As per the guideline,

• Treatment strategy should be based on the tumour burden/location (size and location of primary tumour, number of lesions, extent of lymph node involvement) and biology (pathology, including biomarkers and gene expression), as well as the age, menopausal status, general health status and preferences of the patient
• In younger premenopausal patients, fertility issues and fertility-preservation techniques should be discussed, before the initiation of any systemic treatment

The ESMO 2019 guidelines for early breast cancer treatment provide recommendation for the treatment strategy of breast cancer.

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A. Recommendations for Surgery

Breast-conserving surgery (BCS) utilizing oncoplastic techniques is the preferred local treatment option to maintain good cosmetic outcomes in technically challenging cases. It is important to assess histology of resection margins. No tumour at the inked margin is required and >2 mm for in situ disease is preferred.

Mastectomy

Except for those with inflammatory cancer, immediate breast reconstruction should be offered to all the patients. Selection of the optimal reconstruction technique should take into consideration anatomic, treatment- and patient-related factors and preferences.

Axillary management

Sentinel lymph node biopsy (SLNB), rather than full nodal clearance, is recommended for axillary staging in early, clinically node-negative breast cancer. In case of low axillary disease burden, after positive SLNB, further axillary surgery is not required. Axillary radiation is an option for patients with positive SLNB, irrespective of the type of breast surgery.

Surgery for in situ malignancy (intraepithelial neoplasia)

For ductal carcinoma in situ (DCIS), BCS followed by whole-breast radiotherapy (WBRT) or total mastectomy are recommended. When treated with BCS, a 2-mm margin is adequate in DCIS treated with WBRT. SLNB is generally not recommended in DCIS, apart from patients with large and/or high-grade tumours, especially when mastectomy is required.

Management of occult breast cancer

Axillary lymph node dissection (ALND) and WBRT are the preferred locoregional management option.

Risk-reducing mastectomy

Risk-reducing surgery (with prophylactic bilateral mastectomy and reconstruction) may be offered to high risk patients, such as BRCA1 or BRCA2 mutation carriers or those with previous chest radiation therapy (RT). Genetic assessment and psychological counselling should be done before surgery; the option of intense surveillance should also be discussed. Low risk patients who opt for bilateral mastectomy should be counselled regarding the better survival outcomes in patients treated with BCS than those treated with mastectomy.

Surgery after primary systemic therapy (PST)

Surgery following PST should be performed as per the general rules for early breast cancer and after considering the baseline tumour characteristics as well as the post-treatment outcomes. If BCS is anticipated, marking of the tumour site and breast MRI (before and after treatment) should be carried out.

In clinically negative axilla, post-PST SLNB is preferred. In patients with baseline axillary involvement converting to negative, SLNB may be carried out in selected cases, and, if negative, further axillary surgery may be avoided. ALND is recommended if tumour deposits are identified post-PST SLNB.

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B. Recommendations for the use of Radiotherapy

Postoperative RT is strongly recommended after BCS, while boost RT is recommended to reduce the risk of in-breast relapse in patients at higher risk of local recurrence

Accelerated partial-breast RT after BCS is acceptable in patients with a low risk for local recurrence.

Post-mastectomy RT is recommended for high-risk patients. This includes:

• Those with involved resection margins
• Those with involved axillary lymph nodes and t3–t4 tumours
• Patients with 1–3 positive axillary lymph nodes

Comprehensive nodal RT is recommended for patients with involved lymph nodes. Following ALND, routine axillary irradiation should not be done to the operated part of the axilla.

Postoperative RT can be administered after immediate breast reconstruction - an intensive patient-involving approach is required to individualise the best option.

Moderate hypofractionation schedules (15–16 fractions of ≤3 Gy/fraction) are recommended for routine postoperative RT of breast cancer

WBRT is recommended for the majority of women with DCIS treated with BCS. Radiation can be avoided in patients with low-risk DCIS. Tumour bed boost can be considered for

patients at higher risk for local failure. Post-mastectomy RT (PMRT) is not recommended for DCIS.

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C. Recommendations for the use of Adjuvant systemic treatment

It is recommended to initiate adjuvant systemic treatment within 3–6 weeks after surgery, while neoadjuvant systemic therapy should start as soon as diagnosis and staging is completed (ideally within 2–4 weeks).

Adjuvant systemic therapies should be selected based on an individual’s risk of relapse, the predicted treatment sensitivity, the benefit and toxicities, age, general health, comorbidities and preferences.

Endocrine therapy (ET) should be administered in all luminal-like cancers. Chemotherapy (ChT) is not required in most luminal A-like tumours, except those with high disease burden. ChT use in luminal B-like HER2-negative patients depends on individual risk of recurrence, presumed responsiveness to ET and patient preferences.

After consideration of all clinical and pathological factors, if there is uncertainty regarding indications for adjuvant ChT, expression of uPA-PAI1 or gene expression assays, such as MammaPrint, Oncotype DX, Prosigna, Endopredict or Breast Cancer Index, can be considered.

Luminal B-like HER2-positive tumours should be treated with ChT, ET and anti-HER2 therapy. In some low-risk patients (T1abN0), the combination of anti-HER2 therapy and ET alone may be sufficient.

