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Prognostic value of EndoPredict test in patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer screened for the randomized, double-blind, phase III UNIRAD trial.
No full textBACKGROUND: The purpose of this study was to evaluate the prognostic value of the multigene EndoPredict test in prospectively collected data of patients screened for the randomized, double-blind, phase III UNIRAD trial, which evaluated the addition of everolimus to adjuvant endocrine therapy in high-risk, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. PATIENTS AND METHODS: Patients were classified into low or high risk according to the EPclin score, consisting of a 12-gene molecular score combined with tumor size and nodal status. Association of the EPclin score with disease-free survival (DFS) and distant metastasis-free survival (DMFS) was evaluated using Kaplan-Meier estimates. The independent prognostic added value of EPclin score was tested in a multivariate Cox model after adjusting on tumor characteristics. RESULTS: EndoPredict test results were available for 768 patients: 663 patients classified as EPclin high risk (EPCH) and 105 patients as EPclin low risk (EPCL). Median follow-up was 70 months (range 1-172 months). For the 429 EPCH randomized patients, there was no significant difference in DFS between treatment arms. The 60-month relapse rate for patients in the EPCL and EPCH groups was 0% and 7%, respectively. Hazard ratio (HR) supposing continuous EPclin score was 1.87 [95% confidence interval (CI) 1.4-2.5, P < 0.0001]. This prognostic effect remained significant when assessed in a Cox model adjusting on tumor size, number of positive nodes and tumor grade (HR 1.52, 95% CI 1.09-2.13, P = 0.0141). The 60-month DMFS for patients in the EPCL and EPCH groups was 100% and 94%, respectively (adjusted HR 8.10, 95% CI 1.1-59.1, P < 0.0001). CONCLUSIONS: The results confirm the value of EPclin score as an independent prognostic parameter in node-positive, hormone receptor-positive, HER2-negative early breast cancer patients receiving standard adjuvant treatment. EPclin score can be used to identify patients at higher risk of recurrence who may warrant additional systemic treatments
Adding 6 months of androgen deprivation therapy to postoperative radiotherapy for prostate cancer: a comparison of short-course versus no androgen deprivation therapy in the RADICALS-HD randomised controlled trial.
No full textBACKGROUND: Previous evidence indicates that adjuvant, short-course androgen deprivation therapy (ADT) improves metastasis-free survival when given with primary radiotherapy for intermediate-risk and high-risk localised prostate cancer. However, the value of ADT with postoperative radiotherapy after radical prostatectomy is unclear. METHODS: RADICALS-HD was an international randomised controlled trial to test the efficacy of ADT used in combination with postoperative radiotherapy for prostate cancer. Key eligibility criteria were indication for radiotherapy after radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to radiotherapy alone (no ADT) or radiotherapy with 6 months of ADT (short-course ADT), using monthly subcutaneous gonadotropin-releasing hormone analogue injections, daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as distant metastasis arising from prostate cancer or death from any cause. Standard survival analysis methods were used, accounting for randomisation stratification factors. The trial had 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 80% to 86% (hazard ratio [HR] 0·67). Analyses followed the intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Nov 22, 2007, and June 29, 2015, 1480 patients (median age 66 years [IQR 61-69]) were randomly assigned to receive no ADT (n=737) or short-course ADT (n=743) in addition to postoperative radiotherapy at 121 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 9·0 years (IQR 7·1-10·1), metastasis-free survival events were reported for 268 participants (142 in the no ADT group and 126 in the short-course ADT group; HR 0·886 [95% CI 0·688-1·140], p=0·35). 10-year metastasis-free survival was 79·2% (95% CI 75·4-82·5) in the no ADT group and 80·4% (76·6-83·6) in the short-course ADT group. Toxicity of grade 3 or higher was reported for 121 (17%) of 737 participants in the no ADT group and 100 (14%) of 743 in the short-course ADT group (p=0·15), with no treatment-related deaths. INTERPRETATION: Metastatic disease is uncommon following postoperative bed radiotherapy after radical prostatectomy. Adding 6 months of ADT to this radiotherapy did not improve metastasis-free survival compared with no ADT. These findings do not support the use of short-course ADT with postoperative radiotherapy in this patient population. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society
Sonic Hedgehog activates prostaglandin signaling to stabilize primary cilium length.
