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.

Prognostic value of the Scottish Inflammatory prognostic Score in patients with NSCLC expressing PD-L1 ≥ 50 % progressing on first-line pembrolizumab.

BACKGROUND: Most patients with advanced non-small cell lung cancer (NSCLC) treated with first-line pembrolizumab monotherapy will experience progressive disease (PD). Only a minority will go on to receive subsequent systemic anticancer therapy for which outcomes are guarded. We investigated the prognostic significance of biomarkers of systemic inflammation following failure of first-line pembrolizumab for NSCLC to aid subsequent management decisions. METHODS: Patients with radiological and/or clinical evidence of PD on first-line pembrolizumab for advanced NSCLC at a regional Scottish cancer centre were identified. Inflammatory biomarkers at the time of PD, including serum albumin, neutrophil count and the Scottish Inflammatory Prognostic Score (SIPS; combing albumin and neutrophils), and clinicopathological factors, including age, sex, histology, PDL1 expression and time to PD were recorded. The relationship between these and post-progression overall survival (ppOS) were examined. RESULTS: Data were available for 211 patients. Median ppOS was 2.1 months. Only SIPS was predictive of ppOS on multivariate analysis (HR2.54 (95 %CI 1.81-3.56) (<0.001)), stratifying ppOS from 0.8 months (SIPS2), to 1.8 months (SIPS1), to 8.1 months (SIPS0) (p < 0.001). Thirty (14 %) patients received second-line systemic anticancer therapy with median ppOS 8.7 months. These patients had lower levels of systemic inflammation, as defined by albumin (p < 0.001), neutrophil count (p = 0.002), and SIPS (p = 0.004)), than all other patients. CONCLUSIONS: SIPS, a simple biomarker of systemic inflammation, predicts ppOS after first-line pembrolizumab and may be useful alongside routine assessments of patient fitness to inform individualised discussions about subsequent treatment. We highlight poor outcomes in this patient group and a role for SIPS in signposting transition to best supportive care and early referral to palliative care. It may also help identify a small group of patients most likely to benefit from further lines of therapy.

Early prehabilitation in suspected locally advanced and metastatic lung cancer.

OBJECTIVES: The most common treatment for locally advanced and metastatic lung cancer is best supportive care. Patients with lung cancer are often comorbid with a high symptom burden. We wanted to assess whether early prehabilitation was feasible in patients with likely lung cancer. METHODS: Patients were offered prehabilitation if they were attending the new patient respiratory clinic, had a CT scan suggesting stage III or IV lung cancer and undergoing further investigations. Patients receiving palliative care were ineligible. All prehabilitation patients were referred to a palliative medicine physician, registered dietitian and rehabilitation physiotherapist. RESULTS: 50 patients underwent prehabilitation between June 2021 and August 2022. The median age was 72 years (range 54-89 years). 48 patients had lung cancer. 84% of patients attended all three interventions.Half of the palliative care consultations focused on pain. Half of the patients seen had a change in medication. 25% of patients' weights were stable, 32% required a food-first strategy and 33% required oral nutritional supplements. 57% of patients discussed managing breathlessness with the physiotherapist. CONCLUSIONS: Early prehabilitation is feasible alongside the investigation of locally advanced and metastatic lung cancer. Further work will aim to assess its impact on admission to the hospital, survival and treatment rates.

Immune-Related Adverse Events, Biomarkers of Systemic Inflammation, and Survival Outcomes in Patients Receiving Pembrolizumab for Non-Small-Cell Lung Cancer.

