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Histological intratumoral heterogeneity in pretreatment esophageal cancer biopsies predicts survival benefit from neoadjuvant chemotherapy: results from the UK MRC OE02 trial.

ABSTRACT: Despite the use of multimodal treatment, survival of esophageal cancer (EC) patients remains poor. One proposed explanation for the relatively poor response to cytotoxic chemotherapy is intratumor heterogeneity. The aim was to establish a statistical model to objectively measure intratumor heterogeneity of the proportion of tumor (IHPoT) and to use this newly developed method to measure IHPoT in the pretreatment biopsies from from EC patients recruited to the OE02 trial. A statistical mixed effect model (MEM) was established for estimating IHPoT based on variation in hematoxylin/eosin (HE) stained pretreatment biopsy pieces from the same individual in 218 OE02 trial patients (103 treated by chemotherapy and surgery (chemo+surgery); 115 patients treated by surgery alone). The relationship between IHPoT, prognosis, chemotherapy survival benefit, and clinicopathological variables was assessed. About 97 (44.5%) and 121 (55.5%) ECs showed high and low IHPoT, respectively. There was no significant difference in IHPoT between surgery (median [range], 0.1637 [0-3.17]) and chemo+surgery (median [range], 0.1692 [0-2.69]) patients (P = 0.43). Chemo+surgery patients with low IHPoT had a significantly longer survival than surgery patients (HR = 1.81, 95% CI: 1.20-2.75, P = 0.005). There was no survival difference between chemo+surgery and surgery patients with high IHPoT (HR = 1.15, 95% CI: 0.72-1.81, P = 0.566). This is the first study suggesting that IHPoT measured in the pretreatment biopsy can predict chemotherapy survival benefit in EC patients. IHPoT may represent a clinically useful biomarker for patient treatment stratification. Future studies should determine if pathologists can reliably estimate IHPoT.

SUBMITTER: Davarzani N

PROVIDER: S-EPMC7397482 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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Histological intratumoral heterogeneity in pretreatment esophageal cancer biopsies predicts survival benefit from neoadjuvant chemotherapy: results from the UK MRC OE02 trial.

Davarzani Naser N Hewitt Lindsay C LC Hale Matthew D MD Melotte Veerle V Nankivell Matthew M Hutchins Gordon G A GGA Cunningham David D Allum William H WH Langley Ruth E RE Jolani Shahab S Grabsch Heike I HI

Diseases of the esophagus : official journal of the International Society for Diseases of the Esophagus 20200801 8

Despite the use of multimodal treatment, survival of esophageal cancer (EC) patients remains poor. One proposed explanation for the relatively poor response to cytotoxic chemotherapy is intratumor heterogeneity. The aim was to establish a statistical model to objectively measure intratumor heterogeneity of the proportion of tumor (IHPoT) and to use this newly developed method to measure IHPoT in the pretreatment biopsies from from EC patients recruited to the OE02 trial. A statistical mixed effe ...[more]

