Question

How to detect new breast cancer manifestations?

Recommendation

Detection has the aim of early detection of the locoregional recurrence or a second primary tumour in order to strive for a better survival of patients with a previous breast cancer.

Conclusions

 

Level 1

It has been demonstrated that a combination of various tumour-related predictors for locoregional recurrence (young age, N status, angioinvasive growth) lead to an increase in the risk of locoregional   recurrence.

 

A2        Wallgren 2003, Voogd 2005, Jagsi 2005

 

Level 1

Factors that are determinant for an increased risk of a locoregional recurrence exclusively after BCT are the presence of an extensive in situ component, especially with irradical removal of the tumour, and an age under 40 years on diagnosis.

 

A2        Voogd 2001, Arriagada 2005

 

Level 3

A clear period in which most recurrences develop after BCT cannot be indicated: the risk of a local recurrence is constant in the first 10 year at approximately 0.5-1% per year.

 

A2        Bartelink 2007

 

Level 2

Although two-thirds of locoregional recurrences present as isolated disease, it appears that 60% of patients still develop distant metastases despite treatment with curative intent.

 

B          Recht 1988, van Tienhoven 1999

 

Level 2

Mammography and possibly also clinical examination contribute to early diagnosis of second primary breast tumours (applies to the general population).

 

B          Mellink 1991, Robinson 1993, Roubidoux 1995, Kaas 2001

 

Level 3

Detection of a recurrence via mammography or clinical examination in asymptomatic patients leads to a survival advantage.

 

B          Lu 2009

 

Level 3

Approximately 40% of recurrences after BCT are detected via annual mammography, approximately 40-50% are detected by the patients themselves, and 10-20% via regular clinical examination.

 

C          de Bock 2004, Montgomery 2007, Lu 2010

 

Level 3

Given the low risk of a local recurrence or a second primary tumour, and given the good survival   after a second primary tumour in the current, general population, follow-up with MRI is not expected to improve survival.

 

C          Gorechlad 2008

 

Level 1

Intensive follow-up (using laboratory tests and standard imaging) with the intention of detecting asymptomatic distant metastases is not expected to provide a survival advantage.

 

A1        Rojas 2005, Hayes 2007

A2        Roselli del Turco 2004, GIVIO investigators 2004

Literature summary

Locoregional recurrence

 

Factors that determine an increased risk of a local recurrence after BCT and mastectomy

For women over the age of 40, the risk of a local recurrence is less than 10% after 10 years [Elkhuizen, 1998, Bartelink, 2007]. In a non-randomised retrospective analysis of EORTC trial data, a locoregional recurrence was documented in 5.9% of patients undergoing a mastectomy compared to 10.8% of patients receiving breast-conserving treatment [van der Hage, 2003]. Similar to earlier meta-analysis, no difference was seen in survival between BCT and mastectomy [Morris, 1997; van der Hage, 2003].

A factor that leads to an increased risk of a locoregional recurrence both after BCT and mastectomy is the presence of angioinvasive growth; the risk in both groups is approximately twice as high when this is the case [Voogd, 2001].

Both after mastectomy and BCT, the recurrence rate is inversely proportional to the age at the time of primary diagnosis; after 75 years of age it is extremely rare. The risk is twice to four times as high for women who experienced their first breast cancer before 40 years of age than women who developed breast cancer after 50 years of age [Elkhuizen, 1998; Bartelink, 2007; van der Leest, 2007; De Bock, 2006; van der Sangen, 2010]. A clear period in which most recurrences develop after BCT cannot be indicated: the risk is constant in the first 10 years, approximately 0.5-1% per year [Bartelink, 2007]. Adjuvant systemic therapy reduces the risk by approximately 30-50% [Rose, 1989; Haffty, 1991; Levine, 1992; Haffty, 1994; EBCTCG, 1998; Park, 2000; Buchholz, 2001; van der Leest, 2007].

Two-thirds of locoregional recurrences develop in isolation both after BCT and mastectomy, i.e. without simultaneous distant metastasis [Jager, 1999; Rangan, 2000]. Despite adequate treatment, 60% of patients still develop distant metastases with time [Recht, 1988; van Tienhoven, 1999].