BACKGROUND: Pembrolizumab monotherapy for non-small-cell lung cancer (NSCLC) expressing PD-L1 ≥ 50% doubles five-year survival rates compared to chemotherapy. However, immune-related adverse events (irAEs) can cause severe, long-term toxicity necessitating high-dose steroids and/or treatment cessation. Interestingly, patients experiencing irAEs demonstrate better survival outcomes. Biomarkers of systemic inflammation, including the Scottish Inflammatory Prognostic Score (SIPS), also predict survival in this patient group. This study examines the relationship between inflammatory status, irAEs, and survival outcomes in NSCLC. METHODS: A retrospective analysis was conducted on patients with NSCLC expressing PD-L1 ≥ 50% receiving first-line pembrolizumab monotherapy at a large cancer centre in Scotland. Regression analyses were conducted to examine the relationship between SIPS, irAEs, and survival. RESULTS: 83/262 eligible patients (32%) experienced an irAE. Dermatological, endocrine, gastrointestinal, and hepatic, but not pulmonary, irAEs were associated with prolonged PFS and OS (p <= 0.011). Mild irAEs were associated with better PFS and OS in all patients, including on time-dependent analyses (HR0.61 [95% CI 0.41-0.90], p = 0.014 and HR0.41 [95% CI 0.26-0.63], p < 0.001, respectively). SIPS predicted PFS (HR 1.60 [95% CI 1.34-1.90], p < 0.001) and OS (HR 1.69 [95% CI 1.41-2.02], p < 0.001). SIPS predicted the occurrence of any irAE in all patients (p = 0.011), but not on 24-week landmark analyses (p = 0.174). The occurrence of irAEs predicted favourable outcomes regardless of the baseline inflammatory status (p = 0.015). CONCLUSION: The occurrence of certain irAEs is associated with a survival benefit in patients with NSCLC expressing PD-L1 ≥ 50% receiving pembrolizumab. We find that the association between low levels of systemic inflammation and the risk of irAEs is confounded by their independent prognostic value.

Defining the road map to a UK national lung cancer screening programme.

Lung cancer screening with low-dose CT was recommended by the UK National Screening Committee (UKNSC) in September, 2022, on the basis of data from trials showing a reduction in lung cancer mortality. These trials provide sufficient evidence to show clinical efficacy, but further work is needed to prove deliverability in preparation for a national roll-out of the first major targeted screening programme. The UK has been world leading in addressing logistical issues with lung cancer screening through clinical trials, implementation pilots, and the National Health Service (NHS) England Targeted Lung Health Check Programme. In this Policy Review, we describe the consensus reached by a multiprofessional group of experts in lung cancer screening on the key requirements and priorities for effective implementation of a programme. We summarise the output from a round-table meeting of clinicians, behavioural scientists, stakeholder organisations, and representatives from NHS England, the UKNSC, and the four UK nations. This Policy Review will be an important tool in the ongoing expansion and evolution of an already successful programme, and provides a summary of UK expert opinion for consideration by those organising and delivering lung cancer screenings in other countries.

Real-World Impact of SABR on Stage I Non-Small-Cell Lung Cancer Outcomes at a Scottish Cancer Centre.

INTRODUCTION: Stereotactic ablative body radiotherapy (SABR) offers patients with stage I non-small-cell lung cancer (NSCLC) a safe, effective radical therapy option. The impact of introducing SABR at a Scottish regional cancer centre was studied. METHODS: The Edinburgh Cancer Centre Lung Cancer Database was assessed. Treatment patterns and outcomes were compared across treatment groups (no radical therapy (NRT), conventional radical radiotherapy (CRRT), SABR and surgery) and across three time periods reflecting the availability of SABR (A, January 2012/2013 (pre-SABR); B, 2014/2016 (introduction of SABR); C, 2017/2019, (SABR established)). RESULTS: 1143 patients with stage I NSCLC were identified. Treatment was NRT in 361 (32%), CRRT in 182 (16%), SABR in 132 (12%) and surgery in 468 (41%) patients. Age, performance status, and comorbidities correlated with treatment choice. The median survival increased from 32.5 months in time period A to 38.8 months in period B to 48.8 months in time period C. The greatest improvement in survival was seen in patients treated with surgery between time periods A and C (HR 0.69 (95% CI 0.56-0.86), p < 0.001). The proportion of patients receiving a radical therapy rose between time periods A and C in younger (age ≤ 65, 65-74 and 75-84 years), fitter (PS 0 and 1), and less comorbid patients (CCI 0 and 1-2), but fell in other patient groups. CONCLUSIONS: The introduction and establishment of SABR for stage I NSCLC has improved survival outcomes in Southeast Scotland. Increasing SABR utilisation appears to have enhanced the selection of surgical patients and increased the proportion of patients receiving a radical therapy.

Understanding patient barriers and facilitators to uptake of lung screening using low dose computed tomography: a mixed methods scoping review of the current literature.

