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Long-term cardiovascular disease risk after anthracycline and trastuzumab treatments in US breast cancer survivors.
No full textBACKGROUND: Although breast cancer survivors are at risk for cardiovascular disease (CVD) from treatment late effects, evidence to inform long-term and age-specific cardiovascular surveillance recommendations is lacking. METHODS: We conducted a retrospective cohort study of 10 211 women diagnosed with first primary unilateral breast cancer in Kaiser Permanente Washington or Colorado (aged 20 years and older, survived ≥1 year). We estimated multivariable adjusted hazard ratios (HRs) for associations between initial chemotherapy regimen type (anthracycline and/or trastuzumab, other chemotherapies, no chemotherapy [referent]) and CVD risk, adjusted for patient characteristics, other treatments, and CVD risk factors. Cumulative incidence was calculated considering competing events. RESULTS: After 5.79 median years, 14.67% of women developed CVD (cardiomyopathy and/or heart failure [HF], ischemic heart disease, stroke). Women treated with anthracyclines and/or trastuzumab had a higher risk of CVD compared with no chemotherapy (adjusted HR = 1.53, 95% confidence interval [CI] = 1.31 to 1.79), persisting at least 5 years postdiagnosis (adjusted HR5-<10 years = 1.85, 95% CI = 1.44 to 2.39; adjusted HR≥10 years = 1.83, 95% CI = 1.34 to 2.49). Cardiomyopathy and/or HF risks were elevated among women treated with anthracyclines and/or trastuzumab compared with no chemotherapy, especially for those aged younger than 65 years (adjusted HR20-54years = 2.97, 95% CI = 1.72 to 5.12; adjusted HR55-64years = 2.21, 95% CI = 1.52 to 3.21), differing for older women (adjusted HR≥65 years = 1.32, 95% CI = 0.97 to 1.78), and at least 5 years postdiagnosis (adjusted HR5-<10years = 1.89, 95% CI = 1.35 to 2.64; adjusted HR≥10 years = 2.21, 95% CI = 1.52 to 3.20). Anthracyclines and/or trastuzumab receipt was associated with increased ischemic heart disease risks after 5 or more years (adjusted HR5-<10years = 1.51, 95% CI = 1.06 to 2.14; adjusted HR≥10 years = 1.86, 95% CI = 1.18 to 2.93) with no clear age effects, and stroke risk (adjusted HR = 1.33, 95% CI = 1.05 to 1.69), which did not vary by time or age. There was some evidence of long-term cardiomyopathy and/or HF and ischemic heart disease risks with other chemotherapies. Among women aged younger than 65 treated with anthracyclines and/or trastuzumab, up to 16% developed CVD by 10 years (20-54 years = 6.91%; 55-64 years = 16.00%), driven by cardiomyopathy and/or HF (20-54 years = 3.90%; 55-64 years = 9.78%). CONCLUSIONS: We found increased long-term risks of cardiomyopathy and/or HF and ischemic heart disease among breast cancer survivors treated with anthracyclines and/or trastuzumab and increased cardiomyopathy and/or HF risk among women aged younger than 65 years
A Fragment-based Approach to Identify Small Molecule Inhibitors of Shelterin Complex Assembly
No full textShelterin is a six-subunit complex that binds to telomeres where it protects the chromosome ends
from an unwarranted activation of the DNA damage response and, in collaboration with telomerase,
mediates homeostatic telomere length maintenance. Restored telomere length homeostasis is a
hallmark of cancer initiation and progression, which makes shelterin a promising therapeutic target.
