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SV loads in non-BRCA1/2 HR genes per sample by SV type

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.

Supplementary methods and supplementary figures

Background Fear of disease progression (FOP) is a rational concern for women with Ovarian Cancer (OC) and depression is also common. To date there have been no randomized trials assessing the impact of psychological intervention on depression and FOP in this patient group. Patients and methods Patients with primary or recurrent OC who had recently completed chemotherapy were eligible if they scored between 5 and 19 on the PHQ-9 depression and were randomized 1:1 to Intervention (3 standardized CBT-based sessions in the 6–12 weeks post-chemotherapy) or Control (standard of care). PHQ-9, FOP-Q-SF, EORTC QLQ C30 and OV28 questionnaires were then completed every 3 months for up to 2 years. The primary endpoint was change in PHQ-9 at 3 months. Secondary endpoints were change in other scores at 3 months and all scores at later timepoints. Results 182 patients registered; 107 were randomized; 54 to Intervention and 53 to Control; mean age 59 years; 75 (70%) had completed chemotherapy for primary and 32 (30%) for relapsed OC and 67 patients completed both baseline and 3-month questionnaires. Improvement in PHQ-9 was observed for patients in both study arms at three months compared to baseline but there was no significant difference in change between Intervention and Control. A significant improvement on FOP-Q-SF scores was seen in the Intervention arm, whereas for those in the Control arm FOP-Q-SF scores deteriorated at 3 months (intervention effect = −4.4 (−7.57, −1.22), p-value = 0.008). Conclusions CBT-based psychological support provided after chemotherapy did not significantly alter the spontaneously improving trajectory of depression scores at three months but caused a significant improvement in FOP. Our findings call for the routine implementation of FOP support for ovarian cancer patients.

OBJECTIVE Investigate the clinical landscape of ovarian carcinoma (OC) over time. DESIGN Register-based prospectively collected data. SETTING South East Scotland. SAMPLE A total of 2805 OC patients diagnosed in 1981-2015. METHODS Survival times were visualised using the Kaplan-Meier method; median survival, 5-year survival probabilities and associated restricted mean survival time analyses were used to quantify survival differences. MAIN OUTCOME MEASURES Disease-specific survival. RESULTS A significant increase in disease-specific survival (DSS) from 1981-1985 to 2011-2015 was observed (median 1.73 versus 4.23 years, P

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, Highlights • We identify four subgroups of endometrioid ovarian carcinoma (EnOC) defined by hormone receptor expression patterns. • EnOC patients in the PRhigh (PR+/ER+, PR+/ER−) groups demonstrate markedly favorable outcome. • Stage II EnOC patients in the PRhigh groups display a ten-year survival of approximately 95%. • ERhigh (PR+/ER+, PR−/ER+) EnOC patients had a higher body mass index vs ERlow cases and high grade serous carcinoma patients.

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 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.

Introduction: Chemo-radiotherapy for lung cancer can be a morbid treatment, often in an older and co-morbid population. Our patients are not routinely seen by a dietitian. Methods: As a pilot project, all patients receiving either sequential or concurrent chemo-radiotherapy for lung cancer between May and November 2020, were identified by the lead lung radiographer and bookings team and referred to a specialist oncology dietitian. These patients were offered up to 3 routine fortnightly assessments on treatment. We recorded their symptoms (based on a standardised tool, PG-SGA) and weight during treatment. Results: 15 patients were referred to the dietitian: 7 male, 8 female. All patients accepted dietetic review. The median age was 64 years old;mean age 63 years old (range 50-79). The mean average number of cycles of chemotherapy was 3.4. Concurrent chemo-radiotherapy was given to 11 patients, with the remaining 4 having sequential treatment. Of all patients, 1 had small cell lung cancer, 1 had a mixed adenocarcinoma and small cell. The remaining 13 were non-small cell lung cancers, and of these 6 were adenocarcinomas and 6 were squamous cell carcinomas and 1 mixed histology. All patients were reviewed at least twice whilst on treatment. The most complete data was for the review in weeks 3/4 of radiotherapy. All 15 patients had scores for this time point. Mean number of symptoms was 5.5 (range 3-9). The commonest symptoms were fatigue (100%), loss of appetite (67%), pain (67%) and dysphagia (60%). For 12 patients receiving 6 weeks of radiotherapy median symptom number increased from 5 in 1st 2 weeks, to 5.5 in weeks 2nd 2 weeks, to 6.5 in final 2 weeks. All patients in this group lost weight. Median weight loss during treatment was 6.6% (range 1.8-15.9%). All patients received food fortification advice throughout their treatment and advice on symptom management. The symptom management advice for 12 of the 15 patients either reinforced advice, or, made adjustments to the timing of medications prescribed by medical or nursing staff. The other 3 patients did not have an existing prescription, and so recommendations were made of medications to manage symptoms, e.g. oxcetacaine, anti-emetics and laxatives. Oral nutritional supplements (ONS) were recommended if patients were not meeting their estimated nutritional requirements from dietary assessment. Seven patients received ONS prescription in addition to the food fortification advice. One patient declined an ONS prescription. Conclusion: 1. Routine dietetic review during radical chemo-radiotherapy is feasible and occurred successfully during the COVID-19 pandemic. It led to some simple, but vital changes in practice such as weekly weighing of patients on treatment 2. Patients undergoing chemo-radiotherapy have a high symptom burden. 3. All patients receiving 6 weeks of radiotherapy lost weight during treatment. 4. We received positive feedback from patients. Keywords: Dietitian, Dietician, radiotherapy

