Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Key MessageThis ESMO Clinical Practice Guidelines provide updated state-of-the-art recommendations on management of early breast cancer (diagnosis, treatment and follow-up), compiled by a multidisciplinary author panel and accompanied by level of evidence and grade of recommendation, depending on the strength of supporting data and magnitude of benefit from particular interventions. This ESMO Clinical Practice Guidelines provide updated state-of-the-art recommendations on management of early breast cancer (diagnosis, treatment and follow-up), compiled by a multidisciplinary author panel and accompanied by level of evidence and grade of recommendation, depending on the strength of supporting data and magnitude of benefit from particular interventions. In 2018, the predicted number of new breast cancers in 28 European Union (EU) countries was 404 920, with estimated age-adjusted annual incidence of breast cancer of 144.9/100 000 and mortality of 32.9/100 000, with 98 755 predicted deaths [1.ECIS-European Cancer Information System. https://ecis.jrc.ec.europa.eu (25 March 2019, date last accessed).Google Scholar]. Worldwide, there was about 2.1 million newly diagnosed female breast cancer cases in 2018, accounting for almost one in four cancer cases among women, and ∼630 000 died of it [2.Bray F. Ferlay J. Soerjomataram I. et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424Crossref PubMed Scopus (29029) Google Scholar]. Breast cancer incidence has increased since the introduction of mammography screening and continues to grow with the ageing of the population. The most important risk factors include: genetic predisposition, exposure to oestrogens [endogenous and exogenous, including long-term hormone replacement therapy (HRT)], ionising radiation, low parity, high breast density and a history of atypical hyperplasia. The Western-style diet, obesity and the consumption of alcohol also contribute to the rising incidence of breast cancer [3.McTiernan A. Behavioral risk factors in breast cancer: can risk be modified?.Oncologist. 2003; 8: 326-334Crossref PubMed Scopus (104) Google Scholar]. There is a steep age gradient, with about a quarter of breast cancers occurring before age 50, and <5% before age 35. The estimated 5-year prevalence of breast cancer (people with a diagnosis within the last 5 years and still alive, with or without disease) in Europe in 2012 was 1 814 572 cases [1.ECIS-European Cancer Information System. https://ecis.jrc.ec.europa.eu (25 March 2019, date last accessed).Google Scholar] and a staggering 6 875 099 cases worldwide [2.Bray F. Ferlay J. Soerjomataram I. et al.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA Cancer J Clin. 2018; 68: 394-424Crossref PubMed Scopus (29029) Google Scholar]. Prevalence is increasing, due to increased incidence and improvements in treatment outcomes. In most Western countries, the mortality rate has decreased in recent years, especially in younger age groups, because of improved treatment and earlier detection [4.Autier P. Boniol M. La Vecchia C. et al.Disparities in breast cancer mortality trends between 30 European countries: retrospective trend analysis of WHO mortality database.BMJ. 2010; 341: c3620.Crossref PubMed Scopus (265) Google Scholar, 5.Allemani C. Weir H.K. Carreira H. et al.Global surveillance of cancer survival 1995-2009: analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2).Lancet. 2015; 385: 977-1010Abstract Full Text Full Text PDF PubMed Scopus (421) Google Scholar]. However, breast cancer is still the leading cause of cancer-related deaths for women in Europe and worldwide, although the mortality of lung cancer in women is overcoming breast cancer mortality in some countries. Breast cancer in males is rare, contributing to ∼1% of cases. The major risk factors include clinical disorders carrying hormonal imbalances (especially gynaecomastia and cirrhosis), radiation exposure, a positive family history and genetic predisposition [6.Ottini L. Palli D. Rizzo S. et al.Male breast cancer.Crit Rev Oncol Hematol. 2010; 73: 141-155Crossref PubMed Scopus (86) Google Scholar]. Out of the 28 member states of the EU, 25 were planning, piloting or rolling out (ongoing or completed) national or regional population-based mammography screening programmes, to detect breast cancers at a pre-clinical stage [7.Report on the implementation of the Council Recommendation on Cancer Screening in the European Union. https://ecis.jrc.ec.europa.eu (25 March 2019, date last accessed).Google Scholar]. The European Guidelines for quality assurance in breast cancer screening and diagnosis recommend performance parameters and indicators that should be monitored in any screening programme [8.Perry N. Broeders M. de Wolf C. et al.European guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition—summary document.Ann Oncol. 