Search

Background: This phase II, open-label, multicentre study aimed to evaluate changes in cell proliferation and biomarkers, as well as efficacy of lapatinib in treatment-naïve patients with HER-2-negative primary breast cancer., Patients and Methods: Patients received 1500 mg lapatinib for 28-42 days before surgery with repeat biopsies and measurements. The primary end point was inhibition of cell proliferation measured by Ki67; the secondary end points included clinical response, adverse events and changes in FOXO3a, FOXM1, p-AKT and HER-3., Results: Overall, there was no significant reduction in Ki67 with treatment (assessment carried out in 28 of 31 subjects enrolled). However, four patients (14%) showed a reduction in Ki67 ≥50%. Four of 25 patients (16%) had a partial response to treatment judged by sequential ultrasound measurements. Response, in terms of either Ki67 or ultrasound, did not relate to changes in any biomarker assessed at baseline, including the estrogen receptor (ER) and epidermal growth factor receptor (EGFR). However, all four clinical responders were HER-3 positive, as were three of four Ki67 responders., Conclusions: Overall, a pre-surgical course of lapatinib monotherapy had little effect on this group of patients; however, in subsets of patients, especially those with HER-3-positive tumors, we observed either reduction in proliferation (Ki67) or tumor size; EGFR/ER status had no impact.

Background: Quantification of kinetic parameters of positron emission tomography (PET) imaging agents normally requires collecting arterial blood samples which is inconvenient for patients and difficult to implement in routine clinical practice. The aim of this study was to investigate whether a population-based input function (POP-IF) reliant on only a few individual discrete samples allows accurate estimates of tumour proliferation using [18F]fluorothymidine (FLT)., Methods: Thirty-six historical FLT-PET data with concurrent arterial sampling were available for this study. A population average of baseline scans blood data was constructed using leave-one-out cross-validation for each scan and used in conjunction with individual blood samples. Three limited sampling protocols were investigated including, respectively, only seven (POP-IF7), five (POP-IF5) and three (POP-IF3) discrete samples of the historical dataset. Additionally, using the three-point protocol, we derived a POP-IF3M, the only input function which was not corrected for the fraction of radiolabelled metabolites present in blood. The kinetic parameter for net FLT retention at steady state, Ki, was derived using the modified Patlak plot and compared with the original full arterial set for validation., Results: Small percentage differences in the area under the curve between all the POP-IFs and full arterial sampling IF was found over 60 min (4.2%-5.7%), while there were, as expected, larger differences in the peak position and peak height.A high correlation between Ki values calculated using the original arterial input function and all the population-derived IFs was observed (R2 = 0.85-0.98). The population-based input showed good intra-subject reproducibility of Ki values (R2 = 0.81-0.94) and good correlation (R2 = 0.60-0.85) with Ki-67., Conclusions: Input functions generated using these simplified protocols over scan duration of 60 min estimate net PET-FLT retention with reasonable accuracy.

Purpose: To establish biomarkers indicating clinical response to taxanes, we determined whether early changes in [(18)F]-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 (SUV(60,av) and SUV(60,max)) normalized to body surface area ranged between 1.7 and 17.0 and 5.6 and 26.9 × 10(-5) m(2)/mL, respectively. Docetaxel treatment resulted in a significant decrease in FLT uptake (P = 0.0003 for SUV(60,av) and P = 0.0002 for SUV(60,max)). Reduction in tumor SUV(60,av) was associated with target lesion size changes midtherapy (Pearson R for SUV(60,av) = 0.64; P = 0.004) and predicted midtherapy target lesion response (0.85 sensitivity and 0.80 specificity). Decreases in SUV(60,av) in responders were due, at least in part, to reduced net intracellular trapping of FLT (rate constant, K(i)). Docetaxel significantly reduced K(i) 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., (©2011 AACR.)

Objective: The biological significance of [¹¹C]choline (CHO) uptake in human tumours is unclear and probably linked to choline kinase-α (CHKα) 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 CHKα and the Ki67-labelling index (LIKi67) in tumour biopsies., Methods: Sequential 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 CHKα and LIKi67 in eight cases., Results: Tumours 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 CHKα intensity and between FLT-PET and LIKi67 (P<0.05, one-way analysis of variance)., Conclusion: Choline 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 CHKα expression.

Purpose: This study sought to evaluate the reproducibility of [(11)C]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 [(11)C]choline-PET scan, 10 patients had a second [(11)C]choline-PET scan to examine reproducibility, and 6 patients had a second scan within a month after trastuzumab. Analysis of [(11)C]choline uptake was measured as the semiquantitative standardized uptake value at 30 and 60 minutes (SUV(30) and SUV(60)), 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 [(11)C]choline PET. The difference in tumor versus normal tissue uptake was significant for SUV(30), SUV(60), Ki, and IRF60 minutes (Wilcoxon P < 0.0001). At 60 minutes postinjection, 15.1 +/- 2.16% of plasma radioactivity was due to unmetabolized [(11)C]choline radioactivity. [(11)C]Choline uptake was reproducible in breast tumor lesions (r(2) = 0.9 for SUV, 0.9 for Ki, and 0.8 for IRF60). Early responses to trastuzumab measured by [(11)C]choline-PET were significant in three lesions occurring in two patients who responded clinically., Conclusions: [(11)C]Choline-PET uptake variables can be reproducibly assessed. Initial studies show that trastuzumab decreases [(11)C]choline uptake.

