Breast tumours responding to chemotherapy exhibit decreased [18F]fluoro-2-deoxy-D-glucose ([18F]FDG) incorporation. Underlying mechanisms of these changes is poorly understood. Here, in MCF-7 cells, responding to chemotherapy drugs commonly utilised in the treatment of breast cancer, [18F]FDG incorporation and several pivotal factors associated with [18F]FDG incorporation investigated. Methods. IC50 and subclinical doxorubicin, docetaxel, and tamoxifen doses determined using MTT assay. [18F]FDG incorporation by cells treated with IC50 drug doses for 48 hours and 72 hours were determined and FDG dephosphorylation estimated by measuring loss of 18F from [18F]FDG-preincubated cells (pulse-chase). Glucose transport determined by measuring initial uptake rate of non-metabolised glucose analogue omethylglucose; hexokinase activity and ATP content measured in cell homogenates; Cell cycle distribution determined using flow cytometry of propidium iodide stained nuclei. Results. [18F]FDG incorporation and ATP content decreased in cells after 72 hours treatment with IC50 doses of tamoxifen, doxorubicin, and docetaxel compared with untreated controls. Decreased glucose transport and/or hexokinase activity accompanied decreased [18F]FDG incorporation by MCF-7 cells treated with tamoxifen or doxorubicin but not docetaxel. Conclusions. Tumour cell [18F]FDG incorporation along with ATP content decreased by treatment with tamoxifen, doxorubicin and docetaxel paralleling clinical observations for solid tumours. Effect of each treatment on glucose transport and hexokinase activity was chemotherapy-drug dependent.
Positron emission tomography (PET) is suggested for early monitoring of treatment response, assuming that effective anticancer treatment induces metabolic changes that precede morphology alterations and changes in growth. The aim of this study was to introduce multicellular tumour spheroids (MTS) to study the effect of anticancer drugs and suggest an appropriate PET tracer for further studies.
MTS of the breast cancer cell line MCF7 were exposed to doxorubicin, paclitaxel, docetaxel, tamoxifen or imatinib for 7 days for growth pattern studies and for 3 or 5 days for PET tracer studies. The effect on growth was computed using the semi-automated size determination method (SASDM). The effect on the uptake of PET tracers [18F]3'-deoxy-3'-fluorothymidine (FLT), [1-11C]acetate (ACE), [11C]choline (CHO), [11C]methionine (MET), and 2-[18F]fluoro-2-deoxyglucose (FDG) was calculated in form of uptake/viable volume of the MTS at the end of the drug exposures, and finally the uptake was related to effects on growth rate.
The drugs paclitaxel, docetaxel and doxorubicin gave severe growth inhibition, which correlated well with inhibition of the FLT uptake. FLT had, compared with ACE, CHO, MET and FDG, higher sensitivity in monitoring the therapy effects.
SASDM provides an effective, user-friendly, time-saving and accurate method to record the growth pattern of the MTS, and also to calculate the effect of the drug on PET tracer uptake. This study demonstrate the use of MTS and SASDM in combination with PET tracers as a promising approach to probe and select PET tracer for treatment monitoring of anticancer drugs and that can hopefully be applied for optimisation in breast cancer treatment.
The cytoreductive effects of anti-transferrin receptor (anti-TfnR) immunotoxins (ITs) and of ricin toxin against tumour micromasses have been evaluated in a multicellular tumour spheroid (MTS) model. More than 600 (656) MTSs obtained with human breast carcinoma (MCF7) or rat glioblastoma (9L) cell lines were treated individually with ITs or toxin and the effects induced by the treatment were measured for each MTS as volume variation vs time by applying the Gompertz growth model. Two dose-dependent patterns of MTS growth were observed in MTSs of both cell lines in response to IT or toxin treatment: (1) complete inhibition of MTS growth ('sterilisation'); and (2) partial/complete inhibition ('heterogeneous response'). Within the range of IT or toxin concentrations resulting in partial inhibition of MTS growth, the sensitivity of treated MTSs was extremely heterogeneous (the cytoreductive effects varying between 0.1 and 4 logs of cells killed for a given IT or toxin concentration). Analysis of the post-treatment regrowth kinetics indicated that treated non-sterilised and control MTSs reached the same final limiting volumes. However, the doubling time estimated for the surviving cells of treated MCF7 and 9L MTSs ranged between 15 and 50 h, indicating that each MTS had individual growing potential. In conclusion, our results indicate that at substerilising IT concentrations individual heterogenicity of MTSs may greatly influence the cytoreductive potential of ITs. An implication of our study is that the efficacy of an IT treatment in eradicating disseminated micrometastases may not be predictable a priori. The MTS model that we describe in this paper may help in dissecting out factors limiting the effect of ITs in three-dimensional tumours.
Considering the width and importance of using Multicellular Tumor Spheroids (MTS) in oncology research, size determination of MTSs by an accurate and fast method is essential. In the present study an effective, fast and semi-automated method, SASDM, was developed to determinate the size of MTSs. The method was applied and tested in MTSs of three different cell-lines. Frozen section autoradiography and Hemotoxylin Eosin (H&E) staining was used for further confirmation.