2007; 19: 614-622Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar]. The European Commission Initiative on Breast Cancer (ECIBC) has produced evidence-based recommendations for mammography screening, with the strongest recommendation for women aged 50–69 years and with conditional recommendations for women in younger and older age groups [9.European guidelines for breast cancer screening and diagnosis. https://publications.europa.eu/s/jPcX (25 March 2015, 2019, date last accessed).Google Scholar]. The greatest mortality reduction benefit has been shown in the 50- to 69-year-old age group, while evidence for effectiveness of mammography screening in women aged 40–49 years is more limited, especially for women aged between 40 and 44 years [10.Gotzsche P.C. Nielsen M. Screening for breast cancer with mammography.Cochrane Database Syst Rev. 2011; 1: CD001877Crossref PubMed Google Scholar]. This was also the conclusion in the 2015 breast cancer screening report from the International Agency for Research on Cancer (IARC) [11.Lauby-Secretan B. Scoccianti C. Loomis D. et al.Breast-cancer screening–viewpoint of the IARC Working Group.N Engl J Med. 2015; 372: 2353-2358Crossref PubMed Scopus (137) Google Scholar]. There is no consensus about the exact effect of mammography screening on breast cancer mortality reduction, as the reported estimates vary. In a UK review of the randomised controlled mammography trials, a 20% relative breast cancer mortality reduction was estimated in women aged between 50 and 70 years [12.Independent U.K. The benefits and harms of breast cancer screening: an independent review.Lancet. 2012; 380: 1778-1786Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. It must be noted that the review stresses the importance of taking into account the risk of over-diagnosis and over-treatment, as well as false-positive screening, when balancing the benefits and harms of screening. Screening programmes carry the risk of false-negative results; consequently, a false feeling of security among patients and doctors may be instilled. Nevertheless, mammography screening and population-based awareness programmes, together with improved treatment, contribute to mortality reduction in breast cancer. There is also controversy and no consensus regarding the use of ultrasound (US) as a supplementary screening method. Risk-adapted screening is currently being evaluated in clinical trials. 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, can detect the disease at a more favourable stage compared with mammography screening alone (70% lower risk of being diagnosed with breast cancer stage II or higher). However, it is not known whether breast cancer mortality is lowered [13.Warner E. Messersmith H. Causer P. et al.Systematic review: using magnetic resonance imaging to screen women at high risk for breast cancer.Ann Intern Med. 2008; 148: 671-679Crossref PubMed Google Scholar]. There is no consensus for the use of US. Recommendations:•Regular (annual or every 2 years) mammography is recommended in women aged 50–69 years [I, A]. Regular mammography may also be done for women aged 40–49 and 70–74 years, although the evidence for benefit is less well established [II, B].•In women with a strong familial history of breast cancer, with or without proven BRCA mutations, annual MRI and annual mammography (concomitant or alternating) are recommended [III, A]. The diagnosis of breast cancer is based on clinical examination in combination with imaging and confirmed by pathological assessment (Table 1). Clinical examination includes bimanual palpation of the breasts and regional lymph nodes and assessment for distant metastases (bones, liver and lungs; a neurological examination is only required when symptoms are present).Table 1Diagnostic work-up for early breast cancerAssessment of general health statusHistoryMenopausal statusPhysical examinationFull blood countLiver, renal and cardiac (in patients planned for anthracycline and/or trastuzumab treatment) function tests, alkaline phosphatase and calciumAssessment of primary tumourPhysical examinationMammographyBreast USBreast MRI in selected casesCore biopsy with pathology determination of histology, grade, ER, PgR, HER2 and Ki67Assessment of regional lymph nodesPhysical examinationUSUS-guided biopsy if suspiciousAssessment of metastatic diseasePhysical examinationOther tests are not routinely recommended, unless high tumour burden, aggressive biology or when symptoms suggestive of metastases are presentER, oestrogen receptor; HER2, human epidermal growth factor receptor 2; MRI, magnetic resonance imaging; PgR, progesterone receptor; US, ultrasound. Open table in a new tab ER, oestrogen receptor; HER2, human epidermal growth factor receptor 2; MRI, magnetic resonance imaging; PgR, progesterone receptor; US, ultrasound. Imaging includes bilateral mammography and US of the breast and regional lymph nodes [8.Perry N. Broeders M. de Wolf C. et al.European guidelines for quality assurance in breast cancer screening and diagnosis. Fourth edition—summary document.Ann Oncol. 