Publications
99 results found
Allsopp RC, Guo Q, Page K, et al., 2024, Circulating tumour DNA dynamics during alternating chemotherapy and hormonal therapy in metastatic breast cancer: the ALERT study., Breast Cancer Res Treat
PURPOSE: Although changes in circulating tumour DNA (ctDNA) in breast cancer are well described, the kinetics of their fluctuations has not been described over short timescales. We investigated ctDNA dynamics during alternating cycles of chemotherapy and hormonal treatment in pre-treated patients with oestrogen receptor-positive metastatic breast cancer. METHODS: Patients received alternating, 9-week cycles of eribulin and aromatase inhibitors (AIs). The clinical primary endpoint, progression-free survival (PFS), was monitored at 3, 6 and 9 months; secondary endpoints, clinical benefit rate (CBR), safety and tolerability profiles, were also assessed. Importantly, ctDNA fluctuations were monitored using the Oncomine™ Breast cfDNA assay to test whether biomarkers may change rapidly between chemotherapy and aromatase inhibitor (AI) treatment in the setting of advanced breast cancer, potentially reflecting disease dynamics. RESULTS: The median PFS was 202 days (95% CI: 135-undefined) and 235 days (95% CI: 235-undefined) at 6 and 9 months, respectively, with a 50% CBR at both 6 and 9 months. Dynamic changes in ctDNA were observed in short timescales between chemotherapy and AI treatment and support the clinical benefit (CB) seen in individual patients and, critically, appear informative of acquired resistance in real time. CONCLUSION: Changes in ctDNA can occur rapidly and reflect changes in patients' clinical tumour responses (NCT02681523).
Coombes RC, Howell S, Lord SR, et al., 2023, Author Correction: Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib., Nature Communications, Vol: 14, Pages: 1-1, ISSN: 2041-1723
Charles Coombes R, Howell S, Lord SR, et al., 2023, Dose escalation and expansion cohorts in patients with advanced breast cancer in a Phase I study of the CDK7-inhibitor samuraciclib, Nature Communications, Vol: 14, ISSN: 2041-1723
Samuraciclib is a selective oral CDK7-inhibitor. A multi-modular, open-label Phase I study to evaluate safety and tolerability of samuraciclib in patients with advanced malignancies was designed (ClinicalTrials.gov: NCT03363893). Here we report results from dose escalation and 2 expansion cohorts: Module 1A dose escalation with paired biopsy cohort in advanced solid tumor patients, Module 1B-1 triple negative breast cancer (TNBC) monotherapy expansion, and Module 2A fulvestrant combination in HR+/HER2- breast cancer patients post-CDK4/6-inhibitor. Core study primary endpoints are safety and tolerability, and secondary endpoints are pharmacokinetics (PK), pharmacodynamic (PD) activity, and anti-tumor activity. Common adverse events are low grade nausea, vomiting, and diarrhea. Maximum tolerated dose is 360 mg once daily. PK demonstrates dose proportionality (120 mg-480 mg), a half-life of approximately 75 hours, and no fulvestrant interaction. In dose escalation, one partial response (PR) is identified with disease control rate of 53% (19/36) and reduction of phosphorylated RNA polymerase II, a substrate of CDK7, in circulating lymphocytes and tumor tissue. In TNBC expansion, one PR (duration 337 days) and clinical benefit rate at 24 weeks (CBR) of 20.0% (4/20) is achieved. In combination with fulvestrant, 3 patients achieve PR with CBR 36.0% (9/25); in patients without detectable TP53-mutation CBR is 47.4% (9/19). In this study, samuraciclib exhibits tolerable safety and PK is supportive of once-daily oral administration. Clinical activity in TNBC and HR+/HER2-breast cancer post-CDK4/6-inhibitor settings warrants further evaluation.
