Circulating tumor DNA analysis for outcome prediction in localized esophageal cancer.

4055 Background: Blood-based biomarkers are not used in routine clinical practice in patients with esophageal carcinomas (ECs). Circulating tumor DNA (ctDNA) is an attractive biomarker that could be applied to ECs. We performed a study to explore pre- and post-treatment ctDNA analysis using the next generation sequencing-based CAPP-Seq method as a prognostic biomarker for localized EC. Methods: We prospectively enrolled 29 patients with localized EC treated with chemoradiotherapy (CRT) between June 2011 and October 2015. 12 (43%) patients were treated with CRT alone and 17 (57%) were treated with CRT followed by esophagectomy. Our cohort included patients with stage IB (1; 3.4%), II (7; 24.1%), and III (21; 72.4%) disease. Eight (27.6%) harbored squamous cell carcinoma (SCC) and 21 (72.4%) adenocarcinoma (AC). All patients received pre-treatment evaluation by thoracic CT, PET/CT, and esophagoduodenoscopy. ctDNA levels were quantitated in pre-treatment and post-treatment plasma samples using CAPP-Seq. Results: Median follow-up time was 21 months. We detected ctDNA pre-treatment in 72.4% of cases (N = 21) with a median concentration of 2.69 haploid genome equivalents per mL (hGE/mL; range 0.34-107.3). Pre-treatment ctDNA concentrations were strongly correlated with metabolic tumor volumes (MTV; R2= 0.74; p = 1.7e-07) and were significantly higher in SCC than AC patients (28.2 vs. 2.1 mean hGE/mL; p = 0.002). Overall survival (OS) at 2 years for pretreatment ctDNA+ vs. ctDNA- patients was 47% vs. 86% (HR = 6.0; 95% CI = 0.74-49.2; p < 0.05) and trended toward significance when accounting for stage, histology, and age (p = 0.09). A single post-treatment plasma sample was collected within 3 months of treatment and was available for 19 patients. Post-treatment ctDNA was detected in 3 (15.7%) patients with a median concentration of 11.5 hGE/mL (range 2.2–11.9). Post-treatment ctDNA detection was strongly predictive of poor event-free survival (p < 0.0001) and time to distant metastasis (p < 0.0001). Conclusions: Our data suggest that pre- and post-treatment ctDNA levels may be prognostic for patients with localized EC and could potentially guide risk-adapted adjuvant therapy approaches.

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Predicting response to radical (chemo)radiotherapy (R-CRT) with circulating HPV DNA and tumor DNA (ctDNA) analysis in locally-advanced head and neck squamous cell carcinoma (LAHNC).

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.6043 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 6043-6043

Author(s):

Shreerang Bhide ◽

Jen Lee ◽

Isaac Garcia-Murillas ◽

Ros Cutts ◽

Tara Hurley ◽

...

Keyword(s):

Dna Analysis ◽

Residual Disease ◽

Locally Advanced ◽

Digital Pcr ◽

Circulating Tumor Dna ◽

Surgical Biopsy ◽

Hpv Dna ◽

Pet Ct ◽

Ctdna Analysis ◽

Tumor Dna

6043 Background: Following R-CRT for human papilloma virus positive (HPV+) and negative (HPV-) LAHNC, patients frequently undergo unnecessary neck dissection (ND) and/or repeated biopsies for abnormal PET-CT findings even in the presence of a complete pathological response (pCR), which causes significant morbidity. We assessed the role of circulating tumor DNA analysis in identifying patients with true residual disease. Methods: We prospectively recruited development (DC, n=55) and test (TC, n=33) cohorts of LAHNC patients having R-CRT. For HPV+ tumors we developed a novel amplicon based next generation sequencing assay (HPV-detect) to detect circulating HPV DNA and for HPV- tumors we used personalised droplet digital PCR assays of somatic mutations. Circulating tumor DNA levels at 12 weeks post-R-CRT were correlated to residual disease assessed by PET-CT and surgery. Results: In the DC (27 HPV+), baseline HPV-detect demonstrated 100% sensitivity and 93% specificity, confirmed in the TC (20 HPV+). 37 HPV+ patients (DC&TC) had complete samples-set. 36 had a negative HPV-detect at end of treatment, including 6 patients who underwent ND (3) and repeat primary site biopsies (3) for positive PET-CT but had pCR on surgical/biopsy specimen. 1 patient had positive HPV-detect and positive biopsy, indicating 100% agreement for HPV-detect and residual cancer. In a 10 HPV- patients with complete sample-set, there was 90% agreement between ctDNA and residual disease in HPV- tumors (3 ctDNA positive and tumor present, 1 ctDNA negative but tumor present, and 6 negative ctDNA negative tumor) with 80% sensitivity for residual disease and 100% specificity. Combined agreement between ctDNA testing (HPV+ and -) & residual disease was 98% (Table). Conclusions: Circulating HPV DNA quantified using HPV-detect and ctDNA identifies patients with residual disease post-R-CRT in LAHNC. Further studies are required to validate these findings. [Table: see text]