2007; 19: 614-622Abstract Full Text Full Text PDF PubMed Scopus (348) Google Scholar]. An MRI of the breast is not routinely recommended, but should be considered in cases of:•familial breast cancer associated with BRCA mutations [I, A];•lobular cancers [I, A];•dense breasts [II, B];•suspicion of multifocality/multicentricity (particularly in lobular breast cancer) [I, A];•large discrepancies between conventional imaging and clinical examination [III, B];•before neoadjuvant systemic therapy, and to evaluate the response to this therapy [II, A]; and•when the findings of conventional imaging are inconclusive (such as a positive axillary lymph node status with an occult primary tumour in the breast) [III, A] [14.Sardanelli F. Boetes C. Borisch B. et al.Magnetic resonance imaging of the breast: recommendations from the EUSOMA working group.Eur J Cancer. 2010; 46: 1296-1316Abstract Full Text Full Text PDF PubMed Scopus (582) Google Scholar].•It may also be considered in case of breast implants. Several new techniques are being tested for screening and diagnostic imaging, such as three-dimensional (3D) mammography (digital breast tomosynthesis), 3D US, shear wave elastography and contrast-enhanced mammography/spectral mammography. None of these are yet routinely implemented but they have the potential to increase diagnostic accuracy, especially in women with dense breasts. It is imperative to collect complete personal medical history, family history relating to breast/ovarian and other cancers and the menopausal status of the patient (if in doubt, measure serum oestradiol and follicle-stimulating hormone levels), and to carry out a full physical examination. Apart from imaging, pretreatment disease evaluation includes pathological examination of the primary tumour and cytology/histology of the axillary nodes, if involvement is suspected. Pathological diagnosis should be based on a core needle biopsy, preferably obtained by US or stereotactic guidance. A core needle biopsy (if this is not possible, at least a fine-needle aspiration indicating carcinoma) must be obtained before any type of treatment is initiated. If preoperative systemic therapy is planned, a core needle biopsy is mandatory to ensure a diagnosis of invasive disease and assess biomarkers [I, A]. It is recommended that at least 2–3 cores are obtained. In case of multifocal and multicentric tumours, all lesions should be biopsied [I, A]. A marker (e.g. surgical clip, carbon) should be placed into the tumour at biopsy, to ensure resection of the correct site and to enable pathological assessment of the surgical specimen [V, A]. As a minimum, US-guided fine-needle aspiration or core biopsy of suspicious lymph nodes should be carried out, preferably followed by clip or carbon marking of biopsied lymph nodes [III, A]. An excisional biopsy should not be carried out, except in rare cases of repeated negative core biopsies. Final pathological diagnosis should be made according to the World Health Organization (WHO) classification [15.Lakhani S.R. Ellis I.O. Schnitt S.J. et al.WHO Classification of Tumours.4th edition. 4. IARC Press, Geneva2012Google Scholar] and the eighth edition of the American Joint Committee on Cancer (AJCC) tumour, node, metastasis (TNM) staging system [16.Giuliano A.E. Connolly J.L. Edge S.B. et al.Breast cancer-major changes in the American Joint Committee on Cancer eighth edition cancer staging manual.CA Cancer J Clin. 2017; 67: 290-303Crossref PubMed Scopus (321) Google Scholar]. This staging system, apart from purely anatomical information, includes also prognostic information related to tumour biology [tumour grade, oestrogen receptor (ER), progesterone receptor (PgR), human epidermal growth factor receptor 2 (HER2) and gene expression data if available]. The two most frequent subtypes are invasive carcinoma of the breast, not otherwise specified (NOS, previously named ductal carcinoma) (70%–75%) and lobular carcinoma (12%–15%). The other 18 subtypes exhibit specific morphological traits and are rare (from 0.5% to 5%). Each of these specific subtypes shows a particular prognosis. Of note, a neuroendocrine differentiation can be observed in some cases, without any prognostic or therapeutic consequences for the patient [15.Lakhani S.R. Ellis I.O. Schnitt S.J. et al.WHO Classification of Tumours.4th edition. 