Jingyi Cheng

18F-Fluoromisonidazole PET/CT: A Potential Tool for Predicting Primary Endocrine Therapy Resistance in Breast Cancer

Although endocrine therapy is an effective method to treat estrogen receptor (ER)–positive breast cancer, approximately 30%–40% of all hormone receptor–positive tumors display de novo resistance. The aim of our current study was to analyze whether 18F-labeled fluoromisonidazole (1-(2-nitro-1-imidazolyl)-2-hydroxy-3-fluoropropane [18F-FMISO]) PET/CT could predict primary resistance to hormonal therapy in ER-positive breast cancer. Methods: Postmenopausal women who had ER-α–positive breast cancer, stages II–IV, and had never received prior endocrine therapy were prospectively enrolled in this study. Patients underwent both 18F-FDG and 18F-FMISO PET/CT scans before and after treatment. The hottest 18F-FDG standardized uptake value (SUV) in the tumor foci, the SUVs at 2 and 4 h, and the TBR2 h and TBR4 h for the target lesions were calculated (TBR2 h = SUV2 hT/SUV2 hB and TBR4 h = SUV4 hT/SUV4 hB [TBR is the tumor-to-background ratio]). Clinical outcomes of primary endocrine therapy with letrozole were evaluated according to the criteria of the World Health Organization after at least 3 mo of treatment. Immunohistochemistry for markers of proliferation (Ki67) and hypoxia-induced factor 1α was performed on a subset of tumors that had undergone biopsy or surgery. Pearson and Spearman analysis was used to determine the correlation between the parameters of 18F-FDG and 18F-FMISO uptake and clinical or immunohistochemistry outcomes with a 0.01 threshold for statistical significance. Results: A total of 45 lesions (13 primary, 32 metastatic) from 20 patients met the inclusion criteria in this study. Baseline 18F-FDG and 18F-FMISO PET/CT scans were obtained for 33 lesions from 16 patients. The correlation between baseline 18F-FDG uptake and clinical outcome was weak and did not reach statistical significance (r = 0.37, P = 0.031). However, there was a significantly positive correlation between baseline 18F-FMISO uptake (SUV2 hT, TBR2 h, SUV4 hT, and TBR4 h) and clinical outcomes after ≥3 mo of primary endocrine therapy with letrozole (r = 0.77, 0.76, 0.71, and 0.78, respectively; P < 0.0001). The application of a TBR4 h cutoff of ≥1.2 allowed the prediction of 88% of the cases of progressive disease (15/17). Despite poor correlation between 18F-FMISO uptake and hypoxia-induced factor 1α expression, a marginal positive correlation between TBR4 h and Ki67 expression was measured (r = 0.51, P = 0.011) in a subset of malignant lesions acquired by biopsy or surgery. Conclusion: 18F-FMISO PET/CT can be used to predict primary endocrine resistance in ER-positive breast cancer.

Prevalence and risk of cancer of incidental uptake in prostate identified by fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography

OBJECTIVE The objective was to investigate the prevalence of incidental fluorine-18 fluorodeoxyglucose (FDG) uptake in positron emission tomography/computed tomography. METHODS A total of 11,239 male nonprostate disease patients were included retrospectively. RESULTS The prevalence of incidental prostate FDG uptake was approximately 1.8%. Among 198 incidental lesions, 100 patients had further examinations; 20 lesions were confirmed to be malignant, while 80 lesions were benign. After logistic regression analysis, age, site, and the maximum standard uptake value were the potent predictors for differentiation of malignant prostate lesions. CONCLUSION When focal FDG uptake in the peripheral zone of prostate is detected, especially in elderly men, further clinical evaluation is recommended.

