Alena Novakova

A virtual clinical trial comparing static versus dynamic PET imaging in measuring response to breast cancer therapy

We developed a method to evaluate variations in the PET imaging process in order to characterize the relative ability of static and dynamic metrics to measure breast cancer response to therapy in a clinical trial setting. We performed a virtual clinical trial by generating 540 independent and identically distributed PET imaging study realizations for each of 22 original dynamic fluorodeoxyglucose (18F-FDG) breast cancer patient studies pre- and post-therapy. Each noise realization accounted for known sources of uncertainty in the imaging process, such as biological variability and SUV uptake time. Four definitions of SUV were analyzed, which were SUVmax, SUVmean, SUVpeak, and SUV50%. We performed a ROC analysis on the resulting SUV and kinetic parameter uncertainty distributions to assess the impact of the variability on the measurement capabilities of each metric. The kinetic macro parameter, K i , showed more variability than SUV (mean CV K i   =  17%, SUV  =  13%), but K i pre- and post-therapy distributions also showed increased separation compared to the SUV pre- and post-therapy distributions (mean normalized difference K i   =  0.54, SUV  =  0.27). For the patients who did not show perfect separation between the pre- and post-therapy parameter uncertainty distributions (ROC AUC  <  1), dynamic imaging outperformed SUV in distinguishing metabolic change in response to therapy, ranging from 12 to 14 of 16 patients over all SUV definitions and uptake time scenarios (p  <  0.05). For the patient cohort in this study, which is comprised of non-high-grade ER+  tumors, K i outperformed SUV in an ROC analysis of the parameter uncertainty distributions pre- and post-therapy. This methodology can be applied to different scenarios with the ability to inform the design of clinical trials using PET imaging.

Effect of (18)F-FDG uptake time on lesion detectability in PET imaging of early stage breast cancer.

Prior reports have suggested that delayed 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) oncology imaging can improve the contrast-to-noise ratio (CNR) for known lesions. Our goal was to estimate realistic bounds for lesion detectability for static measurements within 1 to 4 hours between FDG injection and image acquisition. Tumor and normal tissue kinetic model parameters were estimated from dynamic PET studies of patients with early-stage breast cancer. These parameters were used to generate time-activity curves (TACs) for up to 4 hours, for which we assumed both nonreversible and reversible models with different rates of FDG dephosphorylation (k4). For each pair of tumor and normal tissue TACs, 600 PET sinogram realizations were generated, and images were reconstructed using the ordered subsets expectation maximization reconstruction algorithm. Test statistics for each tumor and normal tissue region of interest were output from the computer model observers and evaluated using a receiver operating characteristic analysis, with the calculated area under the curve (AUC) providing a measure of lesion detectability. For the nonreversible model (k4 = 0), the AUC increased in 11 of 23 (48%) patients for 1 to 2 hours after the current standard postradiotracer injection imaging window of 1 hour. This improvement was driven by increased tumor/normal tissue contrast before the impact of increased noise that resulted from radiotracer decay began to dominate the imaging signal. As k4 was increased from 0 to 0.01 min−1, the time of maximum detectability shifted earlier, due to decreasing FDG concentration in the tumor lowering the CNR. These results imply that delayed PET imaging may reveal inconspicuous lesions that otherwise would have gone undetected.

Abstract P4-02-05: Test-retest fidelity of FDG SUVmax in bone and non-boney metastatic breast cancer lesions in local area network PET/CT scanners