BACKGROUND: Targeted lung cancer screening is effective in reducing mortality by upwards of twenty percent. However, screening is not universally available and uptake is variable and socially patterned. Understanding screening behaviour is integral to designing a service that serves its population and promotes equitable uptake. We sought to review the literature to identify barriers and facilitators to screening to inform the development of a pilot lung screening study in Scotland. METHODS: We used Arksey and O'Malley's scoping review methodology and PRISMA-ScR framework to identify relevant literature to meet the study aims. Qualitative, quantitative and mixed methods primary studies published between January 2000 and May 2021 were identified and reviewed by two reviewers for inclusion, using a list of search terms developed by the study team and adapted for chosen databases. RESULTS: Twenty-one articles met the final inclusion criteria. Articles were published between 2003 and 2021 and came from high income countries. Following data extraction and synthesis, findings were organised into four categories: Awareness of lung screening, Enthusiasm for lung screening, Barriers to lung screening, and Facilitators or ways of promoting uptake of lung screening. Awareness of lung screening was low while enthusiasm was high. Barriers to screening included fear of a cancer diagnosis, low perceived risk of lung cancer as well as practical barriers of cost, travel and time off work. Being health conscious, provider endorsement and seeking reassurance were all identified as facilitators of screening participation. CONCLUSIONS: Understanding patient reported barriers and facilitators to lung screening can help inform the implementation of future lung screening pilots and national lung screening programmes.

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.

Hypoalbuminaemia as a Prognostic Biomarker of First-Line Treatment Resistance in Metastatic Non-small Cell Lung Cancer.

Introduction: Despite significant advances in systemic anticancer therapy (SACT) for non-small cell lung cancer (NSCLC), many patients still fail to respond to treatment or develop treatment resistance. Albumin, a biomarker of systemic inflammation and malnutrition, predicts survival in many cancers. We evaluated the prognostic significance of albumin in patients receiving first-line targeted therapy or immunotherapy-based SACT for metastatic NSCLC. Methods: All patients treated with first-line targeted therapy or immunotherapy-based SACT for metastatic NSCLC at a regional Scottish cancer centre were identified. Serum albumin at pre-treatment, after 12-weeks of treatment, and at the time of progressive disease were recorded. The relationship between albumin (≥ 35g/L v <35g/L) and overall survival (OS) was examined. Results: Data were available for 389 patients of both targeted therapy cohort (n = 159) and immunotherapy-based therapy cohort (n = 230). Pre-treatment albumin was predictive of OS in each cohort at HR1.82 (95%CI 1.23-2.7) (p =0.003) and HR2.55 (95%CI 1.78-3.65) (p < 0.001), respectively. Pre-treatment albumin <35 g/L was associated with a significantly higher relative risk of death within 12 weeks in each cohort at RR9.58 (95%CI 2.20-41.72, p = 0.003) and RR3.60 (95%CI 1.74-6.57, p < 0.001), respectively. The 12-week albumin was predictive of OS in each cohort at HR1.88 (95%CI 1.86-4.46) (p < 0.001) and HR2.67 (95%CI 1.74-4.08) (p < 0.001), respectively. 46 out of 133 (35%) evaluable patients treated with targeted therapy and 43 out of 169 (25%) treated with immunotherapy-based therapy crossed over albumin prognostic groups between pre-treatment and 12-week. The prognostic value of 12-week albumin was independent of pre-treatment albumin status. A majority of patients had albumin <35g/L at the time of progressive disease when it was also predictive of survival following progressive disease at HR2.48 (95%CI 1.61-3.82) (p < 0.001) and HR2.87 (95%CI 1.91-4.31) (p < 0.001) respectively). Conclusions: Albumin is a reliable prognostic factor in patients with metastatic NSCLC, predicting survival independent of the class of drug treatment at various time points during the patient journey. Tracking albumin concentrations during systemic therapy may indicate disease activity or treatment response over time.

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.

Structural Variants at the BRCA1/2 Loci are a Common Source of Homologous Repair Deficiency in High-grade Serous Ovarian Carcinoma.

