This review provides an up-to-date summary of the results obtained through the use of the technique of fluorodeoxyglucose positron emission tomography (FDG-PET) for the diagnosis of breast cancer. The article focusses on the use of the technique in, respectively, the detection of primary breast tumours, the staging of axillary lymph nodes, the detection of metastases and recurrent disease and the assessment of response to therapy.
by Dr Sofía Escalona López
Worldwide, breast cancer is the most common malignant neoplasm in woman, with its high incidence and associated mortality making the disease a correspondingly important public health problem. According to the GLOBOCAN database of the International Agency for Research in Cancer (IARC) data, the global incidence of breast cancer in 2002 was as high as 1,151,298 cases with the disease being responsible for as many as 410, 712 deaths .
Positron emission tomography (PET) is one of the techniques used in the diagnosis of breast cancer. This relatively non-invasive, exploratory technique provides physiological information on the uptake of glucose and its metabolism. The technique involves the injection of a radioactive tracer, usually fluorodeoxyglucose (FDG), that emits positrons. Although in itself not a new technique, PET is of growing interest as a means of oncological imaging.
Diagnosis of primary tumours
The ability of FDG-PET to diagnosis primary tumours in women suspected of having breast cancer appears to vary widely, with sensitivities ranging from 48% to 95.7%. The sensitivity of the technique appears to be lower when the tumours are small (<10 mm) and the uptake of FDG is correspondingly reduced. Some authors report that false negative results are significantly more likely when tumours are small (≤10 mm) or when their histological grade is moderate-low. Likewise, it has been found that the sensitivity of the technique is greater with stage III and IV than with stage I and II tumours (83.3% compared to 90.5%) [1, 2]. Several studies have compared the results of FDG-PET to conventional techniques such as mammography, physical examination or ultrasonography. In all cases the diagnostic efficacy of FDG-PET was superior [3]. In studies in which the relevant data were published, the reported tumour size was between 0.3 cm to 12 cm. It has therefore been concluded that the capacity of FDG-PET to detect small tumours is limited. In addition, it has been reported that different histopathological types of breast cancer are associated with a varying degree of FDG uptake. Depending on tumour stage, diagnostic sensitivity varied (47.7% in pT1 stage and 80.6% in pT2) [4]. In ductal carcinoma in situ (DCIS) there was a diffuse uptake with FDG-PET and a higher number of false negatives [5].
Axillary lymph node staging
The diagnostic accuracy of FDG-PET in the staging of axillary lymph nodes is directly related to the size of the metastases and the number of lymph nodes involved. The detection of micrometastases in these lymph nodes is limited by the spatial resolution of FDG-PET and the sensitivity of the technique in this application is very low with a fairly high rate of false negative results [6, 7], which are usually associated with micrometastases in a single lymph node [8, 9]. FDG-PET is limited in its ability to detect metastases in single rather than in multiple axillary lymph nodes. In comparisons of the use of sentinel lymph node biopsy with FDG-PET, some authors have reported that FDG-PET is not as effective for detecting occult axillary metastases or micrometastases as the sentinel lymph node biopsy approach [10, 11]. However, the specificity and predictive value of FDG-PET in axillary lymph node staging are relatively high: 74-100% and 75-100% respectively [10, 12]. A positive FDG-PET result might therefore indicate resection of the axillary lymph nodes, obviating the need for sentinel lymph node biopsy.
Detection of metastases
and recurrent disease
In the detection of metastases and recurrent disease, FDG-PET has usually been compared with conventional imaging techniques, such as mammography, ultrasonography, CT, MRI, X-rays, and bone scintigraphy, which are generally used following treatment for a primary tumour. In a comparison of FDG-PET with bone scintigraphy, it was found that FDG-PET detected more osteolytic-type bone lesions while scintigraphy detected more osteoblastic lesions [13]. FDG-PET appears to be more specific than scintigraphy, although no significant differences in sensitivity were reported with respect to the detection of bone metastases using radiography, CT, MRI or bone biopsy [13,14]. The sensitivity of the technique was reported to range from 92% [15] to 96% [16] for the detection of recurrent disease.
When FDG-PET was compared with MRI for the detection of local or regional recurrent disease or contralateral disease, it was found that there were no statistically significant differences in the sensitivity and specificity of both techniques although FDG-PET did detect additional metastases outside the MRI field. In eight patients examined, FDG-PET was able to detect recurrence in six patients. Combining MRI with FDG-PET when the results indicated a suspected recurrence led to an increase in sensitivity and specificity [17]. FDG-PET also detected unsuspected metastatic or recurrent disease, leading to changes in patient management; results suggested that between 10% and 48% of patients needed their treatment to be modified [18,19].