Aboagye E, Aravind P, Popat S, et al., 2023, A subset of non-small cell lung cancer patients treated with pemetrexed show 18f-fluorothymidine ‘flare’ on positron emission tomography, Cancers, Vol: 15, Pages: 1-14, ISSN: 2072-6694
Thymidylate synthase (TS) remains a major target for cancer therapy. TS inhibition elicits increases in DNA salvage pathway activity, detected as a transient compensatory “flare” in 3′-deoxy-3′-[18F]fluorothymidine positron emission tomography (18F-FLT PET). We determined the magnitude of the 18F-FLT flare in non-small cell lung cancer (NSCLC) patients treated with the antifolate pemetrexed in relation to clinical outcome. Method: Twenty-one patients with advanced/metastatic non-small cell lung cancer (NSCLC) scheduled to receive palliative pemetrexed ± platinum-based chemotherapy underwent 18F-FLT PET at baseline and 4 h after initiating single-agent pemetrexed. Plasma deoxyuridine (dUrd) levels and thymidine kinase 1 (TK1) activity were measured before each scan. Patients were then treated with the combination therapy. The 18F-FLT PET variables were compared to RECIST 1.1 and overall survival (OS). Results: Nineteen patients had evaluable PET scans at both time points. A total of 32% (6/19) of patients showed 18F-FLT flares (>20% change in SUVmax-wsum). At the lesion level, only one patient had an FLT flare in all the lesions above (test–retest borders). The remaining had varied uptake. An 18F-FLT flare occurred in all lesions in 1 patient, while another patient had an 18F-FLT reduction in all lesions; 17 patients showed varied lesion uptake. All patients showed global TS inhibition reflected in plasma dUrd levels (p < 0.001) and 18F-FLT flares of TS-responsive normal tissues including small bowel and bone marrow (p = 0.004 each). Notably, 83% (5/6) of patients who exhibited 18F-FLT flares were also RECIST responders with a median OS of 31 m, unlike patients who did not exhibit 18F-FLT flares (15 m). Baseline plasma TK1 was prognostic of survival but its activity remained unchanged following treatment. Conclusions: The better radiological response and longer survival observed in patients with an 18F-FLT flare suggest the
Fleming B, Edison P, Kenny L, 2023, Cognitive impairment after cancer treatment: mechanisms, clinical characterization, and management, BMJ-BRITISH MEDICAL JOURNAL, Vol: 380, ISSN: 0959-535X
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Kenny L, Hyland P, Cloitre M, et al., 2023, Factor Structure of the Shortened Six-Item Version of the de Jong Gierveld Loneliness Scale (DJGLS-6) A Systematic Review and Testing Factor Models in a Nationally Representative Sample, EUROPEAN JOURNAL OF MENTAL HEALTH, Vol: 18, ISSN: 1788-4934
Kenny L, Beresford M, Brown I, et al., 2022, Eribulin for the treatment of advanced breast cancer: A prospective observational registry study, European Journal of Cancer Care, Vol: 31, ISSN: 0961-5423
Methods:This observational multicentre registry study enrolled 76 patients with locally advanced/metastatic breast cancer who had ≤2 prior chemotherapeutic regimens for advanced disease. Eribulin was administered at a 1.23 mg/m2 dose (days 1 and 8 of every 21-day cycle). Adverse events (AEs) were monitored and effectiveness was assessed per local practice.Results:AEs occurred in 98.7% of patients; 88.2% had eribulin-related AEs. The most common AEs were fatigue (64.5%), alopecia (36.8%), nausea (35.5%) and constipation (30.3%). Serious AEs occurred in 42.1% of patients. The most common grade 3/4 AEs were neutropenia (9.2%), febrile neutropenia (9.2%), dyspnoea (5.3%) and pleural effusion (5.3%). No fatal AEs occurred. Dose reductions occurred in 31.6% of patients, 42.1% experienced dose delays and 9.2% discontinued due to worsening condition. There were complete responses in 2.6% and partial responses in 15.8% of patients. Median time to progression and overall survival were 4.0 and 8.3 months, respectively.Conclusion:Eribulin was well tolerated in real-world clinical practice, comparable to safety and effectiveness reported in other clinical trials.
