Guidance and Standards for Breast Cancer Care in Europe

According to the European Society for Medical Oncology (ESMO), the incidence of breast cancer (BC) estimated in 40 European countries in 2012 was about 94.2/100,000 women, with a mortality rate of 23.1/100,000 [1]. Options for the treatment of BC include surgery, radiotherapy, chemotherapy, anti-HER2 therapy, and endocrine therapy, either sequentially or concomitantly. Although treatment success and prognosis are influenced by intrinsic tumoral factors, drug side effects, inherent toxicities of therapies, and therapy adherence. In order to optimize patient care, clinical practice guidelines (CPG) are formulated by committees of experts as statements that include evidence-based protocols and recommendations for specific patient profiles [2‐5]. CPG recommendations also emphasize the importance of disease diagnosis and treatment being managed by an expert interdisciplinary team who base their treatment approach on the initial spread of the disease, the patient’s clinical condition and autonomy, as well as the availability of resources. However, few comparisons between these guidelines exist in the literature.

Here, we present a restricted comparison between several European guidelines regarding invasive early BC, according to their latest available versions: ESMO, DKG German Cancer Society—Interdisciplinary S3 guidelines for the diagnosis, treatment and follow-up care of BC [4], UK - NICE (National Institute of Clinical Excellence)—Early and locally advanced breast cancer: diagnosis and treatment [6], UK - SIGN (Scottish Intercollegiate Guidelines Network)—Management of breast cancer in women [7], SCR Swedish cancer register [8], the French Breast Cancer Intergroup [9, 10] and the Romanian Breast Cancer Clinical Guideline [11]. Whenever it was possible, we included the level of evidence reported by the cited resource.

According to ESMO guidelines, 18 countries from the EU offer mammography screening programs for the early detection of BC [1]. Screening programs, which consists of offering mammograms to women aged between 50 and 70 years, have been proven to reduce BC-related mortality [12]. ESMO recommends periodically mammography screening for women between 50 and 69 years old (IA) [1]. More specific are the NICE and German guidelines which recommend mammography for women between 50 and 70 years old every 3 and 2 years, respectively [4, 6]. ESMO also recommends yearly screening with MRI and mammography together or alternating every 6 months for women with a family history of BC, starting 10 years prior to the diagnosis age of the earliest case in the family (IIIB) [1].

EBCOG (European Board and College of Obstetrics and Gynaecology) Standards of Care stress the importance of women’s accessibility to “established and validated methods of screening”, in well-established, well-equipped and well-staffed screening units, based on written protocols [13].

The ESMO guidelines and EBCOG Standards of Care advise considering the possibility of false positive and false negative results of BC screening and recommend informing the patient regarding these issues [1, 13].

NICE and ESMO guidelines recommend that patients with BC should be referred to specialized units [1, 13], with written protocols for diagnosis and management of BC [13]. These units must offer access to a multidisciplinary team [14] including personnel specialized in BC care: surgeon, radiation oncologist, medical oncologist, radiologist, pathologist, breast nurse [1] (IVA) and psychologist [13].

All guidelines recommend that the clinically suspected diagnosis must be associated with imaging (mammography, breast ultrasound or MRI) and confirmed pathologically. The imaging diagnosis of BC includes bilateral mammography and ultrasound of breast and regional lymph nodes. NICE guideline recommends a triple assessment (clinical assessment, mammography and/or ultrasound and biopsy) at the first visit to the breast clinic [6]. None of the guidelines recommend routine MRI. The ESMO guidelines recommend MRI in case of familial cases of BC with BRCA mutations, breast implants, multifocal BC (IIIB), to assess the response to chemotherapy, or in the case of inconclusive evidence (IIIA) [1]. Both the ESMO and the NICE guidelines recommend an MRI if the clinical examination and imaging is inadequate, in case of lobular BC (IIIB). NICE guidelines further recommend MRI in case of breast density that hinders the ultrasound examination [6].

ESMO guidelines recommend that the pathological confirmation be established by core needle biopsy, preferably obtained by ultrasound or stereotactic guidance. Core needle biopsy is mandatory in the case of planned preoperative systemic therapy in order to provide the diagnosis of invasive disease and the biomarkers status (IIIA). The pathological report should offer information about the histological type and grade of tumour, hormonal status (ER, PR), HER2 neu and Ki 67 status (IIIA) [1], an aspect also supported by NICE guidelines 2018 [6]. During the biopsy, it is recommended to place a marker (clip) to assure the correct surgical removal of the affected area (VA) [1]. NICE guidelines recommend confirmation by either core biopsy and/or fine needle aspiration cytology [6]. Romanian guidelines recommend the diagnosis of BC to be confirmed either by fine needle cytology, or by open (surgical) biopsy or Tru-cut needle [11].

