scholarly journals O-OGC06 Genomic analysis of response to neoadjuvant chemotherapy in oesophageal adenocarcinoma

2021 ◽  
Vol 108 (Supplement_9) ◽  
Author(s):  
Stella Breininger ◽  
Fereshteh Izadi ◽  
Benjamin Sharpe ◽  
Maria Secrier ◽  
Jane Gibson ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Locally Advanced ◽  
Genomic Analysis ◽  
Standard Of Care ◽  
Response Prediction ◽  
Oesophageal Adenocarcinoma ◽  
Comparative Genomic ◽  
Tumour Regression ◽  
Tumour Regression Grade ◽  
Almost All

Abstract Background Oesophageal adenocarcinoma (OAC) is the ninth most common cancer worldwide, with an estimated mortality of over 500,000 deaths yearly. Neoadjuvant chemotherapy (NAC) followed by surgery is the standard of care (SOC) for locally advanced OAC. Although almost all patients receive chemotherapy as SOC, fewer than 20% obtain a clinically meaningful response and benefit before surgery. The OAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. Methods To identify associations between genomic events and response to NAC in OAC, a comparative genomic analysis was performed in 65 patients using whole-genome sequencing.  We defined response to NAC using Mandard Tumour Regression Grade (TRG), with responders classified as TRG1-2 (n = 27) and non-responders classified as TRG4-5 (n = 38). Results We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs 1.70/Mb, P = 0.036) and elevated copy number variation (CNV) in non-responders (282 vs 136/patient, P<0.001). We identified CNVs unique to each group, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of particular interest was the identification of the Neuron Navigator-3 (NAV3), a known tumour suppressor downstream of EGFR, which was mutated exclusively in non-responders with a frequency of 22%. Conclusions Our work characterises genetic features and mutations that are uniquely associated with response to NAC. We envision a treatment pipeline that incorporates driver mutation profiling in OAC, combining response prediction with targeted therapies to enhance response to NAC and improve survival outcomes.

scholarly journals Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3394
Author(s):  
Fereshteh Izadi ◽  
Benjamin Sharpe ◽  
Stella Breininger ◽  
Maria Secrier ◽  
Jane Gibson ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Esophageal Adenocarcinoma ◽  
Copy Number ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Genomic Analysis ◽  
Tumor Regression Grade ◽  
Comparative Genomic ◽  
Mutation Burden ◽  
Response To Neoadjuvant Chemotherapy

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (20–37%), as is the overall survival benefit at five years (9%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1–2 (n = 27) and non-responders classified as TRG4–5 (n =38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs. 1.70/Mb, p = 0.036) and elevated copy number variation in non-responders (282 vs. 136/patient, p < 0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

646 PREDICTING RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN PATIENTS WITH OESOPHAGEAL ADENOCARCINOMA

2021 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Rebecca Bott ◽  
Gincy George ◽  
Ricardo McEwen ◽  
Janine Zylstra ◽  
William Knight ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Surgical Resection ◽  
Tumour Response ◽  
Oesophageal Adenocarcinoma ◽  
Tumour Regression ◽  
Multivariable Logistic Regression Analysis ◽  
Chemotherapy Response ◽  
Roc Curve Analysis ◽  
Tumour Regression Grade ◽  
Dysphagia Score

Abstract   Neoadjuvant chemotherapy is often used prior to surgical resection for oesophageal adenocarcinoma but remains ineffective in a high proportion of patients. The histological Mandard tumour regression grade is used to determine chemoresponse but is not available at the time of treatment decision-making. The aim of this study was to identify factors that predict chemotherapy response prior to surgery. Methods A prospectively collected database of patients undergoing surgical resection for oesophageal adenocarcinoma from a high-volume UK institution was used. Patients were subcategorised using pathological tumour response into ‘responders’ (Mandard grade 1–3) and ‘non-responders’ (Mandard grade 4&5). Multivariable logistic regression analysis was performed to calculate crude and adjusted odds ratios (OR) with 95% confidence intervals (CI) for responder status adjusting for a variety of parameters. Receiver-operator curves (ROC) were calculated. Results Among 315 patients included, 102 (32%) were responders and 213 (68%) non-responders. A decrease in radiological tumour volume (OR 1.92 95%CI 1.02–3.62; p = 0.05), a ‘partial response’ RECIST score (OR 7.16 95%CI 1.49–34.36; p = 0.01), a clinically improved dysphagia score (OR 2.79 95%CI 1.05–7.04; p = 0.04) and lymphovascular invasion (OR 0.06 95%CI 0.02–0.13; p = 0.000) influenced responder status. ROC curve analysis for responder status utilising all available parameters had an area under the curve (AUC) of 0.86. Conclusion This study has highlighted the potential for using pre-defined factors to identify those patients who have responded to neoadjuvant chemotherapy, prior to surgical resection, potentially facilitating a more individualised therapeutic approach.

