Tumor Regression Grade Research Articles

Profiling complete regression after pre-operative therapy in gastric cancer patients using clinical and pathological data

IntroductionThe consistent use of pre-operative treatment before surgery for gastric cancer (GC) has resulted in increased rates of complete response. However, factors associated with response have been scantly investigated. MethodsPatients with GCs treated between 2017 and 2022 undergoing pre-operative treatment followed by resection were included. Clinicopathological data were analyzed for the association with tumor regression grades (TRG); secondary outcomes included the short-term overall (OS), disease-free (DFS) and disease specific survival (DSS). ResultsAmong 108 patients, 35.1% had an intestinal histotype GC, and 70.4% were treated with FLOT. Complete tumor regression (TRG1) was documented in 6.5% of patients. Univariable analyses documented that a higher pre-operative albumin (p = 0.04) and the expression of HER2 (p = 0.01) were associated to TRG1. In the multinominal regression model, the log-odds of being classified as TRG1 increased with the expression of HER2 by 170.247 times and with higher pre-operative albumin by 34.525 times, while with a higher Charlson Index and a diffuse hystotipe reduced it by 25.467 times and 3759.126 times, respectively. Among 49 patients (mean follow-up: 17.1 months), TRG1-2 was associated to better OS, DFS and DSS curves compared to TRG 3-5 (respectively p < 0.01, p 0.007 and p < 0.01), altogether with the reported negative impact of comorbidities in OS and DSS multivariable analyses (respectively p 0.04 and p 0.006). The random survival forest further confirmed the impact of HER2 and comorbidity on DSS. ConclusionA better clinical profile, HER2 expression and intestinal histotype significantly correlated with GC regression. A complete-major response was an independent factor for survival.

A Comprehensive Prediction Model Based on MRI Radiomics and Clinical Factors to Predict Tumor Response After Neoadjuvant Chemoradiotherapy in Rectal Cancer

To establish a prediction model for the efficacy of neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC), using pretreatment magnetic resonance imaging (MRI) multisequence image features and clinical parameters. Patients with clinicopathologically confirmed LARC were included (training and validation datasets, n=100 and 27, respectively). Clinical data of patients were collected retrospectively. We analyzed MRI multisequence imaging features. The tumor regression grading (TRG) system proposed by Mandard et al was adopted. Grade 1-2 of TRG was a good response group, and grade 3-5 of TRG was a poor response group. In this study, a clinical model, a single sequence imaging model, and a comprehensive model combined with clinical imaging were constructed, respectively. The area under the subject operating characteristic curve (AUC) was used to evaluate the predictive efficacy of clinical, imaging, and comprehensive models. The decision curve analysis method evaluated the clinical benefit of several models, and the nomogram of efficacy prediction was constructed. The AUC value of the comprehensive prediction model is 0.99 in the training data set and 0.94 in the test data set, which is significantly higher than other models. Radiomic Nomo charts were developed using Rad scores obtained from the integrated image omics model, circumferential resection margin(CRM), DoTD, and carcinoembryonic antigen(CEA). Nomo charts showed good resolution. The calibrating and discriminating ability of the synthetic prediction model is better than that of the single clinical model and the single sequence clinical image omics fusion model. Nomograph, based on pretreatment MRI characteristics and clinical risk factors, has the potential to be used as a noninvasive tool to predict outcomes in patients with LARC after nCRT.

Restaging of rectal cancer with hybrid positron emission tomography magnetic resonance imaging after preoperative chemoradiotherapy.

This study determines the sensitivity and specificity of positron emission tomography/magnetic resonance imaging (PET/MRI) parameters in predicting treatment response in patients with localised rectal cancer who have undergone preoperative chemoradiotherapy (CRT). Patients with stage I-III adenocarcinoma of the rectum planned for preoperative CRT followed by surgery were recruited. Patients had PET/MRI scans at baseline and 6-8 weeks post-CRT. Functional MRI and PET parameters were assessed for their diagnostic accuracy for tumour regression grade (TRG). Nonparametric receiver operating characteristic analysis was employed to determine the area under the ROC curve (AUC), and the sensitivity and specificity of each quantile cut-off. A total of 31 patients were recruited, of whom 20 completed study protocol. All patients included had mid or lower rectal tumours. There were 16 patients (80%) with node-positive disease at presentation. The median time to surgery was 75.5 days (range 52-106 days). Histopathological assessment revealed 20% good responders (TRG 1/2), and the remaining 80% of patients had a poor response (TRG 3/4). When predicting good responders, the AUC values for percent maximum thickness reduction and percent apparent diffusion coefficient (ADC) change were 0.82 and 0.73, respectively. A maximum thickness reduction cut-off of >47% and a percent ADC change of >20% yielded a sensitivity and specificity of 75%/95% and 75%/73%, respectively. Parameters such as percent maximum thickness reduction and percent ADC change may be useful for predicting good responders in patients undergoing preoperative CRT for rectal cancer. Larger studies are warranted to establish the utility of PET/MRI in rectal cancer staging.

Study on the recurrence pattern of rectal cancer patients undergoing radical surgery after neoadjuvant chemoradiotherapy

Objective: To analyze the recurrence pattern of rectal cancer patients with radical surgery after neoadjuvant chemoradiotherapy. Methods: The clinicopathological characteristics and follow-up information of rectal cancer patients with radical surgery after neoadjuvant chemoradiotherapy in the Cancer Hospital of the Chinese Academy of Medical Sciences from June 2004 to December 2017 were retrospectively collected. The recurrence pattern including the time and site was investigated. Results: The age of 537 patients was (55.5±11.7) years, of whom 361 were male (67.2%). The median follow-up time [M(Q1,Q3)] was 77.9 (64.5, 95.6) months. Moreover, 30.7% (165/537) of patients had distant metastasis or local recurrence; 26.8% (144/537) of patients had distant metastasis; 5.6% (30/537) of patients had local recurrence; 1.7% (9/537) of patients had both distant metastasis and local recurrence. In all the recurrent patients, 23.6% (39/165) were in the first year after surgery, followed by 27.3% (45/165) in the second year, 17.0% (28/165) in the third year, and 15.8% (26/165) after five years. According to the risk curve drawn by the life table, the highest metastasis risk of patients occurred in the second year after surgery, and the metastasis risk peak occurred again after more than five years. The lung was the most common metastatic organ, accounting for 47.9% (69/144), followed by the liver (18.8%, 27/144). The ratios of the recurrent patients in each ypTNM stage were 9.5% (8/84), 12.0% (12/100), 26.5% (41/155), 52.5% (104/198), respectively. The proportion of recurrent patients in tumor regression grade (TRG) 1-2 and TRG 3-5 patients were 19.2% (38/198) and 37.5% (127/339), respectively. Conclusions: The recurrence pattern of patients undergoing radical surgery after neoadjuvant chemoradiotherapy is mainly distant metastasis. The lung is the primary metastatic organ. The risk of distant metastasis and local recurrence is high in the first three years after surgery, and there is still high risk of recurrence after five years. For patients with ypTNM stage 2, 3 and TRG3-5, the postoperative adjuvant chemotherapy and long-term follow-up should be strengthened.

