Clinical Practice Guideline
The Screening, Diagnosis, Treatment, and Follow-Up of Breast Cancer
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Background: Breast cancer is the most common cancer in women. The German S3 guideline of 2012 has now been updated to take account of advances in the early detection, diagnostic evaluation, treatment, and follow-up care of this disease.
Methods: The updating process was based on the adaptation of identified source guidelines and on reviews of the scientific evidence. A systematic search in multiple literature databases was carried out, and the full texts of the selected articles were evaluated. Suggested recommendations were then proposed by interdisciplinary working groups and modified and graded in a nominal consensus procedure.
Results: The value of mammographic screening is confirmed in the updated guideline. As for the diagnostic evaluation of breast cancer, computed tomography is recommended for staging in patients with a high risk of recurrence, in addition to conventional methods. As for surgical treatment, the evidence supporting locoregional surgery for primary breast cancer now affords an opportunity for de-escalation: complete resection yields the best outcome, but a safety margin of several millimeters is not necessary. Axillary dissection is no longer recommended except in certain defined situations. Radiotherapeutic approaches consist of hypofractionated applications. Adjuvant systemic therapy is indicated for patients in certain high-risk situations defined by a constellation of factors including tumor grade, patient age, node status, Ki-67 antigen expression, hormone receptor status, and human epidermal growth factor receptor 2 (HER2) status. All patients with hormone receptor–positive breast cancer should receive endocrine therapy. The indication for chemotherapy and/or anti-HER2 therapy should be determined in consideration of the expected benefit and side effects.
Conclusion: Consistent implementation of the recommendations in the newly updated guideline can help lessen morbidity and mortality from breast cancer. The actual extent to which breast cancer guidelines are implemented should be a topic of future research.
The rationale behind updating the interdisciplinary S3 guideline (1) is the high epidemiological relevance of breast cancer and the associated relevance for routine health care (Figure 1). The need to update the guideline also arises from the emergence of new scientific knowledge. The recommendations are addressed to all physicians and members of professional groups involved in the health care of individuals undergoing screening and breast cancer patients (gynecologists, general practitioners, radiologists, pathologists, radio-oncologists, medical oncologists, psycho-oncologists, physiotherapists, nursing staff, etc.), as well as all women with breast cancer and their relatives.
Other target groups include:
- Scientific medical societies and professional organizations
- Women’s interest groups (women’s health organizations, patient and self-help organizations)
- Quality assurance bodies at German federal and state level
- Health policy institutions and decision-makers at German federal and state level
- Contract managers for disease management programs and integrated care contracts
- Cost bearers, and
- The public, in order to ensure they are provided with information on an evidence-based approach to breast cancer.
The guideline is published by the “Oncology” guideline program of the German Association of Scientific Medical Societies (Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften e. V., AWMF), the German Cancer Society (Deutsche Krebsgesellschaft e. V., DKG), and German Cancer Aid (Deutsche Krebshilfe, DKH). The members of the guideline steering group (Box 1), the experts invited by the steering group (eTable 1), as well as by the participating specialist societies and organizations (eTable 2) made up the working groups and are the authors of the guideline. Only the elected representatives of the participating specialist societies and organizations were allowed to vote in the consensus process, once all specific conflicts of interest had been excluded. The guideline was drawn up under the direct participation of four patient representatives. Approximately 80% of recommendations were identified as needing revision and thus adapted in accordance with the AWMF rules for guidelines. To this end, source guidelines developed specifically for breast cancer patients were researched. These were then compared with guideline report No. 224 of the German Institute for Quality and Efficiency in Health Care (Institut für Qualität und Wirtschaftlichkeit im Gesundheitswesen, IQWIG) (2). In the case of recommendations that needed to be newly compiled, appropriate research and evaluations of the evidence were defined according to AWMF policy.