SASDM was shown to be effective, user-friendly, and time efficient, and to be more precise than the traditional methods and it was applicable for MTSs of different cell-lines. Furthermore, the results of image analysis showed high correspondence to the results of autoradiography and staining.
The combination of assessment of metabolic condition and image analysis in MTSs provides a good model to evaluate the effect of various anti-cancer treatments.
In head and neck cancer (HNC) various treatment strategies have been developed to improve outcome, but selecting patients for these intensified treatments remains difficult. Therefore, identification of novel pretreatment assays to predict outcome is of interest. In HNC there are indications that pretreatment tumour 18F-fluorodeoxyglucose (FDG) uptake may be an independent prognostic factor. The aim of this study was to assess the prognostic value of FDG uptake and CT-based and FDG PET-based primary tumour volume measurements in patients with HNC treated with (chemo)radiotherapy.
A total of 77 patients with stage II–IV HNC who were eligible for definitive (chemo)radiotherapy underwent coregistered pretreatment CT and FDG PET. The gross tumour volume of the primary tumour was determined on the CT (GTVCT) and FDG PET scans. Five PET segmentation methods were applied: interpreting FDG PET visually (PETVIS), applying an isocontour at a standardized uptake value (SUV) of 2.5 (PET2.5), using fixed thresholds of 40% and 50% (PET40%, PET50%) of the maximum intratumoral FDG activity (SUVMAX) and applying an adaptive threshold based on the signal-to-background (PETSBR). Mean FDG uptake for each PET-based volume was recorded (SUVmean). Subsequently, to determine the metabolic volume, the integrated SUV was calculated as the product of PET-based volume and SUVmean. All these variables were analysed as potential predictors of local control (LC), regional recurrence-free survival (RRFS), distant metastasis-free survival (DMFS), disease-free survival (DFS) and overall survival (OS).
In oral cavity/oropharynx tumours PETVIS was the only volume-based method able to predict LC. Both PETVIS and GTVCT were able to predict DMFS, DFS and OS in these subsites. Integrated SUVs were associated with LC, DMFS, DFS and OS, while SUVmean and SUVMAX were not. In hypopharyngeal/laryngeal tumours none of the variables was associated with outcome.
There is no role yet for pretreatment FDG PET as a predictor of (chemo)radiotherapy outcome in HNC in daily routine. However, this potential application needs further exploration, focusing both on FDG PET-based primary tumour volume, integrated SUV and SUVMAX of the primary tumour.
Head and neck cancer; FDG PET scan; Target volume delineation; Radiation treatment outcome; Functional imaging
This study was aimed 1) to investigate the predictive value of FDG PET/CT (fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography) for histopathologic response and 2) to explore the results of FDG PET/CT by molecular phenotypes of breast cancer patients who received neoadjuvant chemotherapy.
Seventy-eight stage II or III breast cancer patients who received neoadjuvant docetaxel/doxorubicin chemotherapy were enrolled in this study. FDG PET/CTs were acquired before chemotherapy and after the first cycle of chemotherapy for evaluating early metabolic response.
The mean pre- and post-chemotherapy standard uptake value (SUV) were 7.5 and 3.9, respectively. The early metabolic response provided by FDG PET/CT after one cycle of neoadjuvant chemotherapy was correlated with the histopathologic response after completion of neoadjuvant chemotherapy (P = 0.002). Sensitivity and negative predictive value were 85.7% and 95.1%, respectively. The estrogen receptor negative phenotype had a higher pre-chemotherapy SUV (8.6 vs. 6.4, P = 0.047) and percent change in SUV (48% vs. 30%, P = 0.038). In triple negative breast cancer (TNBC), the pre-chemotherapy SUV was higher than in non-TNBC (9.8 vs. 6.4, P = 0.008).
The early metabolic response using FDG PET/CT could have a predictive value for the assessment of histopathologic non-response of stage II/III breast cancer treated with neoadjuvant chemotherapy. Our findings suggest that the initial SUV and the decline in SUV differed based on the molecular phenotype.
FDG PET; breast cancer; neoadjuvant chemotherapy; molecular phenotype
The aim of this was to evaluate FDG-PET (2-(fluorine-18)-fluoro-2-deoxy-D-glucose positron emission tomography) for assessment of residual tumour after primary chemotherapy of large and locally advanced breast cancer in comparison with conventional imaging modalities.
In a prospective multicentre trial, 99 patients underwent one or more breast imaging modalities before surgery in addition to clinical examination, namely, FDG-PET (n=89), mammography (n=47), ultrasound (n=46), and magnetic resonance imaging (MRI) (n=46). The presence of residual tumour by conventional imaging, dichotomised as positive or negative, and the level of FDG uptake (standardised uptake values, SUV) were compared with histopathology, which served as the reference standard. Patients with no residual tumour or only small microscopic foci of residual tumour were classified as having minimal residual disease and those with extensive microscopic and macroscopic residual tumour tissue were classified as having gross residual disease.