4. IARC Press, Geneva2012Google Scholar]. The pathological report should include presence/absence of ductal carcinoma in situ (DCIS), the histological type, grade, immunohistochemistry (IHC) evaluation of ER status (using a standardised assessment methodology, e.g. Allred score or H-score) and, for invasive cancer, IHC evaluation of PgR and HER2 expression or HER2 gene amplification. HER2 gene amplification status may be determined directly from all invasive tumours using in situ hybridisation (ISH) (fluorescent, chromogenic or silver), replacing IHC or only for tumours with an ambiguous (2+) IHC score [II, B] [17.Hammond M.E. ASCO-CAP guidelines for breast predictive factor testing: an update.Appl Immunohistochem Mol Morphol. 2011; 19: 499-500Crossref PubMed Scopus (0) Google Scholar]. HER2 testing should be carried out according to the American Society of Clinical Oncology–College of American Pathologists (ASCO-CAP) guidelines. HER2 is defined as positive by IHC (3+) when more than 10% of the cells harbour a complete membrane staining, and by ISH if the number of HER2 gene copies is ≥6, or the HER2/chromosome 17 (CEP17) ratio is ≥2 and HER2 copies ≥4, or HER2/CEP17 <2 and HER2 copies ≥6 [18.Wolff A.C. Hammond M.E.H. Allison K.H. et al.Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update.J Clin Oncol. 2018; 36: 2105-2122Crossref PubMed Scopus (384) Google Scholar]. Proliferation markers such as the Ki67 labelling index may supply additional useful information, particularly if the assay can be standardised [III, A] [19.Duffy M.J. Harbeck N. Nap M. et al.Clinical use of biomarkers in breast cancer: updated guidelines from the European Group on Tumor Markers (EGTM).Eur J Cancer. 2017; 75: 284-298Abstract Full Text Full Text PDF PubMed Scopus (206) Google Scholar, 20.Penault-Llorca F. Radosevic-Robin N. Ki67 assessment in breast cancer: an update.Pathology. 2017; 49: 166-171Abstract Full Text Full Text PDF PubMed Google Scholar]. Alternatively, these biological markers can be assessed in the definitive surgical specimen if primary systemic therapy (PST) is not planned. However, fixation is better controlled for core biopsies, allowing safer antigen preservation for IHC [21.Mann G.B. Fahey V.D. Feleppa F. Buchanan M.R. Reliance on hormone receptor assays of surgical specimens may compromise outcome in patients with breast cancer.J Clin Oncol. 2005; 23: 5148-5154Crossref PubMed Scopus (110) Google Scholar]. In case of negativity of ER/PgR and HER2 in the biopsy specimen, it is advisable to retest for them in the surgical specimen to account for the putative tumour heterogeneity [III, A] [22.Chen X. Yuan Y. Gu Z. Shen K. Accuracy of estrogen receptor, progesterone receptor, and HER2 status between core needle and open excision biopsy in breast cancer: a meta-analysis.Breast Cancer Res Treat. 2012; 134: 957-967Crossref PubMed Scopus (0) Google Scholar]. In case of discrepancy, the results from the surgical specimen are considered definite. In case of a HER2-positive test on biopsy, retesting for HER2 on the surgical specimen is mandatory for invasive carcinoma NOS grade I, ER- and PgR-positive (including special types such as tubular, mucinous, cribriform) or adenoid cystic carcinoma or secretory carcinoma (both usually triple-negative) [18.Wolff A.C. Hammond M.E.H. Allison K.H. et al.Human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline focused update.J Clin Oncol. 2018; 36: 2105-2122Crossref PubMed Scopus (384) Google Scholar]. For the purpose of prognostication and treatment decision making, tumours should be grouped into surrogate intrinsic subtypes, defined by routine histology and IHC data [III, A] (Table 2) [23.Goldhirsch A. Winer E.P. Coates A.S. et al.Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.Ann Oncol. 2013; 24: 2206-2223Abstract Full Text Full Text PDF PubMed Scopus (1922) Google Scholar, 24.Dai X. Li T. Bai Z. et al.Breast cancer intrinsic subtype classification, clinical use and future trends.Am J Cancer Res. 2015; 5: 2929-2943PubMed Google Scholar]. Luminal A-like tumours are typically low grade, strongly ER-positive/PgR-positive, HER2-negative and have low proliferative fraction. Luminal B-like tumours are ER-positive but may have variable degrees of ER/PgR expression, are higher grade and have higher proliferative fraction [23.Goldhirsch A. Winer E.P. Coates A.S. et al.Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.Ann Oncol. 2013; 24: 2206-2223Abstract Full Text Full Text PDF PubMed Scopus (1922) Google Scholar].Table 2Surrogate definitions of intrinsic subtypes of breast cancer [23.Goldhirsch A. Winer E.P. Coates A.S. et al.Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.Ann Oncol. 2013; 24: 2206-2223Abstract Full Text Full Text PDF PubMed Scopus (1922) Google Scholar]Intrinsic subtypeClinicopathological surrogate definitionLuminal A‘Luminal A-like’ ER-positive HER2-negative Ki67 lowaKi-67 scores should be interpreted in light of local laboratory values: as an example, if a laboratory has a median Ki-67 score in receptor-positive disease of 20%, values of 30% or above could be considered clearly high; those of 10% or less clearly low. PgR highbSuggested cut-off value is 20%; quality assurance programmes are essential for laboratories reporting these results. Low-risk molecular signature (if available)Luminal B‘Luminal B-like (HER2-negative)’ ER-positive HER2-negative and either Ki67 high or PgR low High-risk molecular signature (if available)‘Luminal B-like (HER2-positive)’ ER-positive HER2-positive Any Ki67 Any PgRHER2‘HER2-positive (non-luminal)’ HER2-positive ER and PgR absent‘Basal-like’‘Triple-negative’cThere is ∼80% overlap between ‘triple-negative’ and intrinsic ‘basal’ subtype, but ‘triple-negative’ also includes some special histological types such as carcinoma with a rich lymphocytic stroma (former medullary), secretory carcinoma, low-grade metaplastic carcinoma and adenoid cystic carcinoma. ER and PgR absentcThere is ∼80% overlap between ‘triple-negative’ and intrinsic ‘basal’ subtype, but ‘triple-negative’ also includes some special histological types such as carcinoma with a rich lymphocytic stroma (former medullary), secretory carcinoma, low-grade metaplastic carcinoma and adenoid cystic carcinoma. HER2-negativecThere is ∼80% overlap between ‘triple-negative’ and intrinsic ‘basal’ subtype, but ‘triple-negative’ also includes some special histological types such as carcinoma with a rich lymphocytic stroma (former medullary), secretory carcinoma, low-grade metaplastic carcinoma and adenoid cystic carcinoma.Adapted from the 2013 St Gallen Consensus Conference [23.Goldhirsch A. Winer E.P. Coates A.S. et al.Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.Ann Oncol. 2013; 24: 2206-2223Abstract Full Text Full Text PDF PubMed Scopus (1922) Google Scholar].ER, oestrogen receptor; HER2, human epidermal growth factor receptor 2; PgR, progesterone receptor.a Ki-67 scores should be interpreted in light of local laboratory values: as an example, if a laboratory has a median Ki-67 score in receptor-positive disease of 20%, values of 30% or above could be considered clearly high; those of 10% or less clearly low.b Suggested cut-off value is 20%; quality assurance programmes are essential for laboratories reporting these results.c There is ∼80% overlap between ‘triple-negative’ and intrinsic ‘basal’ subtype, but ‘triple-negative’ also includes some special histological types such as carcinoma with a rich lymphocytic stroma (former medullary), secretory carcinoma, low-grade metaplastic carcinoma and adenoid cystic carcinoma. Open table in a new tab Adapted from the 2013 St Gallen Consensus Conference [23.Goldhirsch A. Winer E.P. Coates A.S. et al.Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013.Ann Oncol. 2013; 24: 2206-2223Abstract Full Text Full Text PDF PubMed Scopus (1922) Google Scholar]. ER, oestrogen receptor; HER2, human epidermal growth factor receptor 2; PgR, progesterone receptor. Tumour-infiltrating lymphocyte (TIL) scoring is demonstrated to have a prognostic value in triple-negative breast cancer (TNBC) and HER2-positive breast cancer. It has been described as a predictor of pathological complete response (pCR) to chemotherapy (ChT) in many prospective neoadjuvant clinical trials and its increase appears linked to an improved prognosis after adjuvant therapy. TIL scoring can be used as a prognostic marker, as shown in a variety of clinical trials (e.g. BIG-2-98, FinHER, Cleopatra), providing a typically 15%–20% relative improvement in survival per 10% increase in TILs [25.Dieci M.V. Radosevic-Robin N. Fineberg S. et al.Update on tumor-infiltrating lymphocytes (TILs) in breast cancer, including recommendations to assess TILs in residual disease after neoadjuvant therapy and in carcinoma in situ: a report of the International Immuno-Oncology Biomarker Working Group on Breast Cancer.Semin Cancer Biol. 2018; 52: 16-25PubMed Google Scholar, 26.Wein L. Savas P. Luen S.J. et al.Clinical validity and utility of tumor-infiltrating lymphocytes in routine clinical practice for breast cancer patients: current and future directions.Front Oncol. 2017; 7: 156.Crossref PubMed Scopus (0) Google Scholar, 27.Loi S. Drubay D. Adams S. et al.Tumor-infiltrating lymphocytes and prognosis: a pooled individual patient analysis of early-stage triple-negative breast cancers.J Clin Oncol. 