The formulation of the respective key questions, as well as systematic research, was performed in a first step on the basis of aggregated sources of evidence (meta-analyses, Cochrane reviews, systematic reviews, etc.). Appropriate lists of titles and abstracts were selected by two independent raters until fulltexts were identified, and evidence tables were compiled by the methods group. The Oxford Centre for Evidence-Based Medicine classification (2009 version) was used as a model to rank levels of evidence. For the purposes of updating the guideline, recommendations were adopted and recommendation grades defined during two consensus conferences using a formal consensus process.
Level 1 or level 2 evidence is available for the majority of recommendations. However, reliable studies are still needed in some areas, as is made evident by the currently low evidence levels (level 3 and level 4, e.g., in the guideline chapters 184.108.40.206: Additional diagnostic imaging in the case of high mammographic density at screening, 5.3.1: Treatment of local (intra-breast) recurrence, 220.127.116.11 and 5: Resection of single liver/lung metastases (1).
Relevant recommendations (and their background) set out in the guideline on primary breast cancer are presented below. Male breast cancer is discussed in a separate chapter of the guideline.
The investigations involved in breast cancer screening are associated not only with benefits, but also with risks. This is all the more important given that the women undergoing screening are primarily healthy individuals, in whom (according to the prevalence round) the annual rate of cases of new-onset disease is only 0.3%. Due to this relatively low number of new cases per year, which add up to a lifetime morbidity rate of >12%, it is essential that the benefits and harms of screening tests are proportionate. False-positive findings are seen as causing anxiety and distress, while false-negative findings illustrate the limitations of the methods used (3, 4).
Participation in the German national mammography screening program is recommended for women aged between 50 and 69 years. Women aged over 70 years should be given the option to undergo screening taking into consideration their individual risk profile and health status, as well as a life expectancy of more than 10 years. An association between screening mammography and a reduction in breast cancer mortality among women aged between 40 and 49 years has also been demonstrated and this outweighs the risks associated with radiation exposure. However, this reduction is lower than in the 50- to 69-year-old age group and yields proportionately more false-positive and false-negative findings. Therefore, the decision to screen should be made on the basis of an individual risk analysis, a benefit–risk assessment, and taking the woman’s preferences into account (5, 6). This approach implies that, by screening women aged between 50 and 69 years (approximately 10 rounds), up to eight lives can be saved out of 1000 currently healthy participants. The evidence for this, however, is highly inhomogeneous and requires long-term results, which are called for in the guideline. The rate of follow-up visits for repeat imaging of what ultimately proves to be a benign finding is around 2% in Europe.
There is insufficient evidence at present that any other imaging examination (tomosynthesis, ultrasound, magnetic resonance imaging [MRI], or other techniques) contributes to a reduction in breast cancer mortality, neither as a supplemental examination nor as a substitute for mammography screening (5). To ensure the best possible quality-assured therapy, breast cancer detected at screening should be treated at certified breast centers.
In addition to a thorough clinical examination, the following investigations are available to patients with breast cancer, equivocal or suspicious findings, or precancerous lesions:
- Diagnostic mammography, including additional mammograms such as magnification mammography (diagnostic mammography refers to mammograms performed outside screening to investigate findings or symptoms)
- Breast ultrasound using high-frequency transducers (7.5–12 MHz as recommended by the German Society for Ultrasound Medicine (Deutsche Gesellschaft für Ultraschall in der Medizin, DEGUM])
- Interventional methods such as large-core needle biopsy and vacuum-assisted biopsy
- Contrast-enhanced MRI
- Pneumocystography (only rarely used today and largely replaced by high-frequency ultrasound techniques)
- Fine-needle aspiration only in special individual cases (e.g., axillary lymph node aspiration).
