30 research outputs found
Author Correction: The copy number and mutational landscape of recurrent ovarian high-grade serous carcinoma
No full textThe original version of this Article mistakenly misspelled “Carolin M. Sauer” from the author list as “Carolyn Sauer,” who is from the ‘CRUK Cambridge Institute, University of Cambridge, Cambridge, UK.’ This has been corrected in both the PDF and HTML versions of the Article. The original version of this Article mistakenly misspelled “Ionut-Gabriel Funingana” from the author list as “Ionat-Gabriel Funingana,” who is from the ‘CRUK Cambridge Institute, University of Cambridge, Cambridge, UK’ and ‘Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK.’ This has been corrected in both the PDF and HTML versions of the Article. The original version of this Article contained an error in Fig. 1a, in which a panel indicating copy number event analysis was missing from the study workflow diagram. This has been corrected in both the PDF and HTML versions of the Article. The original version of this Article contained an error in the Methods section which incorrectly read ‘Fastq sequencing reads were aligned to GRCh37 (g1kp2) using bwa samse.’ The correct version states ‘hs37d5’ in place of ‘glkp2.’ This has been corrected in both the PDF and HTML versions of the Article. The original version of this Article contained an error in the Data Availability Statement stating ‘The pre-processed single nucleotide variant and copy number data are available through a Zenodo data repository and can be downloaded here’ which linked to an incorrect version of the Zenodo repository. The correct link is as follows:. This has been corrected in both the PDF and HTML versions of the Article.</p
Radiomic and Volumetric Measurements as Clinical Trial Endpoints—A Comprehensive Review
No full textSimple Summary The extraction of quantitative data from standard-of-care imaging modalities offers opportunities to improve the relevance and salience of imaging biomarkers used in drug development. This review aims to identify the challenges and opportunities for discovering new imaging-based biomarkers based on radiomic and volumetric assessment in the single-site solid tumor sites: breast cancer, rectal cancer, lung cancer and glioblastoma. Developing approaches to harmonize three essential areas: segmentation, validation and data sharing may expedite regulatory approval and adoption of novel cancer imaging biomarkers. Clinical trials for oncology drug development have long relied on surrogate outcome biomarkers that assess changes in tumor burden to accelerate drug registration (i.e., Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria). Drug-induced reduction in tumor size represents an imperfect surrogate marker for drug activity and yet a radiologically determined objective response rate is a widely used endpoint for Phase 2 trials. With the addition of therapies targeting complex biological systems such as immune system and DNA damage repair pathways, incorporation of integrative response and outcome biomarkers may add more predictive value. We performed a review of the relevant literature in four representative tumor types (breast cancer, rectal cancer, lung cancer and glioblastoma) to assess the preparedness of volumetric and radiomics metrics as clinical trial endpoints. We identified three key areas-segmentation, validation and data sharing strategies-where concerted efforts are required to enable progress of volumetric- and radiomics-based clinical trial endpoints for wider clinical implementation
Radiomic and Volumetric Measurements as Clinical Trial Endpoints—A Comprehensive Review
No full textClinical trials for oncology drug development have long relied on surrogate outcome biomarkers that assess changes in tumor burden to accelerate drug registration (i.e., Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) criteria). Drug-induced reduction in tumor size represents an imperfect surrogate marker for drug activity and yet a radiologically determined objective response rate is a widely used endpoint for Phase 2 trials. With the addition of therapies targeting complex biological systems such as immune system and DNA damage repair pathways, incorporation of integrative response and outcome biomarkers may add more predictive value. We performed a review of the relevant literature in four representative tumor types (breast cancer, rectal cancer, lung cancer and glioblastoma) to assess the preparedness of volumetric and radiomics metrics as clinical trial endpoints. We identified three key areas—segmentation, validation and data sharing strategies—where concerted efforts are required to enable progress of volumetric- and radiomics-based clinical trial endpoints for wider clinical implementation
A Feasibility Study of the Therapeutic Response and Durability of Short-term Androgen-targeted Therapy in Early Prostate Cancer Managed with Surveillance: The Therapeutics in Active Prostate Surveillance (TAPS01) Study.
No full textBackground: Active surveillance (AS) is a preferred management option for men with prostate cancer with favourable prognosis. However, nearly half of men on AS switch to treatment within 5 years, so therapeutic strategies to prevent or delay disease progression could be considered. The androgen receptor is the pre-eminent oncogenic driver in prostate cancer. Objective: To explore image-based tumour responses and the patient impact of short-duration androgen-targeted therapy (ATT) to abrogate disease progression during AS. Design setting and participants: Men on AS with Cambridge Prognostic Group 1 & 2 (low and favourable intermediate risk) prostate cancer and lesions visible on magnetic resonance imaging (MRI) were recruited to an open-label, single-centre, phase 2 feasibility study of short-term ATT (the TAPS01 study). Intervention: Apalutamide 240 mg was administered for 90 days. Outcome measurements and statistical analysis: MRI-measured tumour volume (TV), gland volume (GV), and the TV/GV ratio were calculated at baseline, at day 90 (end of treatment), and at 6- and 18-month follow-up. Quality of life metrics were measured at day 0, day 90, and 6 weeks after ATT. Results and limitations: Eleven patients (40% of eligible men approached) agreed to participate, of whom nine completed treatment. At day 90, the median percentage reduction was -38.2% (range -51.8% to -23.5%) for GV, -54.2% (range -74.1% to -13.8%) for TV, and -27.2% (range -61.5% to -7.5%) for TV/GV (all p < 0.0001). At 6 mo, while GV had returned to baseline (p = 0.95) both TV (-31.9%; p = 0.0007) and TV/GV (-28.7%; p = 0.0009) remained significantly reduced. This reduction was sustained at 18 months (TV -18%, TV/GV -23.8%; p = 0.01). European Organization for Research and Treatment of Cancer QoL core 30-item questionnaire scores for global, physical, role, and social functioning decreased during treatment, but all were recovering by 6 weeks. EQ-VAS scores were unchanged compared to baseline. Conclusions: TAPS01 has demonstrated feasibility and patient tolerability for short-term ATT in men on AS. Our data suggest a selective and durable antitumour effect in the short term and support a larger-scale randomised trial. Patient summary: We investigated the feasibility of short-term treatment with an androgen inhibitor to prevent or delay disease progression for men on active surveillance for prostate cancer. Results for a small group of patients show that 90-day treatment led to a sustained decrease in tumour volume over 18 months. The findings warrant a larger clinical trial for this approach, which could allow patients to delay or even avoid longer-term active treatments
Neoadjuvant treatment for newly diagnosed advanced ovarian cancer: where do we stand and where are we going?
No full textNewly diagnosed high grade serous epithelial ovarian cancer (EOC) patients are treated with radical surgery followed by adjuvant platinum and taxane combination chemotherapy. In EOC patients where upfront surgery is contraindicated for medical reasons (e.g., comorbidities or poor performance status), or where complete cytoreduction cannot be achieved, neoadjuvant chemotherapy (NACT) prior to interval debulking surgery (IDS), and adjuvant chemotherapy is an alternative therapeutic option. There is currently a lack of consensus about who are the best candidates to receive NACT, and some authors have even suggested that this approach could be harmful in a subset of patients via promotion of early chemoresistance. Standard and novel imaging techniques together with a better molecular characterization of the disease have the potential to improve selection of patients, but ultimately well designed randomised clinical trials are needed to guide treatment decisions in this setting. The advent of new and effective treatment options (antiangiogenics and PARP inhibitors), now approved for use in the first line and relapse settings has opened the way to clinical trials aiming to investigate these agents as substitute or in addition to chemotherapy in the neoadjuvant setting in molecularly selected EOC patients. Here, we will review the evidence supporting the use of NACT in newly diagnosed EOCs, data highlighting the importance of its use in selected patients, new imaging methodologies and biomarkers that can guide patient selection
Imaging-based assessment of response to olaparib in platinum-sensitive relapsed ovarian cancer patients
No full textBackgroundHigh-grade serous carcinoma is a highly metastatic disease with a limited longterm disease control from systemic anti-cancer treatment, for which the radiological treatment response assessment metrics are imprecise. In this work, we developed noninvasive imagingbased measurements of spatial and longitudinal heterogeneity in a retrospective analysis of a phase 2 non-randomized study of germline BRCA1/BRCA2 mutated (gBRCAm) ovarian cancer patients treated with combination of PARP inhibitors (PARPi) and immune checkpoint inhibitors (ICIs).MethodsLesions identified in CT images at baseline, week 4 (after PARPi only) and week 12 (after 8 weeks of PARPi + ICIs) were manually segmented. Anatomical networks of the metastatic sites were constructed to represent patterns of disease distribution. Volume and first-order radiomic features were computed and compared to different assessments of treatment response.ResultsThe average number of edges per patient in the anatomical networks and total volumetric burden decreased with treatment were measured, differentiating between responders and nonresponders. Changes in volume at week 4 provided better indication of long-term response than the default RECIST assessment at the same time-point. Significant differences were also found between responders and non-responders in the first-order radiomic feature Energy.ConclusionsIn this feasibility study, we have demonstrated that noninvasive image-based analysis can identify quantitative imaging features associated with the response to the combination of PARPi and ICIs. These can be used to identify markers of response to ICIs from negative trials of a disease with limited response to ICIs
Ultrasound-guided targeted biopsies of CT-based radiomic tumour habitats: technical development and initial experience in metastatic ovarian cancer
No full textPurpose To develop a precision tissue sampling technique that uses computed tomography (CT)-based radiomic tumour habitats for ultrasound (US)-guided targeted biopsies that can be integrated in the clinical workflow of patients with high-grade serous ovarian cancer (HGSOC). Methods Six patients with suspected HGSOC scheduled for US-guided biopsy before starting neoadjuvant chemotherapy were included in this prospective study from September 2019 to February 2020. The tumour segmentation was performed manually on the pre-biopsy contrast-enhanced CT scan. Spatial radiomic maps were used to identify tumour areas with similar or distinct radiomic patterns, and tumour habitats were identified using the Gaussian mixture modelling. CT images with superimposed habitat maps were co-registered with US images by means of a landmark-based rigid registration method for US-guided targeted biopsies. The dice similarity coefficient (DSC) was used to assess the tumour-specific CT/US fusion accuracy. Results We successfully co-registered CT-based radiomic tumour habitats with US images in all patients. The median time between CT scan and biopsy was 21 days (range 7-30 days). The median DSC for tumour-specific CT/US fusion accuracy was 0.53 (range 0.79 to 0.37). The CT/US fusion accuracy was high for the larger pelvic tumours (DSC: 0.76-0.79) while it was lower for the smaller omental metastases (DSC: 0.37-0.53). Conclusion We developed a precision tissue sampling technique that uses radiomic habitats to guide in vivo biopsies using CT/US fusion and that can be seamlessly integrated in the clinical routine for patients with HGSOC
Assessment of early response to neoadjuvant chemotherapy in multi-site high-grade serous ovarian cancer using hyperpolarized-13C MRI
No full textBackground: To evaluate the capability of hyperpolarized [1-13C] pyruvate MRI to predict pathologic response to neoadjuvant treatment in multi-site abdominopelvic disease of high-grade serous ovarian cancer (HGSOC) patients and to compare 13C MRI and [18F]-FDG PET/CT measurements for detecting early treatment response. We recruited eight patients with HGSOC in this prospective study who underwent 13C MRI and [18F]-FDG PET/CT before and after the first cycle of neoadjuvant chemotherapy treatment (NACT). Imaging parameters were compared with clinical and histophatologic parameters. Results: We demonstrate here that 13C MRI of hyperpolarized [1-13C]pyruvate metabolism in multiple abdominal metastases resulted in rapid labeling of the endogenous tumor lactate pool. The rate of labeling was similar between the different anatomical disease sites and independent of tumor volume. The apparent rate constant describing exchange of 13C label between pyruvate and lactate (kPL) was positively correlated with PET standard uptake values (SUVmax) for [18F]-FDG in metastatic tumor deposits in the ovary/pelvis (R = 0.471, P = 0.02). Decreased lactate labeling could be detected after the first cycle of neoadjuvant chemotherapy and was associated with pathological response. There was no overall decrease in lactate labeling in a single patient who lacked a complete histopathologic response. kPL was associated with cancer tissue LDHA concentration (rho = 0.641; P = 0.02). Conclusion: This exploratory study demonstrates the potential of 13C MRI measurements for assessing early response to neoadjuvant chemotherapy in patients with HGSOC
