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).[117][134]​​[153]​​[187][188][189][190]

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).[117]​​[134][187][189]

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:[117][134]​​[187][189]

  • 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

  • Endocrine therapy (for HR-positive disease)

  • HER2-targeted therapy (for HER2-positive disease)

  • Kinase inhibitor (abemaciclib or ribociclib) for HR-positive, HER2-negative disease

  • Poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor (olaparib) for HER2-negative breast cancer

  • Immunotherapy (pembrolizumab, a programmed death receptor-1 [PD-1]-blocking monoclonal antibody) for triple-negative breast cancer (i.e., HR-negative and HER2-negative).

Patients are best managed by a multidisciplinary team of breast cancer specialists comprising medical oncologists, surgeons, radiation oncologists, radiologists, pathologists, and nurses.[117][134]​​[187][189] 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.[117][134]​​

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).[117][134]​​​[189]

Patients may also receive adjuvant (postoperative) systemic treatment (e.g., chemotherapy; endocrine therapy; HER2-targeted therapy; kinase inhibitor for HR-positive, HER2-negative disease; PARP inhibitor for HER2-negative disease; immunotherapy for triple-negative disease) following surgery, depending on disease stage, age, performance status/fitness, and other prognostic factors.[117][134]​​[189]​​​[191][192][193][194][195][196]

Certain patients with early-stage breast cancer should be considered for neoadjuvant (preoperative) systemic treatment, including those with:[117]

  • 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 some people with triple-negative disease or HER2-positive disease who have negative nodes and tumours >1 cm.[117]

Radiotherapy is strongly recommended following lumpectomy.[117][134]​​​[189][Evidence B] Radiotherapy may be considered following total mastectomy in certain high-risk patients.[117][134]​​[189][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.[117][187]

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

Initial treatment for locally advanced breast cancer is usually neoadjuvant (preoperative) chemotherapy (combined with neoadjuvant HER2-targeted therapy, for those with HER2-positive disease) followed by total mastectomy with ALND (i.e., modified radical mastectomy).[117][187][189]​ Patients with clinically node-negative locally advanced breast cancer (e.g., T3 N0 M0) may undergo SLNB instead of ALND.[117]

Radiotherapy is recommended following mastectomy, particularly for patients at high risk of recurrence.[117][187][189][Evidence B]

Some patients who respond well to neoadjuvant systemic treatment may be considered for lumpectomy plus whole-breast radiotherapy instead of mastectomy.[117][187][189][Evidence A]

Patients with HR-positive disease should also receive endocrine therapy for a minimum of 5 years, which is usually given after surgery.[117][187][189]​​ For HER2-positive disease, the endocrine therapy should be combined with HER2-targeted therapy to complete 12 months of HER2-targeted therapy. For patients with triple-negative disease given neoadjuvant pembrolizumab, adjuvant therapy with pembrolizumab should be continued.[192]

Abemaciclib or ribociclib may be considered in combination with endocrine therapy for patients with HR-positive, HER2-negative early breast cancer at high risk of recurrence.[117][196]​​​[197]​​​​

Lumpectomy or total mastectomy

Patients with early-stage breast cancer can choose to undergo lumpectomy or total mastectomy.[198]

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.[117]

Absolute contraindications include:[117]

  • Pregnancy (although if lumpectomy is performed in the third trimester [or in the second trimester followed by adjuvant chemotherapy] this may allow deferral of radiotherapy until after delivery)

  • Diffusely positive pathologic 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:[117]

  • 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

  • Known or suspected genetic risk of 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.[117][199][200]​​​​ The re-excision rate for positive margins following lumpectomy is 14%.[201]​ Risk of local recurrence may be increased in patients with close margins.[202] ​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.[200][203]

Total mastectomy with ALND (following neoadjuvant systemic treatment) is usually recommended for patients with locally advanced breast cancer, particularly those with inflammatory breast cancer.[117][187] 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.[117][204][205][206][207] Adjuvant HER2-targeted and/or endocrine therapies and radiotherapy are delayed until after delivery.

