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National Collaborating Centre for Cancer (UK). Advanced Breast Cancer: Diagnosis and Treatment. Cardiff (UK): National Collaborating Centre for Cancer (UK); 2009 Feb. (NICE Clinical Guidelines, No. 81.)

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  • Since original publication this guideline has been partially updated by NICE: In August 2017, we reviewed the evidence for assessing oestrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status on disease recurrence and changed the recommendations in section 1.1. In July 2014, we reviewed the evidence for exercise for people with lymphoedema and added 2 new recommendations. Parts of this guideline were updated by a standing committee in 2017. One recommendation was deleted (crossed out) and 2 recommendations (marked in grey) in section 2.2 (page 9) were replaced with 1 new recommendation. This can be found in the addendum to this guideline, Advanced breast cancer 81.2.

Since original publication this guideline has been partially updated by NICE: In August 2017, we reviewed the evidence for assessing oestrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status on disease recurrence and changed the recommendations in section 1.1. In July 2014, we reviewed the evidence for exercise for people with lymphoedema and added 2 new recommendations. Parts of this guideline were updated by a standing committee in 2017. One recommendation was deleted (crossed out) and 2 recommendations (marked in grey) in section 2.2 (page 9) were replaced with 1 new recommendation. This can be found in the addendum to this guideline, Advanced breast cancer 81.2.

Cover of Advanced Breast Cancer

Advanced Breast Cancer: Diagnosis and Treatment.

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2Diagnosis and assessment

2.1. Imaging assessment

A new diagnosis of advanced breast cancer may be suspected in patients who have previously been treated for breast cancer, and who present with symptoms such as bone pain, dyspnoea, nausea, abdominal discomfort and general malaise. Occasionally metastatic disease may be suspected at first presentation.

The initial investigation depends on the presenting symptoms, for instance a chest radiograph performed to investigate dyspnoea or radiographs to assess localised bone pain. Once a diagnosis of advanced breast cancer is suspected either clinically or on initial imaging, it is routine practice to confirm the diagnosis and to assess the extent of metastatic disease with more imaging (commonly referred to as staging). This may include assessment of the commoner sites of metastasis including lung, liver and bone. A variety of imaging techniques are available: plain radiography, ultrasound, bone scintigraphy, computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography fused with computed tomography (PET-CT).

Unlike imaging with X-rays or MRI, PET provides functional information by using 18F-deoxyglucose (FDG), a glucose analogue labelled with positron emitting fluorine. Most malignant tumours have a higher glucose metabolism than normal tissue, take up more FDG than the surrounding tissue and emit more positrons, so areas of malignancy show up as areas of increased activity on the scan. When PET is fused with CT functional information can be accurately located anatomically.

Recommendations

Qualifying statement: There was insufficient evidence to support the choice of one imaging modality over another.

  • Use MRI to assess bony metastases if other imaging is equivocal for metastatic disease or if more information is needed (for example, if there are lytic metastases encroaching on the spinal canal).

Qualifying statement: There was GDG consensus that MRI should be used in these situations.

Qualifying statement: There was GDG consensus that PET-CT should be used in this situation.

Clinical Evidence

Two systematic reviews (Isasi et al. 2005 and Shie et al. 2008) and fifteen small comparative studies or case series (Abe et al. 2005; Altehoefer et al. 2001; Bradley et al. 2000; Bristow et al. 2008; Cook et al. 1998; Engelhard et al. 2004; Eubank et al. 2001; Eubank et al. 2004; Fueger et al. 2005; Haubold-Reuter et al. 1993; Kamby et al. 1987; Nakai et al. 2005; Schirrmeister et al. 1999; Schmidt et al. 2008 and Ternier et al. 2006) formed the evidence base for the topic on imaging to determine disease extent. Other than the reviews, papers were generally of poor to medium quality and many were retrospective studies.

MRI and FDG-PET were equal to or better than scintigraphy in visualising bone metastases, other than osteoblastic lesions, but whole body MRI was better than FDG-PET at detecting distant metastases particularly in abdominal organs, brain and bone. MRI also detected previously unidentified metastases, including those that were non-skeletal and, in one study (Bradley et al. 2000), the treatment plan was changed accordingly in ~43% of patients.

CT had a high diagnostic value in detecting local breast cancer recurrence and, when the field was extended to include the pelvis, also had a higher diagnostic accuracy in detecting bone metastases than scintigraphy.

Health Economic Evaluation

The GDG did not consider this topic a health economic priority; therefore the cost-effectiveness literature on this topic has not been reviewed.

2.2. Pathological assessment

Histological verification of metastatic disease is not needed routinely in patients who have a history of previous breast cancer and in whom the pattern of metastatic disease is consistent with breast origin, but sometimes is appropriate. For example:

  • If the imaging findings are equivocal such as a solitary liver lesion not diagnostic of metastatic disease.
  • If a patient presents with metastatic cancer of possible breast origin without a history of a previous primary breast cancer.
  • If patients have a history of more than one different primary cancer in the past and therefore the source of the metastatic disease may be uncertain.

The treatment of patients with advanced breast cancer is guided by a number of factors including the hormone receptor (oestrogen receptor (ER) and progesterone receptor) status and the expression of HER2 of the primary tumour or the metastases. Current practice in some centres is to establish ER and progesterone receptor and HER2 status on all newly diagnosed breast cancers. However there is no evidence that assessing progesterone receptor status adds significant information to ER status in predicting response to hormone treatment (see Chapter 4 of ‘Early and locally advanced breast cancer: diagnosis and treatment’ (NICE clinical guideline 80 [2009]). It is not routine practice to reassess receptor status on recurrence. If the receptor status of the primary tumour is unknown and further analysis is not possible, it may be necessary to biopsy the metastatic disease.