No full textSonic Hedgehog (SHH) is a driver of embryonic patterning that, when corrupted, triggers developmental disorders and cancers. SHH effector responses are organized through primary cilia (PC) that grow and retract with the cell cycle and in response to extracellular cues. Disruption of PC homeostasis corrupts SHH regulation, placing significant pressure on the pathway to maintain ciliary fitness. Mechanisms by which ciliary robustness is ensured in SHH-stimulated cells are not yet known. Herein, we reveal a crosstalk circuit induced by SHH activation of Phospholipase A2α that drives ciliary E-type prostanoid receptor 4 (EP4) signaling to ensure PC function and stabilize ciliary length. We demonstrate that blockade of SHH-EP4 crosstalk destabilizes PC cyclic AMP (cAMP) equilibrium, slows ciliary transport, reduces ciliary length, and attenuates SHH pathway induction. Accordingly, Ep4-/- mice display shortened neuroepithelial PC and altered SHH-dependent neuronal cell fate specification. Thus, SHH initiates coordination between distinct ciliary receptors to maintain PC function and length homeostasis for robust downstream signaling
Investigating the temporal dynamics of T cells following cancer immunotherapy
No full textThe blockade of immune checkpoints PD1 and CTLA4 have become a standard treatment for the treatment of melanoma. However, mechanistic understanding of how the immunotherapy works remains to be achieved. It is largely unknown how tumour-reactive T cells regulate their checkpoint expression in vivo, and how immune checkpoint blockade regulates such activation dynamics. Capturing temporally dynamic changes that occur following T cell activation at a single cell level remains a challenge, due to limitations in methods.
To address this, I used Nr4a3-Timer- of-cell-kinetics-and-activity (Tocky), which allows analysis of temporal dynamics of activated T cells following TCR signalling in vivo. Furthermore, the Tocky method is developed into a multidimensional method for analysing spectrum analyser data and single cell (sc)RNA-seq data, providing a deeper mechanistic understanding of checkpoint blockade.
By analysing melanoma-bearing Nr4a3 Tocky mice, hidden dynamics of tumour-reactive T cells are elucidated in the steady-state. Checkpoint blockade depleted highly activated Treg, while promoting unique effector T cell populations, and thus differentially modulating activation of tumour-reactive T cell populations. Furthermore, multidimensional analysis and seamless analysis of Tocky and expression data revealed a full spectrum of T cell dynamics in response to tumour burden and treatment with checkpoint blockade. Lastly, we propose a rational design of combinatorial therapy to further enhance T cell activities , demonstrating a role for an OX40 agonist in combination with dual checkpoint blockade to increase effector populations and decrease regulatory T cell populations, overall increasing therapeutic benefit compared to dual blockade.
Furthermore, the dynamics of Foxp3 transcription were investigated by Foxp3-Tocky, showing the dynamics of Treg in the Tumour compared to other organs. By investigating Foxp3 dynamics in Foxp3-tocky, we show that dual checkpoint blockade increases New Foxp3 transcription systemically, while being more short lived in the tumour.
Lastly, the role of activation induced cell death in mediating the effects of dual checkpoint immunotherapy was investigated using BIMKO-Nr4a3-tocky mice. This showed that the immunotherapy dynamically controls the composition of antigen-reactive T cells by cell death following TCR signals
Gastrointestinal stromal tumour (GIST): British Sarcoma Group clinical practice guidelines.
No full textBACKGROUND: British Sarcoma Group guidelines for the management of GIST were initially informed by those published by the European Society of Clinical Oncology. This update was written by a group of experts to includes a discussion of the highlight improvements in our knowledge of the disease and recent treatment developments. The guidelines include sections on Incidence, Aetiology, Diagnosis, including risk assessment, Treatment and Follow-up. METHODS: A careful review of the literature was performed to ensure that wherever possible recommendations are supported by the results of clinical trials or substantive retrospective reports. Areas of uncertainty are indicated appropriately. CONCLUSION: Guidelines represent a consensus view of current best clinical practice. Where appropriate, key recommendations are given and the levels of evidence and strength of recommendation gradings are those used by the European Society for Medical Oncology (ESMO)
Duration of androgen deprivation therapy with postoperative radiotherapy for prostate cancer: a comparison of long-course versus short-course androgen deprivation therapy in the RADICALS-HD randomised trial.