 

Factors that determine an increased risk of a local recurrence after BCT

Factors that are determinant for an increased risk of a locoregional recurrence exclusively after BCT are the presence of an extensive in situ component, especially with irradical removal of the tumour, and an age under 40 years on diagnosis [Voogd, 2001; Arriagada, 2005].

 

Locally advanced breast cancer

The five-year locoregional recurrence percentage for locally advanced breast cancer after treatment with a combination of chemotherapy, radiotherapy and almost always also surgery is 20-30% [Piccart, 1988; Merajver, 1997]. Approximately 60% of locoregional recurrences after a mastectomy occur within three years, although recurrences are also observed after many years [Jager, 1999].

 

The value of detecting the local recurrence in relation to prognosis

It was initially thought that the prognosis of a recurrence in the breast after BCT was better than that of a chest wall recurrence after mastectomy, but this is not the case [Whelan, 1994; van Tienhoven, 1999]. A longer interval between the primary treatment and development of the recurrence is positively correlated with a favourable prognosis of salvage treatment [van der Sangen, 2006]. In addition, the size/extent is also mentioned as prognostic factor [Haffty, 1991; van Tienhoven, 1999]. In a meta-analysis of 2,263 patients, Lu (2009) found a better survival if the recurrence was detected by mammography or clinical breast examination, or in patients without symptoms, than if the patient presented with symptoms (HR 2.44; 95%CI 1.78-3.35 vs. HR 1.56; 95%CI 1.36-1.79). This argues for a treatment policy that strives for detection of the locoregional recurrence as early as possible. However, the extent to which a long-term routine follow-up (after five years of annual clinical examination and mammography) would ensure this is not known. Different studies have been conducted to study which part of current monitoring is the most effective in relation to detecting the locoregional recurrence: routine clinical examination by the physician, mammography, breast self-examination/breast awareness by the patient [McCready, 2005].

 

Methods of detection

In a systematic review and meta-analysis of 5,045 patients, de Bock (2004) found that approximately 40% of recurrences were discovered through mammography and/or clinical examination. A distinction could not be made in this study between the contribution made by clinical examination or mammography. Other series found that the recurrence rate detected by mammography after BCT only lies between 15% and 42% [Grosse, 1997; Rutgers, 1989; Montgomery, 2007]. In older studies (before 2000), Montgomery found that only 15% was detected by mammography and 46% by regularclinical examination. These ratios were reversed in the new studies (after 2000) due to improved mammographic techniques: here 40% were detected by mammography and only 15% by regularclinical examination. The authors concluded that there is no evidence that regular clinical examination leads to a survival advantage. Other studies have also shown a downward trend in the contribution of clinical examination by the physician [Drew, 1998; Kramer, 1998]. However, a study by (2010) showed that it may lead to earlier detection of a recurrence in women under 60 years of age, but it could not be demonstrated if this also leads to an improvement in survival. Thirty to forty percent of potentially treatable recurrences are noticed by the patients themselves, despite the fact that clinical examination of the breast after BCT may be problematic as a result of scar retraction or irradiation [Montgomery, 2007].

In summary, approximately 40% of recurrences are detected due to improved quality of mammography, approximately 40-50% by the patients themselves, and 10-20% via regularclinical examination. A meta-analysis has shown that early detection of a recurrence in an asymptomatic patient leads to an improvement in survival. Mammography clearly plays a greater role in this early detection than regularclinical examination.

 

The early detection of a chest wall recurrence after mastectomy is dependent on clinical examination by the physician or patient themselves. Specific imaging or laboratory tests have no added value in early detection [Rutgers, 1989]. An axillary recurrence is usually discovered by the physician, and not by the patient [Montgomery, 2007].

Detection of a 2nd primary tumour

The risk of developing contralateral breast cancer varies in the entire group of patients from 4 to 8 per 1,000 women per year (0.4-0.8%). In patients with a BRCA1/2 mutation, the risk of a second contralateral tumour is much higher: in the order of approximately 2-3% per year [Malone, 2010; Metcalfe, 2011]. It can generally be stated that the risk increases as the age of diagnosis of the first breast cancer decreases, when the first tumour is of the lobular type and when there is a positive family history and/or genetic predisposition [Storm, 1986; Vaittinen, 2000]. If the first breast cancer is diagnosed before the age of 45, there is a 25% risk that a contralateral tumour will manifest before the age of 75. The associated risk factors are largely the same as the risk factors for a first primary tumour (see chapter 1). Modern radiotherapy techniques do not appear to increase the risk of contralateral breast cancer [Obedian, 2000].