Aravind P, Popat S, Barwick TD, et al., 2022, [F-18]Fluorothymidine(FLT)-PET imaging of thymidine kinase 1 pharmacodynamics in non-small cell lung cancer treated with pemetrexed., ASCO, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
Kenny LM, Gilbert FJ, Gopalakrishnan G, et al., 2022, The HERPET study: Imaging HER2 expression in breast cancer with the novel PET tracer [<SUP>18</SUP>F]GE-226, a first-in-patient study., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
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Howell SJ, Kenny LM, Lord S, et al., 2022, A clinical study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced triple negative breast cancer (TNBC), San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Nteliopoulos G, Page K, Hills A, et al., 2021, Comparison of two targeted ultra-deep sequencing technologies for analysis of plasma circulating tumour DNA in endocrine-therapy-resistant breast cancer patients, Breast Cancer Research and Treatment, Vol: 188, Pages: 465-176, ISSN: 0167-6806
PurposeThere is growing interest in the application of circulating tumour DNA (ctDNA) as a sensitive tool for monitoring tumour evolution and guiding targeted therapy in patients with cancer. However, robust comparisons of different platform technologies are still required. Here we compared the InVisionSeq™ ctDNA Assay with the Oncomine™ Breast cfDNA Assay to assess their concordance and feasibility for the detection of mutations in plasma at low (< 0.5%) variant allele fraction (VAF).MethodsNinety-six plasma samples from 50 patients with estrogen receptor (ER)-positive metastatic breast cancer (mBC) were profiled using the InVision Assay. Results were compared to the Oncomine assay in 30 samples from 26 patients, where there was sufficient material and variants were covered by both assays. Longitudinal samples were analysed for 8 patients with endocrine resistance.ResultsWe detected alterations in 59/96 samples from 34/50 patients analysed with the InVision assay, most frequently affecting ESR1, PIK3CA and TP53. Complete or partial concordance was found in 28/30 samples analysed by both assays, and VAF values were highly correlated. Excellent concordance was found for most genes, and most discordant calls occurred at VAF < 1%. In longitudinal samples from progressing patients with endocrine resistance, we detected consistent alterations in sequential samples, most commonly in ESR1 and PIK3CA.ConclusionThis study shows that both ultra-deep next-generation sequencing (NGS) technologies can detect genomic alternations even at low VAFs in plasma samples of mBC patients. The strong agreement of the technologies indicates sufficient reproducibility for clinical use as prognosic and predictive biomarker.
Lythgoe MP, Krell J, Kenny L, et al., 2021, 157P Racial diversity and reporting in FDA registration trials for breast cancer from 2006 to 2021, Annals of Oncology, Vol: 32, Pages: S88-S88, ISSN: 0923-7534
BackgroundIn the USA, there are >250,000 diagnoses of breast cancer (BC) annually, with significant racial disparities in incidence, subtype and outcomes. FDA clinical trials guidance recommend 5 categories of race reporting (White, Black, Asian, American Indian/Alaskan Native [AIAN] & Native Hawaiian/Pacific Islander [NHPI]). Furthermore, International Committee of Medical Journal Editors (ICMJE) guidance recommend authors, as a minimum, provide descriptive data for race. We analysed racial diversity in BC drug registration trials and compliance with FDA/ICMJE guidance.MethodsWe performed a retrospective review of BC FDA market authorisations from 2006 to 2021. Clinical trial publications cited on the licensing label were identified and analysed. If race was under-reported (<3 groups), the study report on clinicaltrials.gov was analysed. The total proportion of racial group participation and number of registration trials with adequate reporting was determined.Results38 new licensing indications were identified, involving 41 trials and 23 drugs. Overall, 36,081 patients participated: 19,495 (54.0%) White, 4194 (11.6%) Asian, 748 (2.1%) Black, 228 (0.6%) AIAN, 8 (0.1%) NHPI, 840 (2.3%) other and 10568 (29.3%) unknown. The table shows breakdown by BC subtype. Race was reported in 29 (70%) licensing trial publications, of which 7 provided only limited data. For licensing trials where no race data was reported, a further 6 (14%) had information within the study report. In the 10 years prior to the introduction of new FDA guidance in 2016 only 50% of registration studies met FDA/ICJME race reporting requirements. Since 2016 this has improved to 85%
