Erin K. Schubert

Quantitative Fluoroestradiol Positron Emission Tomography Imaging Predicts Response to Endocrine Treatment in Breast Cancer

PURPOSE In breast cancer, [(18)F]fluoroestradiol (FES) positron emission tomography (PET) correlates with estrogen receptors (ER) expression and predicts response to tamoxifen. We tested the ability of FES-PET imaging to predict response to salvage hormonal treatment in heavily pretreated metastatic breast cancer patients, predominantly treated with aromatase inhibitors. PATIENTS AND METHODS Initial FES uptake measurements in 47 patients with ER-positive tumors were correlated with subsequent tumor response to 6 months of hormonal treatment. Most patients had bone dominant disease and prior tamoxifen exposure. Response was compared to initial FES-PET uptake, measured qualitatively and quantitatively using standardized uptake value (SUV) and estradiol-binding flux. RESULTS Eleven of 47 patients (23%) had an objective response. While no patients with absent FES uptake had a response to treatment, the association between qualitative FES-PET results and response was not significant (P = .14). However, quantitative FES uptake and response were significantly associated; zero of 15 patients with initial SUV less than 1.5 responded to hormonal therapy, compared with 11 of 32 patients (34%) with SUV higher than 1.5 (P < .01). In the subset of patients whose tumors did not overexpress HER2/neu, 11 of 24 patients (46%) with SUV higher than 1.5 responded. CONCLUSION Quantitative FES-PET can predict response to hormonal therapy and may help guide treatment selection. Treatment selection using quantitative FES-PET in our patient series would have increased the rate of response from 23% to 34% overall, and from 29% to 46% in the subset of patients lacking HER2/neu overexpression. A multi-institutional collaborative trial would permit definitive assessment of the value of FES-PET for therapeutic decision making.

Quantitative Imaging of Estrogen Receptor Expression in Breast Cancer with PET and 18F-Fluoroestradiol

The PET compound 18F-fluoroestradiol (18F-FES) has been developed and tested as an agent for the imaging of estrogen receptor (ER) expression in vivo. 18F-FES uptake has been shown to correlate with ER expression assayed in vitro by radioligand binding; however, immunohistochemistry (IHC) rather than radioligand binding is used most often to measure ER expression in clinical practice. We therefore compared 18F-FES uptake with ER expression assayed in vitro by IHC with both qualitative and semiquantitative measures. Methods: Seventeen patients with primary or metastatic breast cancer were studied with dynamic 18F-FES PET; cancer tissue samples, collected close to the time of imaging, were assayed for ER expression by IHC. For each tumor, partial-volume-corrected measures of 18F-FES uptake were compared with ER expression measured by 3 different ER scoring methods: qualitative scoring (0–3+), the Allred score (0–10), and a computerized IHC index. Results: There was excellent agreement (r = 0.99) between observers using IHC as well as the different methods of measuring ER content (P < 0.001). ER-negative tumors had 18F-FES partial-volume-corrected standardized uptake values of less than 1.0, whereas ER-positive tumors had values above 1.1. Correlation coefficients for the different measures of ER content and the different measures of 18F-FES uptake ranged from 0.57 to 0.73, with the best correlation being between the computerized IHC index and 18F-FES partial-volume-corrected standardized uptake values. Conclusion: Our results showed good agreement between 18F-FES PET and ER expression measured by IHC. 18F-FES imaging may be a useful tool for aiding in the assessment of ER status, especially in patients with multiple tumors or for tumors that are difficult to biopsy.

Use of Serial FDG PET to Measure the Response of Bone-Dominant Breast Cancer to Therapy

RATIONALE AND OBJECTIVES The authors performed this study to determine the feasibility of using quantitative 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) to monitor the response of breast cancer bone metastases to therapy. MATERIALS AND METHODS Twenty-four women with stage IV bone-dominant breast carcinoma were included in this study. Whole-body FDG PET imaging was performed at serial time points during the course of therapy. FDG PET scans were interpreted quantitatively by using the maximum standard uptake value (SUV) of the most conspicuous bone lesion at baseline FDG PET. PET results were compared to the overall assessment of response (response, stable disease, progressive disease) with a combination of conventional imaging, change in tumor marker values, and subjective symptom changes by experienced medical oncologists blinded to the findings at FDG PET. Changes in FDG SUV were also correlated quantitatively to the changes in a particular tumor marker (CA 27.29). RESULTS The changes in FDG SUV with therapy showed correlation with the overall clinical assessment of response (P < .01). The percentage change in FDG uptake with therapy showed strong correlation with the percentage change in tumor marker value (P < .01). CONCLUSION Preliminary results indicate that serial whole-body FDG PET can help quantitatively assess the response of breast cancer bone metastases to therapy. Prospective trials are needed to further investigate its accuracy.