Breast reconstruction

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.[117][208][209]

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.[210] However, immediate breast reconstruction is contraindicated in patients with inflammatory breast cancer due to the need for expeditious postoperative radiotherapy.[117]

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.[211][212][213] 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.[214] 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, patient's 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.[214]

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.[215][216][217][218]

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.[219] 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.[220][221][222][223][224][225][226][227] 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).[220][222] SLNB should not be used routinely in clinically node-negative women aged 70 years or greater with early-stage HR-positive, HER2-negative invasive breast cancer.[228]

Clinically node-negative patients

In patients with early-stage breast cancer who are clinically node-negative or have 1 or 2 suspicious lymph nodes on imaging, an SLNB should be performed during surgery.[117][134]​​[229][230]​ ALND is not recommended if SLNB is negative.[117][230]​ In most cases, if sentinel nodes cannot be identified, level I and II axillary dissection is recommended for staging.[117]

Patients with 1 or 2 positive SLNs having lumpectomy can avoid ALND if whole-breast radiotherapy is planned following surgery.[230][231][232][233]

For patients with 1 or 2 positive SLNs having a mastectomy, adjuvant radiotherapy that includes undissected axilla at risk (with or without regional nodal irradiation [RNI]) may be considered as an alternative to ALND.[117][234][235]

SLNB may be considered in patients with clinically node-negative locally advanced breast cancer (e.g., T3 N0 M0).[117]

Clinically node-positive patients

In patients with early-stage breast cancer with clinically suspicious (palpable) lymph nodes or with 3 or more 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.[117] If the biopsy is positive, ALND is recommended.[117] If the biopsy is negative, SLNB is recommended to determine whether further axillary surgery is warranted.[117]

ALND is generally recommended for patients with clinically node-positive locally advanced breast cancer and inflammatory breast cancer.[230][236][237][238]​ 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.[239][240][241]

Axillary staging after neoadjuvant chemotherapy in node-positive breast cancer

Involves sentinel node surgery, ALND, and/or axillary radiation. This is dependent upon the extent of nodal involvement prior to neoadjuvant therapy.

Those with N2 or N3 disease at diagnosis should be managed with ALND independent of the response to therapy, followed by nodal radiation. In meta-analysis, targeted axillary dissection (SLNB plus excision of a pre-neoadjuvant therapy marked positive lymph node) appeared to be more accurate for axillary staging following neoadjuvant therapy than either intervention alone.[242] Highly selected patients, who become clinically node-negative after preoperative systemic therapy, may be considered for SLNB. The addition of targeted axillary dissection may reduce the rate of false negatives compared with SLNB alone.[117]

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.[243]

Use of a radioactive tracer (e.g., technetium99m sulfur colloid) is deemed to be safe, but use of isosulfan blue and methylene blue is not recommended.[117][244][245]

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:[117]​​

  • 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 to make them operable or to enable lumpectomy, to decrease the need for ALND, and to treat inflammatory breast cancer.[117][187][246][247][248]​​​ Tumour histology, grade, stage, and oestrogen, progesterone, and HER2 expression should be used to guide clinical decisions as to whether to use neoadjuvant chemotherapy.[248]

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.[249][250][251]​​ However, developments in treatments and imaging, and accurate staging before therapy, are likely to reduce the risk of local recurrence.[117] 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).[252][253]​​​ These effects are most dramatic in triple-negative disease and HER2-positive disease.[249][254][255][256][257]

Tumour response should be routinely assessed by clinical examination and imaging (e.g., mammogram, ultrasound, and/or MRI) during neoadjuvant therapy.​[140]​​ 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.[117]

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:[117]

  • 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 or paclitaxel

  • Epirubicin plus cyclophosphamide (EC)

  • Cyclophosphamide plus methotrexate plus fluorouracil (CMF)

  • Docetaxel plus doxorubicin plus cyclophosphamide (TAC)

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

For selected patients with triple-negative disease, paclitaxel plus carboplatin or docetaxel plus carboplatin may be considered preoperatively. However, platinum agents are not recommended as adjuvant therapy or routinely recommended as neoadjuvant therapy for triple-negative breast cancer.​[117]

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.[258][259][260][261][262][263][264][265][266][267][268][269] [ 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.​[264][265][270][271][272]​​​​ 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.[271]

Dose-dense chemotherapy schedules have been shown to lower the risk of recurrence in lymph node-positive early-stage breast cancer, with a 4-year disease-free survival of 82% for dose-dense regimens and 75% for others.[273]

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).[274][275][276]​​​ Improved disease-free and overall survival has been reported with 4 cycles of TC compared with AC (without a taxane) in the adjuvant setting.[275][276][277]​​​ 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.[117][278]