The results of treatment for resectable gastric cancer with microsatellite instability

Background. microsatellite instability (MSI) is a prognostic marker of survival in many malignant diseases and show resistance to chemotherapy at early stages of colorectal cancer and show no benefits from chemotherapy at early stages of colorectal cancer. However, the role of MSI in resectable gastric cancer (GC) remains unknown.Aim. To study the results of treatment of resectable gastric cancer with microsatellite instability.Materials and methods. The study included 286 patients with resectable gC who received treatment at the N. N. Blokhin national medical Research Center of Oncology. All patients underwent PCR testing for MSI-H in 5 markers (BAT25, BAT26, NR21, NR24, NR27). Tumor regression grades (TRG) were evaluated according to the mandard tumour regression score, including disease-free survival and overall survival.Results. MSI indicated in 27 cases (9.44 %) out of 286 resectable gastric cancer. In group patients who received only surgical treatment, 2-year disease-free survival in patients with MSI-H was 77.80 % versus 88.29 % in MSS patients (hazard ratio (HR) 1.82, 95 % confidence interval (CI) 0.37–8.82, p = 0.45), 2-year overall survival in patients with MSI-H was 88.90 % versus 95.36 % in MSS patients (HR 2.03, 95 % CI 0.20–19.8, p = 0.54). In patients who received perioperative chemotherapy, 28.57 % (4 / 14) had progression in MSI-H tumor versus 3.61 % (6 / 166) in MSS tumor (p &lt;0.001). In group patients who received treatment combined with chemotherapy, 2-year disease-free survival in patients with MSI-H was 59.60 % versus 67.36 % (HR 1.96, CI 95 % 0.88–4.35, p = 0.09), 2-year overall survival in patients with MSI-H was 67.30 % versus 85.86 % in MSS patients (HR 1.86, 95 % CI 0.64–5.41, p = 0.25)Conclusion. MSI-H is not a favorable prognosis factor in patients with resectable GC who are treated surgically combined with chemotherapy. The prevalence of progression in patients with MSI-H-status is higher than MSS-status with perioperative chemotherapy (FLOT / FOLFIRINOX).

Genomic and Transcriptomic Remodeling by Neoadjuvant Chemoradiotherapy (nCRT) and the Indicative Role of Acquired INDEL Percentage for nCRT Efficacy in Esophageal Squamous Cell Carcinoma

The effect of genomic factors on the response of patients with esophageal squamous cell carcinoma (ESCC) to neoadjuvant chemoradiotherapy (nCRT), as well as how nCRT influences the genome and transcriptome of ESCC, remain largely unknown. In total, 137 samples from 57 patients with ESCC undergoing nCRT were collected and subjected to whole-exome sequencing and RNA sequencing analysis. Genetic and clinicopathologic factors were compared between the patients achieving pathologic complete response and patients not achieving pathologic complete response. Genomic and transcriptomic profiles before and after nCRT were analyzed. Codeficiency of the DNA damage repair and HIPPO pathways synergistically sensitized ESCC to nCRT. nCRT induced small INDELs and focal chromosomal loss concurrently. Acquired INDEL% exhibited a decreasing trend with the increase of tumor regression grade (P=.06, Jonckheere's test). Multivariable Cox analysis indicated that higher acquired INDEL% was associated with better survival (adjusted hazard ratio [aHR], 0.93; 95% CI, 0.86-1.01; P=.067 for recurrence-free survival [RFS]; aHR, 0.86; 95% CI, 0.76-0.98; P=.028 for overall survival [OS], with 1% of acquired INDEL% as unit). The prognostic value of acquired INDEL% was confirmed by the Glioma Longitudinal AnalySiS data set (aHR, 0.95; 95% CI, 0.902-0.997; P=.037 for RFS; aHR, 0.96; 95% CI, 0.917-1.004; P=.076 for OS). Additionally, clonal expansion degree was negatively associated with patient survival (aHR, 5.87; 95% CI, 1.10-31.39; P=.038 for RFS; aHR, 9.09; 95% CI, 1.10-75.36; P=.041 for OS, with low clonal expression group as reference) and also negatively correlated with acquired INDEL% (Spearman ρ=-0.45; P=.02). The expression profile was changed after nCRT. The DNA replication gene set was downregulated, while the cell adhesion gene set was upregulated after nCRT. Acquired INDEL% was negatively correlated with the enrichment of the DNA replication gene set (Spearman ρ=-0.56; P=.003) but was positively correlated with the enrichment of the cell adhesion gene set (Spearman ρ=0.40; P=.05) in posttreatment samples. nCRT remodels the genome and transcriptome of ESCC. Acquired INDEL% is a potential biomarker to indicate the effectiveness of nCRT and radiation sensitivity.

