ESMO CPGs for primary breast cancer

This article describes the idea behind and principles of the ESMO Clinical Practice Guidelines and presents a summary of the 2015 guidelines on diagnosis, treatment and follow-up of primary breast cancer

Fig. 1: Early breast cancer treatment algorithm. ChT, chemotherapy; BCS, breast-conserving surgery; ET, endocrine therapy; RT, radiotherapy. Permission from Oxford University Press.

• Mammography screening in the 50–70 year age group reduces breast cancer mortality. 
• In women with familial breast cancer, with or without proven BRCA mutations, annual screening with magnetic resonance imaging (MRI) of the breast, in combination with mammography is recommended [III, B].
• Diagnosis and treatment should be carried out in ‘breast units’: specialised institutions caring for a high volume of breast cancer patients, and provided by a multidisciplinary team including at least a surgeon, radiation oncologist, medical oncologist, radiologist, pathologist and a breast nurse (or another trained and specialised healthcare practitioner) – all specialised in and dedicated to breast cancer [V, A]. 
• Imaging includes bilateral mammography and ultrasound of the breast and regional lymph nodes supplemented by ultrasound-guided fine needle aspiration or core biopsy of suspicious lymph nodes. An MRI of the breast is not routinely recommended [III, B]. In early breast cancer, asymptomatic distant metastases are very rare and patients do not profit from comprehensive laboratory and radiological staging.
• Pathological diagnosis of the primary tumour should be based on core needle biopsy [V, A].
• The pathological report should include the histological type, grade, oestrogen receptor (ER) and, for invasive cancer, progesterone receptor (PgR), human epidermal growth factor 2 receptor (HER2) and a proliferation measure such as Ki67. 
• The postoperative pathological assessment of the surgical specimen should be done according to the pTNM system to include: number, location and maximum diameter of the tumour(s) removed, histological type and grade of the tumour(s), vascular invasion, biomarker analysis, evaluation of the resection margins, the total number of removed and number of positive lymph nodes, and the extent of metastases in the lymph nodes [III, A].

• The aims of follow-up are to detect early local recurrences or contralateral breast cancer, to evaluate and treat therapy-related complications, to motivate patients continuing hormonal treatments and to provide psychological support and information in order to enable a return to normal life.
• Regular visits every 3–4 months in the first two years, every six months from years 3–5 and annually thereafter are recommended [V, A].
• Annual ipsilateral (after breast conserving surgery (BCS)) and/or contralateral mammography with ultrasound is recommended [II, A]. In asymptomatic patients no other tests are routinely recommended.
• Patients undergoing ovarian suppression and those taking AIs are at an increased risk of bone loss and should be advised to have adequate calcium and vitamin D3 intake. In addition, periodic assessment of their bone mineral density should be undertaken [I, A].
• Regular exercise should be recommended to all suitable patients after treatment for breast cancer [II, B].
• Nutritional counselling should be recommended as part of the survivor care for all obese patients [III, B].
• The use of hormone replacement therapy (HRT) increases the risk of recurrence and should be discouraged [I, A].