Can Positron Emission Tomography/Computed Tomography with the Dual Tracers Fluorine-18 Fluoroestradiol and Fluorodeoxyglucose Predict Neoadjuvant Chemotherapy Response of Breast Cancer? ----A Pilot Study

Objective To assess the clinical value of dual tracers Positron emission tomography/computed tomography (PET/CT) 18F-fluoroestradiol (18F-FES) and 18F-fluorodeoxyglucose (18F-FDG) in predicting neoadjuvant chemotherapy response (NAC) of breast cancer. Methods Eighteen consecutive patients with newly diagnosed, non-inflammatory, stage II and III breast cancer undergoing NAC were included. Before chemotherapy, they underwent both 18F-FES and 18F-FDG PET/CT scans. Surgery was performed after three to six cycles of chemotherapy. Tumor response was graded and divided into two groups: the responders and non-responders. We used the maximum standardized uptake value (SUVmax) to qualify each primary lesion. Results Pathologic analysis revealed 10 patients were responders while the other 8 patients were non-responders. There was no statistical difference of SUVmax-FDG and tumor size between these two groups (P>0.05). On the contrary, SUVmax-FES was lower in responders (1.75±0.66 versus 4.42±1.14; U=5, P=0.002); and SUVmax-FES/FDG also showed great value in predicting outcome (0.16±0.06 versus 0.54±0.22; U=5, P=0.002). Conclusions Our study showed 18F-FES PET/CT might be feasible to predict response of NAC. However, whether the use of dual tracers 18F-FES and 18F-FDG has complementary value should be further studied.

18F-fluorodeoxyglucose (FDG) PET/CT after two cycles of neoadjuvant therapy may predict response in HER2-negative, but not in HER2-positive breast cancer.

The aim of this prospective study was to assess the ability of 18F-fluorodeoxyglucose (18FDG) positron emission tomography/computed tomography (PET/CT) scanning to predict pathological complete response (pCR) in breast cancer, and to investigate whether timing of the scan and trastuzumab treatment influence the accuracy of pCR prediction in human epidermal growth factor receptor 2 (HER2) positive breast cancer patients. We treated 81 locally advanced breast cancer patients with four cycles of neoadjuvant chemotherapy (NAC). HER2-negative breast cancer patients received NAC alone, while HER2-positive breast cancer patients received NAC plus trastuzumab. 18FDG PET/CT scans were scheduled at baseline and after the second cycle of NAC. Axillary lymph node (ALN) dissection was performed after the last cycle of neoadjuvant therapy. Relative changes in standardized uptake values (SUV) between the two PET/CT scans (ΔSUV) in primary tumors and ALN metastases were calculated. There were 75 patients with 150 PET/CT scans in the final analysis, including 41 HER2-negative and 34 HER2-positive cases. In the HER2-negative group, the ΔSUV predicted overall and ALN pCR; the receiver operating characteristics-areas under curve (ROC-AUC) were 0.87 and 0.80 (P = 0.0014 and 0.031, respectively) and the negative predictive values were 94% and 89% respectively. However, in the HER2-positive group, ΔSUV could predict neither overall nor ALN pCR; the ROC-AUCs were only 0.56 and 0.53, with P = 0.53 and 0.84, respectively. Hence, the ΔSUV after two cycles of neoadjuvant therapy could predict pCR in HER2-negative patients treated with NAC alone, but not in HER2-positive patients treated with NAC plus trastuzumab.

Clinical value of whole body fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography in the detection of metastatic bladder cancer

Objectives:  To investigate the value of whole‐body fluorine‐18 2‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography/computed tomography for the detection of metastatic bladder cancer.

99mTc-labeling and evaluation of a HYNIC modified small-molecular inhibitor of prostate-specific membrane antigen