Comparison of the pathological response to 2 or 4 cycles of neoadjuvant CAPOX in II/III rectal cancer patients with low/intermediate risks: study protocol for a prospective, non-inferior, randomized control trial (COPEC trial)

BackgroundFor patients with low- and intermediate-risk stage II/III rectal cancer, current studies have reached a consensus that preoperative radiotherapy may be dispensed with, and neoadjuvant chemotherapy (NCT) alone might achieve an accepted local control. Our previous phase II study has evidenced that the morphological response of NCT could be better judged at a relatively early stage. Low- and intermediate-risk stage II/III rectal cancer patients could achieve a high rate of tumor shrinkage and downgrade after only 4 cycles of NCT and obvious tumor morphological changes could be observed after 2 cycles of NCT. However, there is still a lack of more detailed stratification and evidence for pathological criteria. The aim of the present study (comparison of the pathological response to 2 or 4 cycles of neoadjuvant CAPOX in II/III rectal cancer patients with low/intermediate risks, COPEC trial) is to determine the pathological tumor regression grade (pTRG) rate of 2 or 4 cycles of NCT in low- and intermediate-risk stage II/III rectal cancer and verify the feasibility of early identification of chemotherapy-insensitive population.Methods/designThis is a multicenter, prospective, non-inferior, randomized controlled trial (RCT) initiated by West China Hospital of Sichuan University and designed to be conducted in fourteen hospitals around China. Eligible patients will be centrally randomized into 2 or 4 cycles of CAPOX in a 1:1 ratio using the central automated randomization system offered by the O-trial online system (https://plus.o-trial.com/) and accept total mesorectal excision after 2 or 4 cycles of CAPOX (oxaliplatin 130 mg/m2, once daily on day 1, every 21 days and capecitabine 1000 mg/m2, twice daily on days 1 to 14, every 21 days). The primary endpoint is the proportion of patients with pathological no-tumor regression (pTRG 3), which is determined postoperatively by each sub-center and verified by the primary center.DiscussionCOPEC trial is designed to verify that the preoperative CAPOX chemotherapy for low- and intermediate-risk stage II/III rectal cancer could achieve a good response judgment after 2 cycles and obtain the tumor pathological response rate after 2 cycles of CAPOX. We hope the COPEC trial could help in establishing a consensus standard of low- and intermediate-risk rectal cancer and the early identification of stage II/III rectal patients with low- and intermediate-risk who are poorly responding to NCT.Trial registrationClinicaltrial.gov NCT04922853. Registered on June 4, 2021.

The role of MRI after neochemoradiotherapy in predicting pathological tumor regression grade and clinical outcome in patients with locally advanced rectal adenocarcinoma.

To evaluate the predictive value of tumor regression grade assessed by MRI (mr-TRG) after neoadjuvant chemoradiotherapy (neo-CRT) for postoperative pathological TRG (pTRG) and prognosis in patients with locally advanced rectal adenocarcinoma (LARC). This was a retrospective study from a single center experience. The patients who were diagnosed with LARC and received neo-CRT in our department between January 2016 and July 2021 were enrolled. The agreement between mrTRG and pTRG was assessed with the weighted κ test. Overall survival (OS), progress-free survival (PFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were calculated by Kaplan-Meier analysis and log-rank test. From January 2016 to July 2021, 121 LARC patients received neo-CRT in our department. Among them, 54 patients had complete clinical data, including MRI of pre- and post-neo-CRT, postoperative tumor samples, and follow-up. The median follow-up time was 34.6 months (range: 4.4-70.6 months). The estimated 3-year OS, PFS, LRFS and DMFS were 78.5%, 70.7%, 89.0%, and 75.2%, respectively. The median time from the completion of neo-CRT to preoperative MRI and surgery was 7.1 weeks and 9.7 weeks, respectively. Out of 54 patients, 5 patients achieved mrTRG1 (9.3%), 37 achieved mrTRG2 (68.5%), 8 achieved mrTRG3 (14.8%), 4 achieved mrTRG4 (7.4%), and no patient achieved mrTRG5 after neo-CRT. Regarding pTRG, 12 patients achieved pTRG0 (22.2%), 10 achieved pTRG1 (18.5%), 26 achieved pTRG2 (48.1%), and 6 achieved pTRG3 (11.1%). The agreement between three-tier mrTRG (mrTRG1 vs. mrTRG2-3 vs. mrTRG4-5) and pTRG (pTRG0 vs. pTRG1-2 vs. pTRG3) was fair (weighted kappa=0.287). In a dichotomous classification, the agreement between mrTRG(mrTRG1 vs. mrTRG2-5)and pTRG(pTRG0 vs. pTRG1-3) also resulted in fair agreement (weighted kappa=0.391). The sensitivity, specificity, positive, and negative predictive values of favorable mrTRG (mrTRG 1-2) for pathological complete response (PCR) were 75.0%, 21.4%, 21.4%, and 75.0%, respectively. In univariate analysis, favorable mrTRG (mrTRG1-2) and downstaging N were significantly associated with better OS, while favorable mrTRG (mrTRG1-2), downstaging T, and downstaging N were significantly associated with superior PFS (p<0.05). In multivariate analysis, downstaging N was an independent prognostic factor for OS. Meanwhile, downstaging T and downstaging N remained independent prognostic factors for PFS. Although the consistency between mrTRG and pTRG is only fair, favorable mrTRG after neo-CRT may be used as a potential prognostic factor for LARC patients.

Total Lymph Node Yield Is Associated with Prolonged Survival after Neoadjuvant Chemotherapy in ypN0 Gastric Cancer Patients

Introduction: Lymph node status after neoadjuvant chemotherapy (NAC) plays the main role in predicting the survival of gastric cancer (GC) patients who underwent curative gastrectomy after NAC. NAC can reduce the number of involved lymph nodes. However, it is unknown whether other variables are associated with the survival outcomes for ypN0 GC patients. It is unknown whether lymph node yield (LNY) has prognostic value in ypN0 GC patients treated with NAC plus surgery. Methods: In this retrospective study, we reviewed the data of patients treated with NAC plus gastrectomy and identified those with ypN0 disease. The LNY cut-off was calculated using the X-tile program to determine the greatest actuarial survival difference. Patients were categorized into the downstaged N0 (cN+/ypN0) and natural N0 (cN0/ypN0) groups based on nodal status. Multivariate analysis was used to identify the prognostic factors and the association between LNY and prognosis. Results: A total of 211 GC patients with ypN0 status were included. The optimal LNY cut-off was 23. Kaplan-Meier analysis revealed no significant difference in overall survival between the natural and downstaged N0 groups, while ypN0 GC patients with an LNY of ≥24 had significantly longer overall survival than those with an LNY of ≤23. Univariate analysis identified that LNY, cT stage, tumor location, ypT stage, perineural invasion, lymphovascular invasion, tumor size, Mandard tumor regression grade, and extent of gastrectomy were significantly associated with overall survival. Multivariate analysis confirmed that perineural invasion (hazard ratio, 4.246; p < 0.001), lymphovascular invasion (hazard ratio, 2.694; p = 0.048), and an LNY of ≥24 (hazard ratio, 0.394; p = 0.011) were independent prognostic factors. Conclusions: Patients with natural and downstaged ypN0 GC had similar overall survival after NAC. LNY was an independent prognostic factor in these patients, and an LNY of ≥24 predicted prolonged overall survival.

