TY - JOUR
T1 - High detection rates of pancreatic cancer across stages by plasma assay of novel methylated DNA markers and CA19-9
AU - Majumder, Shounak
AU - Taylor, William R.
AU - Foote, Patrick H.
AU - Berger, Calise K.
AU - Wu, Chung Wah
AU - Mahoney, Douglas W.
AU - Bamlet, William R.
AU - Burger, Kelli N.
AU - Postier, Neil
AU - De La Fuente, Jaime
AU - Doering, Karen A.
AU - Lidgard, Graham P.
AU - Allawi, Hatim T.
AU - Petersen, Gloria M.
AU - Chari, Suresh T.
AU - Ahlquist, David A.
AU - Kisiel, John B.
N1 - Funding Information:
S. Majumder reports grants and other from Exact Sciences during the conduct of the study, grants and other from Exact Sciences outside the submitted work, and a patent for PCT/US2020/026581 pending. W. Taylor reports grants and other from Exact Sciences during the conduct of the study, grants and other from Exact Sciences outside the submitted work, and a patent for Detecting Neoplasms USA 9506116 issued and licensed to Exact Sciences. P.H. Foote reports other from Exact Sciences during the conduct of the study. C.K. Berger reports other from Exact Sciences during the conduct of the study. C.W. Wu reports personal fees from Exact Sciences outside the submitted work. D.W. Mahoney reports other from Exact Sciences during the conduct of the study, other from Exact Sciences outside the submitted work, and a patent for Detecting Neoplasm USA 9506116 issued and licensed. K.N. Burger reports other from Exact Sciences during the conduct of the study. K.A. Doering reports other from Exact Sciences during the conduct of the study. G.P. Lidgard reports other from Exact Sciences during the conduct of the study, other from Exact Sciences outside the submitted work, and various patents pending. H.T. Allawi reports other from Exact Sciences Corp during the conduct of the study, other from Exact Sciences Corp outside the submitted work, and a patent for Pancreatic cancer methylation markers pending to Exact Sciences Corp. S.T. Chari reports grants from NIH and grants from Pancreatic Cancer Action Network outside the submitted work. J.B. Kisiel reports grants and other from Exact Sciences during the conduct of the study, grants from Exact Sciences outside the submitted work, and a patent for Detecting Neoplasm USA 9506116 issued and licensed to Exact Sciences. No disclosures were reported by the other authors.
Funding Information:
The authors dedicate this work to thememory of D.A. Ahlquist (1951-2020), who inspired this work and played key roles in study concept and design, analysis and interpretation of data, critical review of the article for important intellectual content, and obtained funding. Funding was provided by the Carol M. Gatton Foundation (to D.A. Ahlquist). Exact Sciences (Madison, WI) provided blinded assays and critical assay reagents. S. Majumder was supported by a career enhancement award funded by Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701). This work was partially supported by R37 CA214679 to J.B. Kisiel, and P50 CA 102701 and U01 CA210138 to G.M. Petersen. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
Funding Information:
Funding was provided by the Carol M. Gatton Foundation (to D.A. Ahlquist). Exact Sciences (Madison, WI) provided blinded assays and critical assay reagents. S. Majumder was supported by a career enhancement award funded by Mayo Clinic SPORE in Pancreatic Cancer (P50 CA102701). This work was partially supported by R37 CA214679 to J.B. Kisiel, and P50 CA 102701 and U01 CA210138 to G.M. Petersen. The content of this manuscript is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute or the National Institutes of Health.
Publisher Copyright:
© 2021 American Association for Cancer Research.
