scholarly journals 474 GENOMIC ANALYSIS OF RESPONSE TO NEOADJUVANT CHEMOTHERAPY IN ESOPHAGEAL ADENOCARCINOMA

2020 ◽  
Vol 33 (Supplement_1) ◽  
Author(s):  
F Izadi ◽  
G Devonshire ◽  
R Walker ◽  
M Lloyd ◽  
J Gibson ◽  
...  
Keyword(s):  
Dna Damage ◽  
Neoadjuvant Chemotherapy ◽  
Esophageal Adenocarcinoma ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Chemotherapy Resistance ◽  
Treatment Modalities ◽  
Tumor Regression Grade ◽  
Driver Genes ◽  
The Impact

Abstract   In the UK, neoadjuvant chemotherapy (NAC) for locally advanced esophageal adenocarcinoma (EAC) is the standard of care. Unfortunately, response to NAC, following surgery is often low (<30%) and survival benefit at 2 years is only 5.1%. The EAC genome is complex and heterogeneous between patients, where specific mutagenic processes and mutations may result in chemotherapy resistance. Here we report preliminary results from whole-genome sequencing (WGS) of 48 patients who were subsequently treated with NAC. Methods We defined response as Mandard Tumor Regression Grade (TRG) 1-2 (n = 15) and non-response as TRG4-5 (n = 33). WGS of 50x coverage and calling of genomic events (Strelka2, SCAT/GISTIC) was performed according to Frankell Nat Genet 2019 with modifications, to differentiate driver from passenger mutations (dNdScv, oncodriveCLUST), determine variant allele frequencies (VAF; copy number-adjusted) and mutation signatures (NMF R-package). Following stringent variant QC (Phred score ≥ 30), filtering (VAF >0.02) and annotation (ANNOVAR, cancer census/helper, the 77 known EAC drivers and false positive genes) and visualisation in maftools, we evaluated the data for associations between genomic events and response to NAC. Results COSMIC mutation signatures 2 (TRG1-2; Cosθ = 0.89) and 6 (TRG4-5; Cosθ = 0.82) were enriched, suggesting defective mismatch repair in non-responders. Using 5,193 high-confidence non-silent mutations (TRG1-2,n = 1969; TRG4-5, n = 3224), we identified 39 mutated driver genes (Figure-1) with a median of 2.9(0-5) (TRG1-2) and 2.7(0-9) (TRG4-5) driver events/patient. Shared dysregulated pathways, included DNA-damage (TP53), cell cycle (CDKN2A), TGF-β (SMAD4) and chromatin regulation (ARID1A). There was no difference in the prognostic of SMAD4 and GATA4 genes. Interestingly, NAV3 mutations were only present in non-responders (21%,7/33); and in responders TP53 incidence was higher (93% vs. 58%) with a concomitant reduction in clonal cell fraction (0.25 vs. 0.39;Wilcoxon, p < 0.0001). Conclusion The data suggest that specific genomic events, such as NAV3 mutation and the intra-tumoral heterogeneity of mutated DNA-damage response genes may offer additional predictive value. Ongoing work includes analysis of the impact of non-coding variation on response. While our analysis is limited by sample size and requires validation in additional cohorts, it demonstrates the potential of genomic sequencing to identify NAC response biomarkers and may guide alternative or novel treatment modalities for chemo-resistant tumours.

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.

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.

scholarly journals Radiotherapy Scheme Effect on PD-L1 Expression for Locally Advanced Rectal Cancer

Cells ◽  
2020 ◽  
Vol 9 (9) ◽  
pp. 2071
Author(s):  
Jihane Boustani ◽  
Valentin Derangère ◽  
Aurélie Bertaut ◽  
Olivier Adotevi ◽  
Véronique Morgand ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Advanced Rectal Cancer ◽  
Locally Advanced Rectal Cancer ◽  
Tumor Regression Grade ◽  
The Impact

In locally advanced rectal cancer, radiotherapy (RT) followed by surgery have improved locoregional control, but distant recurrences remain frequent. Although checkpoint inhibitors have demonstrated objective response in several cancers, the clinical benefit of PD-1/PD-L1 blockade remains uncertain in rectal cancer. We collected data from biopsies and surgical specimens in 74 patients. The main objective was to evaluate the impact of neoadjuvant RT and fractionation on PD-L1 expression. Secondary objectives were to study the relation between PD-L1 expression and tumor regression grade (TRG), progression-free survival (PFS), overall survival (OS), and CD8 TILs infiltration. Median rates of cells expressing PD-L1 pre- and post-RT were 0.15 (range, 0–17) and 0.5 (range, 0–27.5), respectively (p = 0.0005). There was no effect of RT fractionation on PD-L1+ cell rates. We found no relation between CD8+ TILs infiltration and PD-L1 expression and no difference between high-PD-L1 or low-PD-L1 expression and TRG. High-to-high PD-L1 expression profile had none significant higher OS and PFS compared to all other groups (p = 0.06). Median OS and PFS were higher in biopsies with >0.08 PD-L1+ cells. High-to-high PD-L1 profile and ypT0-2 were significantly associated with higher OS and PFS. This study did not show the differential induction of PD-L1 expression according to fractionation.

scholarly journals A retrospective comparison of outcome and toxicity of preoperative image-guided intensity-modulated radiotherapy versus conventional pelvic radiotherapy for locally advanced rectal carcinoma

