The clinical significance of loss of DNA mismatch repair in ovarian cancer patients: an immunohistochemical study

Loss of mismatch repair (MMR) and, in particular, loss of MLH1 is associated with acquired cisplatin resistance of ovarian tumour cell line models. The aim of this thesis is to examine in ovarian cancer patients the clinical prognostic significance of the MMR proteins MLH1 and MSH2 when measured at disease presentation. We have developed immunohistochemistry (IHC) and a scoring system for the expression of MLH1 and MSH2 in paraffin embedded tissues. We have scored both the intensity of staining (I-score) and percentage of cells staining (%-score). We have validated this technique with good agreement in scoring over time, between blocks and between observers (inter-observer kappa scores of ≥ 0.629, intra-observer kappa scores of > 0.646 and intra-slide kappa scores of ≥ 0.583). There was a positive correlation of Ki67, (a proliferation marker), with I-MLH1, %-MLHl and %-MSH2 scores (p=0.002; <0.001 and 0.001) but not with p53 scores.We examined prechemotherapy samples from 58 patients with a histological diagnosis of advanced ovarian carcinoma, who were then treated with primary chemotherapy regimens containing cisplatin. Advanced stage was associated with increased percentage cells positive for MLH1, MSH2 and Ki67 (p = 0.0092, 0.0049 and 0.0054 respectively). We performed a multivariate analysis allowing for known clinical prognostic factors, (i.e. type of chemotherapy given, stage, performance status and residual disease). Patients with a loss of intensity of staining for MMR proteins prechemotherapy showed a poor survival (Hazard Ratio, HR=3.64; p=0.0012) and poor progression free survival (HR=2.37; p=0.016). Similarly patients showing a reduced intensity of MLH1 staining showed a poor overall survival (HR=2.17; p=0.031). There was no correlation of MMR proteins and tumour response to treatment.Loss of mismatch repair (MMR) in ovarian tumour cells after cisplatin-based chemotherapy has been shown in both in vitro and in vivo. We have examined paired samples pre and post chemotherapy in 26 ovarian cancer patients. We have seen no consistent changes in MMR proteins, p53 or Ki67 pre and post chemotherapy. On multivariate analysis change in MMR expression did not correlate with survival but it was found that a reduction in intensity of MSH2 staining post chemotherapy was associated with a longer progression free survival (HR 0.52; p=0.011).Although further prospective validation studies will be necessary, our observations support the proposal that low MLH1 and/or MSH2 expression is associated with resistance in vivo of ovarian tumours to cisplatin and hence poor survival of patients after cisplatin-based chemotherapy

Integrated molecular characterisation of endometrioid ovarian carcinoma identifies opportunities for stratification

Endometrioid ovarian carcinoma (EnOC) is an under-investigated ovarian cancer type. Recent studies have described disease subtypes defined by genomics and hormone receptor expression patterns; here, we determine the relationship between these subtyping layers to define the molecular landscape of EnOC with high granularity and identify therapeutic vulnerabilities in high-risk cases. Whole exome sequencing data were integrated with progesterone and oestrogen receptor (PR and ER) expression-defined subtypes in 90 EnOC cases following robust pathological assessment, revealing dominant clinical and molecular features in the resulting integrated subtypes. We demonstrate significant correlation between subtyping approaches: PR-high (PR + /ER + , PR + /ER−) cases were predominantly CTNNB1-mutant (73.2% vs 18.4%, P < 0.001), while PR-low (PR−/ER + , PR−/ER−) cases displayed higher TP53 mutation frequency (38.8% vs 7.3%, P = 0.001), greater genomic complexity (P = 0.007) and more frequent copy number alterations (P = 0.001). PR-high EnOC patients experience favourable disease-specific survival independent of clinicopathological and genomic features (HR = 0.16, 95% CI 0.04–0.71). TP53 mutation further delineates the outcome of patients with PR-low tumours (HR = 2.56, 95% CI 1.14–5.75). A simple, routinely applicable, classification algorithm utilising immunohistochemistry for PR and p53 recapitulated these subtypes and their survival profiles. The genomic profile of high-risk EnOC subtypes suggests that inhibitors of the MAPK and PI3K-AKT pathways, alongside PARP inhibitors, represent promising candidate agents for improving patient survival. Patients with PR-low TP53-mutant EnOC have the greatest unmet clinical need, while PR-high tumours—which are typically CTNNB1-mutant and TP53 wild-type—experience excellent survival and may represent candidates for trials investigating de-escalation of adjuvant chemotherapy to agents such as endocrine therapy

Early prehabilitation reduces admissions and time in hospital in patients with newly diagnosed lung cancer

Objectives Lung cancer is the leading cause of cancer death in the UK. Prehabilitation aims to maximise patient fitness and minimise the negative impact of anticancer treatment. What constitutes prehabilitation before non-surgical anticancer treatment is not well established. We present data from a pilot project of Early prehabilitation In lung Cancer.Methods All new patients with likely advanced lung cancer were offered prehabilitation at respiratory clinic, if fit for further investigation. Prehabilitation included assessment and appropriate intervention from a consultant in palliative medicine, registered dietitian and rehabilitation physiotherapist. Four objective endpoints were identified, namely admissions to hospital, time spent in the hospital, treatment rates and overall survival. Outcomes were to be compared with 178 prehab eligible historical controls diagnosed from 2019 to 2021.Results From July 2021 to June 2023, 65 patients underwent prehabilitation and 72% of patients underwent all 3 interventions. 54 patients had a stage 3 or 4 lung cancer. In the prehab group, fewer patients attended Accident and Emergency (31.5 vs 37.4 attendances per 100 patients) and fewer were admitted (51.9 vs 67.9) when compared with historical controls. Those receiving prehab spent a lot less time in the hospital (129.7 vs 543.5 days per 100 patients) with shorter admissions (2.5 vs 8 days). Systemic anticancer treatment rates increased in the short term but were broadly similar overall. Median survival was higher in the prehabilitation group (0.73 vs 0.41 years, p=0.046).Conclusions Early prehabilitation appears to reduce time spent in the hospital. It may improve survival. Further work is required to understand its full effect on treatment rates.<br/

Optimizing the implementation of lung cancer screening in Scotland: Focus group participant perspectives in the LUNGSCOT study

Introduction: Targeted lung cancer screening is effective in reducing lung cancer and all-cause mortality according to major trials in the United Kingdom and Europe. However, the best ways of implementing screening in local communities requires an understanding of the population the programme will serve. We undertook a study to explore the views of those potentially eligible for, and to identify potential barriers and facilitators to taking part in, lung screening, to inform the development of a feasibility study. Methods: Men and women aged 45–70, living in urban and rural Scotland, and either self-reported people who smoke or who recently quit, were invited to take part in the study via research agency Taylor McKenzie. Eleven men and 14 women took part in three virtual focus groups exploring their views on lung screening. Focus group transcripts were transcribed and analysed using thematic analysis, assisted by QSR NVivo. Findings: Three overarching themes were identified: (1) Knowledge, awareness and acceptability of lung screening, (2) Barriers and facilitators to screening and (3) Promoting screening and implementation ideas. Participants were largely supportive of lung screening in principle and described the importance of the early detection of cancer. Emotional and psychological concerns as well as system-level and practical issues were discussed as posing barriers and facilitators to lung screening. Conclusions: Understanding the views of people potentially eligible for a lung health check can usefully inform the development of a further study to test the feasibility and acceptability of lung screening in Scotland. Patient or Public Contribution: The LUNGSCOT study has convened a patient advisory group to advise on all aspects of study development and implementation. Patient representatives commented on the focus group study design, study materials and ethics application, and two representatives read the focus group transcripts

Enhanced response rate to pegylated liposomal doxorubicin in high grade serous ovarian carcinomas harbouring BRCA1 and BRCA2 aberrations

Abstract Background Approximately 10–15% of ovarian carcinomas (OC) are attributed to inherited susceptibility, the majority of which are due to mutations in BRCA1 or BRCA2 (BRCA1/2). These patients display superior clinical outcome, including enhanced sensitivity to platinum-based chemotherapy. Here, we seek to investigate whether BRCA1/2 status influences the response rate to single-agent pegylated liposomal doxorubicin (PLD) in high grade serous (HGS) OC. Methods One hundred and forty-eight patients treated with single-agent PLD were identified retrospectively from the Edinburgh Ovarian Cancer Database. DNA was extracted from formalin-fixed paraffin-embedded (FFPE) archival tumour material and sequenced using the Ion Ampliseq BRCA1 and BRCA2 panel. A minimum variant allele frequency threshold was applied to correct for sequencing artefacts associated with formalin fixation. Results A superior response rate to PLD was observed in patients with HGS OC who harboured variants likely to affect BRCA1 or BRCA2 function compared to the BRCA1/2 wild-type population (36%, 9 of 25 patients versus 12.1%, 7 of 58 patients; p = 0.016). An enhanced response rate was also seen in patients harbouring only the BRCA1 SNP rs1799950, predicted to be detrimental to BRCA1 function (50%, 3 of 6 patients versus 12.1%, 7 of 58 patients; p = 0.044). Conclusions These data demonstrate that HGS OC patients with BRCA1/2 variants predicted damaging to protein function experience superior sensitivity to PLD, consistent with impaired DNA repair. Further characterisation of rs1799950 is now warranted in relation to chemosensitivity and susceptibility to developing ovarian carcinoma