scholarly journals Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

2021 ◽  
Author(s):  
Fereshteh Izadi ◽  
Benjamin P Sharpe ◽  
Stella P Breininger ◽  
Maria Secrier ◽  
Jane Gibson ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Esophageal Adenocarcinoma ◽  
Copy Number ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Genomic Analysis ◽  
Tumor Regression Grade ◽  
Comparative Genomic ◽  
Mutation Burden ◽  
Response To Neoadjuvant Chemotherapy

Neoadjuvant therapy followed by surgery is the standard of care for locally advanced esophageal adenocarcinoma (EAC). Unfortunately, response to neoadjuvant chemotherapy (NAC) is poor (<20%), as is the overall survival benefit at 5 years (5%). The EAC genome is complex and heterogeneous between patients, and it is not yet understood whether specific mutational patterns may result in chemotherapy sensitivity or resistance. To identify associations between genomic events and response to NAC in EAC, a comparative genomic analysis was performed in 65 patients with extensive clinical and pathological annotation using whole-genome sequencing (WGS). We defined response using Mandard Tumor Regression Grade (TRG), with responders classified as TRG1-2 (n=27) and non-responders classified as TRG4-5 (n=38). We report a higher non-synonymous mutation burden in responders (median 2.08/Mb vs 1.70/Mb, P=0.036) and elevated copy number variation in non-responders (282 vs 136/patient, P<0.001). We identified copy number variants unique to each group in our cohort, with cell cycle (CDKN2A, CCND1), c-Myc (MYC), RTK/PIK3 (KRAS, EGFR) and gastrointestinal differentiation (GATA6) pathway genes being specifically altered in non-responders. Of note, NAV3 mutations were exclusively present in the non-responder group with a frequency of 22%. Thus, lower mutation burden, higher chromosomal instability and specific copy number alterations are associated with resistance to NAC.

Propensity score regression analysis of esophageal cancer treatment with surgery alone or neoadjuvant chemotherapy.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 405-405
Author(s):  
Wyn Griffith Lewis ◽  
Arfon GMT Powell ◽  
Adam Christian
Keyword(s):  
Regression Analysis ◽  
Neoadjuvant Chemotherapy ◽  
Propensity Score ◽  
Positive Margin ◽  
Primary Outcome Measure ◽  
Oesophageal Adenocarcinoma ◽  
Tumour Regression ◽  
Poor Responders ◽  
Tumour Regression Grade ◽  
Cancer Network

405 Background: The aim of this study was to examine the outcomes of oesophageal adenocarcinoma (OC) treatment with either surgery alone (S), or with neoadjuvant chemotherapy (NAC) followed by surgery (NACS), by means of propensity score (PS) regression analysis, in order to examine whether the benefits reported in the MRC OE02 trial were reproducible in UK cancer network clinical practice. Methods: Consecutive patients undergoing potentially curative treatment for OC in a regional cancer network were studied. Multiple regression models, including PS were developed to account for confounding factors and the primary outcome measure was disease-free (DFS) and overall survival (OS). Results: A cohort of 440 patients was included in a regression analysis controlling for confounders (176 S, 264 NACS). NACS was associated with positive margin status (NACS vs. S, 42.4% vs. 26.7%, p<0.05), poor 5-year DFS (32.1% vs. 56.9, p<0.001), and poor 5-year OS (27.5% vs. 47.3%, p<0.001). On regression adjustment based on propensity scores, NACS was not associated with DFS (p=0.220) or OS (p=0.431). Mandard tumour regression grade (TRG) was significantly associated with DFS (hazard ratio (HR) 0.21,95% CI 0.07-0.70) and OS (HR 0.27 (95% CI 0.13-0.59). Five-year DFS and OS related to TRG was 63.6 and 61.5% vs. 8.0 and 8.6% (p<0.001) for good and poor responders respectively. Conclusions: Prescribing NAC to all OC patients risks delay in effective treatment of patients who are relatively chemo-resistant, given the variabilityin pathological response. Identifying OC patients who derive the most NAC benefit should be the focus.

scholarly journals O4 Neural network image capture to predict response of oesophageal adenocarcinoma to neoadjuvant therapy

2021 ◽  
Vol 108 (Supplement_5) ◽  
Author(s):  
S Rahman ◽  
J Early ◽  
B Sharpe ◽  
M Lloyd ◽  
B Grace ◽  
...  
Keyword(s):  
Neural Network ◽  
High Resolution ◽  
Neoadjuvant Therapy ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Oesophageal Adenocarcinoma ◽  
Tumour Regression ◽  
Tumour Regression Grade ◽  
Pre Treatment ◽  
Diagnostic Biopsies

