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The Clinical Value of Measuring Circulating HPV DNA during Chemo-Radiotherapy in Squamous Cell Carcinoma of the Anus.

ABSTRACT: Circulating tumor DNA (ctDNA) is investigated in various cancers. In squamous cell carcinoma of the anus (SCCA) infection with human papilloma virus (HPV) is found in around 90% of cases and here, plasma HPV (pHPV) can be used as ctDNA. Preliminary data have proved the ability to detect pHPV16 and -18 in SCCA. We have developed a highly sensitive method for measurement of six relevant pHPV subtypes, to investigate the elimination pattern of pHPV during chemo-radiotherapy (CRT) for SCCA and its clinical value. Patients treated at Aarhus University Hospital from 2016-2020 were included. P16 status in the primary biopsy was measured and 82% of patients had P16 positive tumor. Blood samples were collected prior to treatment (PT), mid treatment (MT), end of therapy (EOT), and during follow-up (FU). An in-house multiplex digital droplet PCR method measured pHPV subtypes 16, 18, 31, 33, 51, 58. Samples from 88 patients were drawn PT (n = 73), MT (n = 72), EOT (n = 64) and during FU (n = 41). Plasma HPV was detectable in 52 patients and PT pHPV levels correlated to tumor stages. Three elimination patterns were observed during CRT with correlation to outcome: fast responders with no local or distant failures (0/12); slow responders with high risk of local failures (4/20), no distant failures; persistent molecular responders with high risk of distant failures (4/13), but no local failures, p < 0.01. During CRT, pHPV can divide patients with SCCA into three groups with significantly different risk of failure. The use of pHPV can potentially assist in clinical treatment decision.

SUBMITTER: Lefevre AC

PROVIDER: S-EPMC8158133 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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The Clinical Value of Measuring Circulating HPV DNA during Chemo-Radiotherapy in Squamous Cell Carcinoma of the Anus.

Lefèvre Anna C AC Pallisgaard Niels N Kronborg Camilla C Wind Karen L KL Krag Søren R P SRP Spindler Karen-Lise G KG

Cancers 20210518 10

<h4>Background and purpose</h4>Circulating tumor DNA (ctDNA) is investigated in various cancers. In squamous cell carcinoma of the anus (SCCA) infection with human papilloma virus (HPV) is found in around 90% of cases and here, plasma HPV (pHPV) can be used as ctDNA. Preliminary data have proved the ability to detect pHPV16 and -18 in SCCA. We have developed a highly sensitive method for measurement of six relevant pHPV subtypes, to investigate the elimination pattern of pHPV during chemo-radiot ...[more]

PMID: 34070045

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Project description:BackgroundThe potential of circulating tumour DNA (ctDNA) as a reliable biomarker for relapse/metastasis early detection and prognosis in esophageal squamous cell carcinoma (ESCC) after radiotherapy/chemoradiotherapy (RT/CRT) initiation requires comprehensive investigation.MethodsTreatment-naive locally advanced ESCC patients with available baseline plasma samples were prospectively enrolled from November 2018 to January 2020. RT/CRT was delivered with a simultaneous integrated boost of radiation dose. Serial plasma samples were collected at baseline (T0 ), week 4 of RT/CRT (T1 ), 1-3 (T2 ) and 3-6 months post-RT/CRT (T3 ). ctDNA was analysed using next-generation sequencing of 474 cancer-relevant genes.ResultsA total of 128 plasma samples from 40 eligible patients were analysed (median age: 64 [range: 40-78], 88% males, 95% stage III/IV), and the median follow-up time was 20.6 months (range: 12.2-33.3). During the post-RT/CRT surveillance including 36 patients, radiological progression was observed in 16 patients, and 69% (11/16) had detectable post-RT/CRT ctDNA prior to radiological progression, with a median lead time of 4.4 months compared with radiological imaging. ctDNA positivity at T1 (hazard ratio, HR: 3.60, 95% confidence interval, CI: 1.30-10.01) or T2 (HR: 5.45, 95% CI: 1.72-17.26) indicated inferior progression-free survival (PFS). ctDNA clearance between T0 -T1 (HR: 0.31, 95% CI: 0.08-1.13) or T0 -T2 (HR: 0.11; 95% CI: 0.02-0.61) was associated with relatively favourable PFS. Similar results were obtained when focusing on patients without esophagectomy after RT/CRT. Notably, detectable ctDNA at T1 was a potential indicator of high local recurrence risks (HR: 4.43, 95% CI: 1.31-15.04).ConclusionsctDNA was identified as a robust biomarker for early detection of disease progression and post-RT/CRT prognosis stratification in ESCC. Detectable ctDNA at week 4 of RT/CRT might indicate higher local recurrence risks, implying the potential clinical utility of ctDNA tests in guiding post-RT/CRT treatments for locoregional control in ESCC.

Project description:Purpose: The purpose of the research was to assess the prognostic value of three-dimensional (3D) texture features based on diffusion-weighted magnetic resonance imaging (DWI) for esophageal squamous cell carcinoma (ESCC) patients undergoing concurrent chemo-radiotherapy (CRT). Methods: We prospectively enrolled 82 patients with ESCC into a cohort study. Two DWI sequences (b = 0 and b = 600 s/mm2) were acquired along with axial T2WI and T1WI before CRT. Two groups of features were examined: (1) clinical and demographic features (e.g., TNM stage, age and sex) and (2) changes in spatial texture characteristics of the apparent diffusion coefficient (ADC), which characterizes gray intensity changes in tumor areas, spatial pattern and distribution, and related changes caused by CRT. Reproducible feature sets without redundancy were statistically filtered and validated. The prognostic values associated with overall survival (OS) for each parameter were studied using Kaplan-Meier and Cox regression models for univariate and multivariate analyses, respectively. Results: Both univariate and multivariate Cox model analyses showed that the energy of intensity histogram texture (IHIST_energy), radiation dose, mean of the contrast in distance 1 of 26 directions (m_contrast_1), extreme difference of the homogeneity in distance 2 of 26 directions (Diff_homogeneity_2), mean of the inverse variance in distance 2 of 26 directions (m_lnversevariance_2), high-intensity small zone emphasis (HISE), and low-intensity large zone emphasis (LILE) were significantly associated with survival. The results showed that 6 texture parameters extracted from the ADC images before treatment could distinguish among high-, medium-, and low-risk groups (log-rank χ2 = 9.7; P = 0.00773). The biased C-index value was 0.715 (95% CI: 0.708 to 0.732) based on bootstrapping validation. Conclusions: The ADC 3D texture feature can be used as a useful biomarker to predict the survival of ESCC patients undergoing CRT. Combining ADC 3D texture features with conventional prognostic factors can generate reliable survival prediction models.

Project description:Background and purposeTumor-infiltrating lymphocytes (TILs) are associated with locoregional control (LRC) in head-and-neck squamous cell carcinoma (HNSCC) patients undergoing (chemo)radiotherapy. As immunosenescence results in reduced immune activity, the role of TILs in elderly HNSCC patients may differ compared to younger patients, providing a rationale to study the prognostic role of TILs and immune checkpoints (ICs) in this population.Material and methodsSixty-three HNSCC patients aged ≥ 65 years undergoing definitive (chemo)radiotherapy between 2010 and 2019 with sufficient material from pre-treatment biopsies were included in the analysis. Immunohistochemical stainings of CD3, CD4, CD8, PD-L1, TIM3, LAG3, TIGIT and CD96, and of osteopontin as an immunosenescence-associated protein were performed. Overall survival (OS) and progression-free survival (PFS) were determined using the Kaplan-Meier method, and Fine-Gray's models were used for locoregional failure (LRF) analyses.ResultsWhile there was no correlation between patient age and IC expression, osteopontin levels correlated with increasing age (r = 0.322, p < 0.05). Two-year OS, PFS, and LRC were 44%, 34%, and 71%, respectively. Increased LAG3 expression, both intraepithelial (SHR = 0.33, p < 0.05) and stromal (SHR = 0.38, p < 0.05), and elevated stromal TIM3 expression (SHR = 0.32, p < 0.05) corresponded with reduced LRFs. Absent tumoral PD-L1 expression (TPS = 0%) was associated with more LRFs (SHR = 0.28, p < 0.05). There was a trend towards improved LRF rates in elderly patients with increased intraepithelial CD3 + (SHR = 0.52, p = 0.07) and CD8 + (SHR = 0.52, p = 0.09) TIL levels.ConclusionLAG3, TIM3 and TPS are promising biomarkers in elderly HNSCC patients receiving (chemo)radiotherapy. Considering the frequency of non-cancer related deaths in this population, the prognostic value of these biomarkers primarily relates to LRC.

Project description:To investigate the predictive capacity of early post-treatment diffusion-weighted magnetic resonance imaging (MRI) for recurrence or tumor progression in patients with no tumor residue after chemo-radiotherapy (CRT) for head and neck squamous cell carcinoma, and, to assess the predictive capacity of pre-treatment diffusion-weighted MRI for persistent tumor residue post-CRT. A single center cohort study was performed in one French hospital. All patients with squamous cell carcinoma receiving CRT (no surgical indication) were included. Two diffusion-weighted MRI were performed: one within 8 days before CRT and one 3 months after completing CRT with determination of median tumor apparent diffusion coefficient (ADC). The primary endpoint was progression-free survival. 59 patients were included prior to CRT and 46 (78.0%) completed CRT. A post-CRT tumor residue was found in 19/46 (41.3%) patients. In univariate analysis, initial ADC was significantly lower in patients with residue post CRT (0.56 ± 0.11 versus 0.79 ± 0.13; p < 0.001). When initial ADC was dichotomized at the median, initial ADC lower than 0.7 was significantly more frequent in patients with residue post CRT (73.7% versus 11.1%, p < 0.0001). In multivariate analysis, only initial ADC lower than 0.7 was significantly associated with tumor residue (OR = 22.6; IC [4.9-103.6], p < 0.0001). Among 26 patients without tumor residue after CRT and followed up until 12 months, 6 (23.1%) presented recurrence or progression. Only univariate analysis was performed due to a small number of events. The only factor significantly associated with disease progression or early recurrence was the delta ADC (p = 0.0009). When ADC variation was dichotomized at the median, patients with ADC variation greater than 0.7 had time of disease-free survival significantly longer than patients with ADC variation lower than 0.7 (377.5 [286-402] days versus 253 [198-370], p < 0.0001). Conclusion and relevance: Diffusion-weighted MRI could be a technique that enables differentiation of patients with high potential for early recurrence for whom intensive post-CRT monitoring is mandatory. Prospective studies with more inclusions would be necessary to validate our results.

Dataset Information

The Clinical Value of Measuring Circulating HPV DNA during Chemo-Radiotherapy in Squamous Cell Carcinoma of the Anus.

Publications

The Clinical Value of Measuring Circulating HPV DNA during Chemo-Radiotherapy in Squamous Cell Carcinoma of the Anus.

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