Institute of Cancer Research

In the PACE-B study, a nonrandomized comparison of toxicity outcomes between stereotactic body radiation therapy (SBRT) platforms revealed fewer urinary side effects with CyberKnife (CK) compared with conventional linac (CL) SBRT. This analysis compares baseline characteristics and planning dosimetry between the CK-SBRT and CL-SBRT cohorts in PACE-B, aiming to provide insight into possible reasons for differing toxicity outcomes between the platforms. Dosimetric parameters for the surrogate urethra (SU), contoured urethra, bladder, bladder trigone (BT), and rectum were extracted from available computed tomography planning scans of PACE-B SBRT patients. The SU and BT were retrospectively delineated. Dose levels analyzed included maximum point dose (Dmax), D2, D50, and D95, where D(n) represents the dose (Gy) to (n)% of the structure. Baseline characteristics and planning dosimetry between the CK-SBRT and CL-SBRT cohorts were compared using Mann-Whitney U tests, t tests, and χ2 tests. Of the 414 patients who received SBRT, 169 (41%) were treated with CK-SBRT and 245 (59%) with CL-SBRT, with dosimetric parameters available for 94% of patients (390/414). There was a nonstatistically significant trend toward more low-risk prostate cancer in the CK-SBRT cohort (12% vs 6% P = .02 [nonsignificant]). Margins were similar between platforms, except posteriorly, where CK-SBRT had smaller margins. CK-SBRT plans had significantly higher median SU Dmax (45.9 Gy vs 42.8 Gy, P < .0001), D2%, and D50% compared with CL-SBRT plans. Additionally, CK-SBRT plans had significantly higher median BT Dmax (43.4 Gy vs 41.6 Gy, P < .0001), D2%, and D95%, as well as higher median bladder Dmax, D50%, and D95%. CK-SBRT plans had lower median rectal D2% (35.5 Gy vs 36.0 Gy, P < .0001) but higher rectal D50% and D95%. Although the CK-SBRT cohort showed lower urinary toxicity, the planned doses to urinary substructures were actually higher, likely due to heterogeneous dose planning. Factors like intrafraction tracking or other confounding variables may explain the differences in toxicity outcomes between the treatment platforms.

Amivantamab is an EGFR-MET bispecific antibody approved as an intravenous formulation for EGFR-mutated advanced non-small cell lung cancer (NSCLC). Intravenous delivery is frequently associated with infusion-related reaction (IRRs), which require adopting slow infusion rates and splitting the first dose over 2 days. The PALOMA study assessed the safety and feasibility of subcutaneous amivantamab administration and identified the formulation and recommended phase II doses (RP2Ds) for multiple dosing schedules. PALOMA is a phase Ib dose-escalation study in 158 participants with advanced solid malignancies. Primary objectives included pharmacokinetics, safety, and determining RP2Ds for every-2-week (Q2W), every-3-week (Q3W), and every-4-week (Q4W) administration. The safety profile of subcutaneous amivantamab was largely consistent with intravenous monotherapy; most common toxicities reflected on-target EGFR/MET inhibition. Subcutaneous amivantamab resulted in meaningfully shorter administration time (≤ 10 minutes vs. 2.3 hours for intravenous beyond cycle 3) and lower incidence and severity of IRRs versus historical intravenous data, which eliminates the need for split-dose administration. Pharmacokinetic analyses and population pharmacokinetic modeling/simulation were used to estimate subcutaneous amivantamab RP2Ds of 1600 mg (2240 mg, ≥ 80 kg), 2400 mg (3360 mg, ≥ 80 kg), and 3520 mg (4640 mg, ≥ 80 kg) for Q2W, Q3W, and Q4W schedules, respectively. The observed efficacy was consistent with intravenous amivantamab monotherapy. Subcutaneous amivantamab administration substantially reduced IRRs, obviating the need for prolonged infusions and 2-day split-dosing at first administration. The identified RP2Ds for subcutaneous amivantamab are implemented in ongoing studies evaluating amivantamab regimens in NSCLC, colorectal cancer, and head and neck squamous cell carcinoma.

Advanced tumors harboring SWI/SNF mutations are rare and aggressive. Often presenting in young patients, treatment options are limited. This phase II basket study (NCT02601950) assessed oral tazemetostat, an EZH2 inhibitor, at 800 mg twice daily (N = 129). Cohorts included malignant rhabdoid tumors (n = 32, Cohort 1), synovial sarcoma (n = 33, Cohort 2), INI1-negative tumors (n = 32, Cohort 3), renal medullary carcinoma (n = 14, Cohort 4), and poorly differentiated chordoma (n = 18, Cohort 7). Efficacy assessments used a 2-stage Green-Dahlberg design. Stage 1 futility was predefined as objective responses (complete/partial [CR/PR]) <5% (Cohorts 1, 3, 4, 7) or 16-week progression-free survival (PFS) <15% (Cohort 2). Sufficient clinical activity was declared in Stage 2 if ≥5 patients had a CR/PR (Cohorts 1,3,4,7) or ≥9 patients had a CR/PR, or stable disease (Cohort 2; primary endpoints). Responses were observed in malignant rhabdoid tumors (9%; n = 2 PR, n = 1 CR), INI1-negative tumors (9%; n = 3 PR, n = 0 CR), and poorly differentiated chordoma (6%; n = 1 PR, n = 0 CR) but not the remaining 2 cohorts (both 0%). 16-week PFS for synovial sarcoma was 15.2% (n = 5). Grade ≥3 treatment-related adverse events occurred in 10% of patients. Tazemetostat demonstrated preliminary antitumor activity in a subset of poor-prognosis cancers, underscoring the need for combination strategies when EZH2 signaling is not the sole disease driver.