Abstract Introduction Locally advanced oesophageal adenocarcinoma is typically treated with neoadjuvant chemotherapy (NACT) or chemoradiotherapy (NACRT) followed by surgery. Significant benefit to neoadjuvant treatment however is confined to a minority of patients (&lt;25%) and there are no reliable means of establishing prior to treatment in whom this benefit will occur. In this study, we assessed the utility of features extracted from high-resolution digital microscopy of pre-treatment biopsies in predicting response to neoadjuvant therapy in a machine-learning based modelling framework. Method A total of 102 cases were included in the study. Pre-treatment clinical information, including TNM staging, was obtained, along with diagnostic biopsies. Diagnostic biopsies were converted into high-resolution whole slide-images and features extracted using a pre-trained convolutional neural network (Xception). Elastic net regression models were then trained and validated with bootstrapping with 1000 resampled datasets. The response was considered according to Mandard tumour regression grade (TRG). Result There were 45 (44.1%) responders (TRG1-2) and 57 (57%) non-responders (TRG3-5) in the dataset. 34 patients (33.3%) received NACT and 68 (66.7%) received NACRT. A model trained with RNA-seq data achieved fair performance only in predicting response (AUC 0.598 95% CI 0.593–0.603), which was far exceeded by use of segmented diagnostic biopsy images (AUC 0.872 95% CI 0.869–0.875), which also produced well calibrated predictions of risk. Conclusion Despite using a small dataset, impressive performance in classifying response to neoadjuvant treatment can be achieved, particularly using automated image classification. Further study to refine the methodology is required before expansion to clinical settings. Take-home Message Response to neoadjuvant treatment for oesophageal cancer can be predicted from diagnostic biopsies

scholarly journals P-OGC29 Pathological response profiles of FLOT and ECX neoadjuvant chemotherapy in oesophageal adenocarcinoma

2021 ◽  
Vol 108 (Supplement_9) ◽  
Author(s):  
William Knight ◽  
Arion Pepas ◽  
Melody Lee ◽  
Larysa Hlukha ◽  
Andrew Jackson ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Primary Tumour ◽  
Neoadjuvant Treatment ◽  
Tumour Response ◽  
Oesophageal Adenocarcinoma ◽  
Tumour Regression ◽  
Tumour Regression Grade ◽  
Node Negative ◽  
Treatment Regimens ◽  
Nodal Upstaging

Abstract Background 70% of patients undergoing neo-adjuvant ECX chemotherapy for adenocarcinoma of the oesophagus, show little to know response in their primary tumour (Mandard 4,5). However, among these patients, those who have a complete nodal response (cN+ to ypN0) have equivalent survival to those with Mandard 1,2,3 tumours. FLOT chemotherapy has shown a survival advantage to ECX, however, rates of primary tumour response and nodal response are yet to be the focus of published study. Methods Retrospective cohort study comparing patients undergoing ECX and FLOT neoadjuvant chemotherapy between 2014 and 2021. Pathological outcomes were examined including, Mandard tumour regression grade (1-5), complete nodal response (cN+ to ypN0), clinically node negative nodal progression (cN0 to ypN+).   Results 226 patients had data available for analysis (193 ECX and 33 FLOT). 27% (52/193) of patients receiving ECX showed a response in the primary tumour (Mandard 1,2,3) compared to 63% (21/33) with patients undergoing FLOT (p &lt; 0.001). Complete nodal response rates were 25% in ECX patients and 21% FLOT patients (p = 0.556). Clinically node negative nodal upstaging (cN0 to pN+) was higher among FLOT patients 30% (13/33) than ECX patients 12% (24/193) (p &lt; 0.001). Conclusions FLOT chemotherapy confers improved primary tumour response. However, these findings were not echoed in locoregional nodal responses. Survival advantages with FLOT may result from improved responses in primary tumour and not improved systemic coverage. More data will be needed to explore this and over-come the confounding effect of staging inaccuracies. However, understanding systemic and loco-regional responses of different chemotherapy regimens will be needed to tailor future neoadjuvant treatment regimens.

