Kaiyumars B. Contractor

Phase I Trial of the Positron-Emitting Arg-Gly-Asp (RGD) Peptide Radioligand 18F-AH111585 in Breast Cancer Patients

The integrin αvβ3 receptor is upregulated on tumor cells and endothelium and plays important roles in angiogenesis and metastasis. Arg-Gly-Asp (RGD) peptide ligands have high affinity for these integrins and can be radiolabeled for PET imaging of angiogenesis or tumor development. We have assessed the safety, stability, and tumor distribution kinetics of a novel radiolabeled RGD-based integrin peptide-polymer conjugate, 18F-AH111585, and its feasibility to detect tumors in metastatic breast cancer patients using PET. Methods: The biodistribution of 18F-AH111585 was assessed in 18 tumor lesions from 7 patients with metastatic breast cancer by PET, and the PET data were compared with CT results. The metabolic stability of 18F-AH111585 was assessed by chromatography of plasma samples. Regions of interest (ROIs) defined over tumor and normal tissues of the PET images were used to determine the kinetics of radioligand binding in tissues. Results: The radiopharmaceutical and PET procedures were well tolerated in all patients. All 18 tumors detected by CT were visible on the 18F-AH111585 PET images, either as distinct increases in uptake compared with the surrounding normal tissue or, in the case of liver metastases, as regions of deficit uptake because of the high background activity in normal liver tissue. 18F-AH111585 was either homogeneously distributed in the tumors or appeared within the tumor rim, consistent with the pattern of viable peripheral tumor and central necrosis often seen in association with angiogenesis. Increased uptake compared with background (P = 0.002) was demonstrated in metastases in lung, pleura, bone, lymph node, and primary tumor. Conclusion: 18F-AH111585 designed to bind the αvβ3 integrin is safe, metabolically stable, and retained in tumor tissues and detects breast cancer lesions by PET in most anatomic sites.

Male breast cancer: is the scenario changing.

BackgroundThe overall incidence of male breast cancer is around 1% of all breast cancers and is on the rise. In this review we aim to present various aspects of male breast cancer with particular emphasis on incidence, risk factors, patho-physiology, treatment, prognostic factors, and outcome.MethodsInformation on all aspects of male breast cancer was gathered from available relevant literature on male breast cancer from the MEDLINE database over the past 32 years from 1975 to 2007. Various reported studies were scrutinized for emerging evidence. Incidence data were also obtained from the IARC, Cancer Mondial database.ConclusionThere is a scenario of rising incidence, particularly in urban US, Canada and UK. Even though more data on risk factors is emerging about this disease, more multi-institutional efforts to pool data with large randomized trials to show treatment and survival benefits are needed to support the existing vast emerging knowledge about the disease.

Use of [11C]Choline PET-CT as a Noninvasive Method for Detecting Pelvic Lymph Node Status from Prostate Cancer and Relationship with Choline Kinase Expression

Purpose: To evaluate the accuracy and biological basis for [11C]choline-PET-CT in the nodal staging of high risk localized prostate cancer patients. Experimental Design: Twenty-eight patients underwent dynamic [11C]choline-PET-CT of the pelvis and lower abdomen prior to extended laparoscopic pelvic lymph node dissection (eLPL). The sensitivity and specificity of [11C]choline PET, [11C]choline PET-CT, and MRI for nodal detection were calculated. Average and maximal standardized uptake values (SUVave, SUVmax) were compared with choline kinase alpha (CHKα) and Ki67 immunohistochemistry scores. Results: Four hundred and six lymph nodes (LN), in 26 patients, were assessable. Twenty-seven (6.7%) involved pelvic nodes at eLPL were detected in 9 patients. Seventeen of the 27 involved nodes were subcentimeter. The sensitivity and specificity on a per nodal basis were 18.5% and 98.7%, 40.7% and 98.4%, and 51.9% and 98.4% for MRI, [11C]choline PET, and [11C]choline PET-CT, respectively. Sensitivity was higher for [11C]choline PET-CT compared with MRI (P = 0.007). A higher nodal detection rate, including subcentimeter nodes, was seen with [11C]choline PET-CT than MRI. Malignant lesions showed CHKα expression in both cytoplasm and nucleus. SUVave and SUVmax strongly correlated with CHKα staining intensity (r = 0.68, P < 0.0001 and r = 0.63, P = 0.0004, respectively). In contrast, Ki67 expression was generally low in all tumors. Conclusion: This study establishes the relationship between [11C]choline PET-CT uptake with choline kinase expression in prostate cancer and allows it to be used as a noninvasive means of staging pelvic LNs, being highly specific and more sensitive than MRI, including the detection of subcentimeter disease. Clin Cancer Res; 17(24); 7673–83. ©2011 AACR.