[(18)F]Fluorothymidine (FLT) is a cell proliferation marker that undergoes predominantly hepatic metabolism and therefore shows a high level of accumulation in the liver, as well as in rapidly proliferating tumours. Furthermore, the tracer's uptake is substantial in other organs including the heart. We present a nonlinear kinetic filtering technique which enhances the visualization of tumours imaged with FLT positron emission tomography (FLT-PET). A classification algorithm to isolate cancerous tissue from healthy organs was developed and validated using 29 scan data from patients with locally advanced or metastatic breast cancer. A large reduction in signal from the liver and heart of 80% was observed following application of the kinetic filter, whilst the majority of signal from both primary tumours and metastases was retained. A scan acquisition time of 60 min has been shown to be sufficient to obtain the necessary kinetic data. The algorithm extends utility of FLT-PET imaging in oncology research.

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 [(18)F]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 x 10(-5) m(2)/mL, 4.38 x 10(-2) mL plasma/min/mL tissue, and 4.93 x 10(-2)/min, respectively. One hour after capecitabine administration, the standardized uptake value was 13.55 x 10(-5) m(2)/mL (P = 0.004), Ki 7.40 x 10(-2) mL plasma/min/mL tissue (P = 0.004), and impulse response function was 7.40 x 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.

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 [(11)C]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.

Background: Peritoneal metastases are now a significant cause of morbidity and mortality in patients with advanced breast cancer. There are few published data regarding the prognosis, clinical characteristics and management of individuals with peritoneal metastases from breast cancer., Methods: The electronic database at Imperial College Healthcare NHS Trust (Charing Cross Hospital) was searched for the terms 'breast', 'cancer' or 'tumour', 'peritoneal' and 'ascites' from 2000 to 2008. Those with confirmed peritoneal disease from breast cancer, as described on ultrasound or staging CT reports with a clinico-pathologic confirmed diagnosis, were included., Results: A total of 1628 patients were screened and initially 168 patients were identified. A subsequent total of 44 individuals (2.7% of the cohort) were defined as having breast cancer with peritoneal secondaries and were included in the analysis. Of these, the majority (77%) had invasive ductal carcinomas (IDCs). While the median survival from the diagnosis of metastatic breast cancer measured 20.5 months (range 0.1-125 months), the median survival of patients with peritoneal disease was 1.56 months (range 0.2-27 months)., Conclusions: These data demonstrate that the median survival of patients with peritoneal breast cancer metastasis is surprisingly poor, with only a minority surviving more than 6 months. A specific association with invasive lobular carcinoma (ILC) was not observed. The dismal outcome of these individuals, despite further active therapy, merits their inclusion into clinical trials designed specifically for this group of patients.

(18)F-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, (18)F-FDG PET is increasingly being used to monitor the therapeutic response to these agents as well. The impressive outcome of (18)F-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 (18)F-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 (18)F-FDG PET and provides guidance on practical issues to ensure the optimal interpretation of imaging data in drug development and for patient care.

Background: The 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., Methods: Information 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., Conclusion: There 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.

Unlabelled: The integrin alpha v beta3 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 alpha v beta3 integrin is safe, metabolically stable, and retained in tumor tissues and detects breast cancer lesions by PET in most anatomic sites.

Aims: Adjuvant therapy after surgery for colorectal cancer is often denied to the elderly for various reasons. This study was to determine morbidity and mortality risk after surgery in the elderly and whether this is affected by adjuvant therapy., Methods: Data were collected prospectively and entered on a database for all patients undergoing resection of colorectal cancer between January 1994 and July 2000. A total of 304 patients were included, 65 aged 80 years and over., Results: There were 84 deaths, 21 (30%) in the over 80s, and 63 (26%) in the under 80s (P=0.51). The 'in-hospital' mortality was 10.1% in the over 80s and 3.8% in the under 80s (P=0.056). In the over 80s the colon was more affected than the rectum (P=0.002). The over 80s were less likely to be offered adjuvant therapy, 7.2% vs 42.1% (P<0.001). The 5 year survival (all-cause mortality) in the over 80s was 58.5% and 47.6% in the under 80s (P=0.25). Cox's regression analysis of all patients identified the following factors to be independently related to overall survival: age>80 years, post-operative leak, increasing Dukes stage and distant recurrence of disease., Conclusion: This study has demonstrated that surgery should not be denied to elderly patients with colorectal cancer as despite a higher post-operative morbidity and mortality rate and with the absence of adjuvant therapy, favourable long-term outcome can be achieved by resectional surgery alone.