Perioperative immunochemotherapy (mDCF + avelumab) in locally advanced gastro-esophageal adenocarcinoma: A phase II trial.

4055 Background: Perioperative chemotherapy improves cure rate in locally advanced gastro-esophageal adenocarcinoma (GEA). Immune checkpoint inhibitors have activity in GEA. This trial is testing the hypothesis that the addition of avelumab, an anti-PD-L1 antibody, to perioperative mDCF chemotherapy, will increase the pathologic complete response (pCR) rate, a potential surrogate for overall survival, in comparison with a historical pCR rate of 7%. Methods: Single-arm phase II study (NCT03288350) of avelumab + chemotherapy (modified docetaxel/cisplatin/5-FU or mDCF) given every 2 weeks x 4 cycles before and after surgery. Planned sample size of 50 operated patients. The hypothesis cannot be refuted if ≥6 patients show pCR, the primary endpoint. Inclusion criteria: histologically proven GEA, locally advanced disease (cT3-4 and/or N+), adequate organ function, WHO performance status 0-1. Exclusion criteria: other histology, metastatic stage, use of immunosuppressants, serious autoimmune disease, intake &gt;10 mg prednisone/d. Adverse effects prospectively recorded per NCI CTCAE guidelines. Pathological response and tumor regression grade (TRG) determined by CAP criteria: 0=complete;1=near complete; 2=moderate; 3 = poor/no response. Data presented as median (range), KM determined survival. Results: Study accrual completed August 2022: 51 patients enrolled, 45 M/6 F, age 64 (18-79), ECOG 0 (35) and 1 (16). One patient withdrew consent after 2 treatment cycles and is excluded from efficacy analysis. Tumor anatomic site: Esophagus =19(38%)/gastroesophageal junction 21(42%)/subcardia stomach 10(20%). Staging: cT3 (88%), cT4 (6%), N+ (62%). Histology: all adenocarcinoma; dMMR 9/50 in 18%; CPS&lt;1, 1-5, 6-10, &gt;10 in 0%/33%/27%/40% of tumors tested. All 4 pre-operative cycles administered to 48/50 (96%); 36/50 received ≥2 adjuvant treatment cycles and 23/50 (46%) received all 8 cycles. Grade 3-4 toxicity events from neoadjuvant therapy affected: GI tract (diarrhea 4%); respiratory system (pneumonia 4%); endocrine system (adrenal insufficiency 2%). Other common side effects (grades 1-2, incidence &gt; 15%) were: fatigue, diarrhea, skin rash/pruritus. Post-operative mortality at 30 and 90 days was 0/50 (0%) and 1/50 (2%). R0 resection was achieved in 48/50 (96%); a median of 36 (13-78) lymph nodes were resected. Pathological response was TRG 0/1/2/3 in 7/2/16/25 with pCR seen in 7 (14%), meeting the primary endpoint. Major pathologic response (TRG 0 and 1) was seen in 9 (18%), but without correlation with CPS or dMMR biomarker status. At 37.5 (9-71) months follow up, overall survival at 1, 2, and 3 years is 93.6%, 75.7%, and 69.2%. MPR showed a trend to improved survival ( p = 0.06). Conclusions: The neoadjuvant combination of avelumab with chemotherapy (mDCF) shows promising safety and efficacy in gastroesophageal adenocarcinoma, without obvious correlation to known biomarkers. Clinical trial information: NCT03288350 .

Longitudinal circulating tumor DNA monitoring in patients with esophageal squamous cell carcinoma.

3041 Background: The clinical utility of longitudinal monitoring with circulating tumor DNA (ctDNA) as a prognostic and a predictive biomarker was recently reported in patients with resectable colorectal cancer (Kotani D, et al. Nature Medicine 2023). Here we report a prospective, observational study of longitudinal ctDNA monitoring in patients with esophageal squamous cell carcinoma (ESCC) receiving neoadjuvant chemotherapy (NAC) followed by surgery. Methods: Patients with ESCC planned for NAC followed by curative surgery, were prospectively enrolled in this study. As per the protocol, plasma samples were collected at 7 timepoints: pre-NAC, post-NAC, and 4,12, 24, 36, and 48-weeks after surgery. CT scans were conducted every 3 months. Longitudinal ctDNA testing was performed using a personalized, tumor-informed ctDNA assay (Signatera, bespoke mPCR, NGS assay). In this initial report, ctDNA results at 3 time points (pre-NAC, post-NAC, and 4 weeks post-surgery) were analyzed and their association with clinical outcomes and tumor regression grade (TRG) scores were assessed. Results: So far, a total of 83 blood samples from 28 patients with ESCC were collected serially at pre-NAC (N=28), post-NAC (N=27), and post-surgical (N=28) time points. Pre-NAC ctDNA was detectable in 96.4% patients (27/28), and detection rates decreased at the post-NAC (37%; 10/27) and post-surgical (11%; 3/28) timepoints. ctDNA-positivity post-NAC and post-surgery was associated with a significantly shorter recurrence free survival (RFS) with HR of 7.0 (95% CI: 1.4-35.0; p = 0.02) and HR of 14 (95% Cl 3.0-62; p &lt;0.001), respectively. Notably, patients who achieved ctDNA clearance with NAC had favorable RFS as compared to the patients who did not (HR=0.15, 95% CI: 0.03 – 0.75; p = 0.02). Post-NAC ctDNA was also associated with tumor regression grade (TRG) score. None of the patients with TRG3 score (N=3) were ctDNA positive, whereas 7.7% (1/13) patients in the TRG2 category and 81.8% (9/11) in the TRG1 category were ctDNA-positive. Conclusions: Our study demonstrates a strong correlation between ctDNA status and clinical outcomes in ESCC patients. Assessment of ctDNA may be useful monitoring in patients with ESCC post NAC/surgery and may be used in the future to direct post-surgical management in this patient population. Clinical trial information: UMIN000042003 .