BackgroundModelling the long-term effects of disruption of cancer services and minimising any excess cancer mortality due to the Covid-19 pandemic is of great importance. Here we adapted a stage-shift model to inform service planning decisions within NHS Scotland for the ‘‘Detect Cancer Early’ tumours, breast, colorectal and lung cancer which represent 46% of all cancers diagnosed in Scotland.Methods & DataLung, colorectal and breast cancer incidence data for years 2017-18 were obtained from Public Health Scotland Cancer Quality Performance Indicators (QPI), to define a baseline scenario. The most current stage-specific 5-year survival data came from 2009-2014 national cancer registry and South East Scotland Cancer Network (SCAN) QPI audit datasets. The Degeling et al., inverse stage-shift model was adapted to estimate changes in stage at diagnosis, excess mortality and life-years lost from delays to diagnosis and treatment due to Covid-19-related health services disruption. Three and 6-month periods of disruption were simulated to demonstrate the model predictions.ResultsApproximately, 1-9% reductions in stage I/II presentations leading up to 2-10% increases in stage III/IV presentations are estimated across the three cancer types. A 6-month period of service disruption is predicted to lead to excess deaths at 5 years of 32.5 (31.1, 33.9) per 1000 cases for lung cancer, 16.5 (7.9, 24.3) for colorectal cancer and 31.6 (28.5, 34.4) for breast cancer.ConclusionsDisruption of cancer diagnostic services can lead to significant excess deaths in following years. Increasing diagnostic and capacity for cancer services to deal with the backlog of care are needed. Real time monitoring of incidence and referral patterns over the disruption and post-disruption period to reduce excess deaths including more rapid incidence data by stage and other key tumour/clinical characteristics at presentation for key cancer cases (on a quarterly basis). Real time monitoring in cancer care and referral patterns should help inform what type of interventions are needed to reduce excess mortality and whether different population subgroups require public health messaging campaigns. Specific mitigation measures can be the subject of additional modelling analysis to assess the benefits and inform service planning decision making.

PURPOSE: The abundance and effects of structural variation at BRCA1/2 in tumours 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-seq for the majority of tumours (N=150), we have comprehensively characterised mutation and expression at BRCA1/2. RESULTS: In addition to the known spectrum of short somatic mutations (SSMs), we discover that multi-megabase structural variants (SVs) are a frequent, unappreciated source of BRCA1/2 disruption in these tumours, and we find a genome wide enrichment for large deletions at the BRCA1/2 loci across the cohort. These SVs independently affect a substantial proportion of patients (16%) in addition to those affected by SSMs (24%), conferring homologous recombination repair deficiency (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. Further, 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.

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., The molecular classification of endometroid ovarian carcinomas (EnOC) has not been established, preventing the development of stratified therapeutic approaches. Here the authors characterise the molecular landscape of EnOC by whole exome sequencing, identifying clinically distinct disease subtypes.

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. Current outcomes are reported from the ongoing National Lung Matrix Trial, an umbrella trial for the treatment of non-small-cell lung cancer in which patients are triaged according to their tumour genotype and matched with targeted therapeutic agents.