PY - 2021/5/1
Y1 - 2021/5/1
N2 - Purpose: We have previously identified tissue methylated DNA markers (MDMs) associated with pancreatic ductal adenocarcinoma (PDAC). In this case.control study, we aimed to assess the diagnostic performance of plasma MDMs for PDAC. Experimental Design: ThirteenMDMs (GRIN2D,CD1D, ZNF781, FER1L4, RYR2, CLEC11A, AK055957, LRRC4, GH05J042948, HOXA1, PRKCB, SHISA9, and NTRK3) were identified on the basis of selection criteria applied to results of prior tissue experiments and assays were optimized in plasma. Next, 340 plasma samples (170 PDAC cases and 170 controls) were assayed using target enrichment long-probe quantitative amplified signal method. Initially, 120 advanced-stage PDAC cases and 120 healthy controls were used to train a prediction algorithm at 97.5% specificity using random forest modeling. Subsequently, the locked algorithm derived from the training set was applied to an independent blinded test set of 50 early-stage PDAC cases and 50 controls. Finally, data from all 340 patients were combined, and cross-validated. Results: The cross-validated area under the receiver operating characteristic curve (AUC) for the training set was 0.93 (0.89-0.96) for the MDM panel alone, 0.91 (95% confidence interval, 0.87-0.96) for carbohydrate antigen 19-9 (CA19-9) alone, and 0.99 (0.98-1) for the combined MDM-CA19-9 panel. In the test set of early-stage PDAC, the AUC for MDMs alone was 0.84 (0.76-0.92), CA19-9 alone was 0.87 (0.79-0.94), and combined MDM-CA19-9 panel was 0.90 (0.84-0.97) significantly better compared with either MDMs alone or CA19-9 alone (P = 0.0382 and 0.0490, respectively). At a preset specificity of 97.5%, the sensitivity for the combined panel in the test set was 80% (28%-99%) for stage I disease and 82% (68%-92%) for stage II disease. Using the combined datasets, the cross-validated AUC was 0.9 (0.86.0.94) for the MDM panel alone and 0.89 for CA19-9 alone (0.84-0.93) versus 0.97 (0.94-0.99) for the combined MDM-CA19-9 panel (P ≤ 0.0001). Overall, cross-validated sensitivity of MDM-CA19-9 panel was 92% (83%-98%), with an observed specificity of 92% at the preset specificity of 97.5%. Conclusions: PlasmaMDMsin combination with CA19-9 detect PDAC with significantly higher accuracy compared with either biomarker individually.
AB - Purpose: We have previously identified tissue methylated DNA markers (MDMs) associated with pancreatic ductal adenocarcinoma (PDAC). In this case.control study, we aimed to assess the diagnostic performance of plasma MDMs for PDAC. Experimental Design: ThirteenMDMs (GRIN2D,CD1D, ZNF781, FER1L4, RYR2, CLEC11A, AK055957, LRRC4, GH05J042948, HOXA1, PRKCB, SHISA9, and NTRK3) were identified on the basis of selection criteria applied to results of prior tissue experiments and assays were optimized in plasma. Next, 340 plasma samples (170 PDAC cases and 170 controls) were assayed using target enrichment long-probe quantitative amplified signal method. Initially, 120 advanced-stage PDAC cases and 120 healthy controls were used to train a prediction algorithm at 97.5% specificity using random forest modeling. Subsequently, the locked algorithm derived from the training set was applied to an independent blinded test set of 50 early-stage PDAC cases and 50 controls. Finally, data from all 340 patients were combined, and cross-validated. Results: The cross-validated area under the receiver operating characteristic curve (AUC) for the training set was 0.93 (0.89-0.96) for the MDM panel alone, 0.91 (95% confidence interval, 0.87-0.96) for carbohydrate antigen 19-9 (CA19-9) alone, and 0.99 (0.98-1) for the combined MDM-CA19-9 panel. In the test set of early-stage PDAC, the AUC for MDMs alone was 0.84 (0.76-0.92), CA19-9 alone was 0.87 (0.79-0.94), and combined MDM-CA19-9 panel was 0.90 (0.84-0.97) significantly better compared with either MDMs alone or CA19-9 alone (P = 0.0382 and 0.0490, respectively). At a preset specificity of 97.5%, the sensitivity for the combined panel in the test set was 80% (28%-99%) for stage I disease and 82% (68%-92%) for stage II disease. Using the combined datasets, the cross-validated AUC was 0.9 (0.86.0.94) for the MDM panel alone and 0.89 for CA19-9 alone (0.84-0.93) versus 0.97 (0.94-0.99) for the combined MDM-CA19-9 panel (P ≤ 0.0001). Overall, cross-validated sensitivity of MDM-CA19-9 panel was 92% (83%-98%), with an observed specificity of 92% at the preset specificity of 97.5%. Conclusions: PlasmaMDMsin combination with CA19-9 detect PDAC with significantly higher accuracy compared with either biomarker individually.
UR - http://www.scopus.com/inward/record.url?scp=85105329313&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85105329313&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-20-0235
DO - 10.1158/1078-0432.CCR-20-0235
M3 - Article
C2 - 33593879
AN - SCOPUS:85105329313
SN - 1078-0432
VL - 27
SP - 2523
EP - 2532
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -