Which hormonal therapy should be given?


The contribution of chemotherapy to (disease-free) survival advantage is limited in elderly patients with an ER+/low-stage breast cancer, especially if a second generation chemotherapy schedule is not possible due to comorbidity. With such dilemmas, Adjuvant Online may help in recommending only hormonal therapy for this category of patients.



Adjuvant chemotherapy for N +/high-risk N0 patients with a tumour without HER-2-overexpression may consist of:


Third generation schedules:

  • 6 courses of TAC
  • 3 courses of FE100C followed by 3 courses of docetaxel three weekly
  • 4 courses AC followed by 12 courses paclitaxel weekly
  • 4 courses of AC followed by 4 courses of docetaxel three weekly


If a third generation schedule is not desired, treatment with a second generation schedule consisting of 4 courses of TdocetaxelC or a first-generation schedule consisting of 4 courses of AC or 6 courses of classic CMF may be considered.


Adjuvant chemotherapy in patients with a tumour with HER-2-overexpression may consist of:


4 courses of AC chemotherapy followed by 4 courses three weekly docetaxel or weekly administrations of paclitaxel; both in combination with trastuzumab. After completing chemotherapy, trastuzumab treatment is continued to a total treatment duration of 1 year.


Note:Patients with a tumour size ≥ T1b (0.5-1.0 cm) with HER-2-overexpression, may also be eligible for the abovementioned treatment.Other tumour characteristics, toxicity and an as yet uncertain effectiveness should be weighed up against each other.


Given the possible cardiotoxicity of anthracyclines and trastuzumab (the chance increases with age), LVEF should be checked before starting chemotherapy and before starting trastuzumab and subsequently every 3 months until trastuzumab therapy has ended.


Treatment with trastuzumab is sensible if the LVEF ≥ 50- 55% before the start of trastuzumab treatment and if the LVEF ≥ 50% during therapy, and has not reduced by more than 10 EF points from the start value.


Hormonal therapy

Hormonal therapy in postmenopausal women with positive hormone receptor may consist of:


A sequential treatment with two to three years of tamoxifen followed by three to four years of an aromatase inhibitor (or the reverse order) or an aromatase inhibitor for 5 years.


If there is a contraindication for one of the two drugs, treatment with the other drug for 5 years is an alternative.


If bothersome arthralgias occur as a side effect of an aromatase inhibitor, another type of aromatase inhibitor may be tried or treatment with tamoxifen may be given.

There is no particular preference for one of the three registered aromatase inhibitors in the Netherlands.


Continued treatment with an aromatase inhibitor after five years is only advised after 5 years of tamoxifen plus if there is an increased risk of a recurrence after 5 years. This especially applies to patients with axillary node metastases on primary diagnosis. The optimal duration of this extended hormonal therapy is unknown. A minimum treatment duration of 2 to 3 years is recommended:


Hormonal therapy in premenopausal women with a hormone-sensitive breast cancer consists of:


  • tamoxifen for 5 years or
  • the combination of 5 years of tamoxifen with oophorectomy with an LHRH agonist for (2 to) 5 years, (or definitive ovarian inactivation). There is insufficient data regarding superiority of one of these two modalities, although addition of LHRH agonists to chemotherapy (with or without) tamoxifen provides a small additional advantage for women to 40 years of age.


Aromatase inhibitors do not work with intact ovarian function, and are therefore contraindicated as single hormonal therapy in premenopausal women.


Indication and recommendation for adjuvant systemic therapy:


All patients, unless 70+ with a hormone receptor negative tumour (although chemotherapy may be considered for fit 70+ patients with a hormone-negative tumour)

Unfavourable N0:


  • age < 35 years, except with a grade I tumour ≤ 1cm
  • age ≥ 35 years with a tumour of 1.1-2 cm and grade II or higher

(If the tumour is 1.1-2 cm, grade II, HER-2-negative, but ER and PgR > 50%, hormonal therapy without chemotherapy may be considered for postmenopausal patients )

  • age ≥ 35 years with a tumour > 2 cm
  • if HER-2-positive tumour ≥ T1b (0.5-1 cm), treatment may be considered independent of other characteristics. Toxicity and an as yet uncertain effectiveness should be weighed up against each other.


