scholarly journals The Feasibility of Patient-Specific Circulating Tumor DNA Monitoring throughout Multi-Modality Therapy for Locally Advanced Esophageal and Rectal Cancer: A Potential Biomarker for Early Detection of Subclinical Disease

Diagnostics ◽  
2021 ◽  
Vol 11 (1) ◽  
pp. 73
Author(s):  
Christopher Boniface ◽  
Christopher Deig ◽  
Carol Halsey ◽  
Taylor Kelley ◽  
Michael B. Heskett ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Neoadjuvant Therapy ◽  
Cancer Patients ◽  
Feasibility Study ◽  
Locally Advanced ◽  
Circulating Tumor Dna ◽  
Study Patient ◽  
Patient Specific ◽  
Clinical Recurrence ◽  
Tumor Dna

As non-operative management (NOM) of esophageal and rectal cancer is becoming more prevalent, blood-biomarkers such as circulating tumor DNA (ctDNA) may provide clinical information in addition to endoscopy and imaging to aid in treatment decisions following chemotherapy and radiation therapy. In this feasibility study, we prospectively collected plasma samples from locally advanced esophageal (n = 3) and rectal cancer (n = 2) patients undergoing multimodal neoadjuvant therapy to assess the feasibility of serial ctDNA monitoring throughout neoadjuvant therapy. Using the Dual-Index Degenerate Adaptor-Sequencing (DIDA-Seq) error-correction method, we serially interrogated plasma cell-free DNA at 28–41 tumor-specific genomic loci throughout therapy and in surveillance with an average limit of detection of 0.016% mutant allele frequency. In both rectal cancer patients, ctDNA levels were persistently elevated following total neoadjuvant therapy with eventual detection of clinical recurrence prior to salvage surgery. Among the esophageal cancer patients, ctDNA levels closely correlated with tumor burden throughout and following neoadjuvant therapy, which was associated with a pathologic complete response in one patient. In this feasibility study, patient- and tumor-specific ctDNA levels correlated with clinical outcomes throughout multi-modality therapy suggesting that serial monitoring of patient ctDNA has the potential to serve as a highly sensitive and specific biomarker to risk-stratify esophageal and rectal cancer patients eligible for NOM. Further prospective investigation is warranted.

scholarly journals Personalized circulating tumor DNA analysis to detect residual disease after neoadjuvant therapy in breast cancer

2019 ◽  
Vol 11 (504) ◽  
pp. eaax7392 ◽  
Author(s):  
Bradon R. McDonald ◽  
Tania Contente-Cuomo ◽  
Stephen-John Sammut ◽  
Ahuva Odenheimer-Bergman ◽  
Brenda Ernst ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Neoadjuvant Therapy ◽  
Dna Analysis ◽  
Residual Disease ◽  
Circulating Tumor Dna ◽  
Patient Specific ◽  
Molecular Response ◽  
Curative Intent ◽  
Current Limit ◽  
Tumor Dna

Longitudinal analysis of circulating tumor DNA (ctDNA) has shown promise for monitoring treatment response. However, most current methods lack adequate sensitivity for residual disease detection during or after completion of treatment in patients with nonmetastatic cancer. To address this gap and to improve sensitivity for minute quantities of residual tumor DNA in plasma, we have developed targeted digital sequencing (TARDIS) for multiplexed analysis of patient-specific cancer mutations. In reference samples, by simultaneously analyzing 8 to 16 known mutations, TARDIS achieved 91 and 53% sensitivity at mutant allele fractions (AFs) of 3 in 104 and 3 in 105, respectively, with 96% specificity, using input DNA equivalent to a single tube of blood. We successfully analyzed up to 115 mutations per patient in 80 plasma samples from 33 women with stage I to III breast cancer. Before treatment, TARDIS detected ctDNA in all patients with 0.11% median AF. After completion of neoadjuvant therapy, ctDNA concentrations were lower in patients who achieved pathological complete response (pathCR) compared to patients with residual disease (median AFs, 0.003 and 0.017%, respectively, P = 0.0057, AUC = 0.83). In addition, patients with pathCR showed a larger decrease in ctDNA concentrations during neoadjuvant therapy. These results demonstrate high accuracy for assessment of molecular response and residual disease during neoadjuvant therapy using ctDNA analysis. TARDIS has achieved up to 100-fold improvement beyond the current limit of ctDNA detection using clinically relevant blood volumes, demonstrating that personalized ctDNA tracking could enable individualized clinical management of patients with cancer treated with curative intent.