The FOxTROT platform: Clinical trials and exploratory research for personalization of neoadjuvant (NA) therapy in locally advanced colon cancer (LACC)—ISRCTN83842641.

TPS3636 Background: The FOxTROT1 trial demonstrated a significant reduction in 2-year (yr) recurrence with 6 weeks (wks) of oxaliplatin and fluoropyrimidine (OxFp) NA chemotherapy (NAC) in patients (pts) with LACC, establishing NAC as a new therapeutic option. The ongoing FOxTROT platform will refine and personalize NA therapy in LACC. FOxTROT2 is testing NAC in older pts and those with frailty, who are poorly represented in clinical trials. FOxTROT3 is assessing intensified NAC with modified FOLFOXIRI (mFOLFOXIRI; 5-fluorouracil, oxaliplatin, irinotecan) in fit pts. The FOxTROT platform will also test targeted treatments with established safety and efficacy in defined molecular subgroups. FOxTROT4 is investigating the efficacy and safety of NA encorafenib and cetuximab in BRAF-mutant pMMR LACC. Other arms in setup are shown in Table. Methods: FOxTROT platform trials are international, multicenter, open-label, phase II/III RCTs. Pts with resectable, cT3-4 N0-2 M0, biopsy-proven colon adenocarcinoma are eligible for recruitment. Pts whose age or frailty precludes mFOLFOXIRI can be considered for FOxTROT2. Pts suitable for mFOLFOXIRI can be considered for FOxTROT3. BRAF-mutant pMMR pts can be considered for FOxTROT4. Pts are randomized 2:1 between intervention and control arms. FOxTROT2 randomizes between 6 wks OxFp NAC (choice of 100% or 80% dose) vs proceeding straight to surgery. Adjuvant chemotherapy (AC) is per physician choice. Primary outcome is 3-yr DFS. 759 pts will be recruited over 5 yrs. FOxTROT3: 6 wks mFOLFOXIRI NAC vs 6 wks OxFp NAC. All pts receive AC but physicians may de-escalate mFOLFOXIRI to OxFp. Hierarchical co-primary endpoints: tumor regression grade (TRG) (blinded central assessment) and 3-yr DFS. 873 pts over 5 yrs. FOxTROT4: 6 wks NA encorafenib and cetuximab vs 6 wks OxFp NAC. AC is per physician choice. Primary outcome: TRG. 45 pts over 3 yrs. Secondary outcomes include: histopathological endpoints, downstaging, minimal residual disease by ctDNA, safety, toxicity, OS, surgical outcomes and patient-reported outcomes; and DFS in FOxTROT4. The FOxTROT platform opened 7th Feb 2022, funded by Yorkshire Cancer Research. At submission, 50 pts had been randomized at 23 centers. Trial design and management is conducted in partnership with patient representatives. A program of translational and radiomics research is running in parallel. International recruitment in France and India will commence in 2023 with additional international partners joining from 2024. Clinical trial information: ISRCTN83842641 . [Table: see text]

Genomic landscape of locally advanced rectal adenocarcinoma: Comparison between before and after neoadjuvant chemoradiation and effects of genetic biomarkers on clinical outcomes and tumor response.

To explore genomic biomarkers in rectal cancer by performing whole-exome sequencing. Pre-chemoradiation (CRT) biopsy and post-CRT surgical specimens were obtained from 27 patients undergoing neoadjuvant CRT followed by definitive resection. Exomes were sequenced to a mean coverage of 30×. Somatic single-nucleotide variants (SNVs) and insertions/deletions (indels) were identified. Tumor mutational burden was defined as the number of SNVs or indels. Mutational signatures were extracted and fitted to COSMIC reference signatures. Tumor heterogeneity was quantified with a mutant-allele tumor heterogeneity (MATH) score. Genetic biomarkers and frequently occurred copy number alterations (CNAs) were compared between pre- and post-CRT specimens. Their associations with tumor regression grade (TRG) and clinical outcomes were explored. Top five mutated genes were APC, TP53, NF1, KRAS, and NOTCH1 for pre-CRT samples and APC, TP53, NF1, CREBBP, and ATM for post-CRT samples. Several gene mutations including RUNX1, EGFR, and TP53 in pre-CRT samples showed significant association with clinical outcomes, but not with TRG. However, no such association was found in post-CRT samples. Discordance of driver mutation status was found between pre- and post-CRT samples. In tumor mutational burden analysis, higher number of SNVs or indels was associated with worse treatment outcomes. Six single-base substitution (SBS) signatures identified were SBS1, SBS30, SBS29, SBS49, SBS3, and SBS44. The MATH score decreased after CRT on paired analysis. Less than half of CNAs frequent in post-CRT samples were present in pre-CRT samples. Pre- and post-CRT samples showed different genomic landscape. Potential genetic biomarkers of pre-CRT samples found in the current analysis call for external validation.

Dynamic change of immune phenotype assessed by artificial intelligence (AI)-powered analysis of tumor-infiltrating lymphocytes (TILs) during neoadjuvant durvalumab with or without tremelimumab (D+/-T) in head and neck squamous cell carcinoma (HNSCC).