The choice of systemic therapy

(for a quantitative impression of the advantage in (disease-free) survival that may be expected for the treatment selected: see the Adjuvant! programme (AOL)).


Hormonal therapy



If ER+ and/or PgR+ (no maximum age)

Which hormonal therapy?


  • ovarian inactivation (possibly LHRH agonist for 5 years) plus 5 years of tamoxifen or
  • 5 years of tamoxifen


  • 2-3 years of tamoxifen, followed by 3-2 years of an aromatase inhibitor or the reverse order
  • 5 years of an aromatase inhibitor
  • extended (after 5 years tamoxifen) 2 years aromatase inhibitor at a high residual risk (N+)

For men:

  • 5 years of tamoxifen





If ER- and PgR-

  • to 70 years, both N+ and unfavourable N0 (chemotherapy may be considered for fit 70+ patients with a hormone receptor negative tumour)

If ER+ and/or PgR+:

  • to 70 years, both N+ and unfavourable N0.


The added value of chemotherapy alongside hormonal therapy may be limited in elderly patients, it is recommended to consider the calculated advantage using Adjuvant online.

Which chemotherapy?


Take the condition of the patient into account and possibly choose a lighter form of chemotherapy


Identical treatment is recommended for men



Both with N+ and   unfavourable N0

  • 4 x q3wk AC à 12 x q1wk paclitaxel or
  • 4 x q3wk docetaxel


Both courses (at the start of taxane) in combination with trastuzumab, trastuzumab to 1 year



Both for N+ and unfavourable N0

Third generation schedule:

  • 6 x TAC + primary G-CSF or
  • 3 x FE100C à 3 x docetaxel or
  • 4 x AC à 4 x q3wk docetaxel or
  • 4 x AC à 12 x q1wk paclitaxel

If a third generation schedule is not possible or desirable

Second and first generation schedule:

  • 4 x T(docetaxel)C
  • 4 x AC of 6 x CMF



Indication for trastuzumab

HER-2+++ (IHC) and/or FISH+; LVEF ≥ 50-55% shortly prior to starting trastuzumab


Check LVEF before starting chemotherapy and before starting trastuzumab and subsequently every 3 months until completion of trastuzumab.


If LVEF ≥ 50% and has not reduced by more than 10 EF points from the starting value; trastuzumab treatment is justified.



Level 1

Adjuvant treatment with five years of tamoxifen has a favourable influence on the five- and fifteen-year survival of women with a hormone positive, stage I or II breast cancer. Locoregional control also improves as a result of treatment.


A1        EBCTCG 2005


Level 1

Adjuvant treatment with 2-3 years tamoxifen followed by 3-2 years of an aromatase inhibitor, or the reverse order (a total treatment duration of five years) provides a better disease-free survival and total survival than treatment with only five years of tamoxifen, in postmenopausal women with a hormone-positive, stage I or II breast cancer.


A1        Coombes 2006, Coombes 2007, Boccardo 2005, Jackesz 2005, Jackesz 2008, Choueri 2004,   Kaufmann 2007, Dowsett 2010


Level 1

Adjuvant treatment with an aromatase inhibitor for a duration of 5 years leads to a better disease-free survival than 5 years of treatment with tamoxifen, in postmenopausal women with an HR+ stage I or II breast cancer.


A1        Howell 2005, BIG 1-98 2005, Mouridsen 2009, ATAC 2008, Cuzick 2010


Level 3

Adjuvant treatment for a duration of 3 years with an LHRH agonist in combination with an aromatase inhibitor does not lead to a difference in disease-free survival compared to treatment with an LHRH agonist in combination with tamoxifen in premenopausal women.


A2        Gnant 2009


Level 1

Adjuvant inactivation or suppression of ovarian function (through surgery, radiotherapy or LHRH agonists) improves the locoregional control and total survival in premenopausal women with a   hormone-positive stage I or II breast cancer.


A1        EBCTCG 2005


Level 1

Addition of an LHRH agonist to tamoxifen, chemotherapy or the combination of both modalities results in a better disease-free survival in premenopausal women with hormone-positive stage I or   II breast cancer.