Background: Metabolic activity in lesions, measured by FDG-PET, is often used for assessing tumor aggressiveness and response to therapy. Patients may be scanned on different machines, so quantitative measurements should be reproducible. Reducing SUV variability in PET machines throughout a local network can aid in monitoring patient response to therapy and increase access to clinical trials. Methods: Eighteen female patients with advanced or metastatic breast cancer underwent paired FDG PET/CT test-retest studies with 1-15 days between scans, and without interim change in treatment. Ten patients were studied in the same scanner and 8 patients were studied in 2 different scanners. Five different PET/CT scanners were used (2 GE DSTE, 2 Siemens (BioGraph 6 and mCT), 1 Philips Ingenuity TF). Each PET/CT scanner was calibrated using NIST-traceable reference sources to characterize and reduce variability. All of the images were interpreted by two separate reviewers. SUVmax values in lesions, corresponding normal tissue, and normal liver were collected. Linear mixed models with random intercept (patient effects) were fitted to compare differences in log(|SUVmax % difference|+.01) in multiple lesions per patient. Results: SUVmax was assessed in a total of 130 lesions (75 bone). The median number of lesions per patient was 5 (range 1-17). Average SUVmax ranged from 1.0 to 18.2 (mean±SD = 6.0±3.2). The median SUVmax difference was 0.4 (8%) for 47 lesions imaged twice in the same scanner, and was 0.6 (13%) for 83 lesions imaged in two different scanners. In a multivariable linear mixed effects model, SUVmax for different scanners within the same institution did not differ more than for the same scanner (p=0.39), but repeat scans with different scanners and site personnel at had an average of 78% greater percentage difference in SUVmax than for the same scanner (p=0.009). In the same model, the average percent difference in SUVmax for bone lesions was estimated as 30% lower than for other sites (p=0.06, 95% confidence interval 0-50%). Examining normal liver uptake, the median SUVmean was 2.5 (range 1.9-3.1) with an median 6.5% difference between measurements (range 1.1%-23.7%) that did not appear to differ based on scanners used for repeat measurements (p=0.47). Conclusions: The variability in quantitative FDG SUVmax between scans is modest, suggesting reliable reproducibility in appropriately calibrated settings. In our study, bone lesions had somewhat higher fidelity than other tumor sites. Additional studies will address variability in other cancer types. Careful calibration and monitoring of PET/CT scanners, and consistent imaging protocols are necessary in clinical trials that utilize quantitative PET/CT imaging in order to confidently interpret results. Research Support: NIH grant U01-CA148131 and NCI-SAIC Contract 24XS036-004. Citation Format: Linden HM, Peterson LM, Kurland B, Roberts T, Specht J, Shields AT, Novakova A, Christopfel R, Byrd D, Muzi M, Mankoff DA, Kinahan P. Test-retest fidelity of FDG SUVmax in bone and non-boney metastatic breast cancer lesions in local area network PET/CT scanners [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P4-02-05.

Abstract P4-01-02: The role of FLT PET early assessment of response to endocrine therapy for early stage breast cancer

Background: In estrogen receptor positive (ER+) tumors, a low proliferative index (Ki-67) two weeks into endocrine therapy predicts response. FLT PET non-invasively measures tumor proliferation in vivo. The pre-operative window is an opportunity to assess impact of systemic therapies. We tested associations between FLT PET qualitative and quantitative measures and Ki-67 following two weeks of aromatase inhibitor (AI) therapy. Methods: Women with clinical stage I-II ER+ HER2– breast cancer underwent “run-in” of AI monotherapy prior to definitive surgery. Premenopausal women were given GNRH agonist treatment 2 W prior to AI therapy. FLT PET was performed before AI therapy, and 1-7 days before surgery. Ki-67 was measured in baseline core biopsy and surgical specimens. Results: Fourteen patients (8 postmenopausal, 6 premenopausal) have been enrolled. All have undergone baseline FLT PET imaging; 11 have completed imaging and surgery, including one premenopausal patient with no residual invasive carcinoma following 26 days of AI therapy. The majority harbored ductal carcinomas (n = 9, 5 with lobular histology) with the majority histologic grade ≥ 2 (n = 11). The median number of days exposed to AI was 19 (range, 9-42). Baseline SUVmax ranged from 1.2 to 3.9 (median 2.2), and post run-in SUV (6-64 days later) ranged from 1.2 to 2.8 (median 1.8). Baseline Ki-67 ranged from 6-26.2, median 11.6; surgical Ki-67 post AI therapy ranged from 0- 20.3 median 3.7, with seven below 5%. SUV and flux declined in most patients, as did Ki-67. Quantitative FLT flux correlated with tumor response assessed by proliferative index (Ki-67) before the “run-in” period, with a stronger correlation at surgery, Pearson correlation coefficients = 0.41 and 0.82, respectively. FLT SUV and qualitative changes were not strongly associated with Ki-67. Conclusions: Both pre and postmenopausal women with early stage breast cancer showed imaging and tissue response to endocrine therapy. Quantitative, but not qualitative FLT is a promising tool to assess tumor proliferation and response to therapy. Accrual is ongoing and updated results will be reported. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-02.

Abstract P4-01-03: HDACi (vorinostat) in metastatic breast cancer to restore sensitivity to ER-directed (AI) therapy: A phase II clinical trial with FES imaging correlates

