Dataset Information

Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer.

ABSTRACT:

Background

Neoadjuvant chemoradiation therapy (CRT) is a widely used preoperative treatment strategy for locally advanced rectal cancer (LARC). However, a few studies have evaluated the molecular changes caused by neoadjuvant CRT in these cancer tissues. Here, we aimed to investigate changes in immunotherapy-related immunogenic effects in response to preoperative CRT in LARC.

Methods

We analyzed 60 pairs of human LARC tissues before and after irradiation from three independent LARC cohorts, including a LARC patient RNA sequencing (RNA-seq) dataset from our cohort and GSE15781 and GSE94104 datasets.

Results

Gene ontology analysis showed that preoperative CRT significantly enriched the immune response in LARC tissues. Moreover, gene set enrichment analysis revealed six significantly enriched Kyoto Encyclopedia of Genes and Genomes pathways associated with downregulated genes, including mismatch repair (MMR) genes, in LARC tissues after CRT in all three cohorts. Radiation also induced apoptosis and downregulated various MMR system-related genes in three colorectal cancer cells. One patient with LARC showed a change in microsatellite instability (MSI) status after CRT, as demonstrated by the loss of MMR protein and PCR for MSI. Moreover, CRT significantly increased tumor mutational burden in LARC tissues. CIBERSORT analysis revealed that the proportions of M2 macrophages and CD8 T cells were significantly increased after CRT in both the RNA-seq dataset and GSE94104. Notably, preoperative CRT increased various immune biomarker scores, such as the interferon-γ signature, the cytolytic activity and the immune signature.

Conclusions

Taken together, our findings demonstrated that neoadjuvant CRT modulated the immune-related characteristics of LARC, suggesting that neoadjuvant CRT may enhance the responsiveness of LARC to immunotherapy.

SUBMITTER: Seo I

PROVIDER: S-EPMC7949478 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Publications

Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer.

Seo Incheol I Lee Hye Won HW Byun Sang Jun SJ Park Jee Young JY Min Hyeonji H Lee Sung Hwan SH Lee Ju-Seog JS Kim Shin S Bae Sung Uk SU

Journal for immunotherapy of cancer 20210301 3

<h4>Background</h4>Neoadjuvant chemoradiation therapy (CRT) is a widely used preoperative treatment strategy for locally advanced rectal cancer (LARC). However, a few studies have evaluated the molecular changes caused by neoadjuvant CRT in these cancer tissues. Here, we aimed to investigate changes in immunotherapy-related immunogenic effects in response to preoperative CRT in LARC.<h4>Methods</h4>We analyzed 60 pairs of human LARC tissues before and after irradiation from three independent LAR ...[more]

PMID: 33692216

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Project description:BackgroundTo evaluate the value of pretreatment inflammatory-nutritional biomarkers in predicting responses to neoadjuvant chemoradiotherapy (nCRT) and survival in patients with locally advanced rectal cancer (LARC).MethodsPatients with LARC who underwent nCRT and subsequent surgery between October 2012 and December 2019 were considered for inclusion. Neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), lymphocyte to monocyte ratio (LMR), and prognostic nutritional index (PNI) were calculated from according to routine laboratory data within 1 week prior to nCRT. The correlations between baseline inflammatory-nutritional biomarkers and responses were analyzed using Chi-square test or Fisher's exact test, and multivariate logistic regression analysis was performed to identify the independent predictors of pathological responses to nCRT. Univariate and multivariate Cox proportional hazard models were used to assess the correlations of predictors with disease-free survival (DFS) and overall survival (OS).ResultsA total of 273 patients with LARC were enrolled in this study. Higher LMR and PNI were observed in the good-response group, meanwhile higher NLR and PLR were observed in the poor-response group. Multivariate logistic regression analysis results revealed that PLR and PNI independently predicted responses to nCRT. Multivariable Cox regression analysis determined that PNI was an independent predictor of DFS and OS in patients with LARC. The value of pretreatment PNI in predicting responses and survival was continuously superior to those of NLR, PLR, and LMR. The optimal cutoff value of the PNI was approximate 45. Subgroup analyses indicated that the pathological responses and survival in the high PNI group (≥ 45) were significantly better than those in the low PNI group (< 45), especially in patients with clinical stage III rectal cancer.ConclusionThe pretreatment PNI can serve as a promising predictor of response to nCRT and survival in patients with LACR, which is superior to NLR, PLR, and LMR, and the patients with clinical stage III rectal cancer who have a higher PNI are more likely to benefit from nCRT.

