HOw should metastatic breast cancer be diagnosed?


Conventional diagnostics is recommended on clinical suspicion of a metastasis.


After the diagnosis metastasis, complete staging is recommended.


Histological confirmation of the diagnosis metastatic breast cancer is recommended, also for determination of hormone receptor and HER-2-overexpression, and to exclude a benign abnormality or other primary tumour.


Tumour marker determinations of CA27.29, CA15.3 or CEA are recommended if there is no measurable/evaluable disease in order to evaluate the effect of treatment.



Level 3

Skeletal scintigraphy is the examination of choice in the event of clinical suspicion of skeletal metastases, supplemented with conventional images of symptomatic and abnormal areas and MRI where required.


C          Ellis 2000, Frederick 1997, Layer 1999, Nishimura 1999,Sheafor 1999, Hamaoka 2004


Level 3

Chest X-ray and ultrasound are the examination of first choice on clinical suspicion of chest or abdominal metastases. On radiological suspicion this is followed by chest CT or abdominal CT.


C          Costelloe 2009


Level 3

Histological confirmation of the diagnosis metastatic breast cancer is also desirable for determination of hormone receptor and HER-2-overexpression, and to exclude a benign abnormality or other primary   tumour.


C          NCCN guidelines 2010, ESMO guidelines 2010


Level 3

If other parameters are lacking, tumour markers (CA 27.29, CA 15.3 or CEA) may be used to evaluate the effect of system therapy.


C          ASCO guidelines 2007

Literature summary

Metastasis is found in 75% of patients on the basis of complaints [Rutgers, 1989]. Diagnostics is aimed at the nature of the complaints and findings during physical examination. If metastasis is detected after the patient presents with complaints, complete staging must be performed (see paragraph 2.3). The goal of this is to detect other and threatening tumour localisations, determine a prognosis and evaluate the effect of treatment. The localisation and extent of the metastasis may influence the choice of therapy.


Imaging Complaints of the postural and musculoskeletal system

Metastasis to the skeleton occurs in 85% of all patients with metastatic disease [Wood, 2005; Ellis, 2000]. The skeleton is also often the first localisation of metastases, with a preference for the spinal column and pelvis followed by ribs, skull and femur [Hamaoka, 2004].

The skeletal scintigraphy is sensitive and provides a good overview of the entire skeleton, it is the examination of choice and is supplemented with skeletal photos of symptomatic and abnormal areas. This may be further expanded with an MRI scan. A CT scan is the preferred method for evaluation of rib laesions, possibly as part of FDG-PET-CT if complete staging is indicated.


Chest complaints

Intrathoracic metastases of breast cancer often spread to the lungs, pleura, mediastinum and airways. A chest X-ray is recommended for inventory purposes. However, a CT scan of the chest is the most important modality. Pleuritis carcinomatosa is the first symptom of metastasis in 20% of all patients with metastatic disease, frequencies of 15-25% are reported for lung metastasis. Solitary lung laesions appear to be the result of primary bronchial carcinoma in approximately half of cases [Casey, 1984]. Histological confirmation is therefore necessary for adequate staging and planning. The mediastinal lymph nodes are often affected in disseminated disease. Size is the most important criterion for CT evaluation, which is a limitation of the sensitivity. FDG-PET-CT may therefore be of additional value here. Pericardial and myocardial metastases are not common and are usually diagnosed using echocardiography.


Abdominal complaints

In 40-50% of all patients with metastatic disease there is involvement of  the liver [Wood, 2005; Ellis, 2000]. Liver metastases are rarely solitary. Ultrasound is suitable as a screening method, but a CT scan of the abdomen is the examination of choice if there is clinical suspicion of metastases. CT can also be used to evaluate the effect of systemic therapy. MRI may contribute to the differentiation of aspecific laesions [Shah, 2009].


Neurological complaints

Brain metastases occur in 6-16% of patients with a metastatic disease [Wood, 2005; Ellis, 2000].  CT detects most brain metastases, but MRI has a higher sensitivity. If epidural metastases are suspected, MRI is superior. Tumour cells in the cerebrospinal fluid are indicative for meningitis carcinomatosa, see also


Histological analysis

If metastasis is suspected, the diagnosis should in principle be histologically verified in order to confirm and characterise the metastatic disease. Hormone receptors and HER-2-overexpression may display a dynamic pattern in the course of the metastatic disease. Difference in PgR, ER and HER-2 receptor status between primary tumour and metastasis is described in 25%, 10% and 3% of patients respectively [Thompsom, 2010; Hoefnagel 2010]. Loss of hormone receptors may predict insensitivity to hormonal treatment [Kuukasjarvi, 1996] but cannot be excluded due to sampling error. Given the therapeutic consequences, current histological information is desirable. Histological or cytological confirmation is indicated with a solitary metastasis in order to exclude other causes of the abnormality, such as a second primary tumour.


