapy (whole breast or APBI/PBI)

adjuvant radiotherapy (chest wall/reconstructed breast ± comprehensive regional node irradiation)

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

neoadjuvant chemotherapy

Primary options

TC

AC plus paclitaxel

Secondary options

AC

AC plus docetaxel

EC

CMF

TAC

lumpectomy or total mastectomy (± breast reconstruction)

sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND)

neoadjuvant and adjuvant trastuzumab ± pertuzumab

Primary options

adjuvant trastuzumab emtansine

Primary options

adjuvant neratinib (if HR-positive)

Primary options

adjuvant endocrine therapy ± ovarian function suppression or ablation

Primary options

Secondary options

supportive care: bone health

adjuvant abemaciclib or ribociclib (if HER2-negative)

Primary options

adjuvant olaparib (if HER2-negative and BRCA-positive)

Primary options

neoadjuvant or adjuvant endocrine therapy

Primary options

Secondary options

supportive care: bone health

adjuvant abemaciclib or ribociclib (if HER2-negative)

Primary options

adjuvant olaparib (if HER2-negative and BRCA-positive)

Primary options