By applying a threshold SUV of 2.0, the sensitivity of FDG-PET for residual tumour was 32.9% (specificity, 87.5%) and increased to 57.5% (specificity, 62.5%) at a threshold SUV of 1.5. Conventional imaging modalities were more sensitive in identifying residual tumour, but had a low corresponding specificity; sensitivity and specificity were as follows: MRI 97.6 and 40.0%, mammography 92.5 and 57.1%, ultrasound 92.0 and 37.5%, respectively. Breast MRI provided the highest accuracy (91.3%), whereas FDG-PET had the lowest accuracy (42.7%).
FDG-PET does not provide an accurate assessment of residual tumour after primary chemotherapy of breast cancer. Magnetic resonance imaging offers the highest sensitivity, but all imaging modalities have distinct limitations in the assessment of residual tumour tissue when compared with histopathology.
breast cancer; primary systemic therapy; FDG-PET; breast imaging; assessment of treatment response
Increased 2′-deoxy-2′-[18F]fluoro-D-glucose (FDG) uptake is the most commonly used marker for positron emission tomography in oncology. However, a proliferation tracer such as 3′-deoxy-3′-[18F]fluorothymidine (FLT) might be more specific for cancer. 3′-deoxy-3′-[18F]fluorothymidine uptake is dependent on thymidine kinase 1 (TK) activity, but the effects of chemotherapeutic agents are unknown. The aim of this study was to characterise FDG and FLT uptake mechanisms in vitro before and after exposure to chemotherapeutic agents. The effects of 5-fluorouracil (5-FU), doxorubicin and paclitaxel on FDG and FLT uptake were measured in MDA MB231 human breast cancer cells in relation to cell cycle distribution, expression and enzyme activity of TK-1. At IC50 concentrations, 5-FU resulted in accumulation in the G1 phase, but doxorubicin and paclitaxel induced a G2/M accumulation. Compared with untreated cells, 5-FU and doxorubicin increased TK-1 levels by >300. At 72 h, 5-FU decreased FDG uptake by 50% and FLT uptake by 54%, whereas doxorubicin increased FDG and FLT uptake by 71 and 173%, respectively. Paclitaxel increased FDG uptake with >100% after 48 h, whereas FLT uptake hardly changed. In conclusion, various chemotherapeutic agents, commonly used in the treatment of breast cancer, have different effects on the time course of uptake of both FDG and FLT in vitro. This might have implications for interpretation of clinical findings.
[18F]FLT; [18F]FDG; breast cancer cells; thymidine kinase; PET; chemotherapy
This study aimed to test whether [18F]fluoro-D-glucose (FDG) uptake of tumours measured by positron emission tomography (PET) can be used as surrogate marker to define the optimal biological dose (OBD) of mTOR inhibitors in vivo. Everolimus at 0.05, 0.5, 5 and 15 mg kg−1 per day was administered to gastric cancer xenograft-bearing mice for 23 days and FDG uptake of tumours was measured using PET from day 1 to day 8. To provide standard comparators for FDG uptake, tumour volume, S6 protein phosphorylation, Ki-67 staining and everolimus blood levels were evaluated. Everolimus blood levels increased in a dose-dependent manner but antitumour activity of everolimus reached a plateau at doses ⩾5 mg kg−1 per day (tumour volume treated vs control (T/C): 51% for 5 mg kg−1 per day and 57% for 15 mg kg−1 per day). Correspondingly, doses ⩾5 mg kg−1 per day led to a significant reduction in FDG uptake of tumours. Dose escalation above 5 mg kg−1 per day did not reduce FDG uptake any further (FDG uptake T/C: 49% for 5 mg kg−1 per day and 52% for 15 mg kg−1 per day). Differences in S6 protein phosphorylation and Ki-67 index reflected tumour volume and changes in FDG uptake but did not reach statistical significance. In conclusion, FDG uptake might serve as a surrogate marker for dose finding studies for mTOR inhibitors in (pre)clinical trials.
PK/PD; rapamycin; dose finding
The aims of this study were to investigate whether drug sequence (docetaxel followed by anthracyclines or the drugs in reverse order) affects changes in the maximal standard uptake volume (SUVmax) on [18F]flourodeoxyglucose positron emission tomography (FDG-PET) during neoadjuvant chemotherapy in women with locally advanced breast cancer.
Women were randomly assigned to receive either drug sequence, and FDG-PET scans were taken at baseline, after four cycles and after eight cycles of chemotherapy. Tumour response to chemotherapy was evaluated based on histology from a surgical specimen collected upon completion of chemotherapy.