To determine the rates of germline BRCA1 and BRCA2 mutations in Scottish patients with ovarian cancer, before and after a change in testing policy.Retrospective cohort study.Four cancer/genetics centres in Scotland.Patients with ovarian cancer undergoing germline BRCA1 and BRCA2 (gBRCA1/2) sequencing before 2013 (under the 'old criteria', with selection based solely on family history), after 2013 (under the 'new criteria', with sequencing offered to newly presenting patients with non-mucinous ovarian cancer), and in the 'prevalent population' (who presented before 2013, but were not eligible for sequencing under the old criteria but were sequenced under the new criteria).Clinicopathological and sequence data were collected before and for 18 months after this change in selection criteria.Frequency of germline BRCA1, BRCA2, RAD51C, and RAD51D mutations.Of 599 patients sequenced, 205, 236, and 158 were in the 'old criteria', 'new criteria', and 'prevalent' populations, respectively. The frequency of gBRCA1/2 mutations was 30.7, 13.1, and 12.7%, respectively. The annual rate of gBRCA1/2 mutation detection was 4.2 before and 20.7 after the policy change. A total of 48% (15/31) 'new criteria' patients with gBRCA1/2 mutations had a Manchester score of15 and would not have been offered sequencing based on family history criteria. In addition, 20 patients with gBRCA1/2 were identified in the prevalent population. The prevalence of gBRCA1/2 mutations in patients aged70 years was 8.2%.Sequencing all patients with non-mucinous ovarian cancer gives a much higher annual gBRCA1/2 mutation detection rate, with the frequency of positive tests still exceeding the 10% threshold upon which many family history-based models operate.BRCA sequencing all non-mucinous cancer patients increases mutation detection five fold.

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.

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 (P200 and a treatment free interval of ≥180 days are most likely to derive benefit.

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. Electronic supplementary material The online version of this article (10.1186/s12885-017-3981-2) contains supplementary material, which is available to authorized users.

5553 Background: Endometrioid ovarian carcinomas (EC) have been historically under-investigated. We sought to determine the molecular landscape of contemporarily defined EC using whole exome sequencing (WES). Methods: Tumours diagnosed as EC between May 1980 and December 2013 were identified through the Edinburgh Ovarian Cancer Database. Pathology review was performed according to WHO 2014. Other pathologies including WT1 positive HGSOC were excluded. A selected cohort underwent WES and were analysed for single nucleotide and copy number variants across a panel of genes previously reported as mutated in endometrial, ovarian or pan cancer studies. Tissue microarrays were stained for ER, PR and AR. Multivariable analysis for disease specific survival (DSS) was performed. Results: 125 tumours were included. 61 tumours of all grades underwent WES. 5 molecular groups were identified based on the presence of TP53 mutations (45.9%); or an EClike profile (one or more mutations in ARID1A (41.0%); CTNNB1 (31.1%), PTEN (24.6%) or PIK3CA (23.0%)). Tumours with no mutations in EClike genes were termed ECnull. Each group demonstrated differential DSS (table). Some ECnull: TP53mut tumours also displayed mutations in KRAS, APC and mismatch repair genes. Unsupervised clustering analysis based on the top 100 differentially mutated genes across the dataset validated these groups. Somatic copy number alterations were significantly higher in the TP53mu t groups than the TP53wt groups (Plike genes in the ECnull groups. A PR histoscore of >150, but not ER or AR, was more frequent in the TP53wt group compared to the TP53mut groups (P=0.003). TP53mut status (P=0.0182) and PR histoscore ≤150 (P=0.0115) were independently associated with DSS. Conclusions: EC is a heterogeneous disease comprising 5 molecular subgroups each demonstrating differential clinical outcome. TP53 mutations and PR histoscore ≤150 are independently associated with poor prognosis. [Table: see text]

We present a review of 111 patients who were treated over an initial 3-year period with erlotinib. The median treatment time was 68 days and 59% of patients had stopped treatment within the first 3 months. However, 20 patients were on erlotinib for more than 12 months. Performance status and smoking history were the significant prognostic factors. The overall 3-year survival in patients who had never smoked was 26%.