Laboratory analysis

Laboratory tests are performed for two reasons:

  • in case of specific complaints
  • to provide direction to further tests/examination and choice of therapy


Determinations should at least include the following: blood count, liver functions, renal function, calcium and albumin. Existing data on tumour markers for early diagnostics provide insufficient support for routine use [Harris, 2007]. The tumour markers CA27.29, CA15.3 or CEA may be used as a parameter of disease activity when there are no parameters that can be measured well (such as with sclerotic skeletal metastases) [ASCO, 2007]. Marker increase can sometimes allow progression to be determined earlier than with other parameters; however, this does not provide a survival advantage. Without clinical or radiological progression it is generally insufficient reason to change the treatment plan.

A promising new development is measurement of circulating tumour cells (CTC’s) as parameter for the response to therapy. The number of CTC’s determined prior to starting systemic therapy for metastatic breast cancer appears to be a prognostic factor. The number of CTC’s after each course has been found in a few studies to be a measure for the final outcome concerning PFS and OS. CTC’s may be used in the near future as parameter for therapy response in the case of difficult to evaluate disease (e.g. only bone metastases) if accessible to everyone, and if a test validated for this purpose is used [Liu, 2009; Nakamura, 2010; Nole, 2008; Pierga 2011; Miller, 2010].


Introduction of FDG-PET-CT has replaced conventional staging almost everywhere. However, a clear strategy has not yet been developed to deal with aspecific possible false-positive findings. See also paragraph 2.3.3.

Authorization date and validity

Last review : 13-02-2012

Last authorization : 13-02-2012

The national Breast Cancer guideline 2012 is a living guideline, in other words there is no standard term of revision. NABON continually watches at new developments and clinical problems in the areas of screening, diagnostics, treatment and aftercare, and whether this requires an update.

Initiative and authorization

Initiative : Nationaal Borstkanker Overleg Nederland

Authorized by:
  • Nederlandse Internisten Vereniging
  • Nederlandse Vereniging voor Heelkunde
  • Nederlandse Vereniging voor Psychiatrie
  • Nederlandse Vereniging voor Radiologie
  • Nederlandse Vereniging voor Radiotherapie en Oncologie

General details

Approximately 14,000 women (and 100 men) are diagnosed with invasive breast cancer each year in the Netherlands, and about 1,900 have an in situ carcinoma. A woman's risk of having breast cancer over the course of her life is 12-13%. This means that breast cancer is the most common form of cancer in women in the Netherlands. Early detection, particularly via national breast cancer screening, combined with adjuvant therapy followed by locoregional treatment, improves the prognosis in women with breast cancer

The guideline on Breast Cancer Screening and Diagnostics, published in 2000, was updated in 2007. In 2002, the first multidisciplinary National Breast Cancer Guideline was published, it was revised in 2004, 2005 and 2006. In 2008 both guidelines were combined to Breast Cancer Guideline, which 2012 revision is now effected.

Scope and target group

This guideline is written for all the members of the professional groups that have contributed to its development.


This guideline is a document with recommendations and instructions to support daily practice. The guideline is based on the results of scientific research and expert opinion, with the aim of establishing good medical practice. It specifies the best general care for women with (suspected) breast cancer and for those who are eligible for screening. The guideline aims to serve as a guide for the daily practice of breast cancer screening, diagnostics, treatment and aftercare. This guideline is also used in the creation of informational materials for patients, in cooperation with the KWF (Dutch Cancer Society).

Samenstelling werkgroep

A core group consisting of a radiologist, surgeon, pathologist, medical oncologist and radiation therapist began preparing for the revision of the breast cancer practice guidelines in 2009. A multidisciplinary guideline development group was formed in early 2010 to implement the revision. This group consisted of mandated representatives from all of the relevant specialisations concerned with breast cancer, plus two delegates from the BVN (Dutch Breast Cancer Society) (see list of guideline development group members). The benefits of such a multidisciplinary approach are obvious: not only does it best reflect the care, but it offers the greatest possible expertise for the guideline. In composing the development group, geographic distribution of the members, balanced representation of the various organisations and agencies concerned, and a fair distribution in academic background were taken into account as much as possible.


The guideline development group received procedural and administrative support from IKNL (Comprehensive Cancer Centre for the Netherlands) and support on methodology from Bureau ME-TA. Partial funding was obtained from SKMS (Quality Funds Foundation of Dutch Medical Specialists). This subsidy would not have been possible without the extensive assistance provided by the NVvR (Radiological Society of the Netherlands).