Monitoring Predominantly Cytostatic Treatment Response with 18F-FDG PET

18F-FDG PET and, more recently, PET/CT have been established as response biomarkers for monitoring cytotoxic or cytoreductive cancer therapies. With the advent of targeted cancer therapies, which are predominantly cytostatic, 18F-FDG PET is increasingly being used to monitor the therapeutic response to these agents as well. The impressive outcome of 18F-FDG PET studies in patients with gastrointestinal stromal tumors treated with imatinib mesylate brought to the forefront the use of this biomarker for assessing the response to targeted therapies. The use of 18F-FDG PET for this purpose has practical challenges, including quantitative analysis and timing of scans. This review provides a summary of clinical studies of targeted therapies done to date with 18F-FDG PET and provides guidance on practical issues to ensure the optimal interpretation of imaging data in drug development and for patient care.

[18F]-3′Deoxy-3′-Fluorothymidine Positron Emission Tomography and Breast Cancer Response to Docetaxel

Purpose: To establish biomarkers indicating clinical response to taxanes, we determined whether early changes in [18F]-3′deoxy-3′-fluorothymidine positron emission tomography (FLT-PET) can predict benefit from docetaxel therapy in breast cancer. Experimental Design: This was a prospective unblinded study in 20 patients with American Joint Committee on Cancer (AJCC) stage II–IV breast cancer unresponsive to first-line chemotherapy or progressing on previous therapy. Individuals underwent a baseline dynamic FLT-PET scan followed by a scan 2 weeks after initiating the first or second cycle of docetaxel. PET variables were compared with anatomic response midtherapy (after 3 cycles). Results: Average and maximum tumor standardized uptake values at 60 minutes (SUV60,av and SUV60,max) normalized to body surface area ranged between 1.7 and 17.0 and 5.6 and 26.9 × 10−5 m2/mL, respectively. Docetaxel treatment resulted in a significant decrease in FLT uptake (P = 0.0003 for SUV60,av and P = 0.0002 for SUV60,max). Reduction in tumor SUV60,av was associated with target lesion size changes midtherapy (Pearson R for SUV60,av = 0.64; P = 0.004) and predicted midtherapy target lesion response (0.85 sensitivity and 0.80 specificity). Decreases in SUV60,av in responders were due, at least in part, to reduced net intracellular trapping of FLT (rate constant, Ki). Docetaxel significantly reduced Ki by 51.1% (±28.4%, P = 0.0009). Conclusion: Changes in tumor proliferation assessed by FLT-PET early after initiating docetaxel chemotherapy can predict lesion response midtherapy with good sensitivity warranting prospective trials to assess the ability to stop therapy in the event of non–FLT-PET response. Clin Cancer Res; 17(24); 7664–72. ©2011 AACR.

Altered tissue 3'-deoxy-3'-[18F]fluorothymidine pharmacokinetics in human breast cancer following capecitabine treatment detected by positron emission tomography.