Sixty women were enrolled into the study. Thirty-one received docetaxel followed by anthracyclines (Arm A) and 29 received drugs in the reverse order (Arm B). Most women (83%) had ductal carcinoma and 10 women (17%) had lobular or lobular/ductal carcinoma. All but one tumour were downstaged during therapy. Overall, there was no significant difference in response between the two drug regimens. However, women in Arm B who achieved complete pathological response had mean FDG-PET SUVmax reduction of 87.7% after four cycles, in contrast to those who had no or minor pathological response. These women recorded mean SUVmax reductions of only 27% (P < 0.01). Women in Arm A showed no significant difference in SUVmax response according to pathological response. Sensitivity, specificity, accuracy and positive and negative predictive values were highest in women in Arm B.
Our results show that SUVmax uptake by breast tumours during chemotherapy can be dependent on the drugs used. Care must be taken when interpreting FDG-PET in settings where patients receive varied drug protocols.
3′-deoxy-3′-[18F]fluoro-L-thymidine (FLT) and 2′-deoxy-2′-[18F]fluoro-D-glucose (FDG) are used to visualize proliferative and metabolic activity of tumors. In this study we aimed at evaluating the prognostic value of FLT and FDG uptake measured by positron emission tomography (PET) in patients with metastatic non-small cell lung cancer (NSCLC) prior to systemic therapy with erlotinib. FLT and FDG maximum standardized uptake (SUVmax) values per patient were analyzed in 40 chemotherapy naive patients with advanced NSCLC (stage IV) before treatment with erlotinib. Prior therapy median SUVmax was 6.6 for FDG and 3.0 for FLT, respectively. In univariate analysis, patients with an FDG SUVmax <6.6 had a significantly better overall survival (16.3 months [95% confidence interval [CI] 7.1–25.4 months]) compared to patients with an FDG SUVmax ≥6.6 (3.1 months [95% CI 0.6–5.5 months]) (p<0.001, log rank). Similarly, low FLT uptake (SUVmax <3.0) was associated with significantly longer survival (10.3 months (0–23.3 months, 95% CI) compared to high FLT uptake (3.4 months (0–8.1 months, 95% CI) (p = 0.027). The independent prognostic value of baseline FDG uptake was demonstrated in multivariate analysis (p = 0.05, Cox regression). These data suggest that baseline SUVmax values for both FDG and FLT PET might be further developed as markers for prognostic stratification of patients in advanced NSCLC treated with tyrosine kinase inhibitors (TKI) directed against the epidermal growth factor receptor (EGFR).
Clinicaltrials.gov, Identifier: NCT00568841
18F-fluorodeoxyglucose positron emission tomography (FDG-PET) has been used extensively to explore whether FDG Uptake can be used to provide prognostic information for esophageal cancer patients. The aim of the present review is to evaluate the literature available to date concerning the potential prognostic value of FDG uptake in esophageal cancer patients, in terms of absolute pretreatment values and of decrease in FDG uptake during or after neoadjuvant therapy.
A computer-aided search of the English language literature concerning esophageal cancer and standardized uptake values was performed. This search focused on clinical studies evaluating the prognostic value of FDG uptake as an absolute value or the decrease in FDG uptake and using overall mortality and/or disease-related mortality as an end point.
In total, 31 studies met the predefined criteria. Two main groups were identified based on the tested prognostic parameter: (1) FDG uptake and (2) decrease in FDG uptake. Most studies showed that pretreatment FDG uptake and postneoadjuvant treatment FDG uptake, as absolute values, are predictors for survival in univariate analysis. Moreover, early decrease in FDG uptake during neoadjuvant therapy is predictive for response and survival in most studies described. However, late decrease in FDG uptake after completion of neoadjuvant therapy was predictive for pathological response and survival in only 2 of 6 studies.
Measuring decrease in FDG uptake early during neoadjuvant therapy is most appealing, moreover because the observed range of values expressed as relative decrease to discriminate responding from nonresponding patients is very small. At present inter-institutional comparison of results is difficult because several different normalization factors for FDG uptake are in use. Therefore, more research focusing on standardization of protocols and inter-institutional differences should be performed, before a PET-guided algorithm can be universally advocated.
18F-FDG PET plays an increasing role in diagnosis and management planning of head and neck cancer. Hybrid PET/CT has promoted the field of molecular imaging in head and neck cancer. This modality is particular relevant in the head and neck region, given the complex anatomy and variable physiologic FDG uptake patterns. The vast majority of 18F-FDG PET and PET/CT applications in head and neck cancer related to head and neck squamous cell carcinoma. Clinical applications of 18F-FDG PET and PET/CT in head and neck cancer include diagnosis of distant metastases, identification of synchronous 2nd primaries, detection of carcinoma of unknown primary and detection of residual or recurrent disease. Emerging applications are precise delineation of the tumor volume for radiation treatment planning, monitoring treatment, and providing prognostic information. The clinical role of 18F-FDG PET/CT in N0 disease is limited which is in line with findings of other imaging modalities. MRI is usually used for T staging with an intense discussion concerning the preferable imaging modality for regional lymph node staging as PET/CT, MRI, and multi-slice spiral CT are all improving rapidly. Is this review, we summarize recent literature on 18F-FDG PET and PET/CT imaging of head and neck cancer.