Predictive value of circulating tumor DNA in locally advanced rectal cancer patients receiving neoadjuvant radiochemotherapy.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15125-e15125 ◽  
Author(s):  
Min Li ◽  
WeiWei Xiao ◽  
Grace Q. Zhao ◽  
Zhiwei Guo ◽  
Xuexi Yang ◽  
...  
Keyword(s):  
Rectal Cancer ◽  
Predictive Value ◽  
Tumor Response ◽  
Predictive Accuracy ◽  
Locally Advanced ◽  
Advanced Rectal Cancer ◽  
Circulating Tumor Dna ◽  
Locally Advanced Rectal Cancer ◽  
Neoadjuvant Radiochemotherapy ◽  
Tumor Dna

e15125 Background: Neoadjuvant radiochemotherapy (RCT) is rapidly becoming the preferred treatment for patients diagnosed with late-stage locally advanced rectal cancer (LARC). Presently, tumor regression grades (TRG) is used to characterize treatment responsiveness; patients with low TRG scores have been shown to receive no benefit from surgery. To-date, however, there exists no reliable method for identifying low TRG-scoring patients without surgery. Here we propose the use of circulating tumor DNA (ctDNA) to identify low TRG-scoring patients to reduce overtreatment and improve quality of life. Methods: 30 LARC patients undergoing neoadjuvant RCT were prospectively enrolled in our study. Plasma was collected before treatment, immediately preceding cycle 3 chemotherapy, and 2 weeks following cycle 4 chemotherapy. Tumor tissue was also collected before treatment start. CtDNA and tumor DNA were sequenced using Accu-Act, a 61-gene NGS panel. Tumor response was classified as TRG1-5 according to Mandard classification system. Somatic mutation profiles were correlated with tumor response. The accuracy of ctDNA and tumor DNA in predicting TRG scores was calculated using the change of allele frequency. The predictive value of ctDNA was also compared to that of standard CEA and CA199 assays. Patients with CEA and CA199 scores below threshold were also considered for evaluation. Results: 18 of the 30 LARC patients enrolled had complete ctDNA profiling test among whom 13 had already undergone surgery. 17 somatic mutations were identified from the 10 patients with TRG scores of either 1, 2, or 3. Predictive accuracy of pretreatment ctDNA profiling was 70%, compared to that of CEA analysis (66%) and CA199 analysis (50%). TRG prediction using ctDNA successfully evaluated half of patients for whom CEA analysis failed to predict the change in tumor burden. Conclusions: Our findings suggest ctDNA mutation profiling may be a powerful tool for predicting TRG in LARC patients undergoing RCT. Further studies are needed to validate the utility of ctDNA in identifying patients who can be spared from unnecessary surgical treatment in LARC. Clinical trial information: NCT02031939.

Nomogram incorporated the number of adjuvant chemotherapy cycles for predicting the prognosis in stage II-III rectal cancer patients without neoadjuvant therapy.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15163-e15163
Author(s):  
Weiwei Chen ◽  
Wenling Wang
Keyword(s):  
Rectal Cancer ◽  
Colon Cancer ◽  
Overall Survival ◽  
Multivariate Analysis ◽  
Prognostic Factors ◽  
Adjuvant Chemotherapy ◽  
Neoadjuvant Therapy ◽  
Cancer Patients ◽  
Locally Advanced ◽  
Stage Ii