Declaration of interest

Partial funding for the guideline revision was obtained from the Society of Dutch Medical Specialists in the framework of the SKMS. IKNL sponsored some of the cost. On two occasions, as well as at the beginning and end of the process, all of the members of the guideline development group were asked to fill out a statement of potential conflicts of interest, in which they stated their relationship with the pharmaceutical industry. A list of these statements of interest can be found in the appendices.

Patient involvement

In developing this guideline, four clinical questions were formulated. These questions emerge from an inventory of clinical problems collected in the field from professionals, patients and patient representatives.


Also, A multidisciplinary guideline development group was formed in early 2010 to create and implement the revision. This group consisted of mandated representatives from all of the relevant specialisations concerned with breast cancer, plus two delegates from the BVN (Dutch Breast Cancer Society).


Method of development

Evidence based


Feasibility has been taken into account in developing the guideline. This included attention to factors that could promote or hinder putting the advice into practice. Examples include the implementation of an analysis of problems, the multidisciplinary composition of the guideline development group, and making active use of support from the guideline development group members. Presenting the draft guideline to the field and communicating what, if anything, is being done with the responses, also promotes implementation. In this manner, a guideline has been developed that answers current questions in the field.

The guideline is distributed widely and is available in digital form on the Dutch Guideline Database. The guideline may also be brought to the attention of a wider audience in other periodicals or continuing education sessions, for example. To promote use of the guideline, we recommend that the regional tumour working groups and group practices, as well as scientific and professional organisations, repeatedly bring the guideline to the attention of their members. Any problems that may arise in using the guidelines can then be discussed and, when appropriate, submitted to the national guideline development group, as it is a "living" guideline. If desirable, parts of the guideline can be made more explicit by formulating regional additions or translation to the local situation in departmental and/or hospital protocols.

In principle, indicators are determined during development of the guideline that can be used to monitor implementation of the recommendations. Via a documentation project, these indicators can then be used to determine the extent of compliance with the guideline. The information from the documentation project becomes input for the revision of the guideline.

Methods and proces

This module has been evidence-based revised in 2008 and consensus based updated in 2012.


A revision of an existing guideline consists of revised and updated text. Revised text is new text based on an evidence-based review of the medical literature; updated text is the old guideline text which has been edited by the experts without performing a review of medical literature. Each section of the guideline states what type of revision has taken place. Each chapter of the guideline is structured according to a set format, given below. The purpose of this is to make the guideline transparent, so that each user can see on what literature and considerations the recommendations are based on.


Description of the literature

To the greatest extent possible, the answers to the fundamental questions (and therefore the recommendations in this guideline) were based on published scientific research. The articles selected were evaluated by an expert in methodology for their research quality, and graded in proportion to evidence using the following classification system:


Classification of research results based on level of evidence


Research   on the effects of diagnostics on clinical outcomes in a prospectively   monitored, well-defined patient group, with a predefined policy based on the   test outcomes to be investigated, or decision analysis research into the   effects of diagnostics on clinical outcomes based on results of a study of   A2-level and sufficient consideration is given to the interdependency of   diagnostic tests.


Research   relative to a reference test, where criteria for the test to be investigated   and for a reference test are predefined, with a good description of the test   and the clinical population to be investigated; this must involve a large   enough series of consecutive patients; predefined upper limits must be used,   and the results of the test and the "gold standard" must be   assessed independently. Interdependence is normally a feature of situations   involving multiple diagnostic tests, and their analysis must be adjusted   accordingly, for example using logistic regression.


Comparison   with a reference test, description of the test and population researched, but   without the other features mentioned in level A.


Non-comparative   trials


Opinions   of experts, such as guideline development group members



Based on the medical literature, one or more relevant conclusions are made for each section. The most important literature is listed according to the level of evidential strength, allowing conclusions to be drawn based on the level of
evidence. All the medical literature included in the conclusion is described in the bibliography.


Classification of conclusions based on literature analysis


Based   on 1 systematic review (A1) or at least 2 independent A2 reviews.


Based   on at least 2 independent B reviews


Based   on 1 level A2 of B research, or any level C research


Opinions   of experts, such as guideline development group members


Other considerations

Based on the conclusion(s), recommendations are made. However, there are other considerations that contribute to formulation of the recommendation besides literature evidence, such as safety, the patients' preferences, professional expertise, cost-effectiveness, organisational aspects and social consequences. The other considerations are mentioned separately. In this manner, it is clear how the guideline development group arrived at a particular recommendation.



The final wording of the recommendation is the result of the scientific conclusion, taking into account the other considerations. The purpose of following this procedure and drawing up the guidelines  in this format is to increase transparency.



An alphabetical list of literature references can be found at the end of the guideline.


All draft texts have been discussed by the guideline development group.

Search strategy

Searches are available upon request. Please contact the Richtlijnendatabase.