In locally advanced cervical cancer, 18F-fluorodeoxyglucose (FDG) positron emission tomography – computed tomography (PET/CT) has become important in the initial evaluation of disease extent. It is superior to other imaging modalities for lymph node status and distant metastasis. PET-defined cervical tumor volume predicts progression-free and overall survival. Higher FDG uptake in both primary and regional lymph nodes is strongly predictive of worse outcome. FDG-PET is useful for assessing treatment response 3 months after completing concurrent chemo-radiotherapy (CRT) and predicting long-term survival, and in suspected disease recurrence. In the era of image-guided adaptive radiotherapy, accurately defining disease areas is critical to avoid irradiating normal tissue. Based on additional information provided by FDG-PET, radiation treatment volumes can be modified and higher doses to FDG-positive lymph nodes safely delivered. FDG-PET/CT has been used for image-guided brachytherapy of FDG-avid tumor volume, while respecting low doses to bladder and rectum. Despite survival improvements due to CRT in cervical cancer, disease recurrences continue to be a major problem. Biological rationale exists for combining novel non-cytotoxic agents with CRT, and drugs targeting specific molecular pathways are under clinical development. The integration of these targeted therapies in clinical trials, and the need for accurate predictors of radio-curability is essential. New molecular imaging tracers may help identifying more aggressive tumors. 64Cu-labeled diacetyl-di(N(4)-methylthiosemicarbazone) is taken up by hypoxic tissues, which may be valuable for prognostication and radiation treatment planning. PET/CT imaging with novel radiopharmaceuticals could further impact cervical cancer treatment as surrogate markers of drug activity at the tumor microenvironment level. The present article reviews the current and emerging role of PET/CT in the management of cervical cancer.
cervical cancer; positron emission tomography; Fluorodeoxyglucose F18; radiation therapy; Planning Treatment Volumes
The aim of this study was to assess the accuracy of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT to visualize lymph node metastases before the start of neoadjuvant chemotherapy and to determine how often the visualization is sufficiently prominent to allow monitoring of the axillary response.
Thirty-eight patients with invasive breast cancer of >3 cm and/or lymph node metastasis underwent FDG PET/CT before neoadjuvant chemotherapy. The results of the FDG PET/CT were compared with those from ultrasonography with fine-needle aspiration (FNA) cytology or sentinel node biopsy. Patients suitable for response monitoring of the axilla were defined as having either a maximum standardized uptake value (SUVmax) ≥ 2.5 or a tumour to background ratio ≥5 in the most intense lymph node.
The sensitivity and specificity of FDG PET/CT in detecting axillary involvement were 97 and 100%, respectively. No difference existed between the SUVmax of the primary tumour and that from the related most intense lymph node metastasis. Moreover, the mean tumour to background ratio was 90% higher in the lymph nodes compared to the primary tumour (p = 0.006). Ninety-three per cent of the patients had sufficient uptake in the lymph nodes to qualify for subsequent response monitoring of the axilla. A considerable distinction in metabolic activity was observed between the different subtypes of breast cancer. The mean SUVmax in lymph node metastases of oestrogen receptor (ER)-positive, triple-negative and human epidermal growth factor receptor 2 (HER2)-positive tumours was 6.6, 11.6 and 6.6, respectively.
The high accuracy in visualizing lymph node metastases and the sufficiently high SUVmax and tumour to background ratio at baseline suggest that it is feasible to monitor the axillary response with FDG PET/CT, especially in triple-negative tumours.
Breast cancer; Axillary lymph node metastasis; FDG-PET/CT; Neoadjuvant chemotherapy
We compared 68Ga-DOTA-F(ab′)2-herceptin (DOTA is 1,4,7,10-tetraazacyclododecane-N,N′,N″,N‴-tetraacetic acid [HER2 PET]) and 18F-FDG PET for imaging of tumor response to the heat shock protein 90 (Hsp90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17AAG).
Mice bearing BT474 breast tumor xenografts were scanned with 18F-FDG PET and HER2 PET before and after 17AAG treatment and then biweekly for up to 3 wk.
Within 24 h after treatment, a significant decrease in HER2 was measured by HER2 PET, whereas 18F-FDG PET uptake, a measure of glycolysis, was unchanged. Marked growth inhibition occurred in treated tumors but became evident only by 11 d after treatment. Thus, Her2 downregulation occurs independently of changes in glycolysis after 17AAG therapy, and Her2 reduction more accurately predicts subsequent tumor growth inhibition.
HER2 PET is an earlier predictor of tumor response to 17AAG therapy than 18F-FDG PET.
Overexpression of the apoptosis-related protein clusterin is associated with breast cancer development and tumor progression. We describe the use of clusterin-specific antisense oligonucleotides and antibodies to sensitize breast carcinoma cells to anticancer drugs routinely used in breast cancer therapy.