Balachandran K, Williams J, Bell D, et al., 2021, Breast cancer treatment during the first wave of the COVID-19 pandemic at a UK centre, ESMO Breast Cancer Virtual Congress, Publisher: ELSEVIER, Pages: S94-S94, ISSN: 0923-7534
Kenny LM, Gopalakrishnan GS, Barwick TD, et al., 2021, Herpet study- PET imaging of HER2 expression in breast cancer using the novel Affibody tracer [18F]GE-226, a first in patient study, San Antonio Breast Cancer Virtual Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
Krebs MG, Lord S, Kenny L, et al., 2021, First in human, modular study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in patients with advanced solid malignancies, Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: ELSEVIER, Pages: S458-S458, ISSN: 0923-7534
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Howell SJ, Krebs MG, Lord S, et al., 2021, Study of samuraciclib (CT7001), a first-in-class, oral, selective inhibitor of CDK7, in combination with fulvestrant in patients with advanced hormone receptor positive HER2 negative breast cancer (HR plus BC), Congress of the European-Society-for-Medical-Oncology (ESMO), Publisher: ELSEVIER, Pages: S477-S478, ISSN: 0923-7534
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Dubash S, Keat N, Kozlowski K, et al., 2020, Clinical translation of 18F-fluoropivalate – a PET tracer for imaging short-chain fatty acid metabolism: safety, biodistribution, and dosimetry in fed and fasted healthy volunteers, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 47, Pages: 2549-2561, ISSN: 1619-7070
BackgroundFatty acids derived de novo or taken up from the extracellular space are an essential source of nutrient for cell growth and proliferation. Radiopharmaceuticals including 11C-acetate, and 18F-FAC (2-18F-fluoroacetate), have previously been used to study short-chain fatty acid (SCFA) metabolism. We developed 18F-fluoropivalate (18F-FPIA; 3-18F-fluoro-2,2-dimethylpropionic acid) bearing a gem-dimethyl substituent to assert metabolic stability for studying SCFA metabolism. We report the safety, biodistribution, and internal radiation dosimetry profile of 18F-FPIA in 24 healthy volunteers and the effect of dietary conditions.Materials and methodsHealthy volunteer male and female subjects were enrolled (n = 24), and grouped into 12 fed and 12 fasted. Non-esterified fatty acids (NEFA) and carnitine blood measurements were assessed. Subjects received 159.48 MBq (range, 47.31–164.66 MBq) of 18F-FPIA. Radiochemical purity was > 99%. Safety data were obtained during and 24 h after radiotracer administration. Subjects underwent detailed multiple whole-body PET/CT scanning with sampling of venous bloods for radioactivity and radioactive metabolite quantification. Regions of interest were defined to derive individual and mean organ residence times; effective dose was calculated using OLINDA 1.1.ResultsAll subjects tolerated 18F-FPIA with no adverse events. Over 90% of radiotracer was present in plasma at 60 min post-injection. The organs receiving highest absorbed dose (in mGy/MBq) were the liver (0.070 ± 0.023), kidneys (0.043 ± 0.013), gallbladder wall (0.026 ± 0.003), and urinary bladder (0.021 ± 0.004); otherwise there was low tissue uptake. The calculated effective dose using mean organ residence times over all 24 subjects was 0.0154 mSv/MBq (SD ± 0.0010). No differences in biodistribution or dosimetry were seen in fed and fasted subjects
