Are prognostic factors of risk profiling useful?


When deciding whether or not to prescribe systemic therapy in the presence of micrometastases or isolated tumour cells, correcting the risk of recurrence may be considered when using Adjuvant! with a factor of 1.5 (confidence interval of 1.15 – 2.13), if “0’ is entered for the node status. Parallel to this, the predicted benefit in relation to the recurrence-free survival of systemic therapy will somewhat increase.


Too little is known to make a recommendation on  the effect on survival.



Level 2

The prognostic value of the traditional prognostic factors, as incorporated in the Nottingham Prognostic Index, the Sankt Gallen classification and Adjuvant!, has been found to be reproducible in large, independently conducted studies.


B          Boyages 2002, Boyages 2006, Colomer 2004, Lundin 2006, Olivotto 2005, Mook 2009


Level 3

There are indications that the presence of micrometastases or isolated tumour cells has a negative influence on the   disease-free survival with a hazard ratio of 1.5 at a median follow-up of 5   years and that the relative risk reduction in relation to the disease-free survival with adjuvant systemic treatment in this group of patients is no different than in the general breast cancer population.


B          de Boer 2009

Literature summary

There are various classification systems to estimate the chance of metastasis and death of individual patients. The main ones are the Nottingham Prognostic Index (NPI) [Galea, 1992], the St. Gallen classification [Goldhirsch, 2006; Goldhirsch, 2007; Goldhirsch, 2009] and Adjuvant! ( All these classification systems are based on traditional prognostic factors, including tumour size, lymph node status and tumour grading. In addition, the St. Gallen classification also uses age at time of diagnosis, the number of positive lymph nodes, oestrogen receptor status, the presence of peritumoural vascular invasion and overexpression of HER2. Furthermore, Adjuvant! offers the possibility of taking the presence of comorbidity into account at the time of diagnosis when making the prediction.


The prognostic value of the abovementioned traditional prognostic factors, as has been incorporated in the NPI, the St. Gallen classification and Adjuvant! has been found to be reproducible in large, independently conducted studies with unselected, non-overlapping patient populations [Boyages, 2002; Boyages, 2006; Colomer, 2004; Lundin, 2006; Olivotto, 2005]. It appears that improvement in the prognostic value of the NPI by addition of other variables such as progesterone receptor and HER2 is possible, but has not been validated [van Belle, 2010]. A side note with the St. Gallen classification system is that a disproportionate number of patients in the various validation studies with negative lymph nodes (> 70%) are classified as intermediate risk or high risk and are therefore eligible for adjuvant systemic therapy [Boyages, 2002].


Compared to other risk classification systems, Adjuvant! offers the advantage  that an estimation is made per patient in the reduction in risk of death and risk of recurrence that may be realised with the prevailing medication-based treatments. These estimates are derived from the meta-analyses of the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). In this manner, it is a valuable aid in the advising of and decision-making with the patient. The system also provides the possibility to modify estimations on the basis of additional prognostic information, including HER2 status or angioinvasive growth, for example. The risk estimations in Adjuvant! are based on data from several tens of thousands of patients from the Merican Surveillance, Epidemiology and End Result (SEER) registration [Ravdin, 2001]. The predictions of the system have been validated in an independent population-based series of 4,083 Canadian patients [Olivotto, 2005]. The predictions appeared to be largely accurate, with the exception of women under 35 years of age, where the estimation by Adjuvant! of the absolute breast cancer-related risk of death was approximately 10% too low. Partly on the basis of these findings, the predictions in Adjuvant! for women under 35 years of age have been adjusted. In a group of 5,380 patients in the Netherlands with a median follow-up of 11.7 years, the prediction of 10-year total survival and specific survival with Adjuvant! was found to be accurate, with the exception of a too low estimation in the risk of death by 4% for patients under 40 years of age, despite an earlier adjustment on the basis of the Canadian study [Mook, 2009].


Adjuvant systemic therapy in patients with micrometastases or isolated tumour cells in the sentinel lymph node

As outlined in section 3.3, many observational studies have shown the prognostic importance of the presence of micrometastases and isolated tumour cells in the axillary nodes and/or SN. A few retrospective studies have evaluated the benefit of adjuvant systemic treatment in patients with micrometastases or isolated tumour cells in the SN. In a large study in the Netherlands, 995 patients with micrometastases or isolated tumour cells and treated with adjuvant systemic therapy (hormonal therapy and/or chemotherapy) were compared to 856 patients with micrometastases or isolated tumour cells and not treated with such adjuvant therapy [de Boer 2009]. In this non-randomised study, an increase in the five-year disease-free survival was found for both patients with micrometastases and patients with isolated tumour cells after treatment with adjuvant systemic therapy (corrected HR: 0.50; 95%CI 0.35-0.72 and 0.66 95%CI 0.46-0.95 respectively). It should be noted that there was a combined endpoint in relation to local, regional and distant recurrences.


Aside from traditional prognostic factors such as tumour grading, tumour size and lymph node status, numerous other tumour characteristics have been studied for their prognostic value. Factors that have also been found to be of significance in prospective study designs in predicting the prognosis of patients with a lymph node negative breast cancer are the presence of epithelial cancer cells in bone marrow, urokinase-type plasminogen activator (uPA) and the inhibitor of this (PAI-I). However, execution and standardisation of the technique to determine these factors is laborious. The Ki67/MIB1 index is an immunohistochemical proliferation variable with good prognostic value [Yerushalmi, 2010; Azambuja, 2007]. In terms of the histological grade, it has become clear that actually only the mitotic activity expressed as the MAI component of this has prognostic value [Abdel-Fatah, 2010; Genestie, 1998; Le Doussal, 1989]. The MAI has been validated in various prospective studies in the Netherlands for different subgroups [Baak, 2005, 2007, 2008, 2010].


Few studies have been reported in which the effect of systemic therapy in patients with isolated tumour cells or micrometastases has been reported separately . The prognostic importance of micrometastases and isolated tumour cells is described in a recent meta-analysis of studies prior to the SN age, and more recently in studies in which patients underwent a SN procedure. The different studies report a hazard ratio of approximately 1.5 in multivariate analyses corrected for a number of primary tumour characteristics. The recurrence percentage was reduced with additional systemic therapy, comparable to the effect with larger tumours.

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.