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.[117][157][279]​​

Recommended regimens include: docetaxel plus carboplatin plus trastuzumab plus pertuzumab (TCHP); or docetaxel plus carboplatin plus trastuzumab (TCH).[117]

Other regimens that may be considered include: docetaxel plus cyclophosphamide plus trastuzumab; doxorubicin plus cyclophosphamide (AC) followed by docetaxel or paclitaxel plus trastuzumab, with or without pertuzumab; or paclitaxel plus trastuzumab plus pertuzumab.[117]

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.[117]

Alternative taxanes (e.g., paclitaxel, nanoparticle albumin-bound [nab] paclitaxel) may be substituted, if necessary (e.g., if the patient has a hypersensitivity reaction).[117]

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.[279]

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.[280][281][282][283][284][285][286][287][288]​​​ 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.[281][283][284]

Results from one phase 3 study suggest that dual anti-HER2 blockade may avoid the use of anthracycline in the neoadjuvant setting.[289] Pathological complete response was similar for patients receiving neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade, but anthracycline use was associated with a higher risk of febrile neutropenia.[289] This approach requires further investigation.

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.[290] 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.[279][282][291][292]​​​ For those with residual disease following neoadjuvant dual HER2 blockade, trastuzumab emtansine can be used for adjuvant treatment.[293]

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.[117][189][248][294][295][Evidence C]​​​ In these patients, use of aromatase inhibitors (e.g., exemestane, letrozole, or anastrozole) is preferred to tamoxifen.[248][295]​​​ Response rate and breast conservation rate are reported to be higher with aromatase inhibitors compared with tamoxifen in the neoadjuvant setting.[295]

Neoadjuvant pembrolizumab

Pembrolizumab may be considered for patients with T1cN1-2 or T2-4N0 (stage II or III), early-stage triple-negative breast cancer, in combination with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery.[191]​ Among patients with early triple-negative breast cancer, the percentage with a pathological complete response was significantly higher among those who received pembrolizumab plus neoadjuvant chemotherapy than among those who received placebo plus neoadjuvant chemotherapy.[192]

Adjuvant chemotherapy

Patients with early-stage breast cancer with tumours >1.0 cm who are likely to benefit from chemotherapy are usually treated with adjuvant chemotherapy to reduce the risk of recurrence.[117]

Adjuvant chemotherapy may be considered for patients with tumours >0.5 cm to 1.0 cm in greatest diameter if the tumour is triple-negative or HER2-positive.[117] Adjuvant chemotherapy is not usually recommended for those with tumours ≤0.5 cm, although it may be considered for those with HER2-positive disease.[117]

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.[117][134]​​[270][273][274]​​[297]​​[298][299]

Studies indicate that some patients with HR-positive/HER2-negative early-stage breast cancer derive substantially lower benefit from adjuvant chemotherapy (assuming standard endocrine therapy) than those who are HR-negative or HER2-positive.[300] Therefore, patients with HR-positive/HER2-negative early-stage breast cancer who are pathologically node-negative, or some patients who have 1-3 positive nodes, should undergo additional risk assessment with a gene expression assay 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.[117][149][150][151][152][153][154][155][301]​ Several clinical trials (MINDACT, TAILORx, and Plan B) have identified groups of patients who can safely avoid adjuvant chemotherapy.[156][302][303][304]

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. Capecitabine may also be used as maintenance therapy after adjuvant chemotherapy for triple-negative disease.[117][305]

Retrospective analyses suggest that docetaxel chemotherapy is associated with poorer overall and disease-free survival in overweight and obese patients compared with lean patients. This may reflect the increased volume of distribution of lipophilic drugs in overweight and obese patients. There was no difference between overall and disease-free survival between lean, overweight, and obese patients in the non-docetaxel chemotherapy group.[306]

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.[307]

Racial disparities in chemotherapy administration for early-stage breast cancer exist. One systematic review and meta-analysis reported clinically relevant delays in the initiation of adjuvant chemotherapy in black breast cancer patients compared with white patients.[308]

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 with tumours >1 cm to ≤2 cm.[117][188][309][310][311][312]

Adjuvant trastuzumab (combined with adjuvant chemotherapy) may be considered for those with HER2-positive early-stage breast cancer who are node-negative with tumours ≤1 cm.[188]

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).[188][309][310]

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.[309][311]​​ Trastuzumab given concurrently with a taxane (e.g., paclitaxel, docetaxel) appears to be safe and is more effective than if given sequentially.[310]