The aim of this thesis work is to use a fragment-based screening approach to find small-molecule
inhibitors of the protein-protein interactions driving shelterin complex assembly. Such inhibitors would
be useful tool compounds to dissect the precise functions of subunits and subcomplexes of shelterin
and may, depending on their cellular impact, form the foundation for the development of novel
therapeutic anti-cancer strategies. The particular focus of this thesis is on the TRF homology (TRFH)
domain of the shelterin subunit TRF1 (TRF1 TRFH). This domain is crucial for the recruitment of
TRF1 to shelterin through a domain-peptide interaction with a flexible region of TIN2 (TIN2 TBM), the
central scaffold of the shelterin complex. Using a combination of ligand-observed (LO-)NMR and Xray
crystallography fragment screening, a series of fragment hits were found to bind at the TIN2 TBM
binding site of TRF1 TRFH. A novel crystal system of TRF1TRFH was discovered that allowed
routine soaking of fragment hits into the TIN2TBM binding site of TRF1 TRFH. Using a structurebased
in silico approach, further analogues were designed, including compound 58. This compound
was shown to bind to TRF1 TRFH with a KD of 29 μM (95% CI: 20 – 41 μM), as measured by the LONMR
R2KD assay, and displaced a TIN2TBM probe with an IC50 of 74 ± 20 μM in a fluorescence
polarisation assay. The hit matter and the TRF1-TIN2 hot spot characterised in this thesis will serve
as a starting point for the structure-guided development of potent inhibitors of TRF1 protein-protein
interactions to disrupt shelterin complex assembly
Long-Term Outcomes After Concurrent Once- or Twice-Daily Chemoradiation in Limited-Stage Small Cell Lung Cancer: A Brief Report From the CONVERT Trial.
No full textPURPOSE: CONVERT was a phase 3 international randomized clinical trial comparing once-daily (OD) and twice-daily (BD) radiation therapy (RT). This updated analysis describes the 6.5-year outcomes of these regimens delivered with conformal techniques. METHODS AND MATERIALS: CONVERT (NCT00433563) randomized patients 1:1 between OD RT (66 Gy/33 fractions/6.5 weeks) and BD RT (45 Gy/30 fractions/3 weeks), both delivered with concurrent cisplatin/etoposide. Three-dimensional conformal RT was mandatory, intensity-modulated RT was permitted, and elective nodal irradiation was not allowed. Prophylactic cranial irradiation was delivered at the discretion of treating clinicians. RT treatment planning was subject to central quality assurance. RESULTS: Five hundred forty-seven patients were recruited at 73 centers. The median follow-up for the surviving cohort (n = 164) was 81.2 months. The median survival for the OD and BD arms were 25.4 months (95% CI, 21.1-30.9) and 30.0 months (95% CI, 25.3-36.5; hazard ratio, 1.13; 95% CI, 0.92-1.38; P = .247). Performance status and tumor volume were associated with survival on multivariate analysis. No treatment-related deaths occurred subsequent to the initial analysis performed in 2017. Regarding late toxicity, 7 patients in the OD arm developed grade 3 esophagitis, 4 of which went on to develop stricture or fistulation, compared with no patients in the BD arm. Grade 3 pulmonary fibrosis occurred in 2 and 3 patients in the OD and BD arms, respectively. CONCLUSIONS: As the CONVERT trial did not demonstrate the superiority of OD RT and this regimen had a slightly worse toxicity profile after 80 months of follow-up, 45 Gy BD should remain the standard of care in limited stage small cell lung cancer
Quantitative MRI for Monitoring Heterogeneous Radiotherapy Response in Soft-Tissue Sarcoma
No full textThis work explores using quantitative MRI biomarkers to assess treatment-induced changes in Soft-Tissue Sarcomas (STS).
STS are rare heterogeneous tumours that develop in the connective tissues and current image-based treatment response evaluation techniques do not correlate well with histopathological analysis. There is a need for novel imaging biomarkers that can better represent the underlying biological characteristics of these tumours.
In this work a multiparametric, quantitative MRI (qMRI) protocol is developed allowing the extraction of multiple quantitative biomarkers from a single MR exam. In a dedicated clinical trial, STS patients treated by radiotherapy were examined using the qMRI protocol at three time points: before treatment, during early-treatment and post-treatment.
Several quantitative biomarkers were analysed from each imaging time point, including the ADC, FA, FF, MTR, EF, R1 and R2. Relationships between the biomarkers and how they change throughout treatment was assessed. Data from the histopathological clinical reports including sarcoma subtype and histopathological analysis (viable tumour percentage) were compared with the qmri biomarkers.
In addition, a new imaging technique, multi-frequency MR elastography, was developed for use in the clinical trial allowing for the extraction of another qMRI biomarker: wave speed. Phantom and volunteer studies were used to optimise the parameters for MRE within this patient cohort and initial patient measurements were taken.