Robertson JFR, Evans A, Henschen S, et al., 2020, A randomized, open-label, presurgical, window-of-opportunity study comparing the pharmacodynamic effects of the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+ HER2(-) primary breast cancer, Clinical Cancer Research, Vol: 26, Pages: 4242-4249, ISSN: 1078-0432
Purpose: Fulvestrant, the first-in-class selective estrogen receptor (ER) degrader (SERD), is clinically effective in patients with ER+ breast cancer, but it has administration and pharmacokinetic limitations. Pharmacodynamic data suggest complete ER degradation is not achieved at fulvestrant's clinically feasible dose. This presurgical study (NCT03236974) compared the pharmacodynamic effects of fulvestrant with AZD9496, a novel, orally bioavailable, nonsteroidal, potent SERD, in treatment-naïve patients with ER+ HER2− primary breast cancer awaiting curative intent surgery.Patients and Methods: Patients were randomized 1:1 to receive AZD9496 250 mg twice daily from day 1 for 5–14 days, or fulvestrant 500 mg on day 1. On-treatment imaging-guided core tumor biopsies were taken between day 5 and 14 and compared with pretreatment diagnostic biopsies. The primary objective was to compare the effects of AZD9496 and fulvestrant on ER expression. Secondary objectives included changes in progesterone receptor (PR) and Ki-67 pharmacokinetic/pharmacodynamic relationships and safety.Results: Forty-six women received treatment (AZD9496 n = 22; fulvestrant n = 24); 35 paired biopsies were evaluable (AZD9496 n = 15; fulvestrant n = 20). The least square mean estimate for ER H-score reduction was 24% after AZD9496 versus 36% after fulvestrant treatment (P = 0.86). AZD9496 also reduced PR H-scores (−33.3%) and Ki-67 levels (−39.9%) from baseline, but was also not superior to fulvestrant (PR: −68.7%, P = 0.97; Ki-67: −75.4%, P = 0.98). No new safety findings were identified.Conclusions: This was the first presurgical study to demonstrate that an oral SERD affects its key biological targets. However, AZD9496 was not superior to fulvestrant at the dose tested.
Robertson JFR, Evans A, Henschen S, et al., 2020, A pre-surgical, window of opportunity study comparing the novel oral SERD AZD9496 with fulvestrant in patients with newly diagnosed ER+HER2-primary breast cancer, 42nd Annual San Antonio Breast Cancer Symposium, Publisher: AMER ASSOC CANCER RESEARCH, ISSN: 0008-5472
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Coombes RC, Page K, Salari R, et al., 2019, Personalized detection of circulating tumor DNA antedates breast cancer metastatic recurrence, Clinical Cancer Research, Vol: 25, Pages: 4255-4263, ISSN: 1078-0432
Purpose: Up to 30% of patients with breast cancer relapse after primary treatment. There are no sensitive and reliable tests to monitor these patients and detect distant metastases before overt recurrence. Here, we demonstrate the use of personalized circulating tumor DNA (ctDNA) profiling for detection of recurrence in breast cancer.Experimental Design: Forty-nine primary patients with breast cancer were recruited following surgery and adjuvant therapy. Plasma samples (n = 208) were collected every 6 months for up to 4 years. Personalized assays targeting 16 variants selected from primary tumor whole-exome data were tested in serial plasma for the presence of ctDNA by ultradeep sequencing (average >100,000X).Results: Plasma ctDNA was detected ahead of clinical or radiologic relapse in 16 of the 18 relapsed patients (sensitivity of 89%); metastatic relapse was predicted with a lead time of up to 2 years (median, 8.9 months; range, 0.5–24.0 months). None of the 31 nonrelapsing patients were ctDNA-positive at any time point across 156 plasma samples (specificity of 100%). Of the two relapsed patients who were not detected in the study, the first had only a local recurrence, whereas the second patient had bone recurrence and had completed chemotherapy just 13 days prior to blood sampling.Conclusions: This study demonstrates that patient-specific ctDNA analysis can be a sensitive and specific approach for disease surveillance for patients with breast cancer. More importantly, earlier detection of up to 2 years provides a possible window for therapeutic intervention.