INTRODUCTION Prostate-specific membrane antigen (PSMA) is a well-established target in the development of radiopharmaceuticals for the diagnosis and therapy of prostate cancer (PCa). In this study, we evaluated a novel 99mTc-labeled small molecular inhibitor of PSMA. METHODS This new small-molecular inhibitor of PSMA, 6-hydrazinonicotinate-Aminocaproic acid-Lysine-Urea-Glutamate (HYNIC-ALUG) was radiolabeled by 99mTc and was evaluated both in vitro and in vivo using PCa models (PC-3 and LNCaP). Radiation dosimetry was assessed in mice. RESULTS 99mTc-HYNIC-ALUG showed excellent stability in different media. A cell assay preliminarily displayed its specificity for PSMA. The inhibitor showed good pharmacokinetics making it suitable for in vivo imaging. PC-3-derived tumors showed no obvious radioactive uptake; however, the LNCaP-derived tumors showed very high radioactive uptake which was significantly decreased by the selective PSMA inhibitor 2-PMPA. Biodistribution in LNCaP xenografts showed an optimum tumor-to-blood ratio of 24.23±3.54 at 2h. Tumor uptake was also decreased in the inhibition experiment with 2-PMPA (19.45±2.14%ID/g versus 1.42±0.15%ID/g at 2h). The effective dose of the 99mTc-HYNIC-ALUG was 8.4E-04mSv/MBq. CONCLUSIONS A new 99mTc-labeled PSMA inhibitor with specific accumulation in PSMA-positive tumors and low background in other organs was synthesized. The radiopharmaceutical also showed very low radiation dosimetry. This agent may significantly improve the diagnosis, staging, and subsequent monitoring of therapeutic effects in PCa patients.

Indispensability of Chemotherapy in Estrogen Receptor-Negative Early Breast Cancer in Elderly Women with Diabetes Mellitus

To evaluate whether chemotherapy is indispensable in elderly patients with early estrogen receptor (ER)-negative breast cancer and diabetes mellitus (DM), the data on 112 patients, ≥70 years of age, with early, operable ER-negative breast cancer who were treated at the Cancer Hospital of Fudan University, Shanghai, China, between 2000 and 2010, were analyzed. The overall survival (OS), disease-free survival (DFS), and breast cancer-specific survival (BCS) were compared. Survival analysis was performed using the Kaplan-Meier method. The Cox proportional hazards model was used to evaluate the prognostic value of DM and chemotherapy for OS, DFS, and BCS. The univariate Cox regression analysis revealed that DM at diagnosis, the number of positive lymph nodes, and radiotherapy were associated with OS, the number of positive lymph nodes, human epidermal growth factor 2 (HER2/neu) status, and radiotherapy were associated with DFS, and the number of positive lymph nodes, tumor size, HER2/neu status, chemotherapy, and radiotherapy were associated with BCS. The subsequent multivariate analysis identified DM at diagnosis (hazard ratio [HR]=3.797; 95% confidence interval [CI], 1.515-9.520; P=0.004) as an independent prognostic factor for OS (with the addition of chemotherapy regimen). Chemotherapy was not an independent prognostic factor for either OS (HR=1.275; 95% CI, 0.614-2.646; P=0.515) or DFS (HR=0.849; 95% CI, 0.445-1.619; P=0.619) when other possible factors that may affect the results were adjusted. In conclusion, chemotherapy was not found to be indispensable for elderly (≥70 years of age) female patients with early ER-negative breast cancer with DM because, particularly in such patients, the treatment of DM may be more important compared with chemotherapy.

[99mTc]duramycin, a potential molecular probe for early prediction of tumor response after chemotherapy

OBJECTIVE Apoptosis plays a crucial role in many biological processes, especially in cancer. However, real-time monitoring of apoptosis is challenging. [99mTc]duramycin can selectively target an apoptosis biomarker: phosphatidylethanolamine (PE), which is normally located on the intracellular cell-membrane surface but redistributes onto the outer cell-membrane upon apoptosis. Therefore, 99mTc-duramycin is a potential probe for non-invasive detection of apoptosis in real-time. The aim of this study was to evaluate the value of [99mTc]duramycin for detecting early apoptotic response in tumors after chemotherapy, thus providing a tool for early prediction of curative effects in tumors. METHODS Human breast cancer MDA-MB-468 model mice, randomly divided into two groups, were injected with cisplatin or vehicle once per day. [99mTc]duramycin imaging was performed for group 1 before treatment and 24 h after the third day of treatment to evaluate treatment response through animal single-photon emission computed tomography (SPECT/CT). Mice in group 2 were treated for 10 days consecutively, to observe treatment response by tumor volume changes. Treatment response was further demonstrated through TdT-mediated dUTP nick-end labeling (TUNEL) and cleaved caspase-3 (CC3). RESULTS [99mTc]duramycin uptake in MDA-MB-468 tumors was significantly higher in the treatment group than the control group after as few as 3 days of cisplatin treatment (p = 0.0001), and it also increased after treatment as comparison with that before treatment (p = 0.0001). Moreover, [99mTc]duramycin uptake in tumors clearly correlated with immunohistochemistry results (TUNEL: r = 0.892, p = 0.0001, and CC3: r = 0.89, p = 0.0001). Additionally, tumor size reduction, indicating effective treatment, was not observed until the eighth day after treatment, far later than the time when diagnosis could be made through [99mTc]duramycin imaging. CONCLUSIONS [99mTc]duramycin SPECT/CT provides a non-invasive molecular imaging strategy for early detection of tumor apoptosis after chemotherapy and thus may have great potential value in the clinic.