2578 Background: The results of a phase II trial evaluating preoperative durvalumab with or without tremelimumab (D+/-T) in resectable HNSCC (NCT03737968) suggest that the neoadjuvant immunotherapy is associated with pathologic tumor regression with manageable safety profiles. Here, we applied AI-powered spatial TIL analyzer, Lunit SCOPE IO, to tumor specimens of the patients included in the trial to assess the impact of spatial TIL density and inflamed immune phenotype (IIP) on immunotherapy responses. Methods: H&amp;E-stained whole-slide images (WSIs) of pre- and post-treatment tumor specimens from HNSCC pts enrolled in the aforementioned D+/-T trial were collected. Patients with locally advanced but operable HNSCC were randomly assigned in 1:1 to receive a single dose of D (1,500mg) or D+T (1,500mg+75mg) followed by surgery, at Severance Hospital in Seoul, Korea. Lunit SCOPE IO was used to segment tumor epithelium and stroma to identify and quantify intratumoral TIL (iTIL) and stromal TIL. IIP was defined as the proportion of high iTIL area more than 33.3% of analyzable area. Clinical data and the combined positive scores (CPS) of PD-L1 were also collected. Results: A total of 39 paired tumor samples of pre- and post-treatment WSI (23 from D+T and 16 from D) were included. Overall, tumor regression grade 2 (TRG2, ≥ 50% of tumor regression) was achieved in 15.4% (6/39) pts, and downstaging after treatment was achieved in 35.9% (14/39) pts. By pre-treatment WSIs, 38.5% (15/39) samples were classified as IIP, and subgroups of D+T and D had 34.8% (8/23) and 43.8% (7/16), respectively. In the D+T arm, the proportions of TRG2 were 25% (2/8) in IIP versus 13.3% (2/15) in non-IIP, whereas D arm had 28.6% (2/7) TRG2 in IIP, but no TRG2 in non-IIP (0/9), respectively. Comparing the WSI of pre- and post- D+/-T samples, the proportion of IIP was significantly increased to 66.7% from 38.5 ( p = 0.015). The increase in IIP proportion was prominent in the D+T arm (34.8% to 69.6%, p = 0.043), but not in the D arm (43.8% to 62.5%, p = 0.37). Similarly, PD-L1 CPS increased after therapy, especially in the D+T group (mean CPS 6.0 to 20.7, p = 0.009). Interestingly, pts who remained non-IIP in both pre- and post-treatment (25.6%, 10/39) had significantly poor prognosis compared to the others, as the 12-month disease-free survival (DFS) rate was 50.0% vs 93.1% (median DFS 13.4m vs not reached, hazard ratio [HR] 4.26, 95% confidence interval [CI] 1.32-13.8, p = 0.009). This prognostic impact was prominent in the D+T arm (HR 6.75, 95% CI 1.49-30.6, p = 0.004). Conclusions: Neoadjuvant durvalumab +/- tremelimumab promotes dynamic change toward inflamed immune phenotype, resulting in favorable clinical outcomes. Resistance mechanism of stand-still-non-inflamed patients even on D+/-T should be further investigated. Clinical trial information: NCT03737968 .

Circulating tumor DNA as a marker of recurrence risk in locoregional esophagogastric cancers with pathologic complete response.

4066 Background: Following neoadjuvant therapy and definitive surgery, up to one-third of patients (pts) with gastroesophageal adenocarcinoma with a pathologic complete response (pCR; tumor regression grade 0 [TRG0]) will recur, while up to one-half of pts with a near-pCR (TRG1) experience recurrence. Our study aims to evaluate postoperative circulating tumor DNA (ctDNA) as a prognosticator of recurrence in pts with pCR or near-pCR after curative-intent neoadjuvant chemotherapy (NAC) or chemoradiation (CRT) and surgery. Methods: We retrospectively identified pts from 11 institutions with stages I-III esophagogastric cancers who completed neoadjuvant therapy and had TRG0 or TRG1 scores at the time of curative-intent surgery. Postoperative plasma samples were collected for ctDNA analysis within a 16-week molecular residual disease (MRD) window after definitive surgery and serially during follow-up from 9/19/19 to 2/21/22. MRD by ctDNA was assessed using a personalized, tumor-informed ctDNA assay (Signatera mPCR-NGS assay). The primary outcome was recurrence-free survival (RFS), measured from the date of surgery to the first documented sign of radiographic recurrence. Survival analysis was performed using the maximum likelihood bias reduction method for Cox regression. Results: We obtained 250 blood samples from 45 pts with esophageal (N=18), gastroesophageal junction (N=17), and gastric (N=10) adenocarcinomas who received either NAC or CRT. The median follow-up for this cohort was 22.8 months (range: 0.3-81.7 months). Despite pts achieving pCR (N=12) or near-pCR (N=33), ctDNA-positivity in the 16-week MRD window (N=21) correlated with higher rates of recurrence (66.7%; 2/3) compared to the absence of ctDNA (11.1%; 2/18). Detectable ctDNA was associated with a significantly shorter RFS (HR 23.0, 95% CI 2.0-268.1; p=0.012). 35 pts had ctDNA analyzed at any post-surgical time point, where the recurrence rate was 87.5% (7/8) in ctDNA-positive pts compared to 7.4% (2/27) in ctDNA-negative pts, exhibiting a further reduction in RFS (HR 44.8; 95% CI 5.4-369.7; p&lt;0.0001). Out of 8 ctDNA-positive pts, two (25%) converted from ctDNA-positive to ctDNA-negative with subsequent treatment. Conclusions: Within the subgroup of pts with esophagogastric adenocarcinoma and favorable pathologic responses (TRG 0-1) following neoadjuvant treatment, the presence of post-operative ctDNA identified pts with elevated recurrence risk. If validated in larger cohort studies, testing for ctDNA may be a useful biomarker to select pts at risk for recurrence with potential to inform prospective clinical trials for direction of adjuvant therapy.

Pembrolizumab, radiotherapy, and chemotherapy in neoadjuvant treatment of malignant esophago-gastric diseases (PROCEED): Assessment of pathologic response and toxicity in a prospective, phase II single-arm trial.