IntroductionLung cancer survival in Scotland has historically been poor but many changes to the lung cancer services have been introduced and this study was conducted to investigate the impact of these changes on treatment and survival.MethodsData obtained from the Scottish Cancer Registry, South-East Scotland Cancer Network audit and Edinburgh Cancer Centre database were used to conduct a comparison of the management and outcomes of lung cancer patients from South-East Scotland diagnosed in 1995 and in 2002.ResultsData on 971 patients diagnosed in 2002 and 927 in 1995 were analyzed and demonstrated that though the use of treatment overall had not changed (62% in 2002 versus 63% in 1995) the use of potentially curative radiotherapy (15 versus 5% χ2 p < 0.001) and chemotherapy for non-small cell lung cancer (18 versus 7% χ2 p < 0.001) had increased, but not resection rates (11 versus 10%). The use of palliative radiotherapy declined (38% versus 31% χ2 p < 0.001). Patients diagnosed in 2002 had an adjusted hazard of death of 0.7 (95% confidence interval, 0.6–0.8) compared with 1995, with median survival from date of diagnosis of 5.2 versus 4.1 month and 2 year overall survival 15 versus 11% (log rank p = 0.004). Localized disease and younger age were also associated with a reduced hazard of death.ConclusionsPatients diagnosed with lung cancer in Scotland in 2002 had a reduced hazard of death and improved survival compared with 1995. It is hypothesized that this was due in part to improvements in service organization and increased use of treatments likely to increase survival.

Purpose: To evaluate the efficacy of the aromatase inhibitor letrozole in preselected estrogen receptor (ER)–positive relapsed epithelial ovarian cancer patients and to identify markers that predict endocrine-sensitive disease. Experimental Design: This was a phase II study of letrozole 2.5 mg daily until clinical or marker evidence of disease progression in previously treated ER-positive ovarian cancer patients with a rising CA125 that had progressed according to Rustin's criteria. The primary end point was response according to CA125 and response evaluation criteria in solid tumors (RECIST) criteria. Marker expression was measured by semiquantitative immunohistochemistry in sections from the primary tumor. Results: Of 42 patients evaluable for CA125 response, 7 (17%) had a response (decrease of >50%), and 11 (26%) patients had not progressed (doubling of CA125) following 6 months on treatment. The median time taken to achieve the CA125 nadir was 13 weeks (range 10-36). Of 33 patients evaluable for radiological response, 3 (9%) had a partial remission, and 14 (42%) had stable disease at 12 weeks. Eleven patients (26%) had a PFS of >6 months. Subgroup analysis according to ER revealed CA125 response rates of 0% (immunoscore, 150-199), 12% (200-249), and 33% (250-300); P = 0.028, χ2 for trend. Expression levels of HER2, insulin-like growth factor binding protein 5, trefoil factor 1, and vimentin were associated with CA125 changes on treatment. Conclusions: This is the first study of a hormonal agent in a preselected group of ER-positive ovarian cancer patients. A signature of predictive markers, including low HER2 expression, predicts response.

Background: Our previous laboratory and clinical data suggested that one mechanism underlying the development of platinum resistance in ovarian cancer is the acquisition of DNA methylation. We therefore tested the hypothesis that the DNA hypomethylating agent 5-aza-2′-deoxycytodine (decitabine) can reverse resistance to carboplatin in women with relapsed ovarian cancer. Methods: Patients progressing 6–12 months after previous platinum therapy were randomised to decitabine on day 1 and carboplatin (AUC 6) on day 8, every 28 days or carboplatin alone. The primary objective was response rate in patients with methylated hMLH1 tumour DNA in plasma. Results: After a pre-defined interim analysis, the study closed due to lack of efficacy and poor treatment deliverability in 15 patients treated with the combination. Responses by GCIG criteria were 9 out of 14 vs 3 out of 15 and by RECIST were 6 out of 13 vs 1 out of 12 for carboplatin and carboplatin/decitabine, respectively. Grade 3/4 neutropenia was more common with the combination (60% vs 15.4%) as was G2/3 carboplatin hypersensitivity (47% vs 21%). Conclusions: With this schedule, the addition of decitabine appears to reduce rather than increase the efficacy of carboplatin in partially platinum-sensitive ovarian cancer and is difficult to deliver. Patient-selection strategies, different schedules and other demethylating agents should be considered in future combination studies.