Methods to detect circulating tumor DNA (ctDNA) enable minimally invasive responsive monitoring of cancer dynamics. However, sensitive and cost-effective methods are still lacking. Current methods for detecting cancer signals in shallow whole-genome sequencing (sWGS) data from cell-free DNA (cfDNA) via copy number aberration (CNA) analysis typically have a limit of detection of approximately 3% tumor fraction (TF). We developed informCNA, a bioinformatics method that leverages CNA information from sWGS of tumor or pre-treatment plasma samples with high TF as references, enabling ctDNA detection down to 0.2% TF across multiple cancer types. In 177 serial plasma samples from 18 patients with ovarian cancer, informCNA showed high concordance with the standard serum protein marker CA-125 and identified recurrence a median of 3.7 months earlier than CA-125 test. These results demonstrate the potential of personalized CNA analysis through sWGS for estimating ctDNA burden, enabling precise and cost-effective disease monitoring and early detection of relapse.

Cancer Variant Interpretation Group UK was established in 2017 in response to the publication of the 2015 ACMG/AMP v3 guidance for the interpretation of sequence variants. Its initial purpose was to ensure consistency in the UK clinical-laboratory community implementation of ACMG/AMP v3 guidance for cancer susceptibility genes (CSGs). Still convening for monthly national meetings, the remit of CanVIG-UK now encompasses additional activities delivered under the following objectives: 1. Creation of a national multidisciplinary professional network and regular forum. 2. Delivery of training and education. 3. Establishment of a consensus approach to the fundamentals of variant interpretation in cancer susceptibility genes. 4. Development and ratification of gene-specific frameworks for variant interpretation for cancer susceptibility genes. 5. Development and maintenance of an online platform to facilitate information sharing and variant interpretation within the UK clinical-laboratory community. 6. Facilitation of UK contribution to international variant interpretation endeavours. A survey of CanVIG-UK members evaluating the impact of these activities conducted in November 2025 had 163 responses, including 113 clinical scientists/trainees and 27 Clinical Genetics consultants/trainees. The utility of the CanVIG-UK consensus recommendations for variant interpretation in cancer susceptibility genes was highly rated, with 89/145=61.4% of survey respondents reporting using the guidance at least weekly (≥4 times/month) and 124/128=96.9% rating it as extremely/very useful. The usage frequency and utility of the gene-specific guidance reported by survey respondents were similar to those reported for the main consensus specification. Both qualitative and quantitative survey responses clearly demonstrate the value of the CanVIG-UK activities to the clinical-diagnostic community.

The clinical benefits of intensity-modulated proton therapy (IMPT) compared with intensity-modulated radiation therapy (IMRT) for patients with oropharyngeal squamous cell carcinoma remain uncertain with respect to treatment-related effects on physical function and quality of life. We aimed to compare late functional, patient-reported, disease control, and survival outcomes between IMPT and IMRT. We did a phase 3 trial (TORPEdO) in 20 UK National Health Service hospitals. We randomly assigned (2:1) patients with locally advanced oropharyngeal squamous cell carcinoma to IMPT or IMRT (70 Gy in 33 fractions, for 6·5 weeks) with two cycles of high-dose cisplatin (100 mg/m2, every 3 weeks). Co-primary endpoints at 12 months were gastrostomy-tube dependence (use of feeding tube for nutrition) or severe weight loss (≥20% from baseline) and University of Washington quality of life (UW-QoL) mean physical composite score for saliva, taste, chewing, swallowing, speech and appearance. The study was registered with the ISRCTN registry, ISRCTN16424014; recruitment is complete and follow-up is ongoing. Between Feb 25, 2020, and June 13, 2023, we randomly assigned 205 patients (99 [48%] with T3 or T4 disease and 44 [22%] with bilateral neck lymph node involvement (N2[c]); 136 [66%] to IMPT and 69 [34%] to IMRT). 163 (80%) patients were male and 42 (20%) were female. Ethnicity data were self-reported by 177 (86%) patients; most were White British (167 [94%]). At 12 months, gastrostomy-tube dependence occurred in two (2%) of 119 patients in the IMPT group and in one (2%) of 59 patients in the IMRT group and severe weight loss occurred in 20 (18% [97·5% CI 11 to 28]) of 110 patients in the IMPT group and in three (6% [1 to 17]) of 53 patients in the IMRT group (combined odds ratio 2·80 [97·5% CI 0·75 to 10·4]; p=0·079). Mean UW-QoL physical composite scores at 12 months were 78·3 in the IMPT group versus 77·1 in the IMRT group (difference 1·3 [97·5% CI -3·7 to 6·2]; p=0·56). There were 14 serious adverse events in 12 patients (nine assessed as unrelated to the study treatment [four in the IMPT group and five in the IMRT group] and five study treatment-related [one IMPT vs four IMRT]); the most common events were acute kidney injury (five [36%]) and thromboembolism (four [29%]). There were no treatment-related deaths. At a median follow-up of 28·3 months (IQR 26·5 to 39·3), 24-month freedom from loco-regional recurrence rates were 94% (99% CI 86-98) in the IMPT group versus 97% (82-100) in the IMRT group (hazard ratio [HR] 2·6 [99% CI 0·3 to 20·3; 95% CI 0·5-12·4]; p=0·24), and overall survival rates were 95% (86 to 98) in the IMPT group versus 95% (81-99) in the IMRT group (HR 1·6 [99% CI 0·3 to 8·8; 95% CI 0·4 to 5·9; p=0·47). IMPT and IMRT had similar late physical quality of life scores, gastrostomy-tube dependence, local control, and overall survival. In health-care settings where IMPT is not used routinely for oropharyngeal squamous cell carcinoma, IMRT remains the standard of care. Cancer Research UK.