Assessment of response to therapy
When assessing the results of chemotherapy in the treatment of breast cancer, a reduction in FDG uptake is reported to be a potentially better indicator of therapeutic efficacy than the change in tumour dimensions as shown by mammography. (P<0.001 compared to P=0.005). The maximum tumour uptake of FDG decreased promptly with treatment to 78±9.2% of the basal value on day 8 (P<0.003), 68.1±7.5% on day 21 (P<0.025), 60±5.1% on day 42, (P<0.001), and 52.4±4.4% on day 63 (P<0.0001). In a study involving the comparison of the basal level of FDG uptake with that at 63 day post treatment in three non-responding patients, no statistically significant reduction was found in the tumour uptake of FDG (81 ±12% of basal diameter) [20].
The regional uptake of FDG has been reported to be reduced in tumours that respond to the first cycle of chemotherapy, and to become significantly reduced after the second cycle (P<0.05). The histopathological response predicted by FDG-PET after the first chemotherapeutic cycle showed a diagnostic accuracy of 88% (when the threshold fall in the Standardised Uptake Value (SUV) was set to 55% of the baseline value for optimal differentiation between responders and non-responders). However, the technique appears to be unable to distinguish between patients with small amounts of residual tumour and those showing a complete pathological response [21].
As concerns the assessment of the response to tamoxifen therapy, two studies have been carried out with the aim of investigating whether the increased tumour uptake of FDG after tamoxifen therapy predicted a hormonally responsive breast cancer [22, 23]. These two studies found that an increase in FDG uptake after tamoxifen treatment was consistent with the metabolic increase. In the first study, there was an increase in the SUV of FDG of 1.4 ± 0.7 after treatment in responder patients; in non-responders the change in FDG SUV could barely be detected (-0.01 ± 0.4; p = 0.008). In the second study an increase was also observed (28.4 % ± 23.3 %) in responding patients whereas there was no significant change in non-responders. With regard to the basal value there was a significant difference between non-responders and responders (p=0.0002).
Conclusion
The studies described above suggest that FDG-PET is more reliable than conventional techniques such as mammography, ultrasonography or physical examination for the diagnosis of primary breast tumours; the values of diagnostic efficacy for these latter techniques were generally lower than that of FDG-PET.
The sensitivity of FDG-PET was found to be low, as was its negative predictive power, with respect to primary tumour detection. The resolution possible with the technology means that it has certain limitations in the detection of small tumours (<1 cm). On its own, FDG-PET does not therefore appear to be reliable enough to allow the possibility of the presence of a tumour to be excluded; a negative result cannot be trusted to rule out the presence of a small tumour.
Studies that compared FDG-PET with other techniques with regard to the staging of lymph nodes also showed that the sensitivity of the FDG-PET was very low. FDG-PET thus appears to be insufficiently exact to enable negative results to rule out affected lymph nodes.
However, FDG-PET may have an important role to play in the detection of metastases and locally recurrent breast cancer, in which situations the technique appears to have a greater diagnostic efficacy than either mammography or ultrasonography. The results obtained are comparable to those obtained with CT, FDG-PET/CT or MRI. In addition, if unsuspected metastases are detected by FDG-PET, this strongly suggest that the management of the patient should be changed. Sensitivity in the detection of metastases and local and regional disease recurrence is improved when FDG-PET is
combined with MRI.
The diagnostic efficacy of FDG-PET in the detection of bone metastases can be improved by combining the technique with SPECT or bone scintigraphy. Given the limitations of FDG-PET in the detection of osteoblastic lesions, the technique should
however not be used on its own .
The studies that assessed the efficacy of FDG-PET in the monitoring of treatment for breast cancer were heterogeneous in terms of the treatments prescribed, the interpretation of FDG-PET results, and the variables analysed so no reliable conclusions can be drawn regarding the performance of FDG-PET for the evaluation of the response to treatment. Likewise, a possible role of FDG-PET in the prediction of the response to neoadjuvant chemotherapy is unclear. Long-term studies with more patients with different sizes of tumour are needed for conclusions to be drawn.
Based on our review of the literature, we thus conclude that FDG-PET is insufficient to rule out the presence of small tumours and that the technique cannot replace sentinel lymph node biopsy in axillary lymph node staging. It may however be accurate enough in the detection of metastases and recurrent disease.
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The author
Dr Sofía Escalona López
Unidad de Evaluación de Tecnologías Sanitarias.
Agencia Lain Entralgo Consejería de Sanidad
C/ Gran Vía, 27. 7ª planta. • 8013-Madrid, Spain
sofia.escalona@salud.madrid.org