2016 ◽  
Vol 58 (2) ◽  
pp. 247-259 ◽  
Author(s):  
Chun-Ming Huang ◽  
Ming-Yii Huang ◽  
Hsiang-Lin Tsai ◽  
Ching-Wen Huang ◽  
Cheng-Jen Ma ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Tumor Regression ◽  
Locally Advanced ◽  
Survival Rates ◽  
Pathologic Complete Response ◽  
Intensity Modulated Radiotherapy ◽  
Treatment Modalities ◽  
Tumor Regression Grade ◽  
Image Guided ◽  
Intensity Modulated

Abstract The aim of the study was to compare clinical outcomes and toxicity between 3D conformal radiotherapy (3DCRT) and image-guided intensity-modulated radiotherapy (IG-IMRT) administered through helical tomotherapy in locally advanced rectal cancer (LARC) patients receiving preoperative chemoradiotherapy. We reviewed 144 patients with Stage II–III rectal cancer receiving preoperative fluoropyrimidine-based chemoradiotherapy followed by radical resection. Tumor responses following chemoradiotherapy were evaluated using the Dworak tumor regression grade (TRG). Of the 144 patients, 45 received IG-IMRT and 99 received 3DCRT. A significant reduction in Grade 3 or 4 acute gastrointestinal toxicity (IG-IMRT, 6.7%; 3DCRT, 15.1%; P = 0.039) was observed by IG-IMRT. The pathologic complete response (pCR) rate did not differ between the IG-IMRT and the 3DCRT group (17.8% vs 15.1%, P = 0.52). Patients in the IG-IMRT group had the trend of favorable tumor regressions (TRG 3 or 4) compared with those in the 3DCRT group (66.7% vs 43.5%, P = 0.071). The median follow-up was 53 months (range, 18–95 months) in the 3DCRT group and 43 months (range, 17–69 months) in the IG-IMRT group. Four-year overall, disease-free, and local failure–free survival rates of the IG-IMRT and 3DCRT groups were 81.6% and 67.9% (P = 0.12), 53.8% and 51.8% (P = 0.51), and 88% and 75.1% (P = 0.031), respectively. LARC patients treated with preoperative IG-IMRT achieved lower acute gastrointestinal adverse effects and a higher local control rate than those treated with 3DCRT, but there was no prominent difference in distant metastasis rate and overall survival between two treatment modalities.

scholarly journals Body Composition Changes in Gastric Cancer Patients during Preoperative FLOT Therapy: Preliminary Results of an Italian Cohort Study

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 960
Author(s):  
Emanuele Rinninella ◽  
Antonia Strippoli ◽  
Marco Cintoni ◽  
Pauline Raoul ◽  
Raffaella Vivolo ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Body Composition ◽  
Tumor Regression ◽  
Evaluation Criteria ◽  
Tumor Regression Grade ◽  
Skeletal Muscle Index ◽  
Before And After ◽  
Gastric Cancer Patients ◽  
The Impact ◽  
Composition Changes

Background: The impact of the new chemotherapy, fluorouracil plus leucovorin, oxaliplatin, and docetaxel (FLOT) on body composition in gastric cancer (GC) patients remains unknown. We assessed body composition changes of GC patients receiving the FLOT regimen and their impact on treatment outcomes. Methods: Preoperative pre- and post-FLOT computed tomography (CT) scans of advanced GC patients were studied. Lumbar skeletal muscle index (SMI) and adipose indices were calculated before and after FLOT. Results: A total of 26 patients were identified between April 2019 and January 2020. Nineteen patients were sarcopenic at diagnosis. The mean BMI decreased (from 24.4 ± 3.7 to 22.6 ± 3.1; p < 0.0001) as well as the SMI (from 48.74 ± 9.76 to 46.52 ± 9.98; p = 0.009) and visceral adipose index (VAI) (from 49.04 ± 31.06 to 41.99 ± 23.91; p = 0.004) during preoperative FLOT therapy. BMI, SMI, and VAI variations were not associated with toxicity, Response Evaluation Criteria in Solid Tumors (RECIST), response, delay and completion of perioperative FLOT chemotherapy, and the execution of gastrectomy; a decrease of SMI ≥ 5% was associated with a higher Mandard tumor regression grade (p = 0.01). Conclusions: Almost three-quarters (73.1%) of GC patients were sarcopenic at diagnosis. Preoperative FLOT was associated with a further reduction in SMI, BMI, and VAI. These changes were not associated with short-term outcomes.

scholarly journals Neoadjuvant Therapy in Operable Breast Cancer: Application to Triple Negative Breast Cancer

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Foluso O. Ademuyiwa ◽  
Matthew J. Ellis ◽  
Cynthia X. Ma
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Chemotherapy ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Chemotherapy Resistance ◽  
Treatment Strategies ◽  
Surrogate Endpoint ◽  
Complete Response

Systemic treatment for triple negative breast cancer (TNBC: negative for the expression of estrogen receptor and progesterone receptor and HER2 amplification) has been limited to chemotherapy options. Neoadjuvant chemotherapy induces tumor shrinkage and improves the surgical outcomes of patients with locally advanced disease and also identifies those at high risk of disease relapse despite today’s standard of care. By using pathologic complete response as a surrogate endpoint, novel treatment strategies can be efficiently assessed. Tissue analysis in the neoadjuvant setting is also an important research tool for the identification of chemotherapy resistance mechanisms and new therapeutic targets. In this paper, we review data on completed and ongoing neoadjuvant clinical trials in patients with TNBC and discuss treatment controversies that face clinicians and researchers when neoadjuvant chemotherapy is employed.

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