PS02.083: CIRCULATING CELL FREE TUMOR DNA FOR DISEASE MONITORING AFTER NEOADJUVANT CHEMORADIOTHERAPY FOR ESOPHAGEAL CANCER: PROOF-OF-PRINCIPLE

Abstract Background An active surveillance approach has been proposed for patients with a clinically complete response (cCR) after neoadjuvant chemoradiotherapy (nCRT) in esophageal cancer (SANO trial). To justify renouncing surgical resection, patients with residual disease after nCRT should be accurately identified. However, substantial residual disease (TRG3–4) cannot be detected in 10% of patients with current diagnostic tests (preSANO trial). Circulating cell free tumor DNA (ctDNA) potentially improves detection of residual malignancy after nCRT and could be used for disease monitoring. The objective of this study was to investigate the feasibility of using ctDNA as biomarker for disease status after nCRT in esophageal cancer. Methods Twelve typical patients from the preSANO trial with variable pathological responses to nCRT were included. Blood was drawn and processed pretreatment. The feasibility of detecting TP53 mutations in baseline tumor biopsies was investigated using a next generation sequencing (NGS) panel. Subsequently, baseline blood samples of patients in whom specific TP53 mutations could be identified in baseline tumor biopsies or the surgical resection specimen were analyzed for ctDNA using cell free DNA NGS kits with single molecule barcoding (Oncomine Thermo Fisher). Results Baseline biopsy samples were available in 8 out of 12 patients. In 7 of these 8 patients (88%) specific TP53 mutations could be identified in their baseline biopsies. In 11 out of 12 patients (92%) specific TP53 mutations could be identified in baseline biopsies or the resection specimen. Eight of these 11 mutations were potentially detectable by the Oncomine panel. The panel detected TP53 mutational ctDNA in 4 of these 8 samples (50%). Conclusion Specific and clonal TP53 mutations can be identified in pretreatment biopsy samples and in surgical resection specimens of patients with esophageal cancer. These mutations can be matched to ctDNA identified in blood samples. Hence, ctDNA analyses in blood samples can potentially be used for disease monitoring during active surveillance and for disease monitoring in follow-up after surgical resection. Disclosure All authors have declared no conflicts of interest.

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Circulating cell free tumor DNA for disease monitoring after neoadjuvant chemoradiotherapy for esophageal cancer: proof-of-principle

European Journal of Surgical Oncology ◽

10.1016/j.ejso.2018.10.307 ◽

2019 ◽

Vol 45 (2) ◽

pp. e86

Author(s):

B. Eyck ◽

B.J. Noordman ◽

B.J. van der Wilk ◽

M.P. Jansen ◽

P.N. Atmodimedjo ◽

...

Keyword(s):

Esophageal Cancer ◽

Neoadjuvant Chemoradiotherapy ◽

Disease Monitoring ◽

Tumor Dna ◽

Proof Of Principle

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Predictive value of endoscopic esophageal findings for residual esophageal cancer after neoadjuvant chemoradiotherapy

Endoscopy ◽

10.1055/a-1362-9375 ◽

2021 ◽

Author(s):

Ruben D. van der Bogt ◽

Berend J. van der Wilk ◽

Suzan Nikkessen ◽

Kausilia K. Krishnadath ◽

Erik J. Schoon ◽

...

Keyword(s):