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Feasibility and promise of circulating tumor DNA analysis in dogs with naturally-occurring sarcoma

10.1101/2020.08.20.260349 ◽

2020 ◽

Author(s):

Patricia Filippsen Favaro ◽

Samuel D. Stewart ◽

Bradon R. McDonald ◽

Jacob Cawley ◽

Tania Contente-Cuomo ◽

...

Keyword(s):

Dna Analysis ◽

Malignant Tumors ◽

Cost Effective ◽

Circulating Tumor Dna ◽

Molecular Heterogeneity ◽

Naturally Occurring ◽

Cost Effective Approach ◽

Ctdna Analysis ◽

Development And Validation ◽

Tumor Dna

AbstractComparative studies of naturally-occurring canine cancers have provided new insight into many areas of cancer research. The inclusion of pet dogs in the development and validation of circulating tumor DNA (ctDNA) diagnostics may be uniquely informative for human translation for many reasons, including: high incidence of certain spontaneous cancers, repeated access to blood and tumor from the same individuals during the course of disease progression, and molecular heterogeneity of naturally-occurring cancers in dogs. Here, we present a feasibility study of ctDNA analysis performed in 9 healthy dogs and 39 dogs with either benign or malignant splenic tumors (hemangiosarcoma) using shallow whole genome sequencing (sWGS) of cell-free DNA. To enable detection and quantification of ctDNA using sWGS, we adapted two informatic approaches and compared their performance for the canine genome. At presentation, mean ctDNA tumor fraction in dogs with malignant splenic tumors was 11.2%, significantly higher than dogs with benign lesions (3.2%; p 0.001), achieving an AUC of 0.84. ctDNA tumor fraction was 14.3% and 9.0% in dogs with metastatic and localized disease, respectively although this difference was not statistically significant (p 0.227). In paired analysis, ctDNA fraction decreased from 11.0% to 7.9% after resection of malignant tumors (p 0.047). Our results demonstrate that ctDNA analysis is feasible in dogs with hemangiosarcoma using a cost-effective approach such as sWGS. Future studies are underway to validate these findings, and further evaluate the role of ctDNA to assess burden of disease and treatment response during drug development.

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Clinical outcomes in patients with BRAFV600 mutant melanoma and undetectable circulating tumor DNA treated with dabrafenib and trametinib.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.10059 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 10059-10059

Author(s):

Alain Patrick Algazi ◽

Megan Othus ◽

Benjamin Newell Voorhies ◽

Kari Lynn Kendra ◽

Shaker R. Dakhil ◽

...

Keyword(s):

Clinical Trial ◽

Circulating Tumor Dna ◽

Disease Stage ◽

Rank Test ◽

Continuous Therapy ◽

Blood Samples ◽

Phase 2 Clinical Trial ◽

Pre Treatment ◽

Ctdna Analysis ◽

Tumor Dna

10059 Background: Circulating tumor DNA (ctDNA) analysis has been promoted as a less-invasive surrogate assay for tumor-tissue based tumor oncogene analysis. Here, we associate detection of BRAF mutant ctDNA with PFS and OS in patients with tissue-confirmed BRAFV600 mutant melanoma enrolled in S1320, a randomized phase 2 clinical trial of continuous versus intermittent dosing of dabrafenib and trametinib. Methods: Patients with BRAFV600 melanoma received continuous therapy with dabrafenib and trametinib for 8 weeks after which patients were randomized 1:1 to proceed with intermittent treatment on a 3-week-off, 5-week-on schedule or to continue with continuous therapy. Pre-treatment blood samples were interrogated using the Guardant 360 ctDNA assay for all exons of 30 known oncogenes including BRAF and for all exons with known oncogenic mutations in the COSMIC database in 40 additional oncogenes. Clinical responses were assessed at 8-week intervals by RECIST v1.1 and PFS and OS estimates were compared using log-rank test in patients with detectable versus undetectable BRAFV600 mutant ctDNA,. Results: Somatic BRAFV600E or BRAFV600K ctDNA was detected in 34 of 50 patients with baseline (before lead-in cycle 1) blood samples available for analysis including 16 of 23 (70%) patients randomized to continuous dosing, 15 of 21 (71%) randomized to intermittent dosing, and 3 of 6 (50%) who were not randomized due to disease progression at 8 weeks or other factors. Four additional patients had other detectable somatic mutations but no detectable BRAFV600 ctDNA at baseline, and 12 patients had no detectable somatic ctDNA mutations at baseline. Detection of BRAFV600 ctDNA was associated with baseline disease stage (p = 0.008). There was no difference in the overall response rate based on baseline ctDNA detection. Detection of ctDNA at baseline was associated with worse PFS (median BRAFV600 ctDNA positive = 5.8; 95% CI: 4.2-9.6 months, BRAFV600 ctDNA negative = 21.4 mos; 95% CI 10.4-NA; measured from registration to lead-in cycle 1, p = 0.001) and OS (BRAFV600 ctDNA positive = 17.8 mos; 95% CI 9.76-NA, BRAFV600 ctDNA negative = not reached; 95% CI NA-NA, p = 0.0021). Conclusions: The absence of detectable BRAFV600 ctDNA at baseline is associated with improved PFS and OS in patients receiving treatment with dabrafenib and trametinib. Clinical trial information: NCT02196181.