According to ESMO [1] and NICE guidelines [6], the lymph nodes should be evaluated preoperatively by clinical examination and ultrasound (IIIA). All guidelines recommend cytological/histological examination of suspicious axillary lymph nodes. Given the fact that asymptomatic metastases in early BC are rare, ESMO guidelines recommend that staging be directed to locoregional disease in asymptomatic patients (IIID) [1]. Additional radiological investigations such as CT and bone scan are indicated in case of large tumours (> 5 cm), positive axillary nodes, or histological aggressive tumours (IIIB). A PET/CT examination may be useful if the results from conventional methods remain ambiguous (VA). Furthermore, PET/CT is indicated in high-risk patients, who would benefit from neoadjuvant chemotherapy, as well as for locally advanced BC or inflammatory disease, with an increased risk of metastasis (VB). Sonographic cardiac evaluation is necessary for patients who benefit from (neo) adjuvant chemotherapy with anthracyclines and/or trastuzumab (IA) [1]. Romanian guidelines also recommend further investigation (bone X-rays, bone scintigraphy, computed tomography scans of thorax, abdomen, head) only in the case of symptomatic patients (IIIB) [11].

The comparison is limited to the following treatment modalities for BC:

The therapeutic strategy depends on many factors like tumour biology, localization and tumour expansion (size and location of primary tumour, multifocality/multicentricity, the number and extent of lymph nodes), as well as individual considerations such as age, general health status and individual preference [1].

Regarding the level of evidence and grade of recommendation [30], some disparities between guidelines can also be noted. DKG uses the Oxford classification—10 categories of evidence level (1a to 5) and 4 categories of grade recommendation (A, B, 0, GCP) [31], NICE uses eight categories (1 ++ to 4) [6], and SIGN proposes the same NICE—eight categories (1 ++ to 4) and five grades of recommendation (A, B, C, D, E). The ESMO Clinical practice guidelines use 5 levels of evidence (I to V) and 5 grades of recommendation (A to E) [1]. Romanian guidelines use 4 categories of grades recommendation (A to E), and 6 levels of evidence (Ia, Ib, IIa, IIb, III, IV) [11].

Cancer survival can be defined as the clinical period between primary curative cancer treatment and the time of death, while cancer survivorship refers to “a distinct phase in the cancer trajectory between primary treatment and cancer recurrence or end of life” [32]. The goals of follow-up are the early detection of local recurrence or contralateral BC, evaluation of possible treatment—related complications, as much as optimal support of patients to regain capacity to undertake their social and professional activities [1, 2]. However, the follow-up recommendations differ between guidelines.

ESMO guidelines state that in the first 2 years, medical visits at every 3–4 months are recommended; after 3–5 years, every 6 months; after this period, patients should be encouraged to visit annually [1]. Romanian guidelines recommend clinical examination every three months in the first year, every 6 months in the second year and yearly visits beginning with the third year [11].

Annual bilateral mammography is recommended by all guidelines (IIA) and ultrasound can be taken into consideration for lobular invasive carcinomas (IIIB)—cited here are ESMO’s levels of evidence/grades of recommendation [1]. NICE guideline does not recommend ipsilateral mammography after mastectomy [6].

ESMO recommends other factors to be considered during the follow-up period: lipid profile (VA), annual gynaecological ultrasound (VB) for patients receiving tamoxifen, regular bone density for patients under AI and diet counselling for obese patients (IIIB). Hormone replacement therapy is not recommended due to the increased risk of recurrence (IA) [1]. Romanian guidelines recommend routine complete blood count, alkaline phosphatase, and, also, yearly chest X-ray, abdominal ultrasound and gynaecologic examination [11].

EBCOG standards of care recommend patient centred care, with emphasis on the psychological aspects as well as the need to reduce patient anxiety and discomfort. To this end, physicians should receive regular training in communication skills and the delivering of bad news, as well as in the management of vulnerable patients [13].

Finally, the European NCCP (National Cancer Control Programmes) for BC are in the process of continuous innovation and development, their recommendations being updated annually or even more often based on evidence gathered from newly published, relevant clinical trials [33].

Given the tendency of increased incidence and mortality rates due to BC, the existence of clinical guidelines has become of great importance in order to provide optimal BC treatment by identifying the risk factors, improving the screening methods, as well as intensifying the operative methods, application of adjuvant therapy and follow-up care. However, there are significant discrepancies within European guidelines, which could hinder physicians from implementing their recommendations. Therefore, reviewing and updating of the current guidelines is indispensable. Physician still have the responsibility to select the most appropriate management among the available alternatives in order to provide the best care for the patient dealing with this disease.