Esophageal Cancer ◽

Positive Predictive Value ◽

Active Surveillance ◽

Predictive Value ◽

Residual Disease ◽

Neoadjuvant Chemoradiotherapy ◽

Residual Tumor ◽

Scar Tissue ◽

Endoscopic Findings ◽

Resection Specimen

Abstract Background Endoscopic evaluation of the esophageal mucosa may play a role in an active surveillance strategy after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer. This study investigated the yield of endoscopic findings for detection of residual disease. Methods Patients from the multicenter preSANO cohort, who underwent nCRT followed by surgery for esophageal or junctional cancer, were included. Upper endoscopy was performed 6 and 12 weeks after nCRT. Patients with residual disease at 6 weeks underwent immediate surgery. Endoscopic records were reviewed for presence of stenosis, suspicion of residual tumor, scar tissue, and ulceration. Presence and type of endoscopic findings were compared with outcome of the resection specimen. Results 118 of 156 patients (76 %) had residual disease in the resection specimen. Endoscopic suspicion of residual tumor was significantly associated with presence of residual disease. At 6 weeks, 40/112 patients with residual disease and 4/33 patients with complete response had endoscopic suspicion of residual tumor (36 % vs. 12 %; P = 0.01), while this was reported in 16/73 and 0/28 patients, respectively, at 12 weeks (22 % vs. 0 %; P < 0.01). Positive predictive value of endoscopic suspicion of residual tumor was 91 % at 6 weeks and 100 % at 12 weeks. Endoscopic findings of non-passable stenosis, passable stenosis, scar tissue, or ulceration were not associated with residual disease. Conclusions Endoscopic suspicion of residual tumor was the only endoscopic finding associated with residual disease. Based on its positive predictive value, this endoscopic finding may contribute to the diagnostic strategy used in active surveillance.

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PS02.084: PROSPECTIVE EVALUATION OF 18F-FDG PET-CT AFTER NEOADJUVANT CHEMORADIOTHERAPY FOR DETECTING LYMPH NODE METASTASES NEAR THE CELIAC TRUNK IN PATIENTS WITH ESOPHAGEAL CANCER

Diseases of the Esophagus ◽

10.1093/dote/doy089.ps02.084 ◽

2018 ◽

Vol 31 (Supplement_1) ◽

pp. 144-144

Author(s):

Jasper Groen ◽

Suzanne Gisbertz ◽

Mark I Van Berge Henegouwen ◽

Annelijn E Slaman ◽

Sybren Meijer ◽

...

Keyword(s):

Esophageal Cancer ◽

Lymph Node ◽

Lymph Node Metastases ◽

Predictive Value ◽

Neoadjuvant Chemoradiotherapy ◽

Celiac Trunk ◽

Pet Ct ◽

Resection Specimen ◽

Node Metastases ◽

18F Fdg

Abstract Background Celiac trunk metastases are an independent factor for inferior survival in patients with esophageal cancer. Detecting these metastases before esophagostomy would aid clinical decision making. The aim of our study was to evaluate the accuracy of integrated PET and CT (PET-CT) using 18F-FDG in detecting these metastases in patients with esophageal cancer after neoadjuvant chemoradiotherapy (nCRTx) followed by esophagectomy. Methods All patients with a carcinoma of the mid-to-distal esophagus or the gastroesophageal junction (GEJ) who underwent esophageal resection with curative intent following nCRTx between January 2011 and January 2017 were included. The PET-CT scans after nCRTx were reviewed by nuclear radiologists and lymph nodes within a margin of 2 cm around the celiac trunk were expressed in SUVmax. Lymph nodes with SUVmax > 2.0 were deemed positive. The truncal nodes were extracted during esophagectomy and reviewed by different pathologists using standard pathology protocol. To assess the accuracy of the PET-CT in detecting lymph node metastases near the celiac trunk the sensitivity, specificity and positive and negative predictive value were calculated. Results A total of 448 patients were included. There were 24 patients (5.4%) with positive truncal nodes on the PET-CT versus 424 patients (90.6%) with negative truncal nodes on the PET-CT. Out of these 24 patients 20 (83.3%) had truncal node metastases confirmed in the resection specimen (positive predictive value of 83.3%). In the other 424 patients 40 (9.4%) had truncal node metastases confirmed in the resection specimen (negative predictive value of 90.6%). This results in a sensitivity of 33.3% and a specificity of 99.0%. Conclusion The sensitivity and specificity of the PET-CT in detecting lymph node metastases near the celiac trunk in patients with esophageal cancer who underwent nCRTx were respectively 33.3% and 99.0% This shows that the PET-CT is accurate in detecting truncal lymph node metastases in this patient group. Disclosure All authors have declared no conflicts of interest.

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Patient-Specific Circulating Tumor DNA Detection during Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer

Clinical Chemistry ◽

10.1373/clinchem.2016.262337 ◽

2017 ◽

Vol 63 (3) ◽

pp. 691-699 ◽

Cited By ~ 72

Author(s):

Francesca Riva ◽

Francois-Clement Bidard ◽

Alexandre Houy ◽

Adrien Saliou ◽

Jordan Madic ◽

...