A phase 1 trial of human telomerase reverse transcriptase (hTERT) vaccination combined with therapeutic strategies to control immune-suppressor mechanisms
No full textThe presence of inhibitory immune cells and difficulty in generating activated effector T cells remain obstacles to development of effective cancer vaccines. We designed a vaccine regimen combining human telomerase reverse transcriptase (hTERT) peptides with concomitant therapies targeting regulatory T cells (Tregs) and cyclooxygenase-2 (COX2)-mediated immunosuppression. This Phase 1 trial combined an hTERT-derived 7-peptide library, selected to ensure presentation by both HLA class-I and class-II in 90% of patients, with oral low-dose cyclophosphamide (to modulate Tregs) and the COX2 inhibitor celecoxib. Adjuvants were Montanide and topical TLR-7 agonist, to optimise antigen presentation. The primary objective was determination of the safety and tolerability of this combination therapy, with anti-cancer activity, immune response and detection of antigen-specific T cells as additional endpoints. Twenty-nine patients with advanced solid tumours were treated. All were multiply-pretreated, and the majority had either colorectal or prostate cancer. The most common adverse events were injection-site reactions, fatigue and nausea. Median progression-free survival was 9weeks, with no complete or partial responses, but 24% remained progression-free for ≥6months. Immunophenotyping showed post-vaccination expansion of CD4+ and CD8+ T cells with effector phenotypes. The in vitro re-challenge of T cells with hTERT peptides, TCR sequencing, and TCR similarity index analysis demonstrated the expansion following vaccination of oligoclonal T cells with specificity for hTERT. However, a population of exhausted PD-1+ cytotoxic T cells was also expanded in vaccinated patients. This vaccine combination regimen was safe and associated with antigen-specific immunological responses. Clinical activity could be improved in future by combination with anti-PD1 checkpoint inhibition to address the emergence of an exhausted T cell population
A Self-Supervised Image Registration Approach for Measuring Local Response Patterns in Metastatic Ovarian Cancer
No full textHigh-grade serous ovarian carcinoma (HGSOC) is characterised by significant spatial and temporal heterogeneity, typically manifesting at an advanced metastatic stage. A major challenge in treating advanced HGSOC is effectively monitoring localised change in tumour burden across multiple sites during neoadjuvant chemotherapy (NACT) and predicting long-term pathological response and overall patient survival. In this work, we propose a self-supervised deformable image registration algorithm that utilises a general-purpose image encoder for image feature extraction to co-register contrast-enhanced computerised tomography scan images acquired before and after neoadjuvant chemotherapy. This approach addresses challenges posed by highly complex tumour deformations and longitudinal lesion matching during treatment. Localised tumour changes are calculated using the Jacobian determinant maps of the registration deformation at multiple disease sites and their macroscopic areas, including hypo-dense (i.e., cystic/necrotic), hyper-dense (i.e., calcified), and intermediate density (i.e., soft tissue) portions. A series of experiments is conducted to understand the role of a general-purpose image encoder and its application in quantifying change in tumour burden during neoadjuvant chemotherapy in HGSOC. This work is the first to demonstrate the feasibility of a self-supervised image registration approach in quantifying NACT-induced localised tumour changes across the whole disease burden of patients with complex multi-site HGSOC, which could be used as a potential marker for ovarian cancer patient\u27s long-term pathological response and survival
