The Challenges of Improving Breast Cancer Outcome With Diagnostic Imaging Techniques

Positron-emission tomography (PET) technology has drastically improved in the past few years, with the development of hybrid imaging devices combining PET and computed tomography (CT), which have essentially replaced stand-alone PET scanners in most centers. Image quality has also increased with the use of improved PET detectors and image reconstruction techniques. While a few years ago a “neck to thigh” PET scan could take as much as 90 minutes to complete, this procedure can now be performed in less than 15 minutes with modern instruments, leading to faster throughput and improved images. Due to well defined indications for many common malignancies such as lung cancer, colorectal carcinoma, and lymphoma, PET/CT imaging has become commonplace in many industrialized countries.

However, despite Medicare reimbursement in the United States for specific clinical settings, the clinical impact of PET/CT imaging has not been as significant in breast cancer as in other malignancies. In that context, the article by Almubarak, Osman, Marano, and Abraham provides a timely review of the topic. The authors essentially conclude that while the role of [18F]-fluorodeoxyglucose (FDG)-PET/CT imaging is limited in the initial diagnosis and staging of breast cancer, this modality can be useful in detecting suspected recurrence, assessing for distant metastases, and measuring treatment response to chemotherapy.

Importance of Early Detection

Breast cancer is a common cancer that will afflict one out of nine women during their lifetime. Although breast cancer has a high cure rate when detected early, metastatic breast cancer remains an incurable disease, which can be managed by a variety of relatively effective therapies, but with the eventual development of resistance and disease progression.

Mammography is credited with earlier detection and improved survival of women with breast cancer.[1] Because of the limited specificity of this test in some cases, many investigators are looking into second-line imaging techniques to avoid performing invasive procedures for diagnosis. Given the high accuracy and low morbidity of the various breast biopsy techniques, imaging tools would need to be highly accurate to influence management in this setting.

As pointed out by Almubarak and colleagues, PET imaging suffers from a lack of sensitivity for small breast tumors with a diameter less than 1 cm. In addition, some large tumors can be missed because of their low incorporation of FDG. Even relatively large lobular carcinomas and some estrogen receptor–sensitive breast cancers, for example, can sometimes have a very low FDG uptake,[2,3] and the sensitivity of FDG-PET imaging to detect axillary metastases with this histology is much lower than for invasive ductal carcinoma.[4]

Sensitivity vs Specificity

Conversely, since mammography is not highly sensitive either, tools such as magnetic resonance imaging (MRI) and positron-emission tomography (PET) have also been considered for screening high-risk women, particularly those with dense breasts. Although highly sensitive, MRI suffers from a lack of specificity, resulting in positive predictive values as low as 17% in this setting,[5] leading to many biopsies, which can create a strain on the capacity of breast imaging departments.

In this context, PET instruments with the capacity to detect very small tumors in the breast do exist (“positron emission mammography”).[6,7] However, given the close relationship between FDG uptake and tumor biology, as noted by Almubarak et al, it is possible and even likely that some breast cancers will be missed because of low FDG uptake.

An ongoing study scheduled for completion this year should provide further information on the potential benefits of this technology compared to MRI (clinicaltrials.org study #NCT00484614). Further studies are needed in this setting, and perhaps new radiopharmaceuticals will improve the accuracy of positron-emission tomography for the detection of primary breast cancer.

Role of PET

It is fair to say that at this stage, there is no clinical indication for the routine use of PET in the initial diagnosis of breast cancer. Due to its ability to evaluate breast tumor biochemistry, PET imaging may well provide additional prognostic data for women with breast cancer, but whether this information will be complementary or redundant to immunohistochemical findings and other molecular markers of poor prognosis from paraffin-embedded or frozen biopsy specimens remains to be established in the clinical setting.

Likewise, given the low morbidity and high accuracy of sentinel lymph node biopsy for the detection of axillary nodal metastases, there is no indication to perform PET or PET/CT imaging for axillary nodal staging. PET imaging is simply not sufficiently sensitive to detect nodal metastases in clinically negative axillae.[4,8] For detection of distant metastases in untreated patients, PET imaging is more accurate than other conventional imaging modalities, but the cost-effectiveness of using this procedure on a routine basis is not likely to be favorable.

PET/CT is perhaps best reserved for cases with equivocal conventional imaging results when the detection of distant metastases would alter management. PET/CT might be useful when selectively used in staging aggressive lesions such as triple-negative breast cancers, but further studies on this topic will be necessary. The uptake of FDG in primary tumors has been linked with tumor grade[2] and the presence of axillary or distant metastases.[9] Triple-negative tumors also tend to have higher FDG uptake.[10] A recent retrospective study conducted in women with inflammatory breast cancer showed that PET/CT imaging detected distant metastasis in 49% of cases, many of which were not detected by conventional staging.[11]

Troubleshooting Niche

There are certainly data in the literature to suggest that FDG-PET imaging is useful in restaging patients with a newly suspected recurrence based on clinical, laboratory, or radiologic findings. The detection of distant metastases in this setting can alter management, as local recurrence would be treated aggressively with surgery and/or radiation, whereas systemic treatment would be altered in the presence of metastatic disease.