Keyword(s):

Breast Cancer ◽

Neoadjuvant Chemotherapy ◽

Minimal Residual Disease ◽

Triple Negative Breast Cancer ◽

Triple Negative ◽

Residual Disease ◽

Circulating Tumor Dna ◽

Tp53 Mutations ◽

Tumor Dna ◽

Minimal Residual

Abstract BACKGROUND In nonmetastatic triple-negative breast cancer (TNBC) patients, we investigated whether circulating tumor DNA (ctDNA) detection can reflect the tumor response to neoadjuvant chemotherapy (NCT) and detect minimal residual disease after surgery. METHODS Ten milliliters of plasma were collected at 4 time points: before NCT; after 1 cycle; before surgery; after surgery. Customized droplet digital PCR (ddPCR) assays were used to track tumor protein p53 (TP53) mutations previously characterized in tumor tissue by massively parallel sequencing (MPS). RESULTS Forty-six patients with nonmetastatic TNBC were enrolled. TP53 mutations were identified in 40 of them. Customized ddPCR probes were validated for 38 patients, with excellent correlation with MPS (r = 0.99), specificity (≥2 droplets/assay), and sensitivity (at least 0.1%). At baseline, ctDNA was detected in 27/36 patients (75%). Its detection was associated with mitotic index (P = 0.003), tumor grade (P = 0.003), and stage (P = 0.03). During treatment, we observed a drop of ctDNA levels in all patients but 1. No patient had detectable ctDNA after surgery. The patient with rising ctDNA levels experienced tumor progression during NCT. Pathological complete response (16/38 patients) was not correlated with ctDNA detection at any time point. ctDNA positivity after 1 cycle of NCT was correlated with shorter disease-free (P < 0.001) and overall (P = 0.006) survival. CONCLUSIONS Customized ctDNA detection by ddPCR achieved a 75% detection rate at baseline. During NCT, ctDNA levels decreased quickly and minimal residual disease was not detected after surgery. However, a slow decrease of ctDNA level during NCT was strongly associated with shorter survival.

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Endoscopic ultrasound and fine-needle aspiration for the detection of residual nodal disease after neoadjuvant chemoradiotherapy for esophageal cancer

Endoscopy ◽

10.1055/a-1065-1759 ◽

2019 ◽

Vol 52 (03) ◽

pp. 186-192 ◽

Cited By ~ 1

Author(s):

Ruben D. van der Bogt ◽

Berend J. van der Wilk ◽

Jan-Werner Poley ◽

Kausilia K. Krishnadath ◽

Erik J. Schoon ◽

...

Keyword(s):

Esophageal Cancer ◽

Endoscopic Ultrasound ◽

Fine Needle Aspiration ◽

Residual Disease ◽

Histopathological Examination ◽

Neoadjuvant Chemoradiotherapy ◽

Needle Aspiration ◽

Fine Needle ◽

Specificity And Sensitivity ◽

Pet Ct

Abstract Background Endoscopic ultrasound (EUS) and fine-needle aspiration (FNA) are potential tools for the detection of residual disease after neoadjuvant chemoradiotherapy (nCRT) for esophageal cancer. This study investigated yield of EUS and FNA for detection of malignant lymph nodes (LNs) after nCRT. Methods This was a post hoc analysis of the preSANO trial. EUS was performed 10 – 12 weeks after nCRT. 18F-fluorodeoxyglucose positron emission tomography – computed tomography (18F-FDG PET-CT) was used to guide targeting of suspicious LNs. Consecutive FNA sampling was performed for suspicious LNs identified on EUS and/or PET-CT. EUS nodal staging was compared with histopathological examination of the resection specimen. The primary outcome was the proportion of correctly identified patients with malignant LNs by radial EUS. Results 101 consecutive patients were included: 79 patients had no malignant LNs, of whom 62 were classified correctly by EUS (specificity 78 %); 22 patients had malignant LNs, of whom 11 were identified (sensitivity 50 %). Six of these patients had ≥ 1 suspicious LN not fulfilling EUS criteria (round, hypoechogenic, > 5 mm). Malignant LNs in falsely negative patients were predominantly located at distal LN stations. Specificity and sensitivity of conclusive FNA outcomes were 100 % (7/7) and 75 % (3/4), respectively. FNA outcome was uncertain in eight patients, half of whom appeared to have malignant LNs. Conclusions EUS only detected 50 % of patients with malignant LNs 10 – 12 weeks after nCRT. To optimize sensitivity and minimize the risk of missing residual disease, FNA of LNs should be performed even in cases of low endosonographic suspicion.