Anand P, Elsafa E, Privitera R, et al., 2019, Rational treatment of chemotherapy-induced peripheral neuropathy with capsaicin 8% patch: from pain relief towards disease modification, Journal of Pain Research, Vol: 12, Pages: 2039-2052, ISSN: 1178-7090
Purpose: Chemotherapy-induced peripheral neuropathy (CIPN) with associated chronic pain is a common and disabling condition. Current treatments for neuropathic pain in CIPN are largely ineffective, with unfavorable side-effects. The capsaicin 8% patch (capsaicin 179 mg patch) is approved for the treatment of neuropathic pain: a single topical cutaneous application can produce effective pain relief for up to 12 weeks. We assessed the therapeutic potential of capsaicin 8% patch in patients with painful CIPN, and its mechanism of action.Patients and methods: 16 patients with chronic painful CIPN (mean duration 2.5 years), in remission for cancer and not receiving chemotherapy, were treated with 30 min application of capsaicin 8% patch to the feet. Symptoms were monitored using the 11-point numerical pain rating scale (NPRS), and questionnaires. Investigations were performed at baseline and three months after patch application, including skin biopsies with a range of markers, and quantitative sensory testing (QST).Results: Patients reported significant reduction in spontaneous pain (mean NPRS: −1.27; 95% CI 0.2409 to 2.301; p=0.02), touch-evoked pain (−1.823; p=0.03) and cold-evoked pain (−1.456; p=0.03). Short-Form McGill questionnaire showed a reduction in neuropathic (p=0.0007), continuous (p=0.01) and overall pain (p=0.004); Patient Global Impression of Change showed improvement (p=0.001). Baseline skin biopsies showed loss of intra-epidermal nerve fibers (IENF), and also of sub-epidermal nerve fibers quantified by image analysis. Post-patch application skin biopsies showed a significant increase towards normalization of intra-epidermal and sub-epidermal nerve fibers (for IENF: structural marker PGP9.5, p=0.009; heat receptor TRPV1, p=0.027; regenerating nerve marker GAP43, p=0.04). Epidermal levels of Nerve Growth Factor (NGF), Neurotrophin-3 (NT-3), and Langerhans cells were also normalized. QST remained unchanged and there were no systemic side-
Murphy R, Adams L, Brown A, et al., 2019, Impact of Routine Use of CDK4/6 Inhibitor Therapy on Breast Cancer Outpatient Clinic Workload and Patient Experience, Publisher: ELSEVIER SCIENCE LONDON, Pages: E112-E112, ISSN: 0936-6555
Varghese V, Magnani L, Harada N, et al., 2019, FOXM1 modulates 5-FU resistance in colorectal cancer through regulating TYMS expression, Scientific Reports, Vol: 9, ISSN: 2045-2322
Resistance to 5-Fluoruracil (5-FU) has been linked to elevated expression of the main target, thymidylate synthase (TYMS), which catalyses the de novo pathway for production of deoxythymidine monophosphate. The potent oncogenic forkhead box transcription factor, FOXM1 is is regulated by E2F1 which also controls TYMS. This study reveals a significant role of FOXM1 in 5-FU resistance. Overexpression and knock-down studies of FOXM1 in colon cancer cells suggest the importance of FOXM1 in TYMS regulation. ChIP and global ChIP-seq data also confirms that FOXM1 can also potentially regulate other 5-FU targets, such as TYMS, thymidine kinase 1 (TK-1) and thymidine phosphorylase (TYMP). In human colorectal cancer tissue specimens, a strong correlation of FOXM1 and TYMS staining was observed. Elevated FOXM1 and TYMS expression was also observed in acquired 5-FU resistant colon cancer cells (HCT116 5-FU Res). A synergistic effect was observed following treatment of CRC cells with an inhibitor of FOXM1, thiostrepton, in combination with 5-FU. The combination treatment decreased colony formation and migration, and induced cell cycle arrest, DNA damage, and apoptosis in CRC cell lines. In summary, this research demonstrated that FOXM1 plays a pivotal role in 5-FU resistance at least partially through the regulation of TYMS.
