PET Imaging and Breast Cancer

May 15, 2014

Molecular imaging allows accurate detection of metastatic disease. It also allows for noninvasive assessment of tumors and is a predictor of response to therapy.

The review by Clark et al in the current issue of ONCOLOGY highlights the use of molecular imaging to assess response in the treatment of metastatic breast cancer.[1]

The classification of breast cancer into four molecular “intrinsic” breast cancer subtypes has recently been reported. The behavior of each of these subtypes-luminal A, luminal B, human epidermal growth factor receptor 2 (HER2/neu)-enriched, and basal-like breast cancers-is different.[2] Therapeutic interventions with targeted therapies have led to a more tailored approach to breast cancer treatment beyond the usual clinical-pathologic factors, such as tumor size, patient age, and stage. Molecular profiling with additional gene testing of tumor tissue, such as that available with Oncotype DX, MammaPrint, and Prosigna, is also incorporated by medical oncologists into clinical decision making regarding adjuvant chemotherapy. The biologic subtype and gene expression of breast cancer influence clinical outcomes and predict response to treatment.[3]

The importance of estrogen receptor (ER), progesterone receptor (PR), and HER2/neu as biomarkers has been well established. Endocrine therapy is the most common targeted therapy used in patients with ER-positive breast cancer. Determination of these biomarkers is standard clinical practice, and this information is obtained by biopsy of the tumor. However, in the metastatic setting, it is not always feasible to biopsy multiple lesions. Additionally, the presence of an ER may not be predictive of response to endocrine therapy, particularly in patients with metastatic disease who have been previously treated.[4]

Positron emission tomography (PET) is an imaging modality that uses radioactive nuclides. The appeal of this type of molecular imaging includes both the possibility of avoiding invasive biopsy and use of PET in predicting response to therapy. In their article, Clark and colleagues review current published data regarding use of radioactive nuclides in assessing response to therapy, including 18F-fluoro–deoxyglucose [18F-FDG]-PET, 16α-[18F]fluoro-17β-estradiol (FES)-PET, and 18F-fluorothymidine (FLT)-PET. To date, the majority of the published studies are small and from single institutions. Only FDG-PET is currently used in clinical practice, and according to the National Comprehensive Cancer Network (NCCN) practice guidelines, FDG-PET can be considered in evaluation of stage III breast cancer.[5] FDG-PET also shows promise in assessing response to therapy. A recent meta-analysis of FDG-PET demonstrated a high sensitivity and specificity for FDG-PET in assessment of response to therapy (ie, 80.5% and 78.8%, respectively). FDG-PET has also correlated with response to treatment in the neoadjuvant setting.[6]

Another molecular imaging technology, FES PET, is rapidly emerging as a promising predictive study for selecting candidates and monitoring response to endocrine therapy in ER-positive breast cancer. Multiple studies have demonstrated its ability to measure tumor ER expression.[7-12]

Several studies have validated the use of FES-PET in predicting response to endocrine therapy. The studies have included the use of tamoxifen, aromatase inhibitors (AIs), and/or fulvestrant, and have included serial FES-PET imaging. For example, Mortimer et al[10] showed that the level of FES uptake predicted response to tamoxifen in locally advanced and metastatic breast cancer, while Linden et al[13] showed the ability of FES-PET to predict response to endocrine therapy with AIs. Linden et al subsequently[14] reported on a study of serial FES-PET in patients with metastatic breast cancer, comparing results in those receiving an AI vs tamoxifen vs fulvestrant; they noted tumor FES uptake decreased more with ER-blocking therapies than with estrogen-depleting therapies.

Metabolic “flare” reactions, described as short-term disease progression immediately following initiation of a new endocrine therapy, are relatively uncommon. Serial FDG- and FES-PET scans have also been reported to demonstrate these “flare” reactions, and may be good predictors of response.[15,16] Further study on the use of identification of flare reactions with molecular imaging is necessary. The role and timing of serial PET imaging for assessment of response require further clarification. The FES standardized uptake value (SUV) level that reliably predicts response is also an area of ongoing research. Van Krutchen et al reported that an FES SUV below 1.5 predicted for lack of response to endocrine therapy in previously treated patients with ER-positive breast cancer.[17] A low baseline FES may possiblyhelp determine which patients will not respond to endocrine therapy and might benefit from alternative therapies, such as chemotherapy. Also, in previously treated patients, the FES SUV level may allow for tailoring of the treatment regimen. Further larger, multi-institutional studies are necessary to address the question of what FES SUV value will reliably predict response.