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Circulating tumor DNA analysis for assessment of recurrence risk, benefit of adjuvant therapy, and early relapse detection after treatment in colorectal cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.11 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 11-11

Author(s):

Tenna V Henriksen ◽

Noelia Tarazona ◽

Thomas Reinert ◽

Juan Antonio Carbonell-Asins ◽

Derrick Renner ◽

...

Keyword(s):

Colorectal Cancer ◽

High Risk ◽

Adjuvant Therapy ◽

Dna Analysis ◽

Circulating Tumor Dna ◽

Response Monitoring ◽

Risk Of Recurrence ◽

Definitive Therapy ◽

Ctdna Analysis ◽

Tumor Dna

11 Background: Timely detection of recurrence, as well as identification of patients at high risk of recurrence after surgery and after completion of adjuvant therapy, are major challenges in the treatment of colorectal cancer (CRC). Postsurgical circulating tumor DNA (ctDNA) analysis is a promising tool for the identification of patients with minimal residual disease (MRD) and a high risk of recurrence. The objective of this prospective, multicenter study was to determine whether serial postsurgical ctDNA analysis could identify the patients at high risk of recurrence, provide an assessment of adjuvant therapy efficacy and detect relapse earlier than standard-of-care radiological imaging. Methods: The cohort comprises 265 stage I-III CRC patients, the to-date largest cohort assessed for ctDNA. All patients had the tumor resected and a subset of 62.6% (166 /265) was additionally treated with ACT. Plasma samples (n = 1503) were collected at various time points for a median follow-up of 28.4 months (range: 1.2-51.0 months). Individual tumors and matched germline DNA were whole-exome sequenced and somatic single nucleotide variants (SNVs) were identified. Personalized multiplex PCR assays were designed to track tumor-specific SNVs (Signatera, bespoke mPCR NGS assay) in each patient’s plasma sample. Results: Postoperative ctDNA status prior to ACT was assessed in 218 patients, of which 9.17% (20/218) were identified to be MRD-positive and 75% (15/20) eventually relapsed. The remaining 25% (5/20) of MRD-positive patients that did not relapse, received ACT. In contrast, only 13.6% (27/198) of MRD-negative cases relapsed (HR: 11: 95% CI: 5.7-20; p < 0.001). Longitudinal ctDNA-positive status, post-definitive therapy (n = 202) was associated with a HR of 36 (95% CI: 16-81; p < 0.001). For a subset of 155 patients postoperative CEA and ctDNA measurements were compared, wherein, ctDNA-positive status was found to be significantly associated with RFS (HR, 7.1; 95% CI, 3.4-15; P < 0.001) compared to CEA (HR, 1.2; 95% CI, 0.46-3.1; P = 0.73). Serial ctDNA analysis detected MRD up to a median of 8 months (0.56 - 21.6 months) ahead of radiologic relapse. Conclusion: Postoperative ctDNA positive status was associated with markedly reduced RFS compared to CEA. The study also shows that effective therapy can be curative in a portion of MRD-positive patients. In a longitudinal setting, ctDNA analysis predicted the risk of recurrence and is a more reliable biomarker for treatment response monitoring.

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Assessment of Treatment Responses in Children and Adolescents with Ewing Sarcoma with Metabolic Tumor Parameters Derived from 18F-FDG-PET/CT and Circulating Tumor DNA

10.1055/s-0040-1703338 ◽

2020 ◽

Author(s):

C Schmidkonz ◽

M Metzler ◽

M Krumbholz ◽

T Kuwert ◽

M Uder ◽

...