These non-invasive and invasive diagnostic methods, combined with histological analysis of the preoperatively obtained large-core needle biopsies and resultant immunohistochemical findings (estrogen and progesterone receptors, HER2 status [HER2, human epidermal growth factor receptor 2], grading, antigen Ki-67), enable targeted surgical planning in the context of pre-treatment consultation, taking neoadjuvant systemic therapy into account where necessary. Staging (lung, liver, bones), should be performed in the case of newly diagnosed breast cancer from UICC stage II (UICC, Union Internationale Contre le Cancer) with increased risk, as well as stage III and IV with no symptoms of metastasis. The evidence available on the selection of staging methods is limited. Although studies demonstrate the sensitivities and specificities of the individual methods, there are no studies on the influence of the selected methods on survival depending on treatment changes or quality of life. Due to their higher sensitivity and specificity, computed tomography (CT) of the chest/abdomen and bone scintigraphy are replacing previous staging using chest X-ray and abdominal ultrasound (7). Staging should only be performed in women with a high risk for metastasis (N+, >T2) and/or aggressive tumor biology (e.g., HER2+, triple-negative), clinical signs, symptoms, and when systemic chemo-/antibody therapy is planned.
Furthermore, approximately 30% of all women with breast cancer in Germany have a family history of breast cancer and fulfill the inclusion criteria for genetic testing (Box 2).
The majority of women with breast cancer today can be treated by breast-conserving surgery. Although in terms of de-escalation in locoregional treatment procedures, R0 resection (complete resection with tumor-free surgical margins) is defined as highly relevant to prognosis, the previously defined distances between tumor front and surgical margin in invasive cancer were discarded due to a lack of evidence of their effect on the local recurrence rate. A meta-analysis reported that local recurrence was diagnosed in 9.8% with tumor-free margins of 1 mm, in 4.9% with 2 mm, and 4.4 % with 5 mm and described no significant association (8).
These figures relate to ablative and breast-conserving methods, which increasingly take oncoplastic aspects into account (Figure 2). In ductal carcinoma in situ (DCIS), the distance to healthy tissue should be 2 mm. Recommendations on ablative procedures have been modified. Thus, multifocal cancer located outside the quadrants is no longer a mandatory indication for an ablative procedure if R0 resection can be ensured. However, this only applies if the indicated adjuvant treatment measures (systemic treatment and radiotherapy with boost) are carried out (8).
All surgical breast interventions with preoperatively proven malignancy should be combined with sentinel node biopsy (SNB), whereby the technical possibility of using nuclear markers is a prerequisite. Longitudinal data from the Z0011 study confirmed a de-escalation in axillary staging. Patients with pT1–pT2/cN0 tumors receiving breast-conserving surgery followed by percutaneous radiotherapy using opposed tangential fields (tangent radiotherapy) and one or two positive sentinel nodes should not undergo axillary lymph node dissection (9). Patients receiving primary systemic therapy (PST) and showing negative lymph node status based on palpation and ultrasound should undergo SNB following PST (10, 11). Patients receiving PST and with positive pretreatment SNB (pN1) and clinically negative nodal status following PST (ycN0) should undergo axillary lymph node dissection (12, 13). A detailed consultation on the possibilities of breast reconstruction should take place in the context of all ablative procedures.
Following breast-conserving surgery due to invasive cancer, radiotherapy should be performed on the affected breast. In the case of R0 resection and taking the increased risk of local recurrence into consideration after individual consultation, radiotherapy can be dispensed with in patients with clearly limited life expectancy (<10 years), small (pT1), node-negative (pN0), hormone-receptor positive, HER2-negative tumors, and adjuvant endocrine therapy (14–21). Breast irradiation should be hypofractionated (total dose of approximately 40 Gy in 15–16 fractions over 3–5 weeks) or can be performed in conventional fractions (total dose of approximately 50 gy in 25–28 fractions over 5–6 weeks) (22–28). A local boost radiation dose to the tumor bed reduces the rate of local recurrence in the breast, without conferring a significant survival benefit (cumulative incidence, 10.2% with vs. 6.2% without boost) (29).
