Charlie Gourley

PERK and other potential biomarkers of therapy response in LGSOC. A, pERK IHC examples demonstrating negative (0), weak (1+), moderate (2+), and intense (3+) positivity for histoscore calculation. Scale bars, 50 µm. B, Response to trametinib (top) and physician’s choice SOC (bottom) according to KRAS/BRAF/NRAS mutation status (left), pERK status (middle), and chr1 abnormalities (right). C, pERK histoscore according to KRAS/BRAF/NRAS mutation type. Labels specify the numbers within each group that were evaluable for pERK expression levels. D, pERK histoscore by chr1p-loss status. E, Frequency of pERK status between chr1p-loss and -intact groups. Chr1pq-aberrant, chr1p-loss with concurrent chr1q-gain.

Study case flow diagram for WES of translational specimens from patients enrolled in GOG281. One hundred thirty-four samples underwent successful WES, of which 112 were also evaluable for pERK via IHC. Additionally, 36 samples were evaluable for pERK IHC that did not have matching WES.

Molecular landscape of tumor samples from patients enrolled in GOG281/LOGS. MAPK-associated, MAPK-associated genes as defined in the Gene Ontology Term GO:0000165; Chr1pq-aberrant, chr1p-loss with concurrent chr1q-gain.

Purpose:Low-grade serous ovarian carcinoma (LGSOC) is a distinct form of ovarian cancer characterized by younger patient age and relative chemoresistance. The GOG281/LOGS trial (NCT02101788) investigated the efficacy of the MEK inhibitor trametinib compared with physician’s choice standard-of-care (SOC) in patients with LGSOC with persistent/recurrent disease. The study demonstrated significantly improved progression-free survival (PFS) in the trametinib-treated arm.Experimental Design:Two hundred and sixty patients with recurrent/persistent LGSOC were enrolled and randomly assigned in GOG281. We performed molecular analysis of 170 patients with available tumor specimens, comprising whole-exome sequencing and phospho-ERK (pERK) IHC, to identify biomarkers of clinical benefit from trametinib. The demographics of the translational cohort (n = 170) were comparable with those of the total trial cohort.Results:High tumor pERK expression (greater than the median histoscore of 140) was associated with significantly prolonged PFS with trametinib treatment versus SOC (median 20.1 vs. 5.6 months, log-rank P < 0.0001; test for interaction P = 0.023). Tumors harboring canonical RAS–RAF–MAPK mutations (KRAS/BRAF/NRAS: 44/134, 32.8% of cases) had a higher response rate to trametinib (50.0% vs. 8.3%; Barnard’s P = 0.0004; test for interaction P = 0.054), but KRAS/BRAF/NRAS status was not predictive of prolonged PFS (test for interaction P = 0.719). KRAS amplification (n = 5 without KRAS/NRAS/BRAF mutation) and mutation of MAPK-associated genes (n = 25 without KRAS/NRAS/BRAF mutation or KRAS copy number gain) expanded the number of cases with identifiable MAPK defects to 55.2%, but consideration of these events did not improve the discrimination of trametinib responders. Chr1p loss (49% of cases) was associated with lower pERK expression (P = 0.021).Conclusions:This exploratory analysis suggests that pERK expression and mutation of KRAS/BRAF/NRAS are candidate biomarkers of improved PFS and response to trametinib, respectively.

Demographics of translational research population.

Impact of pERK status and KRAS/BRAF/NRAS mutation status on GOG281 patient outcome. A, PFS of GOG281/LOGS patients with low-pERK tumors (pERK ≤ 140) in trametinib versus SOC arms. B, PFS of GOG281/LOGS patients with high-pERK tumors (pERK > 140) in trametinib versus SOC arms. C, PFS of GOG281/LOGS patients with KRAS/BRAF/NRAS WT tumors in trametinib versus SOC arms. D, PFS of GOG281/LOGS patients with KRAS/BRAF/NRAS-mutant tumors in trametinib versus SOC arms. Labeled HR refer to comparison of trametinib versus SOC arm.

Unsupervised hierarchical clustering of chromosome arm-level copy-number alterations across biospecimens from patients enrolled in GOG281/LOGS.

Introduction: Within the UK there are 33 deaths every day from prostate cancer, second only to lung cancer as the most common cause of cancer death in males in the UK. Of the 55 000 new cases each year, up to 50% of these patients will receive radiotherapy either alone or after prostatectomy. Although there have been significant improvements in the accuracy of radiotherapy delivery leading to better tumour targeting and a reduction in dose to normal tissues, significant permanent genito-urinary or gastrointestinal-related side effects are all too common. With nearly 80% of patients with prostate cancer surviving for 10 years or more, minimising life-limiting radiation damage to normal tissues is vitally important. However, at present, it is not possible to identify which patients will suffer a poorer outcome after radiotherapy. The aim of this study, improving radiotherapy in PROS tate cancer using E le C tronic population-based health CA re data (PROSECCA), is to do this by using the existing information in a patient’s digital healthcare record. By linking primary, secondary and tertiary clinical data, including digital image information, with radiotherapy treatment plans and outcome data, the PROSECCA study will identify de novo predictive biomarkers of radiation response and provide clinicians with a tool to individualise a radiotherapy dose and plan to maximise cure and minimise toxicity. Methods and analysis: The PROSECCA study is a large multidisciplinary project, the purpose of which is to analyse healthcare records from up to 15 000 patients with prostate cancer who underwent radiotherapy in the treatment of their cancer in Scotland between 2010 and 2022. Through the linkage of data obtained specifically for radiotherapy and data held within each patient’s unique electronic health record (EHR), the factors that indicate why some patients have a poor response to treatment, or an increased risk of side effects from radiation, will be identified. This will be made possible by the use of artificial intelligence and machine learning (AL/ML), which will help to identify at-risk patients earlier and allow adaptation of their treatment accordingly. Ethics and dissemination: The study is being conducted in accordance with the ethical principles set out in the Declaration of Helsinki and Good Clinical Practice that respects and protects the rights, and maintains confidentiality, of all trial participants. The study protocol (V.1.0) was reviewed by the South Central Oxford A Research Ethics Committee (REC) on 13 December 2021 and received a favourable opinion subject to each National Health Service (NHS) organisation confirming permission for patients treated within their area. Approval for the use of unconsented healthcare record data for patients included in the study and treated at one of the five Scottish Cancer Centres required an application to the NHS Scotland Public Benefit and Privacy Panel for Health and Social Care (HSC-PBPP). Full approval from the HSC-PBPP panel was received on 1 July 2024, which covered the use of pseudoanonymised EHR data for all patients participating in the study. The study is publicly listed on the NHS Health Research Authority site, with IRAS ID 306245 and REC reference 21/SC/0402. Dissemination of the study findings will take place through field-leading cancer, radiation oncology and medical physics journals. All manuscripts will be approved by the main study team and authorship determined by mutual agreement. Trial registration number: NCT06714630 .

Supplementary Fig. S1. [A] Violin plot illustrating the distribution of OxC-EMT scores in 12 independent datasets. [B] Line graph of Hazard Ratios and associated p-values derived from fitting a loop structured cox regression model to the combined set. Y-axis on the left-hand side represents the scale for Hazard Ratio and the y-axis on the right-hand side represents the scale for the p-value. [C] Plot displaying median survival time (in days) for OxC-EMT-high (solid red line) and corresponding 95% CI (dashed red line) and median survival for OxC-EMT-low (solid blue line) and corresponding 95% CI (dashed blue line). [D] Kaplan-Meier survival plot demonstrating the probability of overall survival for OxC-EMT-high/BRCAmutated, OxC-EMT-high/BRCAwildtype, OxC-EMT-low/BRCAmutated and OxC-EMT-low/BRCAwildtype patients in the Scottish cohort. [E] Kaplan-Meier survival plot demonstrating the probability of overall survival for OxC-EMT-low risk patients in the Combined set with Oxford Classic subtypes, Cell Cycle, Differentiated, KRT17 and Mixed.