Background: Histone deacetylase inhibitors (HDACi) have shown pre-clinical promise in estrogen receptor(ER)-modulation and restoring sensitivity to endocrine manipulation, suggesting potential clinical benefit (Sabnis 2011) (Huang 2000) in ER+ breast cancer. Vorinostat is an FDA-approved HDACi for CTCL, and could have a beneficial role in restoring ER-signaling in endocrine-resistant tumors (Munster 2011) (Yardley 2011). [F-18]fluoroestradiol (FES) PET imaging may be used to monitor regional tumor ER expression in patients with breast cancer (Linden 2011). Methods: Patients with metastatic breast cancer with prior clinical benefit from endocrine manipulation who progressed on an AI therapy are eligible for this ongoing trial. In part A, patients were given vorinostat for 2 weeks, then resumed AI for 6 W. In part B (reflecting results of prior HDACi trials) patients are given vorinostat 400mg po daily 5/7 days 3/4 weeks while AI is given continuously. Paired FES and FDG PET are performed at baseline, week 2 and 8; clinical/radiologic assessment of disease is also performed at week 8. Patients with clinical benefit (response or stable disease) may continue on treatment until progressive disease or study withdrawal. Lesion-level analysis of the association between baseline FES uptake (logged) and FES/FDG ratio used generalized estimating equations (GEE) with small-sample adjustments to standard errors. Results: 12/ 20 planned patients have accrued, and the treatment is well tolerated. Enrolled women were postmenopausal, the majority with primary infiltrating ductal tumors, bone/soft tissue dominant with longstanding metastatic disease, exposed to multiple endocrine and chemotherapy regimens. Five patients have had clinical benefit (2/4 on part B with greater HDACi exposure). One patient withdrew from the study due to toxicity. FES and FDG uptake was analyzed in 42 lesions in 11 patients. Average FES uptake was 2.0 (SULmean) for patients with clinical benefit, and 1.2 in patients with progressive disease by 8 weeks (p = 0.09). FES/FDG ratio at baseline was also associated with response (p = 0.04). Conclusions: HDACi therapy is promising in relapsed ER+ breast cancer. Imaging of metabolic pathways in parallel with clinical trials may accelerate understanding of the underlying tumor biology and refine treatment selection. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-03.

Abstract P4-01-01: Serial FDG and 18F-fluoride PET predict response to therapy in patients with breast cancer bone metastases

Background : Assessing response to therapy in patients (pts) with bone-dominant (BD) metastatic breast cancer is challenging by conventional imaging such as CT and bone scintigraphy. In prior retrospective analyses, measures of FDG uptake by FDG PET were predictive of both time to progression (TTP) and the risk of skeletal related events (SRE). Studies have also shown that 18F-fluoride PET improves bone metastasis detection compared to bone scintigraphy and, as a quantitative study, may be better suited to evaluate therapeutic response. We evaluated the utility of serial FDG PET and 18F-fluoride PET to prospectively assess response to therapy in BD metastatic breast cancer. Methods : Pts with BD metastatic breast cancer were evaluated with FDG PET and 18F-fluoride PET prior to starting a new systemic therapy and after approximately 3 months. Serum markers (CA27.29 and CEA) were obtained at baseline and during treatment close to the time of PET imaging. In this analysis, static images from skull base to mid-thighs were analyzed quantitatively using the maximum standardized uptake value (SUV) of up to 5 most prominent lesions. Tumor locations were confirmed by CT and regions-of-interest were drawn on both FDG and 18F-fluoride images. Assessment of clinical endpoints including TTP and time to SRE was determined by independent review of clinical data and analyzed by Cox regression. PET imaging results were reported clinically, but not used to determine endpoints in this analysis. Results : 47 pts (mean age 55, range 39-91) enrolled between 2004 and 2012. Most pts 43/47 (91%) had hormone receptor positive disease (primary or metastatic). 9/47 (19%) of pts had HER2+ disease. Systemic therapy during study was chemotherapy in 20/47 (43%) and endocrine therapy in 31/47 (66%). Most pts 30/47 (64%) received bisphosphonates. Mean time between baseline and follow up FDG and 18F-fluoride PET scans was 4.6 months. 42/47 (89%) pts had disease progression during study follow up (median TTP 5.9 months, 95% CI 4-9.2). Among 24 pts with 2 FDG and 2 18F-fluoride scans, percent change in FDG (>-9% vs ≤-9%) was predictive of TTP, HR = 0.317, p = 0.038. Percent change (>-19% vs ≤-19%) in 18F-fluoride SUV did not predict TTP, HR = 1.05, p = 0.914. Median time to SRE was 48 months. Absolute SUV for baseline FDG and 18F-Fluoride PET were both predictive of time to SRE (FDG SUV >6 vs 25 vs <25; HR = 4.5, p = 0.008). Conclusions : Changes in FDG SUV over the course of treatment were a robust predictor of TTP, while changes in 18F-fluoride PET did not predict response. Both baseline high FDG and 18F-fluoride SUV were associated with earlier SRE occurrence. These results indicate a role for PET, particularly FDG PET, in assessing BD breast cancer and support a role for PET in future clinical trials. Funding support 5R01CA124573-05. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-01.