Both chemotherapy [Bernstein, 1992; Broet, 1995] and hormonal therapy (tamoxifen, aromatase inhibitors) reduce the risk of a second primary tumour by approximately 30-50% [Rose, 1989; Haffty, 1991; Levine, 1992; Haffty, 1994; EBCTCG,1998; Park, 2000; Buchholz, 2001; van der Leest, 2007]. Such a reduction in risk also applies to mutation carriers, although there is no data available on large prospective studies.

In addition to clinical examination, annual mammography contributes to early diagnosis and a better prognosis of the second primary carcinoma [Mellink, 1991; Kaas, 2001]. In older patients (> 60 years) it seems justified to extend the mammography interval to two years after a disease-free interval of at least 10 years [Kaas, 2001]. If the primary surgical treatment consisted of mastectomy, the mammographic follow-up may be organised via the national breast screening programme.

In patients over 75 years of age with a disease-free interval of at least 5 years, it may be decided not to conduct further mammographic follow-up, because screening at this age does not meet the criteria of mortality reduction while retaining a reasonable balance of benefits and disadvantages [Boer, 1995].

 

New developments:MRI

Little is known yet about the role of regular breast MRI scan in the detection of recurrent disease . In a retrospective study in a patient population of 476 patients with primary breast cancer, Gorechlad (2008) determined that a follow-up MRI probably would not have provided a survival advantage to any of the patients with a local recurrence or second primary tumour, given the small dimensions of the local recurrences and the second primary tumours and the extremely good disease-free survival of those with a recurring tumour (10 of the 11). The local recurrences were small and independent of the detection method of the first tumour (also high density on the mammogram). It should be noted that the average follow-up in this study (5.4 years) is relatively short and that it concerns a patient population with an average risk. The American Society of Clinical Oncology does not support follow-up using MRI [Khatcheressian, 2006]. MRI does play a role in problem-solving; it may play an additional role if the scar cannot be distinguished with certainty from a recurrence, if there are unusual post-irradiation signs, if the tumour bed cannot be visualised on mammography, and with autologous breast reconstructions, because the negative predictive value in these situations is high [Preda, 2006; Rieber, 2003].

 

Distant metastasis

The risk of developing distant metastases correlates with the T and N stageof the primary tumour and is favourably influenced by treatment of the primary breast cancer (surgery, radiotherapy, adjuvant systemic therapy). Manifestation of distant metastases means the disease can no longer be cured [Harris, 1986]. Survival of patients with detectable asymptomatic distant metastases was found to be the same as that of a group of patients with symptomatic disease [Joseph, 1998]. There are 2 large randomised studies that have compared survival of patients receiving standard follow-up versus patients receiving intensive follow-up. The standard follow-up consisted of mammography and clinical examination; intensive follow-up involved regular full staging by skeletal scintigraphy, chest X-ray, with or without ultrasound of the liver and laboratory tests [Roselli del Turco, 1994; GIVIO investigators, 1994]. The two studies did not show a difference in survival. In the study by the GIVIO investigators, a difference was also not found in the quality of life; in the study by Roselli del Turco a difference was also not seen in disease-free survival. These two RCT’s were part of the Cochrane review by Rojas (2005). The conclusion was therefore that follow-up consisting of mammography and clinical examination is as effective as more intensive follow-up with laboratory tests and additional imaging, both in terms of survival, disease-free survival and quality of life. These findings are further confirmed in a more recent review by Hayes (2007).

The Cochrane review also showed that follow-up conducted by a trained general practitioner is as effective as follow-up by a medical specialist, in relation to quality of life and timely detection of distant metastases.

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).

Member of workgroup

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

Implementation

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

A1

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.

A2

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.

B

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

C

Non-comparative   trials

D

Opinions   of experts, such as guideline development group members

 

Conclusions

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

1

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

2

Based   on at least 2 independent B reviews

3

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

4

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.

 

Recommendations

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.

 

References

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.