4062 Background: A standard treatment paradigm for locally advanced, resectable, non-metastatic esophageal or gastric adenocarcinomas (EGA) is neoadjuvant chemoradiation (CRT) followed by surgery. Historical pathologic complete response (pCR) rates after CRT with carboplatin/paclitaxel in the CROSS trial are low at 23%. Efficacy of adjuvant immunotherapy has since been shown in this patient population. The main objectives of this trial were to investigate whether neoadjuvant CRT + pembrolizumab improves pCR compared to the historical control of CRT alone, and also determine the associated acute and post-surgical toxicity of this approach. Methods: Single-institution, prospective phase II trial (NCT03064490) evaluating the efficacy and safety of neoadjuvant pembrolizumab + CRT followed by adjuvant pembrolizumab in patients with locally advanced operable EGA. CRT (45 Gy/25 fractions with concurrent weekly carboplatin [AUC 2] and paclitaxel [50 mg/m2 of BSA]) with 3 cycles of pembrolizumab was administered as neoadjuvant therapy. Patients also received 3 cycles of adjuvant pembrolizumab after surgical resection if they did not experience ≥Grade 3 (G3) toxicity during neoadjuvant treatment. Baseline characteristics were collected. Pathologic response was scored from 0-3 per tumor regression grading. The percentage of patients with pCR (score of 0) are described. Acute toxicities are defined per CTCAE v4 and include relevant events occurring within 90 days after treatment. Results: Accrual is complete, with 35 patients with cT2-3N0-2M0 EGA enrolled from 10/10/2017-10/07/2022. 28/32 patients have completed neoadjuvant therapy and surgical resection. 89% of enrolled patients are male, and 94% are white. 97% have an esophageal primary, and 97% underwent R0 resection. 10/28 (35.7%: 95% CI: 17%, 53%) patients achieved a pCR. 22/32 patients have experienced treatment-related ≥G3 non-hematologic toxicity to date (94.2% G3, 5.8% G4). 18 patients experienced ≥G3 toxicity related to neoadjuvant therapy, with 53 events overall, the majority being GI (24.5%) or metabolic/nutritional disorders (24.5%). 10 patients experienced ≥G3 toxicity related to surgery, with 16 events overall, the majority being procedural complications (31.3%) and infectious disorders (31.3%). Conclusions: Patients undergoing neoadjuvant CRT + pembrolizumab for EGA experienced higher rates of pCR and acceptable rates of treatment-related toxicity compared to historical controls. This phase II trial demonstrates the safety and efficacy of this treatment paradigm, which warrants assessment in future prospective studies. Clinical trial information: NCT03064490 .

Toripalimab combined with fluorouracil, leucovorin calcium, oxaliplatin and irinotecan (FOLFIRINOX) regimen or combined with oxaliplatin and tegafur (SOX) regimen in perioperative treatment of locally advanced resectable gastric or gastroesophageal junction adenocarcinoma (G/GEJ): An open-label, randomized, phase II study.

e16090 Background: Currently, NCCN guidelines recommend PD-1 inhibitors for the first-line therapy in gastric cancer patients (pts). However, the role of PD-1 inhibitor treatment in the perioperative setting remains unclear. This phase 2 study aimed to evaluate toripalimab plus FOLFIRINOX or SOX as perioperative treatment regimens in pts with locally advanced resectable G/GEJ. Methods: Pts were 1:1 ratio randomized to A or B groups. Pts in A group received four cycles of toripalimab (240mg, D1, q2w) and FOLFIRINOX regimen (oxaliplatin, 65 mg/m², d1; irinotecan, 150 mg/m², d1; leucovorin, 200 mg/m², d1; and fluorouracil, 2400 mg/m², d1-2, q2w) prior to surgery. Then D2 radical gastrectomy was performed, and another 4 cycles of toripalimab and FOLFIRINOX regimen were given within 2 months after surgery. In B group, chemo was changed to SOX regimen (oxaliplatin, 130 mg/m², d1; S-1, 40-60 mg/m2, d1-14, q3w) and toripalimab (240mg, D1) was administered every 3 weeks. The rest treatments were the same as A group. The primary endpoint was tumor regression grade (TRG, TRG 0-1). Key secondary endpoints included pathologic complete response (pCR) rate, 3-year disease-free survival (DFS), 5-year overall survival (OS) and safty. Results: Up to Jan 28, 2023, 54 eligible pts were enrolled (A 21, B 33) with baseline characteristics as follows: The median (range) age was 67 (23-71) years; 6/54 (11.1%) pts had signet ring cell carcinoma component; 40/54 (74.1%) pts had cT4 tumors and 18/54 (33.3%) had lymph node positive disease. 32/54 (59.3%) pts underwent successful resection. R0 resection rate was 100%. The TRG 0-1 rate was higher but not significant in the B group than in the A group (31.58% vs. 23.08%, P = 0.703). 4 pts (A 2, 15.4%; B 2, 10.5%) had a pCR. 23 (A 8, B 15, 71.9%) pts had tumor downstaged after surgery. Treatment-related adverse events (TRAEs) of any grade occurred in 25/54 (46.3%) pts. Grade ≥3 TRAEs occurred in 10/54 (18.5%) pts: 7 with grade 3-4 neutropenia, 2 with grade 3 thrombocytopenia and 1 with grade 3 myelosuppression. No new safety signals were observed and no TRAEs leading to death in either group. Conclusions: Toripalimab plus FOLFIRINOX or SOX regimens is tolerable and effective for pts with locally advanced resectable G/GEJ in the perioperative treatment setting. There were no significant differences in efficacy and safety between the two groups. Whether intensive or simplified treatment is more suitable for neoadjuvant therapy needs to be further explored. The low pCR rate in both groups may be due to the small sample size and the pts with more advanced primary tumors. This study is ongoing and more data will be released. Clinical trial information: NCT04908566 . [Table: see text]

Neoadjuvant short-course radiotherapy followed by chemotherapy plus camrelizumab versus long-course chemoradiotherapy followed by chemotherapy for patients with locally advanced rectal cancer: A randomized, multicenter, open-label phase 3 trial (Union).