e15163 Background: Current recommendations for adjuvant chemotherapy in rectal cancer are based on the studies in colon cancer. However, it is now known that rectal cancer differs from colon cancer significantly regarding clinical course and biology. No RCTs in the TME era have evaluated the value of postoperative chemotherapy and are unlikely to be performed as neoadjuvant treatment has become a “gold standard” approach. However, we found that not all patients with locally advanced rectal cancer underwent neoadjuvant chemoradiotherapy before TME in real-world clinical practice in China. Whether the number of adjuvant chemotherapy cycles is significantly related to the prognosis of these patients deserves further study. Methods: A total of 246 patients with stage II-III rectal cancer from January 2013 to April 2018 were enrolled. All patients underwent surgery and had not received neoadjuvant therapy. The survival curve was drawn by the Kaplan-Meier method, and the log-rank method was used for statistical analysis. The Cox proportional hazard model was used for multivariate analysis to determine the independent prognostic factors. Then, MFP(Multiple Fractional Polynominal) and stepwiseAIC were used for variable selection. The R software was used to establish the nomogram. The bootstrap method was employed to internal verification. Concordance index(C-index) was applied to evaluate the predictive power of nomogram. Calibration curves were drawn to compare the 3-year overall survival rate predicted by nomogram and that of actual observation. Results: 87.8% of patients received adjuvant chemotherapy including oxaliplatin combined with fluorouracil or capecitabine. Univariate and multivariate analysis showed that the number of adjuvant chemotherapy cycles was independent prognostic factors. Patients who received more than 5 cycles of chemotherapy (HR = 0.09, 95%CI(0.01,0.80)) had a significantly better overall survival than patients with less than 5 cycles (HR = 0.33,95%CI(0.12,0.89)) or no chemotherapy (p < 0.05).Through MFP and the stepwiseAIC screening, a nomogram was established based on CEA, PLR, N, and the number of chemotherapy cycles, and the C-index of the model was 0.86. Conclusions: The number of adjuvant chemotherapy cycles is an independent prognostic factor in stage II-III rectal cancer patients without neoadjuvant therapy. Moreover, nomogram incorporated the number of chemotherapy cycles was accurate and visible.

scholarly journals Circulating tumor DNA as a predictive marker of recurrence for patients with stage II-III breast cancer treated with neoadjuvant therapy

2021 ◽  
Author(s):  
Po-Han Lin ◽  
Ming-Yang Wang ◽  
Chiao Lo ◽  
Li-Wei Tsai ◽  
Tzu-Chun Yen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Risk Factors ◽  
Neoadjuvant Therapy ◽  
Cancer Patients ◽  
Pathologic Complete Response ◽  
Circulating Tumor Dna ◽  
Stage Ii ◽  
Breast Cancer Patients ◽  
Her2 Breast Cancer ◽  
Tumor Dna

Abstract Background:Patients with stage II to III breast cancer have a high recurrence rate. The early detection of recurrent breast cancer remains a major unmet need. Circulating tumor DNA (ctDNA) has been shown to be a marker to detect disease progression in metastatic breast cancer. We aimed to evaluate the prognostic value of ctDNA in the setting of neoadjuvant therapy (NAT).Methods:Plasma was sampled at the initial diagnosis (defined as before NAT) and after NAT and breast surgery (defined as after NAT). We extracted ctDNA from the plasma and performed deep sequencing of a target gene panel. The detection of alterations, such as mutations and copy number variations, were considered to indicate ctDNA positivity.Results:A total of 95 patients were enrolled in this study; 60 patients exhibited ctDNA positivity before NAT, and 31 patients had ctDNA positivity after NAT. A pathologic complete response (pCR) was observed in 13 patients, including one ER(+)Her2(-) patient, six Her2(+) patients and six triple-negative breast cancer (TNBC) patients. Among the entire cohort, multivariate analysis showed that an N3 classification and ctDNA positivity after NAT were independent risk factors that predicted recurrence (N3, hazard ratio (HR) 3.34, 95% confidence interval (CI) 1.26 – 8.87, p = 0.016; ctDNA, HR 4.29, 95% CI 2.06 – 8.92, p < 0.0001). The presence of ctDNA before NAT did not affect the rate of recurrence-free survival. For patients with Her2(+) or TNBC, non-pCR breast cancer patients were associated with a trend of higher recurrence (p = 0.105). Advanced nodal status and ctDNA positivity after NAT were significant risk factors for recurrence (N2 – 3, HR 3.753, 95% CI 1.146 – 12.297, p = 0.029; ctDNA, HR 3.123, 95% CI 1.139 – 8.564, p = 0.027). Two patients who achieved a pCR had ctDNA positivity after NAT; one TNBC patient had hepatic metastases six months after surgery, and one Her2(+) breast cancer patient had brain metastasis 13 months after surgery.Conclusions:This study suggested that the presence of ctDNA after NAT is a robust marker for predicting relapse in stage II to III breast cancer patients.

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