No full textBACKGROUND: Previous evidence supports androgen deprivation therapy (ADT) with primary radiotherapy as initial treatment for intermediate-risk and high-risk localised prostate cancer. However, the use and optimal duration of ADT with postoperative radiotherapy after radical prostatectomy remains uncertain. METHODS: RADICALS-HD was a randomised controlled trial of ADT duration within the RADICALS protocol. Here, we report on the comparison of short-course versus long-course ADT. Key eligibility criteria were indication for radiotherapy after previous radical prostatectomy for prostate cancer, prostate-specific antigen less than 5 ng/mL, absence of metastatic disease, and written consent. Participants were randomly assigned (1:1) to add 6 months of ADT (short-course ADT) or 24 months of ADT (long-course ADT) to radiotherapy, using subcutaneous gonadotrophin-releasing hormone analogue (monthly in the short-course ADT group and 3-monthly in the long-course ADT group), daily oral bicalutamide monotherapy 150 mg, or monthly subcutaneous degarelix. Randomisation was done centrally through minimisation with a random element, stratified by Gleason score, positive margins, radiotherapy timing, planned radiotherapy schedule, and planned type of ADT, in a computerised system. The allocated treatment was not masked. The primary outcome measure was metastasis-free survival, defined as metastasis arising from prostate cancer or death from any cause. The comparison had more than 80% power with two-sided α of 5% to detect an absolute increase in 10-year metastasis-free survival from 75% to 81% (hazard ratio [HR] 0·72). Standard time-to-event analyses were used. Analyses followed intention-to-treat principle. The trial is registered with the ISRCTN registry, ISRCTN40814031, and ClinicalTrials.gov, NCT00541047. FINDINGS: Between Jan 30, 2008, and July 7, 2015, 1523 patients (median age 65 years, IQR 60-69) were randomly assigned to receive short-course ADT (n=761) or long-course ADT (n=762) in addition to postoperative radiotherapy at 138 centres in Canada, Denmark, Ireland, and the UK. With a median follow-up of 8·9 years (7·0-10·0), 313 metastasis-free survival events were reported overall (174 in the short-course ADT group and 139 in the long-course ADT group; HR 0·773 [95% CI 0·612-0·975]; p=0·029). 10-year metastasis-free survival was 71·9% (95% CI 67·6-75·7) in the short-course ADT group and 78·1% (74·2-81·5) in the long-course ADT group. Toxicity of grade 3 or higher was reported for 105 (14%) of 753 participants in the short-course ADT group and 142 (19%) of 757 participants in the long-course ADT group (p=0·025), with no treatment-related deaths. INTERPRETATION: Compared with adding 6 months of ADT, adding 24 months of ADT improved metastasis-free survival in people receiving postoperative radiotherapy. For individuals who can accept the additional duration of adverse effects, long-course ADT should be offered with postoperative radiotherapy. FUNDING: Cancer Research UK, UK Research and Innovation (formerly Medical Research Council), and Canadian Cancer Society
Relative fat fraction of malignant bone lesions from breast cancer, prostate cancer and myeloma are significantly lower than normal bone marrow and shows excellent interobserver agreement.
No full textOBJECTIVES: To compare relative fat fraction (rFF) of active bone lesions from breast, prostate and myeloma malignancies and normal bone marrow; to assess its inter-reader agreement. METHODS: Patients with breast (n = 26), myeloma (n = 32) and prostate cancer (n = 52) were retrospectively evaluated. 110 baseline rFF maps from whole-body MRI were reviewed by two radiologists. Regions of interest for up to four focal active lesions in each patient were drawn on rFF maps, one each at the cervicothoracic spine, lumbosacral spine, pelvis and extremity. The mean and standard deviation of rFF were recorded. The rFF of normal marrow was measured in the pelvis for patients without diffuse bone disease (n = 88). We compared the rFF of malignant bone lesions and normal marrow using Mann-Whitney test. Interobserver agreement was assessed by interclass correlation coefficient. RESULTS: Malignant bone lesions showed significantly lower median rFF (13.87%) compared with normal marrow (89.76%) with little overlap (p 0.017, Bonferroni correction) and in the median rFF of bone disease according to their anatomical locations (p > 0.008, Bonferroni correction). There was excellent interobserver agreement (0.95). CONCLUSION: The low rFF of active bone lesions in breast, prostate and myeloma malignancies provides high image contrast relative to normal marrow that may be used to detect bone metastases. ADVANCES IN KNOWLEDGE: This study shows the importance of rFF towards detecting bone metastases
Influence of modern imaging techniques on management of locally and oligometastatic recurrent prostate cancer with Stereotactic Radiotherapy
No full textEvaluation of the role of novel imaging techniques in the utilisation of stereotactic radiotherapy for recurrent prostate cancer.