Recommendations

  • Patients with tumours of known oestrogen receptor (ER) status whose disease recurs should not have a further biopsy just to reassess ER status.

Qualifying statement: Although there is some evidence from observational studies that ER status can change on recurrence, there was GDG consensus that there are few clinical situations in which re-biopsy can be justified.

Qualifying statement: The evidence about change in HER2 status was poor and there was no evidence about how to manage patients in whom a change was detected.

  • Assess ER and HER2 status at the time of disease recurrence if receptor status was not assessed at the time of initial diagnosis. In the absence of tumour tissue from the primary tumour, and if feasible, obtain a biopsy of a metastasis to assess ER and HER2 status.

Qualifying statement: This recommendation is based on the GDG consensus that knowledge of receptor status will significantly affect management.

Clinical Evidence

The evidence for this topic was provided by seventeen observational studies all of which compared paired (from the same patient) biopsy or fine needle aspirate samples from primary and locoregional or metastatic tumour tissue. HER2 (Niehans et al. 1993; Shimizu et al. 2000; Gancberg et al. 2002; Carlsson et al. 2004; Regitnig et al. 2004; Gong et al. 2005; Zidan et al. 2005; Lorincz et al. 2006; Rom et al. 2006; Pectasides et al. 2006; Tapia et al. 2007 and Santinelli et al. 2008) and/or endocrine receptor (Spataro et al. 1992; Johnston et al. 1995; Lower et al. 2005; Rom et al. 2006; Shimizu et al. 2000 and Brankovic-Magic et al. 2002) status was determined by immunohistochemistry or in situ hybridisation. All study participants had advanced breast cancer.

The majority of papers were concerned with identifying the rate of status change but did not address overall survival, time to progression or quality of life. Approximately 15% of patients showed a change in endocrine receptor status, from positive to negative, comparing primary with locoregional or metastatic tumour samples. 93% of patients tested for HER2 status showed no change between paired samples.

Health Economic Evaluation

The GDG did not consider this topic a health economic priority; therefore the cost-effectiveness literature on this topic has not been reviewed.

2.3. Monitoring disease status

Imaging is useful in assessing how patients respond to treatment. The choice of imaging technique will depend on the site of the patient’s metastatic disease.

The progress of bone metastases is difficult to assess. Those due to breast cancer may be either osteolytic, osteoblastic (sclerotic) or mixed osteolytic and osteoblastic. Plain radiographs are relatively insensitive in assessing lytic bony metastases because 50% of the bone matrix may be destroyed before a lucency is visualised. When osteolytic metastases heal, new bone is laid down and the lesion then appears sclerotic; however new areas of sclerosis could also be due to the development of new osteoblastic metastases. It is therefore not always possible to say whether new sclerotic lesions in bone indicate healing and a response to treatment, or disease progression. Osteoblastic bony metastases are regarded as unassessable on plain radiographs.

There can also be problems with bone scintigraphy which detects bony metastases by the osteoblastic response excited by the presence of the tumour. This means that bone scintigraphy is more sensitive for detecting osteoblastic than lytic metastases but, like plain radiographs, cannot distinguish between healing of previously lytic disease and progression of osteoblastic disease. If a bone scintigram is done early in treatment, a so-called ‘flare reaction’ may be seen in which there is an increase in the degree of abnormal activity on the bone scintigram due to the healing osteoblastic response.

Ultrasound can be used to monitor the progress of liver metastases but is affected by factors such as patient body habitus and inter-operator variability, and is much less reproducible than other cross-sectional techniques such as CT.

CT and MRI are reproducible cross-sectional techniques which can be used to assess disease progress. PET-CT has the potential to provide additional functional information. Estradiol labelled with positron emitting fluorine (FES) has been used as an alternative to 18F-deoxyglucose (FDG) in breast cancer patients who are ER positive and may be helpful in indicating whether the metastatic disease is likely to respond to endocrine therapy.

Recommendations

Qualifying statement: There is a poor evidence base with a single prospective study. There is no evidence that bone scintigraphy can be used to assess the response to treatment.

Qualifying statement: There is no evidence that monitoring with PET-CT improves management compared to standard imaging modalities in patients with advanced breast cancer.

Clinical Evidence

The evidence for this topic was limited comprising six small case series, five of which were retrospective (Ciray et al. 2001; Couturier et al. 2006; Huber et al. 2002; Stafford et al. 2002 and Linden et al. 2006) and one prospective (Mortimer et al. 1996) that described four different imaging methods. All patients had locally advanced or metastatic breast cancer which in most papers was stated to have been bone dominant disease.

MRI fat-suppressed-long-echo-time-inversion images were superior to T1-weighted-sequence images in accurately assessing the response to the treatment of bone metastases.

Radiography detected treatment responses to any form of cancer therapy within three months in 80% of cases and differentiated between regression and progression of disease.

Fluorodeoxyglucose-PET (FDG-PET) scans correlated positively with the levels of tumour markers and clinical category suggesting efficacy in the assessment of tumour response. Semi-quantitative analysis of scan data predicted overall survival and, after three cycles of treatment, correlated with the short term response to chemotherapy. Coupled to fluoroestradiol, PET scans accurately reflected the response to endocrine therapy.

Health Economic Evaluation

The GDG did not consider this topic a health economic priority; therefore the cost-effectiveness literature on this topic has not been reviewed.

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Bookshelf ID: NBK61862
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