PURPOSE: The abundance and effects of structural variation at BRCA1/2 in tumors are not well understood. In particular, the impact of these events on homologous recombination repair deficiency (HRD) has yet to be demonstrated. EXPERIMENTAL DESIGN: Exploiting a large collection of whole-genome sequencing data from high-grade serous ovarian carcinoma (N = 205) together with matched RNA sequencing for the majority of tumors (N = 150), we have comprehensively characterized mutation and expression at BRCA1/2. RESULTS: In addition to the known spectrum of short somatic mutations (SSM), we discovered that multi-megabase structural variants (SV) were a frequent, unappreciated source of BRCA1/2 disruption in these tumors, and we found a genome-wide enrichment for large deletions at the BRCA1/2 loci across the cohort. These SVs independently affected a substantial proportion of patients (16%) in addition to those affected by SSMs (24%), conferring HRD and impacting patient survival. We also detail compound deficiencies involving SSMs and SVs at both loci, demonstrating that the strongest risk of HRD emerges from combined SVs at both BRCA1 and BRCA2 in the absence of SSMs. Furthermore, these SVs are abundant and disruptive in other cancer types. CONCLUSIONS: These results extend our understanding of the mutational landscape underlying HRD, increase the number of patients predicted to benefit from therapies exploiting HRD, and suggest there is currently untapped potential in SV detection for patient stratification.

Molecular stratification of endometrioid ovarian carcinoma predicts clinical outcome.

Endometrioid ovarian carcinoma (EnOC) demonstrates substantial clinical and molecular heterogeneity. Here, we report whole exome sequencing of 112 EnOC cases following rigorous pathological assessment. We detect a high frequency of mutation in CTNNB1 (43%), PIK3CA (43%), ARID1A (36%), PTEN (29%), KRAS (26%), TP53 (26%) and SOX8 (19%), a recurrently-mutated gene previously unreported in EnOC. POLE and mismatch repair protein-encoding genes were mutated at lower frequency (6%, 18%) with significant co-occurrence. A molecular taxonomy is constructed, identifying clinically distinct EnOC subtypes: cases with TP53 mutation demonstrate greater genomic complexity, are commonly FIGO stage III/IV at diagnosis (48%), are frequently incompletely debulked (44%) and demonstrate inferior survival; conversely, cases with CTNNB1 mutation, which is mutually exclusive with TP53 mutation, demonstrate low genomic complexity and excellent clinical outcome, and are predominantly stage I/II at diagnosis (89%) and completely resected (87%). Moreover, we identify the WNT, MAPK/RAS and PI3K pathways as good candidate targets for molecular therapeutics in EnOC.

Publisher Correction: The National Lung Matrix Trial of personalized therapy in lung cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

The National Lung Matrix Trial of personalized therapy in lung cancer.

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.

Hormone receptor expression patterns define clinically meaningful subgroups of endometrioid ovarian carcinoma.

BACKGROUND: Numerous studies have investigated the association between hormone receptor expression and clinical outcome in ovarian carcinoma (OC); however, these have largely focussed on serous OCs, with few studies reporting specifically on endometrioid OCs (EnOC). Where analyses have been stratified by histotype, expression has been assessed using the percentage of positive tumor cells, without accounting for nuclear expression intensity. METHODS: Here we assess the expression levels of progesterone receptor (PR), estrogen receptor alpha (ER) and androgen receptor (AR) using histoscore - a nuclear scoring method incorporating both proportion of positive cells and the intensity of nuclear staining - across a cohort of 107 WT1 negative EnOCs. RESULTS: Hierarchical clustering by PR, ER and AR histoscores identified four EnOC subgroups (PR+/ER+, PR+/ER-, PR-/ER+ and PR-/ER-). EnOC patients in the PR+/ER+ and PR+/ER- groups displayed favorable outcome (multivariable HR for disease-specific survival 0.05 [0.01-0.35] and 0.05 [0.00-0.51]) compared to the PR-/ER+ group. Ten-year survival for stage II PRhigh and PRlow cases was 94.1% and 42.4%. ERhigh EnOC patients (PR+/ER+, PR-/ER+) had higher body mass index compared to ERlow cases (P = 0.015) and high grade serous OC patients (P < 0.001). CONCLUSION: These data demonstrate that endometrioid OC cases with high PR expression display markedly favorable outcome. Stage II EnOCs with high PR expression represent potential candidates for de-escalation of first-line therapy. Future work should seek to characterise the sensitivity of PR and ER positive EnOCs to endocrine therapy.