TPS3638 Background: Short-course preoperative radiotherapy (SCPRT) and long-course chemoradiotherapy (LCCRT) are standard neoadjuvant treatments for locally advanced rectal cancer (LARC). Further, the RAPIDO trial found that SCPRT combined with consolidation chemotherapy produced better short- and long-term outcomes than SCPRT alone for patients with high-risk LARC. A phase 2, single-arm trial of neoadjuvant SCPRT followed by camrelizumab (an anti-PD-1 antibody) plus chemotherapy demonstrated promising short-term outcomes in patients with LARC. The Union trial is evaluating the efficacy and safety of neoadjuvant SCPRT followed by camrelizumab plus chemotherapy versus LCCRT followed by chemotherapy in patients with LARC. Methods: The Union trial is enrolling patients aged 18-75 with histologically confirmed clinical stage T3-4/N+ adenocarcinoma of the rectum, Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1, and a tumor inferior margin less than 10 cm above the anal verge. Eligible patients are randomized in a 1:1 ratio to either arm A or arm B. Patients in arm A receive neoadjuvant treatment with SCPRT (a total of 25 Gy in 5 days) followed by camrelizumab (200 mg/m2 intravenous drip on day 1, every 3 weeks for 2 cycles) plus CAPOX (oxaliplatin 130 mg/m2 intravenous infusion over 2 hours on day 1, capecitabine 1000 mg/m2 oral twice daily, days 1–14, every 3 weeks for 2 cycles), surgery, and adjuvant treatment with camrelizumab plus CAPOX (6 cycles) followed by camrelizumab until the medication duration of camrelizumab reaches one year. Patients in arm B receive neoadjuvant treatment with LCCRT (capecitabine 825 mg/m2 twice daily, 5 days a week, combined with a total dose of 50.4 Gy in 28 days) followed by CAPOX (2 cycles), surgery, and adjuvant treatment with CAPOX (6 cycles). Randomization is stratified by clinical T stage (≤T3 vs T4) and clinical N stage (N0 vs N+). The primary endpoint is pathologic complete response (pCR). The secondary endpoints are 3-year event-free survival rate, overall survival, R0 resection rate, completion rate of neoadjuvant treatment, 3-year disease-free survival rate, tumor regression grading, safety, and quality of life. pCR is evaluated per the AJCC 8th Edition TRG scoring system as assessed by the blinded independent central review. Adverse events are graded by the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0. Quality of life is assessed by the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. This study began enrollment in July 2021 with a planned enrollment of 230 patients. Clinical trial information: NCT04928807 .

Neoadjuvant tislelizumab plus chemotherapy for resectable locally advanced esophageal squamous cell carcinoma (ESCC): Interim analysis of a phase 2 study.

e16087 Background: Esophageal cancer (EC), as the sixth most frequently diagnosed cancer and the fourth leading cause of cancer death, poses a major health threat in China. Neoadjuvant treatment is recommended for resectable diseases with high recurrent risks; however, benefits with platinum-doublet chemotherapy are modest. Although the addition of tislelizumab, a anti-PD-1 antibody to chemotherapy has shown survival benefit in unresectable or metastatic EC, data are lacking to support such combination as a neoadjuvant modality. Here, we report the interim analysis of efficacy and safety of a prospective, phase 2 clinical trial evaluating tislelizumab plus chemotherapy as neoadjuvant treatment for locally advanced ESCC. Methods: Adults with clinical stage II-IVA (T3-T4 and/or node positive), potentially resectable ESCC, ECOG PS 0-1, and no known PD-1 expression were enrolled to receive tislelizumab (200mg) plus chemotherapy (docetaxel 75mg/m2 plus cisplatin 75mg/m2 or carboplatin AUC = 5 if CCr &lt; 60ml/min) every 3 weeks for 4 cycles. Adjuvant tislelizumab up to 9 months were optional according to patients’ will. The primary endpoint was pathological complete response (pCR). Secondary endpoints include R0 resection, disease free survival (DFS), adverse events (AE), and biomarkers for predicting efficacy. Results: Between November 11, 2020 and Feburary 10, 2023, 28 patients with clinical stage III (n = 13) or IVA (n = 15) diseases were enrolled. 27 completed neoadjuvant treatment and 5 withdrew early because of disease progression (n = 2), serious AEs (n = 2) and bronchoesophageal fistula (n = 1). 21 patients underwent McKeown MIE and 20 (95.2%) acheived R0 resection. One patient was awaiting surgery. pCR (ypT0N0) was achieved in 33.3% (7/21) patients. According to the CAP tumor regression grading system, 3 (14.3%) cases were categorized as grade 1, 7(33.3%) were categorized as grade 2 and 4 (19%) were categorized as grade 3 in primary tumor. Most treatment related AEs (TRAEs) during neoadjuvant setting were mainly of grade 1 or 2. Grade 3 or 4 TRAEs occurred in 37.0% patients (10/27) and 14.8% (4/27) was considered immune-related. Surgical complications of any grade occurred in 4 patients (19.0%), 3 of which were grade 3. No grade 5 events were noted. 14 (66.7%) patients were able to continue adjuvant tislelizumab after surgery. Conclusions: Neoadjuvant tislelizumab plus chemotherapy has achieved encouraging pCR rate and tolerable safety activity in this study. Clinical trial information: ChiCTR2100043772 .

Effect and imaging analysis of cetuximab combined with radiotherapy in patients with rectal carcinoma

ABSTRACT Objective. To analyze the effect of cetuximab combined with radiotherapy in patients with rectal carcinoma (RC) by imaging analysis. Methods. The clinical data of 104 RC patients at our hospital from February 2021 to February 2022 were retrospectively analyzed. They were separated into control group (n = 52) and experimental group (n = 52) according to the order of admission, with the former treated with radiotherapy alone and the latter receiving cetuximab and radiotherapy. The clinical efficacy, tumor marker levels and imaging parameters of different treatment regimens were compared, and Quality of Life questionnaire (QLQ-C30) was used to evaluate the quality of life. Results. The incidence of tumor regression grade (TRG) downgrade, T stage downgrade and N stage downgrade was remarkably higher in the experimental group than in the control group (P < 0.05). The experimental group had remarkably lower tumor marker levels (P < 0.001) and higher mean score of EORTC Core QLQ-C30 (P < 0.001) than those in the control group. The relative signal intensity of tumor (SIT/M), relative signal intensity reduction rate of tumor (SIT/MRR) and apparent diffusion coefficient (ADC) values were remarkably higher (P < 0.001) and the absolute signal intensity of tumor (SIT) value was remarkably lower (P < 0.001) in the experimental group than the control group. Conclusion. Treatment with cetuximab and radiotherapy can greatly reduce serum tumor marker levels in RC patients and bring them health benefits, and further studies will help establish a better solution for such patients.