Tumor Metabolism and Blood Flow Changes by Positron Emission Tomography: Relation to Survival in Patients Treated With Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer

PURPOSE Patients with locally advanced breast carcinoma (LABC) receive preoperative chemotherapy to provide early systemic treatment and assess in vivo tumor response. Serial positron emission tomography (PET) has been shown to predict pathologic response in this setting. We evaluated serial quantitative PET tumor blood flow (BF) and metabolism as in vivo measurements to predict patient outcome. PATIENTS AND METHODS Fifty-three women with primary LABC underwent dynamic [(18)F]fluorodeoxyglucose (FDG) and [(15)O]water PET scans before and at midpoint of neoadjuvant chemotherapy. The FDG metabolic rate (MRFDG) and transport (FDG K(1)) parameters were calculated; BF was estimated from the [(15)O]water study. Associations between BF, MRFDG, FDG K(1), and standardized uptake value and disease-free survival (DFS) and overall survival (OS) were evaluated using the Cox proportional hazards model. RESULTS Patients with persistent or elevated BF and FDG K(1) from baseline to midtherapy had higher recurrence and mortality risks than patients with reductions. In multivariable analyses, BF and FDG K(1) changes remained independent prognosticators of DFS and OS. For example, in the association between BF and mortality, a patient with a 5% increase in tumor BF had a 67% higher mortality risk compared with a patient with a 5% decrease in tumor BF (hazard ratio = 1.67; 95% CI, 1.24 to 2.24; P < .001). CONCLUSION LABC patients with limited or no decline in BF and FDG K(1) experienced higher recurrence and mortality risks that were greater than the effects of clinical tumor characteristics. Tumor perfusion changes over the course of neoadjuvant chemotherapy measured directly by [(15)O]water or indirectly by dynamic FDG predict DFS and OS.

Fluoroestradiol Positron Emission Tomography Reveals Differences in Pharmacodynamics of Aromatase Inhibitors, Tamoxifen, and Fulvestrant in Patients with Metastatic Breast Cancer

Purpose: To determine, by molecular imaging, how in vivo pharmacodynamics of estrogen-estrogen receptor (ER) binding differ between types of standard endocrine therapy. Experimental Design: The ER has been a highly successful target for breast cancer treatment. ER-directed treatments include lowering ligand concentration by using aromatase inhibitors (AI) and blocking the receptor with agents like tamoxifen (TAM) or fulvestrant (FUL). We measured regional estrogen-ER binding by using positron emission tomography with 18F-fluoroestradiol (FES PET) prior to and during treatment with AI, TAM, or FUL in a series of 30 metastatic breast cancer patients. FES PET measured in vivo estrogen binding at all tumor sites in heavily pretreated women with metastatic bone soft tissue–dominant breast cancer. In patients with uterus (n = 16) changes in uterine FES uptake were also measured. Results: As expected, tumor FES uptake declined more markedly on ER blockers (TAM and FUL, average 54% decline) compared with a less than 15% average decline on estrogen-depleting AIs (P < 0.001). The rate of complete tumor blockade [FES standardized uptake value (SUV) ≤1.5] following TAM (5/5 patients) was greater than the blockade rate following FUL (4/11; 2-sided mid P = 0.019). Percent FES SUV change in the uterus showed a strong association with tumoral change (ρ = 0.63, P = 0.01). Conclusions: FES PET can assess the in vivo pharmacodynamics of ER-targeted agents and may give insight into the activity of established therapeutic agents. Imaging revealed significant differences between agents, including differences in the efficacy of blockade by different ER antagonists in current clinical use. Clin Cancer Res; 17(14); 4799–805. ©2011 AACR.