Clinical and molecular characterization of ovarian carcinoma displaying isolated lymph node relapse.

BACKGROUND: Disease relapse is the primary cause of death from ovarian carcinoma. Isolated lymph node relapse is a rare pattern of ovarian carcinoma recurrence, with a reported median postrelapse survival of 2.5 to 4 years. To date, investigations have not compared isolated lymph node relapse ovarian carcinoma directly to a matched extranodal relapse cohort or performed molecular characterization of cases that subsequently experience isolated lymph node relapse. OBJECTIVE: Here we seek to compare the clinical outcome, tumor-infiltrating lymphocyte burden, and frequency of known prognostic genomic events in isolated lymph node relapse ovarian carcinoma vs extranodal relapse ovarian carcinoma. STUDY DESIGN: Forty-nine isolated lymph node relapse ovarian carcinoma patients were identified and matched to 49 extranodal relapse cases using the Edinburgh Ovarian Cancer Database, from which the clinical data for identified patients were retrieved. Matching criteria were disease stage, histologic subtype and grade, extent of residual disease following surgical debulking, and age at diagnosis. Clinicopathologic factors and survival data were compared between the isolated lymph node relapse and extranodal relapse cohorts. Genomic characterization of tumor material from diagnosis was performed using panel-based high-throughput sequencing and tumor-infiltrating T cell burden was assessed using immunohistochemistry for CD3+ and CD8+ cells. RESULTS: Isolated lymph node relapse cases demonstrated significantly prolonged postrelapse survival and overall survival vs extranodal relapse upon multivariable analysis (HRmulti = 0.52 [0.33-0.84] and 0.51 [0.31-0.84]). Diagnostic specimens from high-grade serous ovarian carcinomas that subsequently displayed isolated lymph node relapse harbored significantly greater CD3+ and CD8+ cell infiltration compared to extranodal relapse cases (P = .001 and P = .009, Bonferroni-adjusted P = .003 and P = .019). Isolated lymph node relapse high-grade serous ovarian carcinoma cases did not show marked enrichment or depletion of cases with BRCA1/2 mutation or CCNE1 copy number gain when compared to their extranodal relapse counterparts (24.4% vs 19.4% and 18.2% vs 22.6%, P = .865 and P = .900). CONCLUSION: Isolated lymph node relapse ovarian carcinoma represents a distinct clinical entity with favorable outcome compared to extranodal relapse. There was no clear enrichment or depletion of BRCA1/2 mutation or CCNE1 gain in the isolated lymph node relapse ovarian carcinoma cohort compared with extranodal relapse cases, suggesting that these known prognostic genomically defined subtypes of disease do not display markedly altered propensity for isolated lymph node relapse. Diagnostic tumor material from isolated lymph node relapse patients demonstrated greater CD3+ and CD8+ cell infiltration, indicating stronger tumor engagement by T cell populations, which may contribute to the more indolent disease course of isolated lymph node relapse.

An international, phase III randomized trial in patients with mucinous epithelial ovarian cancer (mEOC/GOG 0241) with long-term follow-up: and experience of conducting a clinical trial in a rare gynecological tumor.

OBJECTIVES: We evaluated four different treatment regimens for advanced-stage mucinous epithelial ovarian cancer. METHODS: We conducted a multicenter randomized factorial trial (UK and US). Patients were diagnosed with primary mEOC: FIGO stage II-IV or recurrence after stage I disease. Treatment arms were paclitaxel-carboplatin, oxaliplatin-capecitabine, paclitaxel-carboplatin-bevacizumab, or oxaliplatin-capecitabine-bevacizumab. Chemotherapy was given 3-weekly for 6 cycles, and bevacizumab (3-weekly) was continued as maintenance (for 12 cycles). Endpoints included overall-survival (OS), progression-free survival (PFS), toxicity and quality of life (QoL). RESULTS: The trial stopped after 50 patients were recruited due to slow accrual. Median follow-up was 59 months. OS hazard ratios (HR) for the two main comparisons were: 0.78 (p = 0.48) for Oxal-Cape vs. Pac-Carbo (each with/without bevacizumab), and 1.04 (p = 0.92) for bevacizumab vs. no bevacizumab. Corresponding PFS HRs were: 0.84 and 0.80. Retrospective central pathology review revealed only 45% (18/40) cases with available material had confirmed primary mEOC. Among these, OS HR for Oxal-Cape vs. Pac-Carbo was 0.36 (p = 0.14); PFS HR = 0.62 (p = 0.40). Grade 3-4 toxicity was seen in 61% Pac-Carbo, 61% Oxal-Cape, 54% Pac-Carbo-Bev, and 85% Oxal-Cape-Bev. QoL was similar between the four arms. CONCLUSION: mEOC/GOG0241 represents an example of a randomized rare tumor trial. Logistical challenges led to early termination, including difficulties in local histopathological diagnosis and accessing drugs outside their labelled indication. There was misalignment between central funders who support clinical trials in rare cancers and the deprioritisation of such work by those managing and funding research at a local level. Rare cancer trials should include centralised pathology review before treatment. Clinical trial registry number: ISRCTN83438782.

Endocrine treatment of high grade serous ovarian carcinoma; quantification of efficacy and identification of response predictors.

OBJECTIVES: The role of endocrine therapy (ET) in high grade serous ovarian carcinoma (HGSOC) is poorly defined due to the lack of phase III data and significant heterogeneity of clinical trials performed. In this study, we sought to identify predictive factors of endocrine sensitivity in HGSOC. METHODS: HGSOC patients who received at least four weeks of ET for relapsed disease following one line of chemotherapy at the Edinburgh Cancer Centre were identified. Exclusion criteria were use of endocrine therapy as maintenance therapy or of unknown duration. Duration of therapy and best CA125 response as per modified GCIG criteria were recorded. Oestrogen receptor (ER) histoscore, treatment free interval, prior lines of chemotherapy, and type of ET were evaluated as predictive factors. RESULTS: Of 431 patients identified, 269 were eligible (77.0% letrozole, 18.6% tamoxifen, 2.2% megesterol acetate, 2.2% other). The median duration of therapy was 126 days (range 28-1427 days). 32.7% remained on ET for ≥180 days and 14.1% for ≥365 days. The CA125 response and clinical benefit rates (response or stable disease) were 8.1% and 40.1% respectively. ER histoscore >200 (P = 0.0016) and a treatment free interval of ≥180 days (P < 0.0001) were independent predictive factors upon multivariable analysis. CONCLUSIONS: ET should be considered as a viable strategy to defer subsequent chemotherapy for relapsed HGSOC. Patients with an ER histoscore >200 and a treatment free interval of ≥180 days are most likely to derive benefit.

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

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.

Histologic assessment of tumor-associated CD45(+) cell numbers is an independent predictor of prognosis in small cell lung cancer.

BACKGROUND: Small cell lung carcinoma (SCLC) continues to have a poor prognosis, with a 2-year survival of < 20%. Studies have suggested that SCLC may affect the immune system to allow it to evade immunologic responses. We hypothesized that any such effect would be characterized by a decrease in the lymphoid cells associated with the tumor in biopsy specimens and that this might relate to patient outcome. METHODS: Sixty-four SCLC biopsy specimens were immunohistochemically stained with anti-CD45 antibody to identify immune cells associated with the tumor. A mean CD45 count per high-power field for each case was obtained, and the results were correlated with age, sex, stage, performance status (PS), treatment with chemotherapy/radiotherapy, and overall survival. RESULTS: The median CD45 count for all cases was taken as 40 (CD45(40)). Kaplan-Meier plots demonstrated better survival for patients with a CD45(40) > 40 ( P < .009). No relationship between CD45 40 and age, sex, stage, or treatment by chemotherapy or radiotherapy was identified. Although PS was a significant predictor of survival ( P = .014), it did not correlate with CD45 40. In patients with better Eastern Cooperative Oncology Group PS (≤ 2), the CD45(40) demonstrated a highly significant survival advantage for those with CD45(40) > 40 ( P < .0001). CONCLUSIONS: The data indicate that (1) simple immunohistochemical assessment of immune cell infiltrates in routinely processed and stained biopsy specimens of primary tumors can provide prognostic information in SCLC and (2) tumor-associated CD45(+) cells in SCLC biopsy specimens may be a good clinical marker to identify patients with poor prognosis despite good PS.