Purpose: We showed in preclinical models that thymidylate synthase (TS) inhibition leads to redistribution of the nucleoside transporter, ENT1, to the cell membrane and hence increases tissue uptake of [18F]fluorothymidine (FLT). In this study, we assessed for the first time the altered pharmacokinetics of FLT in patients following administration of capecitabine, a drug whose mode of action has been reported to include TS inhibition. Experimental Design: We analyzed 10 lesions from six patients with breast cancer by positron emission tomography before and after treatment with capecitabine. Although drug treatment did not alter tumor delivery pharmacokinetic variables (K1 and permeability product surface area) or blood flow, tumor FLT retention variables increased with drug treatment in all but one patient. Results: The baseline average standardized uptake value at 60 minutes, rate constant for the net irreversible transfer of radiotracer from plasma to tumor (Ki), and unit impulse response function at 60 minutes were 11.11 × 10−5 m2/mL, 4.38 × 10−2 mL plasma/min/mL tissue, and 4.93 × 10−2/min, respectively. One hour after capecitabine administration, the standardized uptake value was 13.55 × 10−5 m2/mL (P = 0.004), Ki 7.40 × 10−2 mL plasma/min/mL tissue (P = 0.004), and impulse response function was 7.40 × 10−2/min (P = 0.002). FLT pharmacokinetics did not change in normal tissues, suggesting that the effect was largely restricted to tumors (P = 0.55). Conclusions: We have identified FLT positron emission tomography retention parameters that could be used in future early clinical studies to measure the pharmacodynamics of TS inhibitors, as well as for identifying patients who are unlikely to benefit from TS inhibition. (Clin Cancer Res 2009;15(21):6649–57)

Reproducibility of [11C]Choline-Positron Emission Tomography and Effect of Trastuzumab

Purpose: This study sought to evaluate the reproducibility of [11C]choline-positron emission tomography and the effect of trastuzumab in breast cancer. Experimental Design: Twenty-one patients with newly diagnosed and recurrent breast cancer stage II-IV had a baseline dynamic [11C]choline-PET scan, 10 patients had a second [11C]choline-PET scan to examine reproducibility, and 6 patients had a second scan within a month after trastuzumab. Analysis of [11C]choline uptake was measured as the semiquantitative standardized uptake value at 30 and 60 minutes (SUV30 and SUV60), and quantitatively as the net irreversible retention of the radiotracer at steady-state (Ki) and plasma to tissue exchange at 60 minutes (IRF60min). Results: Breast tumor lesions in all patients were visualized by [11C]choline PET. The difference in tumor versus normal tissue uptake was significant for SUV30, SUV60, Ki, and IRF60 minutes (Wilcoxon P < 0.0001). At 60 minutes postinjection, 15.1 ± 2.16% of plasma radioactivity was due to unmetabolized [11C]choline radioactivity. [11C]Choline uptake was reproducible in breast tumor lesions (r2 = 0.9 for SUV, 0.9 for Ki, and 0.8 for IRF60). Early responses to trastuzumab measured by [11C]choline-PET were significant in three lesions occurring in two patients who responded clinically. Conclusions: [11C]Choline-PET uptake variables can be reproducibly assessed. Initial studies show that trastuzumab decreases [11C]choline uptake. Clin Cancer Res; 16(16); 4236–45. ©2010 AACR.

[11C]Choline Positron Emission Tomography in Estrogen Receptor–Positive Breast Cancer

Purpose: Novel radiotracers could potentially allow the identification of clinically aggressive tumor phenotypes. As choline metabolism increases during malignant transformation and progression of human mammary epithelial cells, we examined the ability of [11C]choline (CHO) positron emission tomography imaging to detect clinically aggressive phenotype in patients with estrogen receptor (ER)–positive breast cancer in vivo. Experimental Design: CHO positron emission tomography was done in 32 individuals with primary or metastatic ER–positive breast cancer. Semiquantitative (standardized uptake value) and fully quantitative (net irreversible transfer rate constant of CHO, Ki) estimates of CHO uptake in the tumors were calculated and compared with tumor grade, size, involved nodes, and also ER, progesterone receptor, Ki-67, and human epidermal growth factor receptor-2 scores. Results: Breast tumors were well visualized in 30 of 32 patients with good tumor background ratios. A wide range of uptake values were observed in primary and metastatic tumors. CHO uptake variables correlated well with tumor grade. For most imaging variables, a poor association was found with tumor size, ER, progesterone receptor, human epidermal growth factor receptor-2, Ki-67, and nodal status. Conclusions: CHO showed good uptake in most breast cancers and merits further investigation as a breast cancer imaging agent. (Clin Cancer Res 2009;15(17):5503–10)