Kinetic analysis of 18F-fluoride PET images of breast cancer bone metastases

The most common site of metastasis for breast cancer is bone. Quantitative 18F-fluoride PET can estimate the kinetics of fluoride incorporation into bone as a measure of fluoride transport, bone formation, and turnover. The purpose of this analysis was to evaluate the accuracy and precision of 18F-fluoride model parameter estimates for characterizing regional kinetics in metastases and normal bone in breast cancer patients. Methods: Twenty metastatic breast cancer patients underwent dynamic 18F-fluoride PET. Mean activity concentrations were measured from serial blood samples and regions of interest placed over bone metastases, normal vertebrae, and cardiac blood pools. This study examined parameter identifiability, model sensitivity, error, and accuracy using parametric values from the patient cohort. Results: Representative time–activity curves and model parameter ranges were obtained from the patient cohort. Model behavior analyses of these data indicated 18F-fluoride transport and flux (K1 and Ki, respectively) into metastatic and normal osseous tissue could be independently estimated with a reasonable bias of 9% or less and reasonable precision (coefficients of variation ≤ 16%). Average 18F-fluoride transport and flux into metastases from 20 patients (K1 = 0.17 ± 0.08 mL·cm−3·min−1 and Ki = 0.10 ± 0.05 mL·cm−3·min−1) were both significantly higher than for normal bone (K1 = 0.09 ± 0.03 mL·cm−3·min−1 and Ki = 0.05 ± 0.02 mL·cm−3·min−1, P < 0.001). Conclusion: Fluoride transport and flux can be accurately and independently estimated for bone metastases and normal vertebrae. Reasonable bias and precision for estimates of K1 and Ki from simulations and significant differences in values from patient modeling results in metastases and normal bone suggest that 18F-fluoride PET images may be useful for assessing changes in bone turnover in response to therapy. Future studies will examine the correlation of parameters to biologic features of bone metastases and to response to therapy.

PET Tumor Metabolism in Locally Advanced Breast Cancer Patients Undergoing Neoadjuvant Chemotherapy: Value of Static versus Kinetic Measures of Fluorodeoxyglucose Uptake

Purpose: Changes in tumor metabolism from positron emission tomography (PET) in locally advanced breast cancer (LABC) patients treated with neoadjuvant chemotherapy (NC) are predictive of pathologic response. Serial dynamic [18F]-FDG (fluorodeoxyglucose) PET scans were used to compare kinetic parameters with the standardized uptake value (SUV) as predictors of pathologic response, disease-free survival (DFS), and overall survival (OS). Experimental Design: Seventy-five LABC patients underwent FDG PET prior to and at midpoint of NC. FDG delivery (K1), FDG flux (Ki), and SUV measures were calculated and compared by clinical and pathologic tumor characteristics using regression methods and area under the receiver operating characteristic curve (AUC). Associations between K1, Ki, and SUV and DFS and OS were evaluated using the Cox proportional hazards model. Results: Tumors that were hormone receptor negative, high grade, highly proliferative, or of ductal histology had higher FDG Ki and SUV values; on an average, FDG K1 did not differ systematically by tumor features. Predicting pathologic response in conjunction with estrogen receptor (ER) and axillary lymph node positivity, kinetic measures (AUC = 0.97) were more robust predictors than SUV (AUC = 0.84, P = 0.005). Changes in K1 and Ki predicted both DFS and OS, whereas changes in SUV predicted OS only. In multivariate modeling, only changes in K1 remained an independent prognosticator of DFS and OS. Conclusion: Kinetic measures of FDG PET for LABC patients treated with NC accurately measured treatment response and predicted outcome compared with static SUV measures, suggesting that kinetic analysis may hold advantage of static uptake measures for response assessment. Clin Cancer Res; 17(8); 2400–9. ©2011 AACR.

Tumor Metabolism and Blood Flow as Assessed by Positron Emission Tomography Varies by Tumor Subtype in Locally Advanced Breast Cancer