• The choice of treatment strategy is based on biology (pathology including biomarkers, gene expression) and tumour extent/location (size and location of primary tumour, number of lesions, number and extent of lymph node involvement) as well as on the age, body habitus and general health status of the patient and her/his preferences.
• Ductal carcinoma in situ (DCIS) may be treated with BCS, provided clear resection margins can be achieved, or with mastectomy.
• Whole breast radiation therapy (WBRT) after BCS for DCIS decreases the risk of local recurrence with survival equal to that after mastectomy [I, A].
• Following local treatment for DCIS, tamoxifen might be considered to decrease the risk of contralateral breast cancer in patients who are at a high risk of new breast tumours [II, B].
• Breast conservation (wide local excision and radiation therapy [RT]) is the local treatment of choice in the majority of patients with invasive cancer. In some circumstances, mastectomy may still be carried out because of tumour size (relative to breast size), tumour multicentricity, prior radiation to the chest wall or breast, or patient choice.
• Breast reconstruction, preferably immediate, should be available to women requiring mastectomy.
• Sentinel lymph node biopsy (SLNB), rather than full axillary nodal clearance, is now the standard of care, unless axillary node involvement is proven [II, A].
• Patients with isolated tumour cells (<0.2mm) in the sentinel node and patients with limited involvement of the sentinel lymph nodes undergoing tangential breast irradiation may not need to have any further axillary procedures [II, B].
• Postoperative RT is strongly recommended after BCS [I, A]. Boost irradiation gives a further 50% risk reduction and is indicated for patients with unfavourable risk factors for local control [I, A].
• Postmastectomy RT is recommended for patients with involved axillary nodes and/or with T3–T4 tumours, especially in the presence of additional risk factors [I, A].
• Although clinically apparent lymph node relapses (especially axillary and internal mammary) are rare, nodal irradiation remains indicated for patients with involved lymph nodes [I, B]
• Shorter fractionation schemes (for example, 15 to 16 fractions with 2.5–2.67 Gy single dose) have been validated in large prospective studies and are generally recommended [I, A].
• The decision on systemic adjuvant therapies is based on the surrogate intrinsic phenotype determined by ER/PgR, HER2 and Ki67 assessment or on the genomic-based intrinsic subtype.
• All patients with detectable ER expression, defined as ≥1% of invasive cancer cells, should be offered endocrine therapies (ET) [I, A]. For premenopausal patients, tamoxifen is a standard [I, A] and ovarian suppression may improve disease-free survival (DFS) in patients remaining premenopausal after having received chemotherapy. For some premenopausal patients the combination of an aromatase inhibitor (AI) and ovarian suppression can be an option, although long term follow-up and survival data are still lacking. For postmenopausal patients, AIs (both non-steroidal and steroidal) and tamoxifen are valid options [I, B).
• Extended adjuvant therapy should be discussed with all postmenopausal patients, except the ones with a very low risk, although the optimal duration and regimen of adjuvant ET is currently unknown [I, C].
• Chemotherapy is recommended in the vast majority of triple negative, HER2-positive breast cancers and in high risk luminal HER2-negative tumours [I, A]. 
• For luminal HER2(−) cancers, the indications for chemotherapy depend on the individual risk of relapse, presumed responsiveness to ET and patient preferences. Most luminal A tumours, except those with the highest risk of relapse (extensive nodal involvement), require no chemotherapy [I, A].
• In cases of uncertainty regarding indications for adjuvant chemotherapy (after consideration of other tests), gene expression assays, such as MammaPrint, Oncotype DX, Prosigna and Endopredict may be used, where available [IV, A].
• Luminal B HER2(+) tumours are treated with chemotherapy, ET and trastuzumab [I, A]. 
• HER2(+) (non-luminal) cancers, should be treated with chemotherapy plus trastuzumab [I, A].
• Due to its cardiotoxicity, trastuzumab should not be routinely administered concomitantly with anthracyclines [I, B]. Combination with taxanes is safe and has been demonstrated to be more effective than sequential treatment [I, A].
• Triple negative tumours benefit from adjuvant chemotherapy, with possible exclusion of low risk ‘special histological subtypes’, such as secretory juvenile or adenoid cystic carcinomas [I, A].
• Chemotherapy usually consists of 4–8 cycles of anthracycline- and/or taxane-based regimen. The addition of taxanes improves the efficacy of chemotherapy, independently of age, nodal status, tumour size or grade, steroid receptor expression or tamoxifen use [I, A]. Sequential use of anthracyclines and taxanes, instead of concomitant, is recommended [I, B]. Non-anthracycline- and taxane-based regimens may be used as an alternative [I, A].
• The use of dose-dense schedules (with granulocyte colony-stimulating factor (G-CSF) support) should be considered particularly in highly proliferative tumours [I, B].
• RT may be delivered safely during trastuzumab, ET and non-anthracycline-, non-taxane-based chemotherapy [III, B].
• Prophylactic use of bisphosphonates may be discussed in women with a low-oestrogen status (postmenopausal or undergoing ovarian suppression) [I, B]. In patients with treatment-related bone loss, bisphosphonates decrease the risk of skeletal complications [I, A].
• In elderly patients, standard multidrug regimens should be used whenever feasible [V, A]. 
• In locally advanced and large ‘operable’ cancers, in particular when mastectomy is required due to tumour size, primary systemic therapy (used before local treatment) may allow for achieving operability or decreasing the extent of surgery [I, A]. If chemotherapy is used, it is recommended to deliver all planned treatment without unnecessary breaks, irrespective of the magnitude of tumour response [V, B].

References

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4. Senkus E et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.  Ann Oncol 2013;24(Suppl 6):vi7–vi23