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Accuracy of 18F-FDG PET/CT in Predicting Residual Disease After Neoadjuvant Chemoradiotherapy for Esophageal Cancer

Journal of Nuclear Medicine ◽

10.2967/jnumed.118.224196 ◽

2019 ◽

Vol 60 (11) ◽

pp. 1553-1559 ◽

Cited By ~ 3

Author(s):

Maria J. Valkema ◽

Bo Jan Noordman ◽

Bas P.L. Wijnhoven ◽

Manon C.W. Spaander ◽

Katharina Biermann ◽

...

Keyword(s):

Esophageal Cancer ◽

Fdg Pet ◽

Residual Disease ◽

Neoadjuvant Chemoradiotherapy ◽

Pet Ct ◽

18F Fdg ◽

Fdg Pet Ct

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Editorial on “Can CT-PET and endoscopic assessment post-neoadjuvant chemoradiotherapy predict residual disease in esophageal cancer”

Journal of Thoracic Disease ◽

10.21037/jtd.2017.09.117 ◽

2017 ◽

Vol 9 (10) ◽

pp. 3645-3648

Author(s):

Chia-Ju Liu ◽

Wei Lu

Keyword(s):

Esophageal Cancer ◽

Residual Disease ◽

Neoadjuvant Chemoradiotherapy ◽

Endoscopic Assessment

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Accuracy of Detecting Residual Disease After Cross Neoadjuvant Chemoradiotherapy for Esophageal Cancer (preSANO Trial): Rationale and Protocol

JMIR Research Protocols ◽

10.2196/resprot.4320 ◽

2015 ◽

Vol 4 (2) ◽

pp. e79 ◽

Cited By ~ 43

Author(s):

Bo Jan Noordman ◽

Joel Shapiro ◽

Manon CW Spaander ◽

Kausilia K Krishnadath ◽

Hanneke WM van Laarhoven ◽

...

Keyword(s):

Esophageal Cancer ◽

Residual Disease ◽

Neoadjuvant Chemoradiotherapy

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Towards an Organ-Sparing Approach for Locally Advanced Esophageal Cancer

Digestive Surgery ◽

10.1159/000493435 ◽

2018 ◽

Vol 36 (6) ◽

pp. 462-469 ◽

Cited By ~ 3

Author(s):

Berend Jan van der Wilk ◽

Ben M. Eyck ◽

Manon C.W. Spaander ◽

Roelf Valkema ◽

Sjoerd M. Lagarde ◽

...

Keyword(s):

Esophageal Cancer ◽

Active Surveillance ◽

Residual Disease ◽

Tumor Regression ◽

Locally Advanced ◽

Neoadjuvant Chemoradiotherapy ◽

Distant Metastases ◽

Phase Iii ◽

Tumor Regression Grade ◽

Surveillance Strategy

Background: Active surveillance after neoadjuvant therapies has emerged among several malignancies. During active surveillance, frequent assessments are performed to detect residual disease and surgery is only reserved for those patients in whom residual disease is proven or highly suspected without distant metastases. After neoadjuvant chemoradiotherapy (nCRT), nearly one-third of esophageal cancer patients achieve a pathologically complete response (pCR). Both patients that achieve a pCR and patients that harbor subclinical disseminated disease after nCRT could benefit from an active surveillance strategy. Summary: Esophagectomy is still the cornerstone of treatment in patients with esophageal cancer. Non-surgical treatment via definitive chemoradiotherapy (dCRT) is currently reserved only for patients not eligible for esophagectomy. Since salvage esophagectomy after dCRT (50–60 Gy) results in increased complications, morbidity and mortality compared to surgery after nCRT (41.4 Gy), the latter seems preferable in the setting of active surveillance. Clinical response evaluations can detect substantial (i.e., tumor regression grade [TRG] 3–4) tumors after nCRT with a sensitivity of 90%, minimizing the risk of development of non-resectable recurrences. Current scarce and retrospective literature suggests that active surveillance following nCRT might not jeopardize overall survival and postponed surgery could be performed safely. Key Message: Before an active surveillance approach could be considered standard treatment, results of phase III randomized trials should be awaited.

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