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 (combined with adjuvant chemotherapy). Dual anti-HER2 blockade has been found to improve response rate and disease-free survival rate with minimal additional toxicity compared with trastuzumab alone.[280][288][313]

High-risk patients can be considered for extended HER2-targeted therapy with neratinib for 1 year following initial adjuvant trastuzumab-based HER2-targeted therapy.[314][315]​​ 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.[315]

Patients with low-risk HER2-positive early-stage breast cancer (e.g., node-negative and small tumours <3 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.[188][316][317][318]​​ A 7-year disease-free survival rate of 93% has been reported with this approach.[318]

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.[188][291][292][319][320][321][322][323][324]

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.[325]

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.[290] The FDA has also approved a fixed-dose subcutaneous combination of trastuzumab/pertuzumab/hyaluronidase.

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.[293][326]​​ Trastuzumab emtansine reduced the risk of recurrence or death by approximately 50% compared with trastuzumab alone in these patients.[293] Reports of fatigue, thrombocytopenia, and peripheral neuropathy were increased with trastuzumab emtansine.[293]

Adjuvant 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).[117][134]​​​[187][189]

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.[117]

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).[327][328]​​​ 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.[117][134]​​[329]​​

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.[330][331][332][333]​​​​ 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.[334]

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).[335][336]​​​ Toxicity (including the rate of endometrial cancer) may be increased with extended tamoxifen treatment.[337]​ Those taking an aromatase inhibitor as initial endocrine therapy may consider continuing it for a further 3-5 years.[117]

Temporary ovarian function suppression with gonadotrophin-releasing hormone agonists may be considered during chemotherapy to preserve ovarian function and fertility in pre-menopausal women.[117] One meta-analysis reported a higher pregnancy rate in women who received temporary ovarian suppression during chemotherapy, compared with controls. There was no significant difference in disease-free survival or overall survival between the groups.[338]

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).[117][134]​​[187][189]

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.[117]

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 is continued for 5 years. Alternatively, an aromatase inhibitor may be given after 2 or 3 years of tamoxifen (to complete 5 years of endocrine therapy).[117][134]​ Adjuvant aromatase inhibitors have been shown to improve disease-free survival by 18% to 21% compared with adjuvant tamoxifen.[339][340][341][342]​​​ The improved efficacy of aromatase inhibitors compared with tamoxifen is maintained over the long term.[343]

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.[344][345][346]​​​​ The optimal duration is unknown; extended regimens reduce the risk of recurrence, particularly in higher-stage cancers, but risk of adverse effects is higher.[345][347][348]​​​​

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.[117]​​

Adjuvant abemaciclib and ribociclib

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.[197][349]​​ Benefit has been shown to continue beyond completion of treatment with abemaciclib (5-year follow-up).[350]​ 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 either ≥4 positive axillary lymph nodes, or 1-3 positive axillary lymph nodes, and at least one of the following criteria: tumour size ≥5 cm or histological grade 3. Abemaciclib is recommended for 2 years in combination with endocrine therapy (plus ovarian suppression/ablation if indicated).[117][197][196]

  • Ribociclib may be considered for patients who have any lymph node involvement, or with tumour size >5 cm, or with 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).[117][349][196]

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).[117]

Adjuvant olaparib

Olaparib can be offered to patients with early-stage, HER2-negative breast cancer with high risk of recurrence and germline BRCA1 or BRCA2 pathogenic or likely pathogenic variants.[193][194][195] One year of adjuvant olaparib should be offered after completion of neoadjuvant chemotherapy and local treatment, including radiation.

In patients eligible for both adjuvant olaparib and abemaciclib, the optimal sequence of therapy is not known.[117]

Adjuvant pembrolizumab

Pembrolizumab may be considered for patients with T1cN1-2 or T2-4N0 (stage II or III) early-stage triple-negative breast cancer, in combination with neoadjuvant chemotherapy, followed by adjuvant pembrolizumab after surgery.[191]

Recommended regimen for high-risk triple-negative disease: pembrolizumab plus carboplatin plus paclitaxel, followed by pembrolizumab plus cyclophosphamide plus doxorubicin or epirubicin, followed by adjuvant pembrolizumab.[117]

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.[117]

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.[117][134]​​​​​​​[351][352][353][354]​​​​​ Boost radiotherapy and RNI therapy can further reduce the risk of recurrence in patients with high-risk disease.[134][355][356][357][358]​​​​​ 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).[117][134][189]​​​​​​[359][360]​​​​​​​ Radiotherapy is given after completion of adjuvant chemotherapy (except capecitabine and olaparib, which are given after radiotherapy, and CMF, which can be given concurrently).[117] Radiotherapy can be given concurrently with adjuvant trastuzumab in HER2-positive patients.[361]​​​​​​​​​

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.[117][134][189]

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.[117]

  • 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, ER-negative, or extensive lymphovascular invasion).