Patients with TNBC, except those with low-risk ‘special histological subtypes’ such as secretory or adenoid cystic carcinomas or very early (T1aN0) tumours, should be offered ChT.

HER2-positive cancers (except those with very low risk, such as T1aN0 tumours) should be treated with ChT plus anti-HER2 therapy.

ChT should not be used concomitantly with ET (except gonadotropin-releasing hormone (GnRH) analogues used for ovarian protection).

Anti-HER2 therapy can be administered with non-anthracycline-based ChT, ET and RT. RT may be delivered safely during anti-HER2 therapy, ET and non-anthracycline, non-taxane-based ChT. If ChT and RT are to be used, ChT should usually precede RT.

Adjuvant systemic treatment for premenopausal women

For premenopausal women, tamoxifen for 5–10 years is a standard of care; a switch to letrozole should be considered, in those becoming postmenopausal during the first 5 years of tamoxifen.

Addition of ovarian function suppression (OFS) to ET should be strongly considered in patients requiring ChT and who recover menses (in particular in the first year but acceptable within the first 2 years).

Tamoxifen can be replaced with an AI in high-risk patients; this step mandates effective OFS, with regular biochemical control of oestrogen levels.

OFS during ChT provides some protection of ovarian function and has no negative impact on oncological outcomes; however, it should not be the sole fertility preservation method used, in case of desired pregnancy.

Adjuvant systemic treatment for postmenopausal women

For postmenopausal women, aromatase inhibitors (AIs) (both non-steroidal and steroidal) and tamoxifen are considered standard treatments. AIs can be used:

• Upfront (non-steroidal AI and exemestane),
• After 2–3 years of tamoxifen (non-steroidal AI and exemestane)
• As extended adjuvant therapy, after 5 years of tamoxifen (letrozole and anastrozole)

In patients undergoing OFS and taking AIs, adequate calcium and vitamin D3 intake is advised. Periodic assessment of bone mineral density is also required in such cases.

The study of CYP2D6 polymorphisms as a decision aid regarding the use of adjuvant tamoxifen is not proven and is hence not recommended.

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D. Recommendations for the use of Chemotherapy

ChT should be administered for 12–24 weeks (4–8 cycles) - sequential anthracycline/taxane-based regimen is the standard for the majority of patients.

In selected lower-risk patients, 4 cycles of anthracycline- or taxane-based ChT or cyclophosphamide/methotrexate/5-fluorouracil (CMF) may be used. Non-anthracycline regimens may be used in patients with cardiac risk.

Anthracycline-based regimens should not include 5-fluorouracil (5-FU); epirubicin plus cyclophosphamide (EC) or doxorubicin and cyclophosphamide (AC) is the standard.

The use of Platinum compounds in the adjuvant setting is not recommended. Dose-dense schedules [with granulocyte colony-stimulating factor (G-CSF) support] should be considered, particularly in highly proliferative tumours.

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E. Recommendations for the use of Anti-HER2 therapy

(Neo)Adjuvant trastuzumab is recommended to all HER2-positive early breast cancer patients (except selected cases with very low risk, such as T1aN0 tumours).

HER2-targeted therapy may be considered, if a HER2 test result is ultimately deemed to be equivocal, even after reflex testing with an alternative assay.

One year of (neo) adjuvant trastuzumab is the standard for the vast majority of HER2-positive patients. In highly selected, low-risk patients who receive anthracycline/taxane-based ChT, shortening trastuzumab duration to 6 months may be considered.

The concomitant use of trastuzumab is more effective than sequential treatment. Trastuzumab should, however, not be given concomitantly with anthracycline-based ChT; it can be safely combined with non-anthracycline-based ChT (i.e. taxanes).

Regular cardiac monitoring is mandatory prior to and during trastuzumab treatment.

Dual blockade with trastuzumab/lapatinib is not recommended. Dual blockade with trastuzumab/pertuzumab can be considered in high-risk patients, defined as N-positive or ER-negative, for the duration of 1 year, starting before or after surgery.

In cases of residual invasive disease after completion of neoadjuvant ChT combined with anti-HER2 therapy, adjuvant trastuzumab should be replaced by adjuvant trastuzumab emtansine (T-DM1).

In selected high-risk patients, not previously treated with dual blockade, extended anti-HER2 therapy with neratinib may be considered.

Recommendations for the use of Primary (neoadjuvant) systemic therapy

PST reduces the extent of surgery in locally advanced and large operable cancers, especially when mastectomy is required due to tumour size. PST is recommended in all patients with tumours > 2 cm for which ChT is deemed necessary, in particular with triple-negative and HER2-positive subtypes.

In triple-negative tumours and/or in patients with deleterious BRCA1/2 mutations, the addition of a platinum compound may be considered.

All ChT should be delivered preoperatively if PST is used. In high-risk, triple-negative patients not achieving pathological complete response (pCR) after standard neoadjuvant ChT, the addition of 6–8 cycles of capecitabine postoperatively may be considered. In postmenopausal patients with ER-positive/HER2-negative cancers requiring PST and without a clear indication for ChT, preoperative ET (4–8 months or until maximum response) should be considered and continued postoperatively.