2019; 37: 559-569Crossref PubMed Scopus (176) Google Scholar] and its use as a prognostic factor is endorsed by the 2019 St Gallen Consensus. However, TIL scoring should not be used to take treatment decisions nor to escalate or de-escalate treatment. Genetic counselling and testing for germline BRCA1 and BRCA2 mutations should be offered to breast cancer patients in high-risk groups, i.e. those with:•strong family history of breast, ovarian, pancreatic and/or high grade/metastatic prostate cancer;•diagnosis of breast cancer before the age of 50;•diagnosis of TNBC before the age of 60; and•personal history of ovarian cancer or second breast cancer or male sex [II, A] [28.National Comprehensive Cancer Network guidelines for treatment of breast cancer. http://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (12 February 2019, date last accessed).Google Scholar, 29.Paluch-Shimon S. Cardoso F. Sessa C. et al.Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening.Ann Oncol. 2016; 27: v103-v110Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. Other high-risk mutations may also be tested, if deemed appropriate by the treating physician/genetic counsellor. For details regarding genetic testing and management of BRCA carriers, please refer to the appropriate ESMO Clinical Practice Guidelines [29.Paluch-Shimon S. Cardoso F. Sessa C. et al.Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening.Ann Oncol. 2016; 27: v103-v110Abstract Full Text Full Text PDF PubMed Scopus (150) Google Scholar]. Recommendations:•Breast imaging should involve bilateral mammogram and US of breasts and axillae in all cases [I, A]; MRI is recommended in case of uncertainties following standard imaging and in special clinical situations [I, A].•Pathological evaluation includes histology from the primary tumour and cytology/histology of the axillary nodes (if involvement is suspected) [I, A].•Pathological report should include histological type, grade, IHC evaluation of ER, PgR (for invasive cancer), HER2 (for invasive cancer) and some form of proliferation markers (e.g. Ki67 for invasive cancer) [I, A]. Tumours should be grouped into surrogate intrinsic subtypes, defined by routine histology and IHC data [I, A].•TIL scoring is of prognostic value and may be used to add on information on patient’s prognosis. It should not, however, be used to take treatment decisions nor to escalate or de-escalate treatment.•Genetic counselling and testing for germline BRCA1 and BRCA2 mutations should be offered to breast cancer patients in high-risk groups [II, A]. Disease stage should be assessed according to the eighth edition of the AJCC TNM staging system [16.Giuliano A.E. Connolly J.L. Edge S.B. et al.Breast cancer-major changes in the American Joint Committee on Cancer eighth edition cancer staging manual.CA Cancer J Clin. 2017; 67: 290-303Crossref PubMed Scopus (321) Google Scholar]. In early breast cancer, routine staging evaluations are directed at locoregional disease. Asymptomatic distant metastases are rare, and most patients do not benefit from comprehensive laboratory tests (including tumour markers [30.Krop I. Ismaila N. Andre F. et al.Use of biomarkers to guide decisions on adjuvant systemic therapy for women with early-stage invasive breast cancer: American Society of Clinical Oncology clinical practice guideline focused update.J Clin Oncol. 2017; 35: 2838-2847Crossref PubMed Scopus (149) Google Scholar]) and radiological staging [III, D]. Minimum blood work-up (a full blood count, liver and renal function tests, alkaline phosphatase and calcium levels) is recommended before surgery and systemic (neo)adjuvant therapy [V, A]. A computed tomography (CT) scan of the chest, abdominal imaging (US, CT or MRI scan) and a bone scan can be considered for patients with:•clinically positive axillary nodes;•large tumours (e.g. ≥5 cm);•aggressive biology; and•clinical signs, symptoms or laboratory values suggesting the presence of metastases [III, A]. Dual imaging methods combining functional and anatomical information such as fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT may be useful when conventional methods are inconclusive [V, A]. PET-CT scanning can also replace traditional imaging for staging in high-risk patients [V, B] [31.Koolen B.B. Vrancken Peeters M.J. Aukema T.S. et al.18F-FDG PET/CT as a staging procedure in primary stage II and III breast cancer: comparison with conventional imaging techniques.Breast Cancer Res Treat. 2012; 131: 117-126Crossref PubMed Scopus (96) Google Scholar], although in cases of lobular cancers and low-grade tumours, PET-CT may be less sensitive. C