Given the high clinical impact of PET imaging in the management of patients with recurrent breast cancer,[12] this tool fills a niche in troubleshooting many complex cases where recurrence is suspected clinically while conventional imaging remains negative or equivocal. Demonstrating this benefit in a prospective clinical trial remains difficult in light of the biologic heterogeneity of breast cancer and the number of treatment options that can be offered in various clinical scenarios. Although somewhat limited in high-quality prospective studies, current data support the selective use of PET/CT imaging in the diagnosis of recurrent breast cancer when the results are reasonably expected to affect clinical management.

Assessing Response to Therapy

PET imaging can provide faster assessment of disease response to therapy. A PET scan performed after three cycles of chemotherapy is predictive of survival, as shown in some studies in the neoadjuvant[13] and metastatic settings.[14] This approach may reduce unnecessary treatments that may carry the risk of significant toxicity despite limited benefits to women with resistant cancers. It may also provide a quick surrogate indicator of response in clinical trials for the evaluation of new drugs.

In clinical practice, whether interventions guided by PET imaging translate into improved outcomes-ie, reduced toxicity and/or improved survival compared to traditional clinical and conventional imaging response assessment methods-will remain debated until large scale, well designed prospective studies address this question.[8] The lack of a definite cure for metastatic breast cancer creates challenges in identifying measurable endpoints for the use of imaging techniques in patients who are likely to be subjected to multiple rounds of diverse diagnostic and therapeutic procedures over several years.

Financial Disclosure:The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Elmore JG, Armstrong K, Lehman CD, et al: Screening for breast cancer. JAMA 293:1245-1256, 2005.
2. Crippa F, Seregni E, Agresti R, et al: Association between [18F]fluorodeoxyglucose uptake and postoperative histopathology, hormone receptor status, thymidine labelling index and p53 in primary breast cancer: A preliminary observation. Eur J Nucl Med 25:1429-1434, 1998.
3. Mavi A, Cermik TF, Urhan M, et al: The effects of estrogen, progesterone, and C-erbB-2 receptor states on 18F-FDG uptake of primary breast cancer lesions. J Nucl Med 48:1266-1272, 2007.
4. Wahl RL, Siegel BA, Coleman RE, et al: Prospective multicenter study of axillary nodal staging by positron emission tomography in breast cancer: A report of the staging breast cancer with PET study group. J Clin Oncol 22:277-285, 2004.
5. Lehman CD, Schnall MD: Imaging in breast cancer: Magnetic resonance imaging. Breast Cancer Res 7:215-219, 2005.
6. Berg WA, Weinberg IN, Narayanan D, et al: High-resolution fluorodeoxyglucose positron emission tomography with compression (“positron emission mammography”) is highly accurate in depicting primary breast cancer. Breast J 12:309-323, 2006.
7. Rosen EL, Eubank WB, Mankoff DA: FDG PET, PET/CT, and breast cancer imaging. Radiographics 27(suppl 1):S215-S229, 2007.
8. Hodgson NC, Gulenchyn KY: Is there a role for positron emission tomography in breast cancer staging? J Clin Oncol 26:712-720, 2008.
9. Basu S, Mavi A, Cermik T, et al: Implications of standardized uptake value measurements of the primary lesions in proven cases of breast carcinoma with different degree of disease burden at diagnosis. Mol Imaging Biol 10:62-66, 2008.
10. Basu S, Chen W, Tchou J, et al: Comparison of triple-negative and estrogen receptor-positive/progesterone receptor-positive/HER2-negative breast carcinoma using quantitative fluorine-18 fluorodeoxyglucose/positron emission tomography imaging parameters. Cancer 112:995-1000, 2008.
11. Carkaci S, Macapinlac H, Cristofanilli M, et al: Retrospective study of 18F-FDG PET/CT in the diagnosis of inflammatory breast cancer: Preliminary data. J Nucl Med 50:231-238, 2009.
12. Souvatzoglou M, Buck A, Schmidt S, et al: PET/CT for restaging breast cancer: Impact on patient management and patient outcome. J Nucl Med 49(suppl 1):18P, 2008.
13. Rousseau C, Devillers A, Sagan C, et al: Monitoring of early response to neoadjuvant chemotherapy in stage II and III breast cancer by [18F]fluorodeoxyglucose positron emission tomography. J Clin Oncol 24:5366-5372, 2006.
14. Couturier O, Jerusalem G, N’Guyen JM, et al: Sequential positron emission tomography using [18F]fluorodeoxyglucose for monitoring response to chemotherapy in metastatic breast cancer. Clin Cancer Res 12:6437-6443, 2006.