An additional project which looked at radiomic features in retroperitoneal sarcomas (completed during the coronavirus lockdown) was also completed. The repeatability of radiomic features from ADC maps and the ability to change post-treatment was analysed using a previous patient cohort. An independent repeatable subset of radiomic features that change following treatment was identified as potential imaging biomarkers
Repeatability of quantitative MR fingerprinting for T1 and T2 measurements of metastatic bone in prostate cancer patients.
No full textOBJECTIVES: MR fingerprinting (MRF) has the potential to quantify treatment response. This study evaluated the repeatability of MRF-derived T1 and T2 relaxation times in bone metastasis, bone, and muscle in patients with metastatic prostate cancer. MATERIALS AND METHODS: This prospective single-centre study included same-day repeated MRF acquisitions from 20 patients (August 2019-October 2020). Phantom and human data were acquired on a 1.5-T MR scanner using a research MRF sequence outputting T1 and T2 maps. Regions of interest (ROIs) across three tissue types (bone metastasis, bone, muscle) were drawn on two separate acquisitions. Repeatability of T1 and T2 was assessed using Bland-Altman plots, together with repeatability (r) and intraclass correlation (ICC) coefficients. Mean T1 and T2 were reported per tissue type. RESULTS: Twenty patients with metastatic prostate cancer (mean age, 70 years ± 8 (standard deviation)) were evaluated and bone metastasis (n = 44), normal-appearing bone (n = 14), and muscle (n = 20) ROIs were delineated. Relative repeatability of T1 measurements was 6.9% (bone metastasis), 32.6% (bone), 5.8% (muscle) and 21.8%, 32.2%, 16.1% for T2 measurements. The ICC of T1 was 0.97 (bone metastasis), 0.94 (bone), 0.96 (muscle); ICC of T2 was 0.94 (bone metastasis), 0.94 (bone), 0.91 (muscle). T1 values in bone metastasis were higher than in bone (p < 0.001). T2 values showed no difference between bone metastasis and bone (p = 0.5), but could separate active versus treated metastasis (p < 0.001). CONCLUSION: MRF allows repeatable T1 and T2 measurements in bone metastasis, bone, and muscle in patients with primary prostate cancer. Such measurements may help quantify the treatment response of bone metastasis. KEY POINTS: Question MR fingerprinting has the potential to characterise bone metastasis and its response to treatment. Findings Repeatability of MRF-based T1 measurements in bone metastasis and muscle was better than for T2. Clinical relevance MR fingerprinting allows repeatable T1 and T2 quantitative measurements in bone metastasis, bone, and muscle in patients with primary prostate cancer, which makes it potentially applicable for disease characterisation and assessment of treatment response
Treatment planning for very high energy electrons: Studies that indicate the potential of the modality.
No full textBACKGROUND AND PURPOSE: Radiotherapy using Very High Energy Electrons (VHEE) has the potential to reduce dose to organs at risk compared to photons. This article therefore reviews treatment planning for VHEE, to clarify the potential benefit of the modality. MATERIALS AND METHODS: Articles on VHEE were identified and those which focused on treatment planning were manually selected, particularly those which contained results on patient datasets. Benefits in absorbed dose to organs at risk were converted to percentages of prescription dose so as to provide uniform, clinically relevant reporting. RESULTS: Increased beam energy was found to reduce electron scatter and give rise to a narrower penumbra but lead to a rather constant depth dose curve, which was not as useful for sparing normal tissues as that of protons. The sharp penumbra of VHEE was of benefit in treatment planning for producing treatment plans with conformal dose shaping, with improved dose to critical structures being demonstrated for several treatment sites. Mean dose to critical structures, relative to the prescribed dose, was in the order of 0-10% lower than photons and 0-10% higher than protons. The delivery technology and dose distributions were also promising for radiotherapy with ultra-high dose rate (FLASH). CONCLUSION: At present, the potential clinical benefit of VHEE relative to photons or protons is small. Further studies are needed to more precisely quantify the relative performance of broad beams versus pencil beam scanning and to investigate treatment sites that might benefit maximally from the use of VHEE beams
Multivariable models of outcomes with [177Lu]Lu-PSMA-617: analysis of the phase 3 VISION trial.