Dubash SR, Merchant S, Heinzmann K, et al., 2018, Clinical translation of [F-18]ICMT-11 for measuring chemotherapy-induced caspase 3/7 activation in breast and lung cancer, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 45, Pages: 2285-2299, ISSN: 1619-7070
BackgroundEffective anticancer therapy is thought to involve induction of tumour cell death through apoptosis and/or necrosis. [18F]ICMT-11, an isatin sulfonamide caspase-3/7-specific radiotracer, has been developed for PET imaging and shown to have favourable dosimetry, safety, and biodistribution. We report the translation of [18F]ICMT-11 PET to measure chemotherapy-induced caspase-3/7 activation in breast and lung cancer patients receiving first-line therapy.ResultsBreast tumour SUVmax of [18F]ICMT-11 was low at baseline and unchanged following therapy. Measurement of M30/M60 cytokeratin-18 cleavage products showed that therapy was predominantly not apoptosis in nature. While increases in caspase-3 staining on breast histology were seen, post-treatment caspase-3 positivity values were only approximately 1%; this low level of caspase-3 could have limited sensitive detection by [18F]ICMT-11-PET. Fourteen out of 15 breast cancer patients responded to first–line chemotherapy (complete or partial response); one patient had stable disease. Four patients showed increases in regions of high tumour [18F]ICMT-11 intensity on voxel-wise analysis of tumour data (classed as PADS); response was not exclusive to patients with this phenotype. In patients with lung cancer, multi-parametric [18F]ICMT-11 PET and MRI (diffusion-weighted- and dynamic contrast enhanced-MRI) showed that PET changes were concordant with cell death in the absence of significant perfusion changes.ConclusionThis study highlights the potential use of [18F]ICMT-11 PET as a promising candidate for non-invasive imaging of caspase3/7 activation, and the difficulties encountered in assessing early-treatment responses. We summarize that tumour response could occur in the absence of predominant chemotherapy-induced caspase-3/7 activation measured non-invasively across entire tumour lesions in patients with breast and lung cancer.
Kramer GM, Liu Y, de Langen AJ, et al., 2018, Repeatability of quantitative18F-FLT uptake measurements in solid tumors: an individual patient data multi-center meta-analysis, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 45, Pages: 951-961, ISSN: 1619-7070
INTRODUCTION: 3'-deoxy-3'-[18F]fluorothymidine (18F-FLT) positron emission tomography (PET) provides a non-invasive method to assess cellular proliferation and response to antitumor therapy. Quantitative18F-FLT uptake metrics are being used for evaluation of proliferative response in investigational setting, however multi-center repeatability needs to be established. The aim of this study was to determine the repeatability of18F-FLT tumor uptake metrics by re-analyzing individual patient data from previously published reports using the same tumor segmentation method and repeatability metrics across cohorts. METHODS: A systematic search in PubMed, EMBASE.com and the Cochrane Library from inception-October 2016 yielded five18F-FLT repeatability cohorts in solid tumors.18F-FLT avid lesions were delineated using a 50% isocontour adapted for local background on test and retest scans. SUVmax, SUVmean, SUVpeak, proliferative volume and total lesion uptake (TLU) were calculated. Repeatability was assessed using the repeatability coefficient (RC = 1.96 × SD of test-retest differences), linear regression analysis, and the intra-class correlation coefficient (ICC). The impact of different lesion selection criteria was also evaluated. RESULTS: Images from four cohorts containing 30 patients with 52 lesions were obtained and analyzed (ten in breast cancer, nine in head and neck squamous cell carcinoma, and 33 in non-small cell lung cancer patients). A good correlation was found between test-retest data for all18F-FLT uptake metrics (R2 ≥ 0.93; ICC ≥ 0.96). Best repeatability was found for SUVpeak(RC: 23.1%), without significant differences in RC between different SUV metrics. Repeatability of proliferative volume (RC: 36.0%) and TLU (RC: 36.4%) was worse than SUV. Lesion selection methods based on SUVmax ≥ 4.0 improved the repeatability of volumetric metrics (RC: 26-28%), but did not affect the repe