The largest reduction in the risk of a recurrence due to treatment with an LHRH agonist after chemotherapy (with or without addition of tamoxifen) is found in women under 40 years of age.


A1        LHRH-agonists in Early Breast Cancer Overview Group 2007


Level 1

Extended adjuvant hormonal therapy with an aromatase inhibitor after five years of tamoxifen in postmenopausal women with a hormone-positive stage I or II breast cancer, only has a favourable   influence on the disease-free survival and total survival in patients with axillary node metastases.


A1        Goss 2003, Mamounas 2006, Jakesz 2007

Literature summary

Suppression of ovarian function

The EBCTCG-meta-analysis of 2005 analysed the effect of inactivating or suppressing ovarian function in 8,000 women under 50 years of age with a hormone-positive breast cancer. Suppressing the ovarian function was found to have a favourable effect on both locoregional control and total survival, although the authors indicate that the result is less substantial than that found in earlier analyses. The recurrence percentage after 15 years was 47.5% for women with oophorectomy compared to 51.6% for the control group (p=0.00001), and the mortality 40.3% compared to 43.5% for the control group (p=0.004).


However, retrospective analyses of different studies suggest that patients experiencing amenorrhoea after treatment with chemotherapy have a better (disease-free) survival than patients who continue to menstruate after chemotherapy [Davidson, 2001; Pagani, 1998; del Mastro, 1997]. This data has increased the interest in oophorectomy. A few large randomised studies have researched the effectiveness of chemotherapy plus inactivating ovarian function (either in or not in combination with tamoxifen) compared to the effect of chemotherapy only [Davidson, 1999; Baum, 2001; IBCSG, 2003; Baum, 2003].


A recent meta-analysis studied the effect of treating premenopausal patients with hormone-positive breast cancer using LHRH agonists, administered as monotherapy or in combination treatments [LHRH-agonists in Early Breast Cancer Overview Group, 2007], in which the LHRH agonist was administered after chemotherapy for a duration of 2-5 years.


The combination of an LHRH agonist plus tamoxifen as the only systemic therapy compared to no treatment resulted in a reduction in the recurrence rate of 58.4% (p<0.0001) and death rate of 46.6% (p=0.04) after a recurrence. When treatment with an LHRH agonist with or without tamoxifen was compared to treatment with chemotherapy (mainly CMF regimes), no significant difference was found in effectiveness.


Addition of an LHRH agonist to tamoxifen (n=1,013), to chemotherapy (n=2,376) or to chemotherapy plus tamoxifen (n=365), did show a trend in reduction in the chance of recurrence and death, although the differences were not significant. Combined analysis of the last two groups (n=2,741) did show a significant reduction of 12.2% (p=0.04) in recurrence and a reduction of 15.0% (p=0.04) in mortality after recurrence.


Addition of the combination of an LHRH agonist plus tamoxifen to treatment with chemotherapy compared to treatment with chemotherapy only, did show a reduction in the chance of recurrence of 26.7% (p=0.001) and a reduction in the mortality after recurrence of 24.4% (p=0.01). Combined analysis of the effect of adding an LHRH agonist to tamoxifen, chemotherapy or the combination of both modalities resulted in a reduction in the recurrence rate of 12.7% (p=0.02) and of 15.1% (p=0.03) in death rate after an earlier recurrence. The abovementioned analyses were also performed separately for different age groups. The greatest reduction in the risk of recurrence following treatment with an LHRH agonist after chemotherapy (with or without tamoxifen) was found in women of 35 years and younger (HR 0.66); the effect was still significant in the group to 40 years of age (HR 0.77), but was no longer significant in women over 40 years. While the advantage provided by the addition of an LHRH agonist to chemotherapy was identical regardless of tamoxifen administration, so few patients were treated in studies in which tamoxifen was administered in both arms that a pronouncement cannot be made yet regarding the extent of the advantage due to addition of an LHRH agonist in this context. It must also be taken into consideration that CMF chemotherapy was administered in most studies, a regime in which a high percentage of women experienced amenorrhoea (increasing with age), so that the effect of the LHRH agonist added may have been influenced.