Post-mastectomy radiotherapy (PMRT) of the chest wall should be performed in the following situations:
- pT3 pN0 R0 and additional risk factors (L1, G3, premenopausal status, age <50 years)
- R1/R2 resection and R0 impossible to achieve in repeat resection
- PMRT should be performed in the case of >3 positive axillary lymph nodes
- PMRT should be performed in the case of 1–3 positive axillary lymph nodes if there is an increased risk of recurrence (e.g., HER2-positive, triple-negative, G3, L1, Ki-67 >30%, >25% of removed lymph nodes are positive, age ≤ 45 years, and additional risk factors such as medial tumor localization, tumor size >2 cm, or ER-negative).
PMRT is not necessary in the case of 1–3 positive axillary lymph nodes and low risk of tumor recurrence (at least three of the following must apply: pT1, G1, ER-positive, HER2-negative).
In all other patients with 1–3 positive axillary lymph nodes, the individual indication should be made on an interdisciplinary basis.
Adjuvant irradiation of the regional lymphatic drainage improves disease-free survival and overall survival in defined subgroups of patients (30–32). The effects of radiotherapy diminish in higher age groups.
Adjuvant drug therapy
The recommendations on adjuvant treatment of breast cancer take into account tumor size, lymph node status, grading, hormone-receptor status, HER2 status, menopausal status, and age as the most important factors when deciding on the need for and type of adjuvant therapy (33, 34).
The 2009 St. Gallen recommendations refer to endocrine sensitivity and the 2011 recommendations to the molecular subtypes as the decisive criteria in establishing the indication for adjuvant chemotherapy (34). The immunohistochemically determined markers ER, PgR, HER-2, and Ki-67 are considered surrogate parameters for the molecular subtypes (33). ER- and/or PgR-positive, HER2-negative tumors with low proliferation rates are considered “Luminal A” disease, while tumors with higher proliferation rates are considered “Luminal B.” One must bear in mind here that there is no validated threshold level for Ki-67 (e.g., to classify tumors into Luminal A vs. B or to guide the decision for/against adjuvant chemotherapy).
Indications for adjuvant chemotherapy
- HER2-positive tumors: simultaneous anti-HER2-targeted treatment with trastuzumab for 1 year combined with (neo-)adjuvant chemotherapy is standard
- Non–endocrine sensitive tumors (ER- and PgR-negative)
- Equivocally endocrine-sensitive tumors
- Node-positive tumors: studies are currently evaluating whether adjuvant chemotherapy can be dispensed with in patients with low node involvement (1–3 positive nodes) and favorable tumor biology (Luminal A)
- G 3
- Young age at onset (<35 years).
Chemotherapy is always indicated if the individual anticipated benefit is greater than the possible side effects. This requires that patients be provided with differentiated information, particularly if the expected benefit is only slight. Chemotherapy can be administered in a neo-adjuvant and an adjuvant setting and should include anthracycline and taxane. In the case of moderate clinical risk (<3 positive lymph nodes), six cycles of TC (docetaxel and cyclophosphamide) can represent an anthracycline-free alternative. For HER2-positive tumors and in cases where neo-adjuvant chemotherapy is indicated, trastuzumab treatment should be performed. HER2-positive status and high-risk situations (clinical/ultrasound or large-core needle biopsy N+, tumor size >2 cm) require that treatment be supplemented with pertuzumab.
To avoid over-treatment in hormone receptor–positive tumors, risk assessment by means of multigene assays can be helpful in selected cases where the clinical situation and profile of conventional markers fail to establish a clear indication for or against chemotherapy.
Patients with ER- and/or PgR-positive invasive tumors should receive endocrine treatment irrespective of any potential chemotherapy. This should be initiated only once chemotherapy has been completed, but can be performed parallel to radiotherapy.