PMID: 32591823

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Project description:BackgroundThe importance of 2-yr postradiotherapy prostate biopsy status remains uncertain.ObjectiveTo assess the value of 2 year post treatment biopsies in a randomised trial of radiotherapy dose escalation.Design, setting, and participantsBetween 1998 and 2001, 843 men with localised prostate cancer were randomised to receive either control-64Gy or escalated-74Gy conformal radiotherapy (CFRT) in the MRC RT01 trial in combination with 3-6-mo neoadjuvant androgen deprivation therapy. Prostate biopsies were planned at 2 yr from start of CFRT in suitable men.Outcome measurements and statistical analysisProstate biopsy results and prostate-specific antigen (PSA) levels performed at 2 yr post-CFRT were evaluated with long-term biochemical progression free survival (bPFS) and overall survival. Outcome measures were timed from the 2-yr biopsy using a landmark approach.Results and limitationsA 2-yr biopsy was performed in 312/843 patients. One hundred and seventy-seven patients were included in the per-protocol group with median follow-up of 7.8 yr from biopsy. Median PSA at biopsy was 0.5ng/ml. Sixty-four bPFS events were reported: 46/145 (32%) in patients with negative, 6/18 (33%) suspicious, and 12/14 (86%) positive biopsies. A positive biopsy was prognostic of worse bPFS, going forward, compared with negative and suspicious biopsies, hazard ratio (HR)=4.81 (95% confidence interval [CI]: 2.50-9.26, p<0.001). The estimate for survival was HR=1.58 (95% CI: 0.52-4.78, p=0.42). PSA values at 2 yr between 1.01ng/ml and 2.09ng/ml were also associated with subsequent PSA failures (HR=2.71, 95% CI: 1.98-3.71), bPFS events (HR=2.45, 95% CI: 1.81-3.32), and prostate cancer-specific survival (HR=2.87, 95% CI: 1.08-7.64) compared with PSA ≤1.0ng/ml.ConclusionsTwo-year postradiotherapy prostate biopsies have limited value in patients with PSA control but both positive biopsy and higher PSA status are strongly associated with future bPFS events. A policy of selected biopsy may provide an opportunity for early salvage interventions.Patient summaryRoutine 2-yr postradiotherapy biopsy is not recommended but can be considered in selected patients with unfavourable post-treatment prostate-specific antigen levels who are suitable for early salvage treatments.

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:ImportanceWhile neoadjuvant chemoradiation for esophageal cancer improves oncologic outcomes for a broad group of patients with locally advanced and/or node-positive tumors, it is less clear which specific subset of patients derives most benefit in terms of overall survival (OS).ObjectiveTo determine whether neoadjuvant chemoradiation based on esophageal adenocarcinoma histology has similar oncologic outcomes for patients treated with surgery alone when stratified by clinical nodal status.Design, setting, and participantsA retrospective analysis using the American College of Surgeons National Cancer Database from 1998 to 2006. Patients with esophageal adenocarcinoma histology and clinical stage T1bN1-N3 or T2-T4aN-/+M0 were divided into 2 treatment groups: (1) neoadjuvant chemoradiation followed by surgery and (2) surgery alone. Subset analysis within each treatment group was performed for clinically node-negative patients (cN-) vs node-positive patients (cN+) in conjunction with pathological nodal status. A propensity score-adjusted analysis, which included patient demographics, comorbidity status, and clinical T stage, was also performed.Main outcome and measuresThe primary outcome was 3-year OS. Secondary outcomes included margin status, postoperative length of stay, unplanned readmission rate, and 30-day mortality.ResultsA total of 1309 patients were identified, of whom 539 received neoadjuvant chemoradiation followed by surgery and 770 received surgery alone. Of the 1309 patients, 41.2% (n = 539) received neoadjuvant chemoradiation and 47.2% (n = 618) were cN+. Median follow-up for the entire cohort was 73.3 months (interquartile range, 64.1-93.5 months). The 3-year OS was better for neoadjuvant chemoradiation followed by surgery compared with surgery alone (49% vs 38%, respectively; P < .001). Stratifying based on clinical nodal status, the propensity score-adjusted OS was significantly better for cN+ patients who received neoadjuvant chemoradiation (hazard ratio, 0.52; 95% CI, 0.42-0.66; P < .001). In contrast, there was no difference in OS for cN- patients based on treatment (hazard ratio, 0.84; 95% CI, 0.65-1.10; P = .22).Conclusions and relevancePatients with cN+ esophageal adenocarcinoma benefit significantly from neoadjuvant chemoradiation. However, patients with cN- tumors treated with neoadjuvant chemoradiation plus surgery do not derive a significant OS benefit compared with surgery alone. This finding may have significant implications on the use of neoadjuvant chemoradiation in patients with cN- disease.

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Histological intratumoral heterogeneity in pretreatment esophageal cancer biopsies predicts survival benefit from neoadjuvant chemotherapy: results from the UK MRC OE02 trial.

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Histological intratumoral heterogeneity in pretreatment esophageal cancer biopsies predicts survival benefit from neoadjuvant chemotherapy: results from the UK MRC OE02 trial.

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