308 Background: Risk stratification in localised prostate cancer (PCa) based on clinicopathological parameters is inadequate, leading to under- and over-treatment. We used CHHiP trial data to externally validate a previously-developed MMAI prognostic model with potential for cost-effective improved treatment personalisation. Methods: H&amp;E slides from CHHiP translational substudy patients were centrally reviewed by a uro-pathologist between 2013 and 2015, with Gleason grade group (GGG) rescored using contemporary guidelines. GGG was reassigned in 52% of cases. We evaluated the locked ArteraAI prostate MMAI algorithm v1.2 which combines age, T-stage, and PSA with digital prostate biopsy H&amp;E images. Multivariable cox regression analysis of biochemical/clinical recurrence (BCR; trial primary endpoint) and development of distant metastases (DM) were performed with models including age and MMAI as continuous (per 0.1 increase) and categorical (ArteraAI pre-validated 3-tier risk groups) variables. The additional prognostic value of MMAI beyond UK-recommended Cambridge Prognostic Group (CPG) and NCCN risk group models was assessed by change in Concordance Index and Likelihood Ratio Test (LRT). Results: Of 1854 patients with centrally-reviewed pathology, 1797 (97%) had clinical data and H&amp;E with sufficient tumour for MMAI analysis. Median follow up was 14.3 years. Patients were classified as MMAI High (129, 7.2%), Intermediate (885, 49.2%) or Low (783, 43.6%). In univariable analysis, high MMAI score was significantly associated with increased BCR risk, as both a categorical variable (MMAI High risk hazard ratio (HR) = 5.07, 95%CI = 3.77-6.81, p=&lt;0.001, MMAI Intermediate-risk HR = 1.90, 1.52-2.36, p=&lt;0.001), and continuous variable (MMAI raw score HR = 1.55, 1.44-1.67, p=&lt;0.001). MMAI was also significantly associated with DM. Addition of MMAI to CPG and NCCN multivariable models significantly improves discrimination (C-index) and overall fit (change in LRT) for BCR and DM (Table 1). Conclusions: ArteraAI MMAI improves prediction of BCR and DM in CHHiP over standard criteria. This first large-scale external validation in a contemporary UK cohort of localised PCa with rigorously standardized care will inform future prospective trials of MMAI biomarker-guided PCa treatment selection. Endpoint Model C index (MMAI risk group) ΔLRT χ² (p) C index (MMAI raw score) ΔLRT χ² (p) BCR CPG + ageCPG + age + MMAI 0.620.65+0.03 p=&lt;0.001 55.6 p=&lt;0.001 0.620.67+0.05 p=&lt;0.001 67.5 p=&lt;0.001 BCR NCCN + ageNCCN + age + MMAI 0.590.64+0.05 p=&lt;0.001 67.2 p=&lt;0.001 0.590.66+0.07 p=&lt;0.001 80.9 p=&lt;0.001 DM CPG + ageCPG + age + MMAI 0.650.71+0.06 p=0.001 35.3 p=&lt;0.001 0.650.73+0.08p=&lt;0.001 47.0 p=&lt;0.001 DM NCCN + ageNCCN + age + MMAI 0.610.70+0.09 p=&lt;0.001 43.4 p=&lt;0.001 0.610.72+0.11 p=&lt;0.001 55.8 p=&lt;0.001 Total, n=1794. Events BCR, n = 426 (23.7%), DM, n = 121 (6.7%).