In the meta-analysis published by the EBCTCG in 2005, it was found that 1-2 years of treatment with tamoxifen compared to no treatment provided an advantage with a hazard ratio of 0.79 (SE=0.02) in relation to locoregional control (5.8% recurrences per year vs 7.1%). These results were even more pronounced after 5 years of treatment with tamoxifen: HR 0.69 (SE=0.03), i.e. recurrences in the tamoxifen groups were 3.2% vs 4.5% in the control groups.


The figures are comparable for total survival. The mortality rate after 1-2 years in the tamoxifen group was lower than that in the control groups (33.6% vs 37.7%; HR 0.85 (SE=0.02). Results are more favourable after treatment with tamoxifen for 5 years. The hazard ratio in favour of tamoxifen is then 0.76 (SE=0.03). Results over fifteen years have also become available. The recurrence percentage after 15 years was 33.2%, while this was 45.0% in the control groups for women with oestrogen-receptor positive tumours (p<0.00001). These differences were also found for the mortality rate: after 15 years, the mortality rate in all tamoxifen groups together was 25.6% versus 34.8% in the control groups (p<0.00001). For all subgroups (with different doses tamoxifen, age, menopausal status, node status, presence or absence of toxicity and different chemotherapy combinations), it was shown that there is an advantage to tamoxifen treatment.


The absolute advantage is of course dependent on the absolute risk of recurrence. The 5-year survival advantage for node-negative (N0) low-risk patients is 3.7%, for N0 with intermediate risk 7%, for high-risk and node-positive (N+) patients 12%. The effect of tamoxifen with an ER-negative but PgR-positive breast cancer has only been studied in a small group of patients. There is an advantage in this category, but it is limited. The advantage of adjuvant tamoxifen with an ER-, PgR-breast cancer is limited to halving the chance of contralateral breast cancer.

Aromatase inhibitors

The effect of treatment with aromatase inhibitors has not yet been incorporated in the meta-analysis published by the EBCTCG in 2005, but it has been in the meta-analysis performed in 2006. Systematic reviews were published in 2004 and 2007 concerning the role of aromatase inhibitors in the treatment of postmenopausal women with breast cancer [Choueiri, 2004; Eisen, 2007]. This review analysed the characteristics of anastrozole, letrozole and exemestane in the different phases of breast cancer. Three types of adjuvant studies have been conducted with aromatase inhibitors:

a)    comparative studies in which tamoxifen is compared with an aromatase inhibitor after locoregional treatment and adjuvant chemotherapy, both administered for a duration of 5 years, also called upfront studies;

b)    sequential studies in which treatment with 2-3 years tamoxifen, followed by 3-2 years of an aromatase inhibitor, or an aromatase inhibitor for a duration of 2 years followed by 3 years of tamoxifen is compared with five years of tamoxifen or five years of an aromatase inhibitor;

c)    extension studies that research if continuing treatment with an aromatase inhibitor after 5 years of tamoxifen use provides a positive contribution to the recurrence-free period and survival

Studies with extended hormonal therapy after 5 years of an aromatase inhibitor or after a sequence of tamoxifen followed by an aromatase inhibitor are in progress and have yielded insufficient data for application outside a research context.


Up-front studies

There are three upfront studies worldwide: the Anastrozole, Tamoxifen, Alone or in Combination (ATAC) trial began with three treatment arms. However, inclusion in the combination arm was ceased after the first interim analysis because no advantage was seen compared to tamoxifen monotherapy, while an advantage was observed for anastrozole.

The second double-blind study was organised by the Breast International Group, the BIG 1/98 study, and had four treatment arms: 5 years of tamoxifen, 5 years of letrozole, 2 years sequential tamoxifen à 3 years of letrozole or 2 years of letrozole à 3 years of tamoxifen. Both studies show an advantage for aromatase inhibitors in relation to disease-free survival (ATAC HR 0.86; 95%CI 0.78-0.95, p=0.003; BIG 1-98 HR 0.88; CI:0.78-0.99, p=0.03) but (as yet) no survival advantage after a median follow-up of 120 and 76 months respectively [Howell, 2005; ATAC, 2008; Cuzick, 2010; Thurliman, 2005; BIG 1-98, 2009].