MCF-7 and MDA-MB-231 cells were treated with the oligonucleotide or antibody, chemotherapeutic agents (doxorubicin or paclitaxel), tamoxifen, or with combinations of these.
Treatments that include antisense clusterin oligonucleotide or antibody to clusterin have been shown to reduce the number of viable cells more effectively than treatment with the drugs alone. We also demonstrate that dexamethasone pretreatment of breast cancer cell lines inhibits chemotherapy-induced cytotoxicity and is associated with the transcriptional induction of clusterin. However, anticlusterin treatment increases chemotherapy-induced cytotoxicity, even in the presence of glucocorticoids, suggesting a possible role for these proteins in glucocorticoid-mediated survival.
These data suggest that combined treatment with antibodies to clusterin or antisense clusterin oligodeoxynucleotides and paclitaxel, doxorubicin, or tamoxifen could be a novel and attractive strategy to inhibit the progression of breast carcinoma by regulation of the clusterin function. Moreover, glucocorticoid activation in breast cancer cells regulates survival signaling by the direct transactivation of genes like clusterin which encode proteins that decrease susceptibility to apoptosis. Given the widespread clinical administration of dexamethasone before chemotherapy, understanding glucocorticoid-induced survival mechanisms is essential for achieving optimal therapeutic responses.
To evaluate the clinical significance of incidental focal prostate fluorodeoxyglucose (FDG) uptake, we reviewed 18-F-FDG positron emission tomography (PET)/CT scans from 2003 to 2007 and selected cases with focal FDG uptake in prostate. Cases of known prostate cancer were excluded. The maximum standardised uptake value (SUVmax), site (central or peripheral) and pattern (discrete or ill-defined) of FDG uptake, calcification (present or absent) and prostate volume (<30 or ≥30 cc) were recorded. The PET/CT findings were correlated with serum prostate-specific antigen (PSA) levels, imaging studies, clinical follow-up and biopsy. Of a total of 5119 cases, 63 (1.2%) demonstrated focal FDG uptake in prostate. Eight cases were lost to follow-up. Among the 55 cases with follow-up, malignancy was confirmed by biopsy in 3 (5.4%). The three malignant cases had SUVmax values of 3.3, 3.6 and 2.3, and all were noted in the peripheral portion of prostate; two of these cases had a discrete FDG uptake pattern, none had calcification corresponding to the FDG uptake area and one had a prostatic volume greater than 30 cc. The mean SUVmax of 52 benign cases was 3.2 ± 1.7 and focal FDG uptake was noted in the peripheral portion in 34 (65%), 20 (38%) cases showed a discrete FDG uptake pattern, 35 (67%) were accompanied by calcification and 32 (62%) had a prostatic volume greater than 30 cc. The majority of cases demonstrating focal FDG uptake in prostate were benign and no PET/CT finding could reliably differentiate benign from malignant lesions; however, when discrete focal FDG uptake without coincidental calcification is seen, particularly in the peripheral zone of the prostate, further clinical evaluation is recommended.
In breast cancer endocrine therapy, post-therapy Ki-67 assay of biopsy material predicts recurrence-free survival but is invasive and prone to sampling error. [18F]Fluorodeoxyglucose (FDG) positron emission tomography (PET) has shown an early agonist or ‘flare’ response to tamoxifen and estradiol, but has not been tested in response to estrogen-lowering aromatase inhibitors (AIs). We hypothesized that decreased agonistic response to AIs would result in early FDG uptake decline. We also measured early response to trastuzumab (T), another targeted agent for breast cancer with differing mechanisms of action. Our study was designed to test for an early decline in FDG uptake in response to AI or T and to examine association with Ki-67 measures of early response.
Patients with any stage of newly diagnosed or recurrent breast cancer were eligible and enrolled prior to initiation (or resumption) of AI or T therapy. FDG PET and tissue biopsy were planned before and after 2 weeks of AI or T therapy, with pretreatment archival tissue permitted. Cutoffs of ≥20% decline in standardized uptake value (SUV) as FDG PET early response and ≤5% post-treatment expression as Ki-67 early response were defined prior to analysis.
Forty-two patients enrolled, and 40 (28 AI, 12 T) completed serial FDG-PET imaging. Twenty-two patients (17 AI, 5 T) had newly diagnosed disease, and 23 (14 AI, 9 T) had metastatic disease (5 newly diagnosed). Post-treatment biopsy was performed in 25 patients (63%) and was either refused or not feasible in 15. Post-treatment biopsy yielded tumor in only 17/25 cases (14 AI, 3 T). Eleven of 14 AI patients with post-therapy tissue showed FDG PET early response, and there was 100% concordance of PET and post-therapy Ki-67 early response. For the T group, 6/12 showed an FDG PET early response, including 2/3 patients with post-therapy biopsy, all with Ki-67 >5%.
Substantial changes in FDG PET SUV occurred over 2 weeks of AI therapy and were associated with low post-therapy proliferation. SUV decline was seen in response to T, but few tissue samples were available to test association with Ki-67. Our results support further investigation of FDG PET as a biomarker for early response to AI therapy.