  • Hypofractionated regimens (with fewer, higher dose fractions over a shorter period) are typically recommended for whole-breast radiotherapy.[117][362][363][364][365][366] [ Cochrane Clinical Answers logo ] ​ Hypofractionated radiotherapy reduces the risk of breast oedema, telangiectasia, and acute skin​​ radiation toxicity compared with conventional regimens.[367]​ 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).[117]​ Ultra-hypofractionated regimens have shown similar results when compared with hypofractionated regimens.[189][368][369]

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.[360] 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.​[360]

  • 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.[370][371][372][373][374]​​​​​​​​​[375][376]​​ EBRT once daily or on alternate days is associated with improved cosmesis and reduced acute and late toxicities compared with whole-breast radiotherapy.[370]​​​​[372][377]​ Twice-daily regimens are associated with worse late toxicity and cosmesis.[359][371]​​ Multi-catheter brachytherapy has shown similar late toxicity outcomes to whole-breast radiotherapy, with improved cosmesis.​[373][375][378] 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.[117]

  • Hypofractionated regimens (with fewer, higher dose fractions over a shorter period) are recommended for whole-breast radiotherapy.[117][363][362][364][365][366] [ Cochrane Clinical Answers logo ] Hypofractionated radiotherapy reduces the risk of breast oedema, telangiectasia, and acute skin radiation toxicity compared with conventional regimens.[367]

Radiotherapy post-mastectomy

Post-mastectomy radiotherapy reduces the risk of local recurrence and increases survival rates in patients with node-positive breast cancer.[379][380][381][382][383]

Post-mastectomy radiotherapy (including irradiation of the chest wall, mastectomy scar, drain sites, infraclavicular and supraclavicular areas, internal mammary nodes, and axillary bed) is recommended for node-positive patients (particularly if ≥4 positive nodes), and for node-negative patients with tumours >5 cm or positive surgical margins.[117][134]​​​[187][381][384]​​​​ 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).[117]

Some guidelines recommend hypofractionated and ultra-hypofractionated regimens for chest-wall radiation, as for whole-breast radiation.[189]

Axillary radiotherapy is associated with a similar 10-year overall survival, distant metastasis-free survival, and locoregional recurrence to ALND in women with a positive SLNB. Second primary cancers, including contralateral primary breast cancers, occurred slightly more frequently in the axillary radiotherapy group, compared with the ALND group.[385]

Supportive care: bone health

Breast cancer can negatively impact bone health.[386] 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.[386] Use of endocrine therapy (e.g., aromatase inhibitors) further reduces bone mineral density.[387]

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.[388]

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]).[388][389]

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 endocrine therapy.[117][389][390][391][392][393][394] [ 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.[117][389][392][393][395][396][397] Early use is recommended.[389]

ASCO recommends offering bone-modifying agents to patients with:[388]

  • 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).[398] 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.[399]

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.[400]

Systemic therapy following recurrence should take account of prior treatment. For completely resected isolated locoregional recurrences of breast cancer, adjuvant chemotherapy should be considered.[401]

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.[402][403][404]

Men with primary invasive breast cancer are usually offered total mastectomy.[117] 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.[405]​​ Breast-conserving surgery is increasingly performed in men (often older patients) and studies suggest that outcomes are similar to mastectomy.[404][406]​​[407]​​ Decisions about breast-conserving surgery should be made using similar criteria as for women.[117]

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.[408][409][410][411]

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.[117][409]

Adjuvant tamoxifen for 5 years is recommended for men with HR-positive breast cancer.[117][134]​​​[187][189][402] In retrospective studies, tamoxifen was associated with a 5-year actuarial survival of 61% versus 44% for historic controls (P=0.006).[412] Single-agent adjuvant tamoxifen provides superior outcomes compared with adjuvant aromatase inhibitors in men with HR-positive breast cancer.[413]

Use of radiotherapy for men with breast cancer follows the same principles as for women with breast cancer.[117]​​[187]

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