Project description:Purpose: Intratumoral genetic heterogeneity (ITGH) is a common feature of solid tumors. However, little is known about the effect of neoadjuvant chemoradiation (nCRT) in ITGH of rectal tumors that exhibit poor response to nCRT. Here, we examined the impact of nCRT in the mutational profile and ITGH of rectal tumors and its adjacent irradiated normal mucosa in the setting of incomplete response to nCRT. Methods and Materials: To evaluate ITGH in rectal tumors, we analyzed whole-exome sequencing (WES) data from 79 tumors obtained from The Cancer Genome Atlas (TCGA). We also compared matched peripheral blood cells, irradiated normal rectal mucosa and pre and post-treatment tumor samples (PRE-T and POS-T) from one individual to examine the iatrogenic effects of nCRT. Finally, we performed WES of 7 PRE-T/POST-T matched samples to examine how nCRT affects ITGH. ITGH was assessed by quantifying subclonal mutations within individual tumors using the Mutant-Allele Tumor Heterogeneity score (MATH score). Results: Rectal tumors exhibit remarkable ITGH that is ultimately associated with disease stage (MATH score stage I/II 35.54 vs. stage III/IV 44.39, p = 0.047) and lymph node metastasis (MATH score N0 35.87 vs. N+ 45.79, p = 0.026). We also showed that nCRT does not seem to introduce detectable somatic mutations in the irradiated mucosa. Comparison of PRE-T and POST-T matched samples revealed a significant increase in ITGH in 5 out 7 patients and MATH scores were significantly higher after nCRT (median 41.7 vs. 28.8, p = 0.04). Finally, we were able to identify a subset of "enriched mutations" with significant changes in MAFs between PRE-T and POST-T samples. These "enriched mutations" were significantly more frequent in POST-T compared to PRE-T samples (92.9% vs. 7.1% p < 0.00001) and include mutations in genes associated with genetic instability and drug resistance in colorectal cancer, indicating the expansion of tumor cell subpopulations more prone to resist to nCRT. Conclusions: nCRT increases ITGH and may result in the expansion of resistant tumor cell populations in residual tumors. The risk of introducing relevant somatic mutations in the adjacent mucosa is minimal but non-responsive tumors may have potentially worse biological behavior when compared to their untreated counterparts. This was an exploratory study, and due to the limited number of samples analyzed, our results need to be validated in larger cohorts.

Project description:BackgroundThere is recent interest in treating locally advanced rectal cancer (LARC) patients with total neoadjuvant therapy (TNT). However, whether TNT is associated with improved overall survival (OS) remains unknown. This study compares outcomes following TNT and following neoadjuvant chemoradiation therapy (nCRT) in patients with LARC, clinically defined cT3/4 or node positive disease, using the National Cancer Database.MethodsLARC patients diagnosed between 2004-2015 were included. TNT was defined as multi-agent chemotherapy given at least 2 months before RT followed by pre-operative chemoradiation therapy and definitive surgery without adjuvant chemotherapy. nCRT was defined as pre-operative RT and chemotherapy started within 2 weeks from each other followed by definitive surgery with or without adjuvant chemotherapy. Kaplan-Meier curve with logrank test and multivariable Cox proportional hazards regression modelling were used to analyse the primary endpoint of overall survival (OS). Multivariable logistic regression modelling was used for secondary outcomes to determine if TNT is associated with pathological complete response (pCR), defined as ypT0N0, and negative circumferential resection margin (CRM).FindingsData from 372 TNT patients and 707 nCRT patients were analysed after a 2:1 propensity matching with replacement. Kaplan-Meier curve showed that OS with TNT was comparable to that with nCRT (p = 0•16). The 5-year OS rates for TNT and nCRT were 73•6% vs. 78•5% (p = 0•20). Multivariable Cox proportional hazards regression modelling confirmed no difference in OS between TNT and nCRT (HR = 1•21, p = 0•25). With TNT, 16•9% patients achieved pCR, whereas 13•1% patients achieved pCR with nCRT (p = 0•12). TNT was not found to be significantly associated with pCR (OR = 1•36, p = 0•13) or negative CRM (OR = 1•77, p = 0•19) in multivariable logistic regression modelling.InterpretationWith results from current clinical trials pending, our data suggested that TNT and nCRT resulted in similar survival, while TNT led to higher pCR and CRM negative rate, albeit not statistically significant.

Dataset Information

Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer.

Background

Methods

Results

Conclusions

Publications

Neoadjuvant chemoradiation alters biomarkers of anticancer immunotherapy responses in locally advanced rectal cancer.

Similar Datasets

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