FDG PET; Ki-67; Breast cancer; Aromatase inhibitor; Trastuzumab; Pharmacodynamic response; Early response
Heterogeneity of estrogen receptor (ER) expression may be an important predictor of breast cancer therapeutic response. 18F-fluoroestradiol PET produces in vivo quantitative measurements of regional estrogen binding in breast cancer tumors. We describe within-patient (site-to-site) and between-patient heterogeneity of lesions in patients scheduled to receive endocrine therapy.
In 91 patients with a prior ER-positive biopsy, 505 lesions were analyzed for both 18F-fluoroestradiol and 18F-FDG uptake and the 18F-fluoroestradiol/18F-FDG uptake ratio. Standardized uptake values (SUVs) were recorded for up to 16 lesions per patient, of 1.5 cm or more and visible on 18F-FDG PET or conventional staging. Linear mixed-effects regression models examined associations between PET parameters and patient or lesion characteristics and estimated variance components. A reader study of SUV measurements for 9 scans further examined sources of within-patient variability.
Average 18F-fluoroestradiol uptake and 18F-fluoroestradiol/18F-FDG ratio varied greatly across these patients, despite a history of ER-positive disease: about 37% had low or absent 18F-fluoroestradiol uptake even with marked 18F-FDG uptake. 18F-fluoroestradiol SUV and 18F-fluoroestradiol/18F-FDG ratio measurements within patients with multiple lesions were clustered around the patient’s average value in most cases. Summarizing these findings, the intraclass correlation coefficient (proportion of total variation that is between-patient) was 0.60 (95% confidence interval, 0.50–0.69) for 18F-fluoroestradiol SUV and 0.65 (95% confidence interval, 0.56–0.73) for the 18F-fluoroestradiol/18F-FDG ratio. Some within-patient variation in PET measures (22%–44%) was attributable to interobserver variability as measured by the reader study. A subset of patients had mixed uptake, with widely disparate 18F-fluoroestradiol SUV or 18F-fluoroestradiol/18F-FDG ratio for lesions in the same scan.
18F-fluoroestradiol uptake and the 18F-fluoroestradiol/18F-FDG ratio varied greatly between patients but were usually consistent across lesions in the same scan. The average 18F-fluoroestradiol SUV and 18F-fluoroestradiol/18F-FDG ratio for a limited sample of lesions appear to provide a reasonable summary of synchronous ER expression for most patients. However, imaging the entire disease burden remains important to identify the subset of patients with mixed uptake, who may be at a critical point in their disease evolution.
estrogen receptor imaging; 18F-FES PET; heterogeneity; breast cancer
Purpose. The aim of this study was to prospectively evaluate whether FDG-PET allows an accurate assessment of histopathologic response to neoadjuvant treatment in adult patients with primary bone sarcomas. Methods. Twelve consecutive patients with resectable, primary high grade bone sarcomas were enrolled prospectively. FDG-PET/CT imaging was performed prior to the initiation and after completion of neoadjuvant treatment. Imaging findings were correlated with histopathologic response. Results. Histopathologic responders showed significantly more pronounced decreases in tumor FDG-SUVmax from baseline to late follow up than non-responders (64 ± 19% versus 29 ± 30 %, resp.; P = .03). Using a 60% decrease in tumor FDG-uptake as a threshold for metabolic response correctly classified 3 of 4 histopathologic responders and 7 of 8 histopathologic non-responders as metabolic responders and non-responders, respectively (sensitivity, 75%; specificity, 88%). Conclusion. These results suggest that changes in FDG-SUVmax at the end of neoadjuvant treatment can identify histopathologic responders and non-responders in adult primary bone sarcoma patients.
Since the development and evaluation of novel anti-cancer therapies require molecular insight in the disease state, both FDG-PET and BLI imaging were evaluated in a Burkitt B-cell lymphoma xenograft model treated with cyclophosphamide or temsirolimus. Daudi xenograft mice were treated with either cyclophosphamide or temsirolimus and imaged with BLI and FDG-PET on d0 (before treatment), d2, d4, d7, d9 and d14 following the start of therapy. Besides tumor volume changes, therapy response was assessed with immunohistochemical analysis (apoptosis). BLI revealed a flare following both therapeutics that was significantly higher when compared to control tumors. FDG-PET decreased immediatelly, long before the tumor reduced in size. Late after therapy, BLI signal intensities decreased significantly compared to baseline subsequent to tumor size reduction while apoptosis was immediately induced following both treatment regimen. Unlike FDG, BLI was not able to reflect reduced levels of viable cells and was not able to predict tumor size response and apoptosis response.
Bioluminescence imaging; therapy response; FDG-PET
To determine whether treatment response to the Aurora B kinase inhibitor, AZD1152, could be monitored early in the course of therapy by non-invasive [18F]FDG and/or [18F]FLT PET imaging.