796 OUTCOMES OF DELAYED SURGERY IN PATIENTS WITH RESIDUAL DISEASE AFTER NEOADJUVANT CHEMORADIOTHERAPY FOR OESOPHAGEAL CANCER

2021 ◽  
Vol 34 (Supplement_1) ◽  
Author(s):  
Hidde Overtoom ◽  
Ben Eyck ◽  
Berend Wilk ◽  
Bo Noordman ◽  
Pieter Sluis ◽  
...  
Keyword(s):  
Postoperative Complications ◽  
Oesophageal Cancer ◽  
Cox Regression ◽  
Residual Disease ◽  
Locally Advanced ◽  
Neoadjuvant Chemoradiotherapy ◽  
Progression Free Survival ◽  
Tumour Regression ◽  
Tumour Regression Grade ◽  
Negative Effect

Abstract   Standard treatment for locally advanced oesophageal cancer is neoadjuvant chemoradiotherapy (nCRT), plus surgery 6-8 weeks later. Time to surgery (TTS) after nCRT seems safe up to 12 weeks, and possibly improves patient condition and pathological response. However, it is unknown whether prolonged TTS is safe in patients with residual disease. The aim of this study was to investigate whether prolonged TTS leads to inferior surgical outcomes and survival in patients with residual disease after nCRT. Methods Patients with pathologically confirmed residual disease 4-6 weeks after nCRT who underwent preoperative PET/CT and surgery were selected from the preSANO-trial and SANO-trial. Patients were stratified by TTS ≤12 weeks versus TTS &gt;12 weeks after completion of nCRT. Primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), peroperative unresectability, microscopically radical resections (R0), tumour regression grade (TRG), postoperative complications and risk of distant dissemination. Effects of TTS on OS, PFS and distant dissemination were analysed with Cox regression, adjusted for Charlson comorbidity index (CCI) at baseline, as well as WHO performance score and weight loss after nCRT. Results Forty-two patients were included in the TTS &gt;12 weeks and 132 patients in the TTS ≤12 weeks group. Median follow-up was 20.6 months (IQR 16.1-30.3). Adjusted hazard ratios for OS and PFS were 0.50 (95% CI: 0.24-1.02) and 0.47 (95% CI: 0.25-0.91), respectively, in favour of TTS &gt;12 weeks. Patients with TTS &gt;12 weeks had more postoperative complications (89% vs 72%, p = 0.049), but comparable peroperatively unresectable tumours (11.9% vs. 3.8%, p = 0.11), R0-resections (89% vs 87%, p = 0.89), and TRG-scores (p = 0.97) compared to patients with TTS ≤12 weeks. Patients with TTS &gt;12 weeks showed less distant dissemination (HR 0.40, 95% CI: 0.18-0.88). Conclusion Prolonged TTS beyond 12 weeks in patients with clinically proven residual disease after nCRT did not have a negative effect on OS and on PFS, but was correlated with an increase in postoperative complications. The (non-significantly) better survival outcomes for TTS &gt;12 weeks may be explained by the fact that patients had a lower risk of developing distant dissemination, which may reflect improved selection prior to surgery.

scholarly journals Comparative genomic analysis of Methanimicrococcus blatticola provides insights into host adaptation in archaea and the evolution of methanogenesis

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Courtney M. Thomas ◽  
Najwa Taib ◽  
Simonetta Gribaldo ◽  
Guillaume Borrel
Keyword(s):  
Gut Microbiota ◽  
Large Scale ◽  
Genomic Analysis ◽  
Host Adaptation ◽  
Comparative Genomic Analysis ◽  
Comparative Genomic ◽  
Methyl Branch ◽  
Mechanisms Of Adaptation ◽  
Hydrogenotrophic Methanogens ◽  
Almost All

AbstractOther than the Methanobacteriales and Methanomassiliicoccales, the characteristics of archaea that inhabit the animal microbiome are largely unknown. Methanimicrococcus blatticola, a member of the Methanosarcinales, currently reunites two unique features within this order: it is a colonizer of the animal digestive tract and can only reduce methyl compounds with H2 for methanogenesis, a increasingly recognized metabolism in the archaea and whose origin remains debated. To understand the origin of these characteristics, we have carried out a large-scale comparative genomic analysis. We infer the loss of more than a thousand genes in M. blatticola, by far the largest genome reduction across all Methanosarcinales. These include numerous elements for sensing the environment and adapting to more stable gut conditions, as well as a significant remodeling of the cell surface components likely involved in host and gut microbiota interactions. Several of these modifications parallel those previously observed in phylogenetically distant archaea and bacteria from the animal microbiome, suggesting large-scale convergent mechanisms of adaptation to the gut. Strikingly, M. blatticola has lost almost all genes coding for the H4MPT methyl branch of the Wood–Ljungdahl pathway (to the exception of mer), a phenomenon never reported before in any member of Class I or Class II methanogens. The loss of this pathway illustrates one of the evolutionary processes that may have led to the emergence of methyl-reducing hydrogenotrophic methanogens, possibly linked to the colonization of organic-rich environments (including the animal gut) where both methyl compounds and hydrogen are abundant.

Sign in / Sign up

Export Citation Format

Share Document