In the BIG 1-98 study, neither of the two sequential arms showed a significant difference with 5 years of letrozole (HR 1.05 (95%CI 0.84-1.32) for tamoxifen/letrozole versus letrozole and 0.96 (95%CI 0.76-1.21) for letrozole/tamoxifen versus letrozole respectively). An advantage was mainly seen in the ATAC study in patients who had not received chemotherapy and patients with negative axillary nodes. The opposite was observed in the BIG 1-98 study. In an unplanned, retrospective analysis of PA specimens from 1,792 patients from the ATAC study (30% of the total number), no preferential advantage for anastrozole could be determined in patients with an ER+PgR- breast cancer or with a breast cancer with HER-2-overexpression [Dowsett, 2006]. In the BIG 1-98 study, letrozole prevented an early recurrence in patients with unfavourable prognostic characteristics, in which no single unfavourable prognostic factor was predictive of the effect of letrozole [Mauriac, 2007].

The third upfront study was conducted in Austria with premenopausal women who were all treated with an LHRH agonist for three years, in which patients were randomised between 3 years of tamoxifen (n=900) or 3 years of anastrozole (n=903). In addition, a second randomisation was conducted with and without intravenous zoledronate every 6 months [ABCSG-12, 2009]. After a median follow-up of 47.8 months, there was no difference in disease-free survival between patients treated with tamoxifen or anastrozole (HR 1.10; 95%CI 0.70-1.53). However, there was a significant difference between patients who had and had not been treated with zoledronate [Gnant, 2009].


Sequential studies

There are two types of sequential studies. Firstly, studies in which patients who had received tamoxifen for 2-3 years were randomised between continuing tamoxifen or treatment with an aromatase inhibitor for a total duration of 5 years. A selection occurred here, because only those patients who were still disease-free after 2-3 years of tamoxifen were included in the study. The Intergroup Exemestane Study (IES), the Italian Tamoxifen Anastrozole (ITA) study, and the Arimidex Nolvadex 95 (ARNO95) study belong to this type of sequential study.

All studies showed an improvement in the disease-free survival for sequential therapy: HR 0.75 (95%CI 0.65-0.87) after a median follow-up of 58 months in the IES [Coombes, 2006; Coombes, 2007], HR 0.35 (95%CI 0.18-0.68) after a median follow-up of 36 months in the ITA study [Boccardo, 2005] and HR 0.53 (95%CI 0.28-0.99) in the ARNO-95 [Kaufmann, 2007].

In the IES, a survival advantage was reported for 4,724 patients after omitting 122 patients with negative hormone receptors: HR 0.83 (95%CI 0.69-1.00, p=0.05). A survival advantage was also found in the ARNO95 study [Kaufmann, 2007].


In the second type of sequential study, patients at the start of adjuvant hormonal therapy are randomised between monotherapy (with tamoxifen or an aromatase inhibitor) or sequential therapy (with tamoxifen and subsequently an aromatase inhibitor or the other way around). The sequential arms of the BIG 1-98 study, the ABCSG-8 study and the Tamoxifen Exemestane Adjuvant Multicenter (TEAM) study are such a sequential study.

In the ABCSG-8 study, there was an almost significant advantage in disease-free survival between the patients treated 2 years with tamoxifen followed by 3 years of anastrozole (n=1,865) versus 5 years of tamoxifen (n=1,849); (HR 0.85; 95%CI 0.71-1.01; p=0.067) while a significant survival advantage was observed; (HR 0,78; 95%CI 0,62-0,98, p=0,032) [Jakesz, 2008]. A meta-analysis of sequential trials in which 5 years of tamoxifen was compared to the sequential tamoxifen aromatase inhibitor, showed a survival advantage for sequential treatment [Dowsett, 2010].

No difference was found in disease-free survival and total survival in the TEAM study after a median follow-up of 61 months between patients who were treated with exemestane (n=4,868) or with a sequential treatment of 2.5-3 years tamoxifen followed by 2.5-2 years exemestane (n=4,898); (HR 0.97, 95%CI 0.88-1.08) [vd Velde, 2011]. There was also no difference in disease-free survival between exemestane and tamoxifen in this study after 2.75 years, although there was a significant advantage over time in distant metastasis in favour of exemestane. After a median follow-up of 5.3 years, a survival advantage was found in favour of IFN-a, but the difference was no longer significant after 5 years. So far it has not been possible to identify a subgroup that benefits from the use of an aromatase inhibitor from the very start.