No full textBACKGROUND: [177Lu]Lu-PSMA-617 (177Lu-PSMA-617) prolonged life in patients with metastatic castration-resistant prostate cancer (mCRPC) in VISION (NCT03511664). However, distinguishing between patients likely and unlikely to respond remains a clinical challenge. We present the first multivariable models of outcomes with 177Lu-PSMA-617 built using data from VISION, a large prospective phase 3 clinical trial powered for overall survival. METHODS: Adults with progressive post androgen receptor pathway inhibitor and taxane prostate-specific membrane antigen (PSMA)-positive mCRPC received 177Lu-PSMA-617 plus protocol-permitted standard of care (SoC) or SoC alone. In this post hoc analysis, multivariable Cox proportional hazards models of overall survival (OS) and radiographic progression-free survival (rPFS), and a logistic regression model of prostate-specific antigen response (≥50% decline; PSA50) were constructed and evaluated using C-index or receiver operating characteristic (ROC) analyses with bootstrapping validation. Nomograms were constructed for visualisation. FINDINGS: Patients were randomised between June 2018 and October 2019. Data from all 551 patients in the 177Lu-PSMA-617 arm were analysed in multivariable modelling. The OS nomogram (C-index, 0.73; 95% confidence interval [CI], 0.70-0.76) included whole-body maximum standardised uptake value (SUVmax), time since diagnosis, opioid analgesic use, aspartate aminotransferase, haemoglobin, lymphocyte count, presence of PSMA-positive lesions in lymph nodes, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and neutrophil count. The rPFS nomogram (C-index, 0.68; 0.65-0.72) included SUVmax, time since diagnosis, opioid analgesic use, lymphocyte count, presence of liver metastases by computed tomography, LDH, and ALP. The PSA50 nomogram (area under ROC curve, 0.72; 95% CI, 0.68-0.77) included SUVmax, lymphocyte count and ALP. Performances of the OS and rPFS models were maintained when they were reconstructed excluding SUVmax. INTERPRETATION: These models of outcomes with 177Lu-PSMA-617 are the first built using prospective phase 3 data. They show that a combination of pretreatment laboratory, clinical, and imaging parameters, reflecting both patient and tumour status, influences outcomes. These models are important for aiding treatment selection, patient management, and clinical trial design. FUNDING: Novartis
Exploiting the Vulnerability of ARID1A Deficient Ovarian Cancers for Therapeutic Potential
No full textThe switching defective/sucrose non-fermenting (SWI/SNF) chromatin remodelling complex is important for the cellular response to replication stress. 20% of cancers harbour modifications in SWI/SNF complex subunits. ARID1A, a key component of the SWI/SNF complex, is mutated across a variety of cancers, and notably in 35-57% of ovarian clear cell carcinomas (OCCC). Clinically applicable targeted therapies for this aggressive, chemo-resistant disease remains an unmet need. G-quadruplexes (G4s) are thermodynamically stable secondary DNA structures which are a consequence of folding of guanine-rich DNA sequences. Treatment with G4 stabilising ligands, some of which have entered clinical trials, leads to DNA double strand breaks (DSBs). This represents a therapeutic vulnerability for cancers with defects in the response to G4 ligands and resulting DNA DSBs. Here, isogenic cell line models were generated using CRISPR-Cas9 gene editing and genetic complementation of ARID1A to study the potential contribution of ARID1A to genotoxic stress. We found that ARID1A deficient cells show selective sensitivity to G4 stabilising ligands, and that there is evidence of delayed repair of DNA damage when ARID1A is deficient. Mechanistically, we discovered that NHEJ factors fail to mobilise onto chromatin after treatment with stabilising ligand PDS when ARID1A is deficient. Furthermore, we showed that inhibitor of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs), a protein ensuring effective NHEJ functions, when combined with PDS leads to synergistic decrease in cell viability in ARID1A deficient cells. These data provide new insights into G4 ligands-induced DNA damage and their repair in ARID1A-defective models. This knowledge could be exploited for a new therapeutic approach to treat ARID1A deficient ovarian cancer
Tracking tumour evolution through adjuvant therapy in Triple Negative Breast Cancer
No full textAbstract
Relapsed Triple Negative Breast Cancer (TNBC) carries a poor prognosis. Improved understanding of the molecular features of early disease, and the evolution of TNBC from early to relapsed disease, is likely to be key to developing therapies to overcome treatment resistance.