Purpose: Dynamic positron emission tomography (PET) imaging can identify patterns of breast cancer metabolism and perfusion in patients receiving neoadjuvant chemotherapy (NC) that are predictive of response. This analysis examines tumor metabolism and perfusion by tumor subtype. Experimental Design: Tumor subtype was defined by immunohistochemistry in 71 patients with locally advanced breast cancer undergoing NC. Subtype was defined as luminal [estrogen receptor (ER)/progesterone receptor (PR) positive], triple negative [TN; ER/PR negative, human epidermal growth factor receptor 2 (HER2) negative], and HER2 (ER/PR negative, HER2 overexpressing). Metabolic rate (MRFDG) and blood flow (BF) were calculated from PET imaging before NC. Pathologic complete response (pCR) to NC was classified as pCR versus other. Results: Twenty-five (35%) of 71 patients had TN tumors; 6 (8%) were HER2 and 40 (56%) were luminal. MRFDG for TN tumors was on average 67% greater than for luminal tumors (95% confidence interval, 9-156%) and average MRFDG/BF ratio was 53% greater in TN compared with luminal tumors (95% confidence interval, 9-114%; P < 0.05 for both). Average BF levels did not differ by subtype (P = 0.73). Most luminal tumors showed relatively low MRFDG and BF (and did not achieve pCR); high MRFDG was generally matched with high BF in luminal tumors and predicted pCR. This was not true in TN tumors. Conclusion: The relationship between breast tumor metabolism and perfusion differed by subtype. The high MRFDG/BF ratio that predicts poor response to NC was more common in TN tumors. Metabolism and perfusion measures may identify subsets of tumors susceptible and resistant to NC and may help direct targeted therapy. Clin Cancer Res; 16(10); 2803–10. ©2010 AACR.

Dynamic and Static Approaches to Quantifying 18F-FDG Uptake for Measuring Cancer Response to Therapy, Including the Effect of Granulocyte CSF

The response of cancer to chemotherapy can be quantified using 18F-FDG to indicate changes in tumor metabolism. Quantification using the standardized uptake value (SUV) is more feasible for clinical practice than is the metabolic rate of 18F-FDG (MRFDG), which requires longer, dynamic scanning. The relationship between MRFDG and SUV depends in part on how each accounts for blood clearance of tracer. We tested whether chemotherapy and treatment with granulocyte colony-stimulating factor (CSF) changed the blood clearance curves and therefore affected the relationship between MRFDG and SUV. Methods: Thirty-nine patients with locally advanced breast cancer underwent 18F-FDG PET before and after chemotherapy, including granulocyte CSF. The area under the curve (AUC) for blood clearance was determined before and after therapy. MRFDGs were determined by graphical analyses, whereas SUVs were calculated using the standard formula normalized by body weight. MRFDG and SUVs were compared with each other and with tumor response. Paired percentage changes in MRFDG and SUV were also divided into tertiles based on pretherapy SUV to investigate differences in the relative sensitivity of SUV changes to MRFDG changes due to baseline tumor uptake. Results: Despite a small but statistically significant 6% decrease in blood AUCs after therapy (P = 0.02), SUV and MRFDG did not differ significantly in slope (P = 0.53) or in correlation before and after therapy (r = 0.95 for both). Percentage changes in MRFDG and SUV between serial scans correlated with each other (r = 0.84) and with patient response (P ≤ 0.06). The maximum detectable percentage change in SUV and the slope of percentage changes in MRFDG versus SUV for the patient tertile with the lowest baseline SUVs (65% ± 5% [±SE], slope (m) = 0.40 ± 0.12, n = 13) were significantly lower than for the other patients (86% ± 3%, m = 0.85 ± 0.10, n = 26, P = 0.01 for both). Conclusion: Chemotherapy and granulocyte CSF treatment resulted in a lower 18F-FDG blood AUC. The maximum detectable percentage change in 18F-FDG uptake is less when quantifying via static SUV than via dynamic MRFDG. This effect is small in most patients but may have clinical significance for measuring the response of patients with a low pretherapy 18F-FDG uptake.

[Tc-99m]-sestamibi uptake and washout in locally advanced breast cancer are correlated with tumor blood flow

OBJECTIVES To determine the influence of breast tumor blood flow on MIBI kinetics, we compared MIBI uptake and washout to [O-15]-water PET estimates of blood flow in patients with locally advanced breast cancer. METHODS Prior to therapy, 37 patients underwent MIBI and [O-15]-water PET imaging; 22/37 also had MIBI washout analysis. Twenty-five patients underwent serial imaging over the course of chemotherapy. RESULTS MIBI uptake and blood flow had a significant positive correlation pre-therapy. The change in MIBI uptake over the course of therapy also correlated with the change in blood flow. The half-time of MIBI washout inversely correlated with blood flow, indicating faster MIBI washout with higher blood flow. CONCLUSIONS Blood flow strongly influences early MIBI uptake and can be a factor affecting the rate of MIBI washout in breast tumors. We present a model of MIBI kinetics in tumors which forms a hypothesis for further mechanistic studies of MIBI uptake and washout in breast cancer.