Extension studies

The extension studies are the Mammary-17 (MA-17), the ABCSG-6A study and the NSABP B-33 study. The MA-17 randomised between letrozole or placebo after 5 years of tamoxifen and was ended prematurely because the absolute difference in disease-free survival between both arms was significantly (4.7%) in favour of treatment with letrozole [Goss, 2003]. Patients from the placebo group could subsequently choose treatment with letrozole; of these, 1,579 (73%) of the 2,268 patients who were disease-free made use of this option [Goss, 2008]. Patients who still chose letrozole treatment were generally somewhat younger, more commonly had axillary metastases during primary treatment and had received adjuvant chemotherapy more often in comparison to the 804 patients who did not end up choosing treatment with letrozole. After a median follow-up of 5.3 years, there was an advantage for the group who was still treated with letrozole (median time after tamoxifen of 2.8 years) compared to the group who did not choose to do so, both in disease-free survival (HR 0.37; 95%CI 0.23-0.61; p<0.0001) and distant disease-free survival (HR 0.39; 95%CI 0.20-0.74; p=0.004). The ABCSG-6A study and the NSABP B-33 study also showed an advantage for anastrozole after 5 years tamoxifen [Jakesz, 2007] (HR for disease-free survival 0.62; 95%CI 0.40-0.96; p=0.031) and 2 years exemestane after 5 years of tamoxifen respectively [Mamounas, 2006].


Side-effects of hormonal therapy

While the most important side-effects of tamoxifen are thrombo-embolic complications and a slight increase in the risk of developing endometrial carcinoma, the side effects of aromatase inhibitors are mostly complaints of the postural and musculoskeletal system. Aromatase inhibitors may cause irritating arthralgias, probably as a result of minor fluid accumulation in joints and tendon sheaths. In addition, osteoporosis or osteopaenia may develop due to the extremely low level of oestrogen. As a result, the incidence of osteoporotic fractures increases during use of aromatase inhibitors. Monitoring bone density and possible treatment of osteopaenia and osteoporosis consisting of a healthy lifestyle, taking sufficient calcium and vitamin D and a bisphosphonates (if required) is therefore indicated (see Chapter 12). Some studies with aromatase inhibitors have also reported an increase in the incidence of cardiovascular complications. However, the absolute percentages are low and often not significantly different than with tamoxifen treatment, for example.


The studies mentioned on the effects of adjuvant hormonal therapy (including chemotherapy-induced loss of ovarian function) found that such treatment lead to a significant reduction in the chance of contralateral hormone-positive breast cancer (relative reduction in the chance of 30 to 70 %) [EBCTCG, 2005; Bertelsen, 2008].


In premenopausal patients with a hormone-sensitive breast cancer, inactivation of the ovarian function in combination with tamoxifen is an acceptable alternative if treatment with chemotherapy is not desirable (on medical grounds) or if the patient declines chemotherapy.

There is insufficient data indicating that variants in the CYP2D6 genotype influence the action of tamoxifen. It is therefore not recommended that the CYP2D6 genotype is determined outside of a research context.


Strong CYP2D6 inhibitors should be avoided in the use of tamoxifen. If an antidepressant is still desired, a drug should be chosen with as little inhibitory effect on CYP2D6 as possible. For selective serotonin reuptake inhibitors this concerns venlafaxine, escilatropam and mirtazapine [Sideras, 2010].


The physician informs the patient about the possibilities regarding the choice of hormonal adjuvant treatment, taking the risk profile, types of hormonal treatments (upfront aromatase inhibitor versus sequential), side effects and the possibility of preventing osteoporosis into account. The physician and patient make a choice together.

The advantage of chemotherapy is especially limited in older patients with a (small) N0 tumour. If a second generation schedule is not possible due to comorbidity, Adjuvant! (AOL) may help in the decision to recommend hormonal therapy only in this category of patients.


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.