Long-term data also demonstrate that adjuvant endocrine therapies significantly reduce the probability of recurrence. Thus, tamoxifen use over 5 years in patients with ER-positive breast cancer reduces the absolute risk of recurrence from 4.8% to 2.9% (33, 35–37).
The beneficial effects of endocrine therapy are only achieved if treatment is adequately adhered to. However, only around 50% of women with breast cancer adhere to treatment over the recommended 5-year period. This lack of compliance is associated with significantly increased breast cancer–specific mortality (an absolute risk reduction in breast cancer–specific mortality from 27.1% to 19.3% as a result of tamoxifen use for 5 years) (33, 38). Thus, it is highly relevant to treatment success to convince patients of the need for therapy, to take a thorough history in order to heighten awareness of side effects as well as of symptoms that are unrelated to treatment, and to treat these adequately. In the case of severe side effects that reduce therapy adherence, a swap from an aromatase inhibitor to tamoxifen and vice versa or between aromatase inhibitors (steroidal vs. non-steroidal) can be considered in post-menopausal patients. Successfully increasing therapy adherence in this way is more effective than performing chemotherapy. Pre-menopausal patients should receive tamoxifen therapy (20 mg/day) for at least 5 years. Depending on the risk of recurrence, one should consider tamoxifen use over a period of 10 years from initial diagnosis or until recurrence.
Ovarian suppression (GnRH analogues or bilateral ovariectomy) in addition to tamoxifen or an aromatase inhibitor should only be considered in the case of high risk of recurrence and pre-menopausal status following adjuvant chemotherapy. Adjuvant endocrine therapy in postmenopausal patients with ER-positive breast cancer should include an aromatase inhibitor (37).
An overall concept must include quality assured screening, professional diagnostic imaging, histopathological investigations, excellent surgical techniques, systematic radiotherapy, pharmacological therapy including the most up-to-date treatment methods, and professional follow-up over the entire treatment duration and beyond. Consistent implementation of the guideline recommendations makes it possible to optimize quality along the treatment chain (Table) and can lead to a reduction in the morbidity and mortality of breast cancer. It is essential for implementation to be accompanied by interdisciplinary and cross-sectoral evaluation in the context of health services research.
Conflict of interest statement
Prof. Wöckel received consultancy fees and the reimbursement of participation fees from Pfizer, Novartis, Roche, Amgen, Celgene, and Eisai. He received lecture fees from Novartis, Pfizer, Roche, Amgen und Celgene.
Prof. Albert received fees for expertise activities from Medexo and for consultancy activities from Pfizer. She received fees from the WSG Study Group for conducting clinical studies.
Prof. Scharl received consultancy fees from Celgene, Roche, Novartis, Amgen, Myriad, Eisai, Riemser, Zeiss, Janssen-Cilag, AstraZeneca, and TEVA. He was reimbursed for participation fees and travel or accommodation costs by Celgene. He received fees for a lecture or conference preparation from Roche, Novartis, TEVA, Amgen, AstraZeneca, Celgene, GlaxoSmithKline, Eisai, Riemser, Zeiss, and Janssen-Cilag Celgene, GlaxoSmithKline, Eisai, Riemser, Zeiss, and Janssen-Cilag.
Dr. Stüber received lecture fees from Roche.
The remaining authors state that they have no conflicts of interest.
Manuscript submitted on 14 February 2018, revised version accepted
on 19 February 2018
Translated from the original German by Christine Schaefer-Tsorpatzidis
Prof. Dr. med. Achim Wöckel
Frauenklinik und Poliklinik
97080 Würzburg, Germany
AWMF-Institute for Medical Knowledge Management, c/o Philipps Universität Marburg:
Prof. Dr. med. Ute-Susann Albert
Department of Obstetrics and Gynaecology, Ulm University: Prof. Dr. med. Wolfgang Janni,
Prof. Dr. med. Rolf Kreienberg
Frauenklinik St. Marien, Amberg: Prof. Dr. med. Anton Scharl
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