However, it is becoming ever clearer that tumor characteristics can change during the course of disease. Given this change over time, other supporting techniques for guiding therapy would be of value. Molecular radionuclide imaging with positron emission tomography (PET) can potentially fulfill this need.
Increasingly, breast cancer patients are treated based on tumor characteristics. These can be determined through analysis of tissue obtained during initial surgery or from a biopsy. However, it is becoming ever clearer that tumor characteristics can change during the course of disease, across lesions within a patient, and within a lesion. For example, for the estrogen receptor (ER), discordance between primary tumor and metastases are observed in ~20% of patients, and for human epidermal growth factor receptor 2 (HER2/neu) this discordance occurs in ~8%. Additionally, multiple biopsies from different metastatic sites in 119 breast cancer patients showed heterogeneous ER expression among lesions in 33% of patients. Given this change over time and intra-patient heterogeneity across lesions, as well as the fact that often not all lesions can be biopsied, other supporting techniques for guiding therapy would be of value. Molecular radionuclide imaging with positron emission tomography (PET) can potentially fulfill this need.
Clark et al, in their article in this issue of ONCOLOGY, focus on the reliability of radiotracer imaging to detect metastatic disease in breast cancer, and to predict response to therapy in the neoadjuvant and metastatic settings. We were very interested in their description of ER imaging. Because standard systemic therapy for breast cancer patients is influenced by expression of ER and HER2/neu, we would like to focus in this commentary on PET imaging of these relevant drug targets.
Clark et al discuss how ER expression can be visualized with 18F-fluoroestradiol (FES). This technique might be supportive in several clinical settings. In breast cancer patients, FES-PET can potentially aid diagnosis in instances of diagnostic dilemmas, such as the presence of metastases of unknown origin in a patient with previous ER-positive primary breast cancer plus another cancer. In an exploratory study, FES-PET improved diagnostic understanding in 88% of the patients and supported therapy changes in 48%. Assessing the presence of FES uptake in tumor lesions before treatment may help clinicians select patients for hormonal treatment. It might also provide insight into the relevance of FES-PET whole body imaging for prediction of a uniform or heterogeneous tumor response in patients undergoing hormonal treatment. If effective, one could even envision that selective radiotherapy for lesions not showing FES uptake might be of interest. In this respect, knowing the optimal timing for an FES-PET scan following earlier treatment with ER-blocking agents, such as tamoxifen and fulvestrant, is critical but not yet established. Based on our preliminary data, the currently accepted period of 5-week withdrawal prior to FES-PET imaging may be too short. For example, the ER-blocking drug fulvestrant, with a half-life of 40 days, may reduce tumor FES uptake for an even longer period. If this interferes with FES uptake, that would have major logistic consequences for applicability of the FES-PET scan.
The vast majority of patients with ER-positive metastatic breast cancer present with bone-dominant disease; in ~63%, bone is the first distant site of recurrence. Response assessment in the case of bone metastases is difficult, given that these lesions are considered nonmeasurable by Response Evaluation Criteria in Solid Tumors (RECIST). Changes in tumor FES binding during antihormonal therapy may aid early response assessment. Data on serial FES-PET imaging are limited, but several studies evaluating the ability of FES-PET to predict or assess response to endocrine therapy, such as with fulvestrant and estrogen, are ongoing.
Recent research showed recurring somatic mutations in codons 537 and 538 within the ligand-binding domain of the ER gene in ER-positive metastatic disease. These mutations were not detected in primary or treatment-naive ER-positive breast cancer. The authors suggest that these mutations are potential drivers of endocrine resistance during the progression of ER-positive breast cancer. Combining FES-PET scanning with analyses of tumor biopsies or even circulating tumor DNA would allow us to study whether FES tumor uptake is influenced by ER mutations.
As pointed out by Clark et al, the optimum threshold for quantified tumor FES to predict response still needs to be validated in prospective trials.
Besides the ER, the androgen receptor (AR) also is overexpressed in ~60% of breast cancers and, interestingly, in ~12% of patients with triple-negative breast cancer. This receptor is not yet a target for standard care in breast cancer patients. It is, however, increasingly considered of interest as a potential drug target in breast cancer. In a recent study in 28 postmenopausal heavily pretreated women with metastatic ER-negative/AR-positive breast cancer, the selective AR-antagonist bicalutamide offered a clinical benefit rate of 19% and was well tolerated. The novel anti-androgen abiraterone acetate, a CYP17-inhibitor, showed preliminary efficacy and was well tolerated in a phase I dose-escalation study. Results of studies with the AR-antagonist enzalutamide in breast cancer are awaited.
In prostate cancer patients, the AR has been extensively imaged with 18F-fluoro-5Î±-dihydrotestosterone (FDHT). FDHT-PET showed that the AR antagonist enzalutamide substantially reduced tumor FDHT uptake. A study exploring the feasibility of FDHT PET to assess AR expression in metastatic breast cancer is ongoing (Clinicaltrials.gov ID NCT01988324). When successful, the effects of anti-androgens on tumor FDHT uptake can potentially aid in identifying the optimum dose to block AR in metastatic breast cancer.