Keyword(s):

Children And Adolescents ◽

Ewing Sarcoma ◽

Fdg Pet ◽

Circulating Tumor Dna ◽

Pet Ct ◽

18F Fdg ◽

Treatment Responses ◽

Fdg Pet Ct ◽

Tumor Dna

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Circulating Tumor DNA Analysis to Optimize the Operative and Postoperative Treatment for Patients With Colorectal Cancer - Intervention Trial 2

Case Medical Research ◽

10.31525/ct1-nct04084249 ◽

2019 ◽

Author(s):

Keyword(s):

Colorectal Cancer ◽

Dna Analysis ◽

Circulating Tumor Dna ◽

Postoperative Treatment ◽

Intervention Trial ◽

Cancer Intervention ◽

Tumor Dna

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Plasma ctDNA is a tumor tissue surrogate and enables clinical-genomic stratification of metastatic bladder cancer

Nature Communications ◽

10.1038/s41467-020-20493-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Gillian Vandekerkhove ◽

Jean-Michel Lavoie ◽

Matti Annala ◽

Andrew J. Murtha ◽

Nora Sundahl ◽

...

Keyword(s):

Tumor Tissue ◽

Treatment Options ◽

Circulating Tumor Dna ◽

Molecular Stratification ◽

Clinical Biomarkers ◽

Surgery Patient ◽

Metastatic Urothelial Carcinoma ◽

Ctdna Analysis ◽

Clinical Genomic ◽

Tumor Dna

AbstractMolecular stratification can improve the management of advanced cancers, but requires relevant tumor samples. Metastatic urothelial carcinoma (mUC) is poised to benefit given a recent expansion of treatment options and its high genomic heterogeneity. We profile minimally-invasive plasma circulating tumor DNA (ctDNA) samples from 104 mUC patients, and compare to same-patient tumor tissue obtained during invasive surgery. Patient ctDNA abundance is independently prognostic for overall survival in patients initiating first-line systemic therapy. Importantly, ctDNA analysis reproduces the somatic driver genome as described from tissue-based cohorts. Furthermore, mutation concordance between ctDNA and matched tumor tissue is 83.4%, enabling benchmarking of proposed clinical biomarkers. While 90% of mutations are identified across serial ctDNA samples, concordance for serial tumor tissue is significantly lower. Overall, our exploratory analysis demonstrates that genomic profiling of ctDNA in mUC is reliable and practical, and mitigates against disease undersampling inherent to studying archival primary tumor foci. We urge the incorporation of cell-free DNA profiling into molecularly-guided clinical trials for mUC.

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18F-FDG-PET/CT in radiation therapy-induced parotid gland inflammation

European Journal of Hybrid Imaging ◽

10.1186/s41824-020-00091-x ◽

2020 ◽

Vol 4 (1) ◽

Author(s):

Alaa Mouminah ◽

Austin J. Borja ◽

Emily C. Hancin ◽

Yu Cheng Chang ◽

Thomas J. Werner ◽

...

Keyword(s):

Parotid Gland ◽

Fdg Pet ◽

Standardized Uptake Value ◽

Post Treatment ◽

Parotid Glands ◽

Positron Emission ◽

Pet Ct ◽

Average Maximum ◽

Pre Treatment ◽

Fdg Pet Ct

Abstract Background 18F-fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) is used in the clinical management of oncologic and inflammatory pathologies. It may have utility in detecting radiotherapy (RT)-induced damage of oral tissues. Thus, the aim of the present study was to use FDG-PET/CT to evaluate parotid gland inflammation following RT in patients with head and neck cancer (HNC). Methods This retrospective study included patients with HNC treated with photon, proton, or combined photon/proton RT, in addition to chemotherapy. All patients received FDG-PET/CT imaging pre-treatment and 3 months post-treatment. The average mean standardized uptake value (Avg SUVmean) and the average maximum standardized uptake value (Avg SUVmax) of the left and right parotid glands were determined by global assessment of FDG activity using OsiriX MD software. A two-tailed paired t test was used to compare Avg SUVmean and Avg SUVmax pre- and post-RT. Results Forty-seven HNC patients were included in the study. Parotid gland Avg SUVmean was significantly higher at 3 months post-treatment than pre-treatment (p < 0.05) in patients treated with photon RT, but no significant differences were found between pre- and post-treatment Avg SUVmean in patients treated with proton RT or combined photon/proton RT. Conclusion Our results suggest that photon RT may cause radiation-induced inflammation of the parotid gland, and that proton RT, which distributes less off-target radiation, is a safer treatment alternative.

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