CYR61 Confers the Sensitivity to Aromatase Inhibitor Letrozole in ER Positive Breast Carcinoma

BACKGROUND Studies have demonstrated that cysteine-rich 61 (CYR61) may be involved in tumor proliferation and invasion. However, the role of CYR61 plays in endocrine therapy response is largely unknown. PATIENTS AND METHODS We tested the levels of CYR61 expression of 36 primary breast cancer patients who received neo-adjuvant endocrine therapy for at least 3 months by immunohistochemistry staining before and after administrating letrozole, an oral non-steroidal aromatase inhibitor (AI) for the treatment of hormone-responsive breast cancer. The expression levels of CYR61 and ki67 were compared between pre-treatment and post-treatment samples by using the paired t test. Chi-square test was used to determine the relationship between baseline CYR61 expression and clinical response. RESULTS In the clinical case series analysis, a positive correlation was observed between baseline CYR61 expression and clinical outcomes (p=0.02). CYR61 expression was significantly increased in the residual tumors after treatment (indicating insensitivity to endocrine therapy) compared with that in the baseline biopsy samples, which was irrespective of the efficacy of primary endocrine treatment. In addition, the ki67 level was significantly decreased after neo-adjuvant endocrine therapy, compared with that in the baseline samples. CONCLUSION This study provides evidence that CYR61 may confer the sensitivity to letrozole treatment and may offer an opportunity to target CYR61 to improve endocrine resistance in ER-positive breast cancer.

Nodal ratio of positive to excised nodes, but not number of positive lymph nodes is better to predict group to avoid chemotherapy among postmenopausal ER-positive, lymph node-positive T1-T2 breast cancer patients

AIM OF STUDY To identify whether nodal ratio (NR) of positive to excised nodes is superior to number of positive lymph nodes to predict group to avoid chemotherapy among postmenopausal ER-positive, lymph node-positive, T1-T2 breast cancer patients. MATERIALS AND METHODS Postmenopausal estrogen receptor (ER)-positive, lymph node-positive patients who received endocrine therapy (n = 173) with complete baseline data in our hospital between 2000 and 2006 were included. The disease-free survival (DFS) was compared. Survival analysis was performed using Kaplan-Meier method. Cox proportional hazard models were used to evaluate the prognostic value of chemotherapy with different NR for DFS. P--values less than 0.05 were regarded as significant. RESULTS The median follow-up was 72 months. Three of 13 variables analyzed remained significantly prognostic for survival in the Cox proportional hazards model. These included age (hazard ratio (HR) =1.642, 95% confidence interval (CI) =1.154-2.337, P = 0.006); histological grade (HR = 2.463,95% CI = 1.389-4.367, P = 0.002); and NR (HR = 2.280, 95% CI = 1.113-4.671, P = 0.024). Subgroup analysis by NR status showed that in patients with NR ≥ 0.20, chemotherapy significantly improves DFS (HR = 0.360, 95% CI = 0.195-0.663, P = 0.001); while in patients with NR < 0.20, chemotherapy did not significantly affect DFS (HR = 0.677, 95% CI = 0.227-2.107, P = 0.493). Radiotherapy is an important factor that improves DFS in lymph node-positive patients, so it is considered in all analysis. CONCLUSION This retrospective analysis demonstrates that NR of positive to excised nodes, but not number of positive lymph nodes is better to predict group to avoid chemotherapy among postmenopausal ER-positive, lymph node-positive T1-T2 breast cancer patients.