Palmieri C, Stein RC, Liu X, et al., 2018, Correction to: IRIS study: a phase II study of the steroid sulfatase inhibitor Irosustat when added to an aromatase inhibitor in ER-positive breast cancer patients (vol 165, pg 343, 2017), Breast Cancer Research and Treatment, Vol: 167, Pages: 407-407, ISSN: 0167-6806
Palmieri C, Szydlo R, Miller M, et al., 2017, IPET study: an FLT-PET window study to assess the activity of the steroid sulfatase inhibitor irosustat in early breast cancer, Breast Cancer Research and Treatment, Vol: 166, Pages: 527-539, ISSN: 0167-6806
BACKGROUND: Steroid sulfatase (STS) is involved in oestrogen biosynthesis and irosustat is a first generation, irreversible steroid sulfatase inhibitor. A pre-surgical window-of-opportunity study with irosustat was undertaken in estrogen receptor-positive (ER+) breast cancer to assess the effect of irosustat on tumour cell proliferation as measured by 3'-deoxy-3'-[18F] fluorothymidine uptake measured by PET scanning (FLT-PET) and Ki67. METHODS: Postmenopausal women with untreated ER+ early breast cancer were recruited, and imaged with FLT-PET at baseline and after at least 2 weeks treatment with irosustat, 40 mg once daily orally. The primary endpoint was changed in FLT uptake; secondary endpoints included safety and tolerability of irosustat, changes in tumoral Ki67 and steroidogenic enzymes expression and circulating steroid hormone levels. RESULTS: Thirteen women were recruited, and ten started irosustat for 2 weeks, followed by repeat FLT-PET scans in eight. Defining response as decreases of ≥20% in standardized uptake value (SUV) or ≥30% in Ki, 1 (12.5% (95% CI 2-47%, p = 0.001)) and 3 (43% (95% CI 16-75%, p = <0.001) patients, respectively, responded. 6 out of 7 patients had a Ki67 reduction (range = -19.3 to 76.4%), and median percentage difference in Ki67 was 52.3% (p = 0.028). In one patient with a low baseline STS expression, a 19.7% increase in Ki67 was recorded. STS decreases were seen in tumours with high basal STS expression, significant decreases were also noted in aromatase, and 17β-hydroxysteroid dehydrogenase type 1 and 2. Irosustat was generally well tolerated with all adverse event CTCAE Grade ≤2. CONCLUSIONS: Irosustat resulted in a significant reduction in FLT uptake and Ki67, and is well tolerated. These data are the first demonstrating clinical activity of irosustat in early breast cancer. Baseline expression of STS may be a biomarker of sensitivity to irosustat.
Dubash SR, Merchant S, Mauri F, et al., 2017, Clinical translation of the caspase 3/7 specific PET radiotracer [<SUP>18</SUP>F]ICMT-11 for measuring chemotherapy induced apoptosis in breast and lung cancer, Publisher: SPRINGER, Pages: S378-S379, ISSN: 1619-7070
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Saleem A, Searle GE, Kenny LM, et al., 2017, Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer (vol 5, 30, 2015), EJNMMI RESEARCH, Vol: 7, ISSN: 2191-219X
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Saleem A, Searle GE, Kenny LM, et al., 2017, Erratum to: Lapatinib access into normal brain and brain metastases in patients with Her-2 overexpressing breast cancer., EJNMMI Research, Vol: 7, Pages: 74-74, ISSN: 2191-219X
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