One of the newest PET imaging technologies is FLT-PET, which has been the subject of very limited studies to date. The small studies with FLT-PET demonstrated that reduction in FLT correlated with response to treatment. However, a recent study with FDG- and FLT-PET presented at the San Antonio Breast Cancer Symposium in 2013 demonstrated that only change in FDG-and not FLT-was associated with time to progression.[18]

Conclusion

Molecular imaging allows accurate detection of metastatic disease. It also allows for noninvasive assessment of tumors and is a predictor of response to therapy. The authors of this review highlight the promises of molecular imaging through review of the published literature and identification of areas of future study. Further larger, prospective studies are necessary that will help determine the role of these imaging studies for both research and clinical practice. In this modern era of targeted therapies, molecular imaging holds promise in helping guide treatment for patients with metastatic breast cancer.

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. Clark AS, McDonald E, Lynch MC, Mankoff D. Using nuclear medicine imaging in clinical practice: update on PET to guide treatment of patients with metastatic breast cancer. Oncology (Williston Park). 2014;28:425-30.

2. Sorlie T, Perou CM, Tibshirani R, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci USA. 2001;98:10869-74.

3. Paik S, Tang G, Shak S, et al. Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer. J Clin Oncol. 2006;24:3726-34.

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5. National Comprehensive Cancer Network (NCCN) Guidelines. Invasive breast cancer. Version 1.2014. Available from: www.nccn.org. Accessed March 31, 2014.

6. Mghanga FP, Lan X, Bakari KH, et al. Fluorine-18 fluorodeoxyglucose positron emission tomography-computed tomography in monitoring the response of breast cancer to neoadjuvant chemotherapy: a meta-analysis. Clin Breast Cancer. 2013;13:271-9.

7. Mintun MA, Welch MJ, Siegel BA, et al. Breast cancer: PET imaging of estrogen receptors. Radiology. 1988;169:45-8.

8. Linden HM, Kurland BF, Peterson LM, et al. Fluoroestradiol positron emission tomography reveals differences in pharmacodynamics of aromatase inhibitors, tamoxifen, and fulvestrant in patients with metastatic breast cancer. Clin Cancer Res. 2011;17:4799-805.

9. McGuire AH, Dehdashti F, Siegel BA, et al. Positron tomographic assessment of 16 alpha-[18F] fluoro-17 beta-estradiol uptake in metastatic breast carcinoma. J Nucl Med. 1991;32:1526-31.

10. Dehdashti F, Mortimer JE, Siegel BA, et al. Positron tomographic assessment of estrogen receptors in breast cancer: comparison with FDG-PET and in vitro receptor assays. J Nucl Med. 1995;36:1766-74.

11. Mortimer JE, Dehdashti F, Siegel BA, et al. Positron emission tomography with 2-[18F]Fluoro-2-deoxy-D-glucose and 16alpha-[18F]fluoro-17beta-estradiol in breast cancer: correlation with estrogen receptor status and response to systemic therapy. Clin Cancer Res. 1996;2:933-9.

12. Peterson LM, Kurland BF, Link JM, et al. Factors influencing the uptake of 18F-fluoroestradiol in patients with estrogen receptor positive breast cancer. Nucl Med Biol. 2011;38:969-78.

13. Linden HM, Stekhova SA, Link JM, et al. Quantitative fluoroestradiol positron emission tomography imaging predicts response to endocrine treatment in breast cancer. J Clin Oncol 2006;24:2793-9.

14. Linden HM, Kurland BF, Peterson LM, et al. Fluoroestradiol positron emission tomography reveals differences in pharmacodynamics of aromatase inhibitors, tamoxifen, and fulvestrant in patients with metastatic breast cancer. Clin Cancer Res. 2011;17:4799-805.

15. Mortimer JE, Dehdashti F, Siegel BA, et al. Metabolic flare: indicator of hormone responsiveness in advanced breast cancer. J Clin Oncol. 2001;19:2797-803.

16. Dehdashti F, Mortimer JE, Trinkaus K, et al. PET based estradiol challenge as a predictive biomarker of response to endocrine therapy in women with estrogen-receptor positive breast cancer. Breast Can Res Treat. 2009;113:509.

17. Van Kruchten M, de Vries EG, Brown M, et al. PET imaging of oestrogen receptors in patients with breast cancer. Lancet Oncol. 2013;14:e465-75.

18. Montgomery SK, Barlow WE, Linden HM, et al. Serial FDG and 18F-fluoride PET predict response to therapy in patients with breast cancer bone metastases. Proceedings of the San Antonio Breast Cancer Symposium. San Antonio, TX. Dec 10-14, 2013. Poster P4-01-01.