Biological basis of [11C]choline-positron emission tomography in patients with breast cancer: comparison with [18F]fluorothymidine positron emission tomography

ObjectiveThe biological significance of [11C]choline (CHO) uptake in human tumours is unclear and probably linked to choline kinase-&agr; (CHK&agr;) expression and cell proliferation. We directly compared CHO with [18F]fluorothymidine (FLT), an imaging biomarker of proliferation, by positron emission tomography (PET) in patients with breast cancer to investigate whether cell proliferation is an important determinant of CHO uptake. Furthermore, we evaluated CHK&agr; and the Ki67-labelling index (LIKi67) in tumour biopsies. MethodsSequential CHO-PET and FLT-PET within the same imaging session were performed in 21 patients with oestrogen receptor (ER)-positive breast cancer (28 lesions). Average and maximum CHO standardized uptake values (SUV) at 60 min: SUV60,av, and SUV60,max, and the rate constant of net irreversible uptake, Ki, were compared with FLT uptake at 60 min: SUV60,av and SUV60,max. Biopsies were stained for CHK&agr; and LIKi67 in eight cases. ResultsTumours were equally visible on CHO-PET and FLT-PET imaging. Tumour CHO-PET strongly correlated with FLT imaging variables (Pearson’s r=0.83; P<0.0001 for CHO-SUV60,max vs. FLT-SUV60,max). A statistically significant association was found between CHO-PET variables and categorical scores of cytoplasmic CHK&agr; intensity and between FLT-PET and LIKi67 (P<0.05, one-way analysis of variance). ConclusionCholine metabolism and proliferation as assessed by PET were correlated in ER-positive breast cancer, indicating that high CHO uptake is a measure of cellular proliferation in this setting. CHO uptake was also found to be related to cytoplasmic CHK&agr; expression.

Exploring the potential of [11C]choline-PET/CT as a novel imaging biomarker for predicting early treatment response in prostate cancer.

ObjectivesThe aim of the study was to assess the effects of neoadjuvant androgen deprivation (NAD) and radical prostate radiotherapy with concurrent androgen deprivation (RT-CAD) on prostatic [11C]choline kinetics and thus develop methodology for the use of [11C]choline-PET/computed tomography (CT) as an early imaging biomarker. Materials and methodsTen patients with histologically confirmed prostate cancer underwent three sequential dynamic [11C]choline-PET/CT pelvic scans: at baseline, after NAD and 4 months after RT-CAD. [11C]Choline uptake was quantified using the average and maximum standardized uptake values at 60 min (SUV60,ave and SUV60,max), the tumour-to-muscle ratios (TMR60,max) and net irreversible retention of [11C]choline at steady state (Kimod-pat). ResultsThe combination of NAD and RT-CAD significantly decreased tumour [11C]choline uptake (SUV60,ave, SUV60,max, TMR60,max or Kimod-pat) and prostate-specific antigen (PSA) levels (analysis of variance, P<0.001 for all variables). Although the magnitude of reduction in the variables was larger after NAD, there was a smaller additional reduction after RT-CAD. A wide range of reduction in tumour SUV60,ave (38–83.7%) and SUV60,max (22.2–85.3%) was seen with combined NAD and RT-CAD despite patients universally achieving PSA suppression (narrow range of 93.5–99.7%). There was good association between baseline SUV60,max and initial PSA levels (Pearson’s r=0.7, P=0.04). The reduction in tumour SUV60,ave after NAD was associated with PSA reduction (r=0.7, P=0.04). This association occurred despite the larger reduction in PSA (94%) compared with SUV60,ave (58%). ConclusionThis feasibility study shows that [11C]choline-PET/CT detects metabolic changes within tumours following NAD and RT-CAD to the prostate. A differential reduction in [11C]choline uptake despite a global reduction in PSA following NAD and RT-CAD could provide prognostic information and warrants further evaluation as an imaging biomarker in this setting.