HER2 expression has been visualized by 89Zr-trastuzumab–, 111In-trastuzumab–, and 64Cu-DOTA-trastuzumab–PET in metastatic breast cancer patients.[13-15] An ongoing study in our center is evaluating whether 89Zr-trastuzumab–PET can aid diagnosis and support therapy decisions in breast cancer patients presenting with a clinical dilemma (Clinicaltrials.gov ID NCT01832051) where a metastatic biopsy is difficult or impractical to obtain. In a prospective multicenter trial with an anticipated enrollment of 200 patients with newly diagnosed metastatic breast cancer, the impact of FES-PET and 89Zr-trastuzumab–PET on treatment decision and outcome is compared with the golden standard, tumor biopsy (NCT01957332). This study should be able to fill many still-existing knowledge gaps concerning the visualization of drug targets in breast cancer patients.
Acknowledgements:Ongoing imaging research in breast cancer is supported by the Dutch Cancer Society (grant RUG 2009-4529), the Centre for Translational Molecular Medicine-Mammary Carcinoma Molecular Imaging for Diagnosis and Therapeutics (CTMM-MAMMOTH) Project (grant 03O-201), and the Dutch Cancer Society Alpe d’HuZes Project (grant RUG 2012-5400): IMPACT: IMaging PAtients for Cancer drug selecTion-Metastatic Breast Cancer.
Financial Disclosure:Dr. de Vries has received a research grant made available to the University Medical Center Groningen from Roche. The other authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
1. Burrell RA, McGranahan N, Bartek J, et al. The causes and consequences of genetic heterogeneity in cancer evolution. Nature. 2013;501:338-45.
2. Aurilio G, Disalvatore D, Pruneri G, et al. A meta-analysis of estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer. 2014;50:277-89.
3. LindstrÃ¶m LS, Karlsson E, Wilking UM, et al. Clinically used breast cancer markers such as estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 are unstable throughout tumor progression. J Clin Oncol. 2012;20:30:2601-8.
4. Clark AS, McDonald E, Lynch MC, Mankoff D. Using nuclear medicine in clinical practice: update on PET to guide the treatment of metastatic breast cancer patients. Oncology (Williston Park). 2014;28:425-30.
5. 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.
6. van Kruchten M, Glaudemans AW, de Vries EF, et al. PET imaging of estrogen receptors as a diagnostic tool for breast cancer patients presenting with a clinical dilemma. J Nucl Med. 2012;53:182-90.
7. Sihto H, Lundin J, Lundin M, et al. Breast cancer biological subtypes and protein expression predict for the preferential distant metastasis sites, a nationwide cohort study. Breast Cancer Res. 2011;13:R87.
8. Merenbakh-Lamin K, Ben-Baruch N, Yeheskel A, et al. D538G mutation in estrogen receptor-alpha: a novel mechanism for acquired endocrine resistance in breast cancer. Cancer Res. 2013;73:6856-64.
9. Vera-Badillo FE, Templeton AJ, de Gouveia P, et al. Androgen receptor expression and outcomes in early breast cancer: a systematic review and meta-analysis. J Natl Cancer Inst. 2014;106:djt319.
10. Gucalp A, Tolaney S, Isakoff SJ, et al. Phase II trial of bicalutamide in patients with androgen receptor positive, hormone receptor negative metastatic breast cancer. Clin Cancer Res. 2013;19:5505-12.
11. Basu B, Ang JE, Crawley D. Phase I study of abiraterone acetate in patients with estrogen receptor– or androgen receptor positive advanced breast carcinoma resistant to standard endocrine therapies. J Clin Oncol. 2011;29(suppl):Abstr 2525.
12. Scher HI, Beer TM, Higano CS, et al. Antitumour activity of MDV3100 in castration-resistant prostate cancer: a phase 1-2 study. Lancet. 2010;24:375:1437-46.
13. Dijkers EC, Oude Munnink TH, Kosterink JG, et al. Biodistribution of 98Zr-trastuzumab and PET imaging of HER2-positive lesions in patients with metastatic breast cancer. Clin Pharmacol Ther. 2010:87:586-92.
14. Perik PJ, Lub-De Hooge MN, Gietema JA, et al. Indium-111–labeled trastuzumab scintigraphy in patients with human epidermal growth factor receptor 2–positive metastatic breast. J Clin Oncol. 2006;24:2276-82.
15. Mortimer JE, Bading JR, Colcher DM, et al. Functional imaging of human epidermal growth factor receptor 2–positive metastatic breast cancer using 64Cu-DOTA-Trastuzumab PET. J Nucl Med. 2014;55:23-9.