AZD1152-treated and control HCT116 and SW620 xenograft-bearing animals were monitored for tumor size and by [18F]FDG and [18F]FLT PET imaging. Additional studies assessed the endogenous and exogenous contributions thymidine synthesis in the two cell lines.
Both xenografts showed a significant volume-reduction to AZD1152. In contrast, [18F]FDG uptake did not demonstrate a treatment response. [18F]FLT uptake decreased to less than 20% of control values in AZD1152-treated HCT116 xenografts, whereas [18F]FLT uptake was near background levels in both treated and untreated SW620 xenografts. The EC50 for AZD1152-HQPA was ~10 nM in both SW620 and HCT116 cells; in contrast, SW620 cells were much more sensitive to Methotrexate (MTX) and 5-Fluorouracil (5FU) than HCT116 cells. Immunoblot analysis demonstrated marginally lower expression of thymidine kinase in SW620 compared to HCT116 cells. The above results suggest that SW620 xenografts have a higher dependency on the de novo pathway of thymidine utilization than HCT116 xenografts.
AZD1152 treatment showed anti-tumor efficacy in both colon cancer xenografts. Although [18F]FDG PET was inadequate in monitoring treatment-response, [18F]FLT PET was very effective in monitoring response in HCT116 xenografts, but not in SW620 xenografts. These observations suggest that de novo thymidine synthesis could be a limitation and confounding factor for [18F]FLT PET imaging and quantification of tumor proliferation, and this may apply to some clinical studies as well.
Colon cancer; HCT116; SW620; Positron-Emission Tomography; AZD1152; Methotrexate - MTX; 5-Fluorouracil – 5-FU; Fluorodeoxythymidine – FLT; Fluorodeoxyglucose – FDG
Tumor glycolytic phenotyping can be accomplished with 18F-FDG PET. Tumor 18F-FDG uptake correlates with tumor grade in several cancers. However, the role of 18F-FDG PET for the grading of soft-tissue sarcomas (STSs) warrants further research.
One hundred two patients (48 men and 54 women; mean age ± SD, 50 ± 17 y) with 12 STS subtypes underwent 18F-FDG PET/CT before treatment. Tumor 18F-FDG uptake, expressed as maximum standardized uptake value (SUVmax), was compared among subtypes and correlated with histopathologic grade. Two frequently used sarcoma grading systems—the 3-tier system of the French Federation of Cancer Centers Sarcoma Group (Fédération Nationale des Centres de Lutte Contre le Cancer [FNCLCC]) and a 2-tier system (low grade vs. high grade)—were used.
More than 90% of STSs (93/102) exhibited a strong glycolytic phenotype (SUV-max, 2.7–52.2 g/mL). Tumor SUVmax differed significantly among tumor grades (P < 0.001 for the 3- and 2-tier grading systems). The FNCLCC and 2-tier grading systems predicted tumor grade with similar accuracy (area under the curve, 0.83 and 0.85, respectively; P = 0.35). SUVmax differed significantly among histologic subtypes (P = 0.03) in the entire population but not when high-grade STSs were analyzed separately (P = 0.31).
The tumor glycolytic phenotype correlated significantly with histologic grade as determined by both the FNCLCC and 2-tier (high vs. low) grading systems. 18F-FDG PET cannot be used to reliably distinguish among grade 2 and 3 STSs (by FNCLCC) and the various subtypes.
sarcoma; PET; 18F-FDG; glycolytic phenotype
Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG-PET) has increasingly been used to evaluate the efficacy of anticancer agents. We investigated the role of FDG-PET as a predictive marker for response to mammalian target of rapamycin (mTOR) inhibition in advanced solid tumor patients and in murine xenograft models.
Patients and Methods
Thirty-four rapamycin-treated patients with assessable baseline and treatment FDG-PET and computed tomography scans were analyzed from two clinical trials. Clinical response was evaluated according to Response Evaluation Criteria in Solid Tumors, and FDG-PET response was evaluated by quantitative changes and European Organisation for Research and Treatment of Cancer (EORTC) criteria. Six murine xenograft tumor models were treated with temsirolimus. Small animal FDG-PET scans were performed at baseline and during treatment. The tumors were analyzed for the expression of pAkt and GLUT1.
Fifty percent of patients with increased FDG-PET uptake and 46% with decreased uptake had progressive disease (PD). No objective response was observed. By EORTC criteria, the sensitivity of progressive metabolic disease on FDG-PET in predicting PD was 19%. Preclinical studies demonstrated similar findings, and FDG-PET response correlated with pAkt activation and plasma membrane GLUT1 expression.
FDG-PET is not predictive of proliferative response to mTOR inhibitor therapy in both clinical and preclinical studies. Our findings suggest that mTOR inhibitors suppress the formation of mTORC2 complex, resulting in the inhibition of Akt and glycolysis independent of proliferation in a subset of tumors. Changes in FDG-PET may be a pharmacodynamic marker for Akt activation during mTOR inhibitor therapy. FDG-PET may be used to identify patients with persistent Akt activation following mTOR inhibitor therapy.