The current evidence surrounding the diagnosis, management, and areas of clinical need in recurrent prostate cancer are outlined.
Studies evaluating the role of novel imaging techniques in stereotactic radiotherapy are outlined,
1. Interobserver variation in target volume delineation for stereotactic radiotherapy to non-spinal bone metastases in prostate cancer: CT, MRI and PET/CT fusion
2. Prostate cancer recurrence after primary radiation therapy: A retrospective comparison of detection and outcomes after PSMA and Choline PET/CT
3. Analysis of outcomes of patients treated with SBRT to recurrent oligometastases: focus on long term survivors and diagnostic imaging
4. Planning study of local prostate cancer recurrence after primary radiotherapy: Partial vs whole gland robotic SBRT
Evaluation of evidence provided and influence on the field is described
Stereotactic radiosurgery for brain metastases: efficacy and toxicity
No full textStereotactic radiosurgery (SRS) is increasingly being used as a treatment for brain metastases. Four research topics in the management of brain metastases in clinical practice have been chosen, with the unifying theme of investigating SRS efficacy and toxicity. The first topic is an investigation of patients who receive primary SRS (i.e., SRS of unresected metastases), but who die within six months of treatment. Possible causes for this are explored with the aim of proposing some new eligibility criteria for treatment. The role of SRS to the post-operative surgical cavity after complete resection of brain metastasis has been less widely studied than that of primary SRS. The second topic of investigation is the local control benefit of SRS to the post-operative surgical cavity, after complete resection of brain metastases, using the CyberKnife (CK) SRS platform and fractionated SRS. Conventional brain magnetic resonance imaging (MRI) is used to assess treatment response post-SRS, but it can be difficult to reliably differentiate tumour recurrence/progression from radiotherapy-related treatment-effects, also known as radionecrosis (RN). As the management of these processes are different, this makes subsequent clinical decision-making complex. The third topic of investigation is an evaluation of contrast clearance analysis MRI, also known as treatment response assessment maps (TRAMs), to differentiate recurrent/progressive tumour from RN. RN is an important late toxicity of SRS that can lead to neurological complications, and there is currently no gold-standard predictive biomarker. The fourth topic is an investigation of dose-volume metrics, to determine whether this can reliably estimate the likelihood of RN, in those who receive primary SRS
Translational Aspects of Epithelioid Sarcoma: Current Consensus.
No full textEpithelioid sarcoma (EpS) is an ultra-rare malignant soft-tissue cancer mostly affecting adolescents and young adults. EpS often exhibits an unfavorable clinical course with fatal outcome in ∼50% of cases despite aggressive multimodal therapies combining surgery, chemotherapy, and irradiation. EpS is traditionally classified in a more common, less aggressive distal (classic) type and a rarer aggressive proximal type. Both subtypes are characterized by a loss of nuclear INI1 expression, most often following homozygous deletion of its encoding gene, SMARCB1-a core subunit of the SWI/SNF chromatin remodeling complex. In 2020, the EZH2 inhibitor tazemetostat was the first targeted therapy approved for EpS, raising new hopes. Still, the vast majority of patients did not benefit from this drug or relapsed rapidly. Further, other recent therapeutic modalities, including immunotherapy, are only effective in a fraction of patients. Thus, novel strategies, specifically targeted to EpS, are urgently needed. To accelerate translational research on EpS and eventually boost the discovery and development of new diagnostic tools and therapeutic options, a vibrant translational research community has formed in past years and held two international EpS digital expert meetings in 2021 and 2023. This review summarizes our current understanding of EpS from the translational research perspective and points to innovative research directions to address the most pressing questions in the field, as defined by expert consensus and patient advocacy groups