c-TRAK TN recruited 161 patients with early-stage moderate-high risk TNBC into prospective ctDNA surveillance for Molecular Residual Disease (MRD) with digital PCR (dPCR) assays after completion of curative treatment. A subset of patients who relapsed provided a relapse biopsy. Tissue samples were whole exome sequenced (WES) and relapse plasma DNA was subject to error-corrected WES. Digitalised pathology and multiplexed immunofluorescence characterised the immune microenvironment of early tumour tissue samples. Clonal evolution analysis was performed in patients with a minimum of two samples which completed WES, where MRD was detected, or with paired samples before and after neoadjuvant chemotherapy. Individual clones were tracked through plasma samples taken every three months from trial entry until relapse using ctDNA personalised sequencing assays.
The rate of germline pathogenic variants of BRCA1/BRCA2 in this cohort was lower than other published cohorts of TNBC. Neoadjuvant chemotherapy was associated with a loss of heterogeneity of the HLA alleles and a reduction in CD20+ cells. MRD was first detected by personalised sequencing assays in 47.9% of patients, 0% first detected by dPCR assays, and 52.1% with both assays simultaneously. Clonal structures were constructed for 56 patients. Subclones from the primary cancer frequently metastasised. Neoadjuvant chemotherapy provided a substantial evolutionary bottle neck, with subclones detected post neoadjuvant chemotherapy most likely to persist into the MRD and contribute to relapsed disease.
This is the largest and most detailed study of clonal evolution in triple negative breast cancer, and the first to investigate clonal evolution through MRD. Sub-clonal persistence poses a key therapeutic challenge in overcoming treatment resistance
A first-in-human phase I study of the PD-1 inhibitor, retifanlimab (INCMGA00012), in patients with advanced solid tumors (POD1UM-101).
No full textBACKGROUND: Retifanlimab is a humanized, hinge-stabilized immunoglobulin G4κ monoclonal antibody against human programmed cell death protein 1 (PD-1). This first-in-human, phase I study assessed the safety and efficacy of retifanlimab in patients with advanced solid tumors and identified optimal dosing. PATIENTS AND METHODS: POD1UM-101 was conducted in two parts: (i) dose escalation-evaluated retifanlimab [1 mg/kg every 2 weeks (q2w), 3 or 10 mg/kg q2w or every 4 weeks (q4w)] in patients with relapsed/refractory, unresectable, locally advanced or metastatic solid tumors; (ii) cohort expansion-biomarker-unselected tumor-specific cohorts [endometrial, cervical, sarcoma, non-small-cell lung cancer (NSCLC)] received retifanlimab 3 mg/kg q2w, and tumor-agnostic cohorts received flat dosing [375 mg every 3 weeks (q3w), or 500 and 750 mg q4w]. Primary objectives were safety and tolerability; secondary objective was efficacy in selected tumor types. RESULTS: Thirty-seven patients were enrolled in dose escalation, 134 in PD-1 therapy-naïve tumor-specific cohort expansion (endometrial, n = 29; cervical, NSCLC, soft tissue sarcoma, each n = 35), and 45 in flat dosing (375 mg q3w, 500 and 750 mg q4w, each n = 15). No dose-limiting toxicities occurred during dose escalation; maximum tolerated dose was not reached and 3-mg/kg q2w expansion dose was selected based on safety and pharmacokinetic data. Immune-related adverse events were experienced by 40 patients (30%) in tumor-specific cohorts (most frequently hypothyroidism, hyperthyroidism, colitis, nephritis) and 6 (13%) in flat dosing (most frequently hypothyroidism, hyperthyroidism). Objective response rate (95% confidence interval) was 14% (4.8 to 30.3), 14% (3.9 to 31.7), 20% (8.4 to 36.9), and 3% (0.1 to 14.9) in advanced NSCLC, endometrial, cervical, and sarcoma tumor-specific cohorts that progressed after multiple prior systemic therapies. CONCLUSIONS: Retifanlimab demonstrated clinical pharmacology, safety, and antitumor activity consistent with the programmed death (ligand)-1 inhibitor class. POD1UM-101 results support further exploration of retifanlimab as monotherapy and backbone immunotherapy in combination treatments, with recommended doses of 500 mg q4w and 375 mg q3w