Time-varying impact of established prognostic factors in resected pancreatic ductal adenocarcinoma

Ammar A. Javed; Asad Saulat Fatimi; Ingmar F. Rompen; Omar Mahmud; Iris W. J. M. van Goor; Joseph R. Habib; Paul Andel; Brady A. Campbell; Thijs J. Schouten; Fabio Bagante; Nabiha A. Mughal; Thomas F. Stoop; Kelly J. Lafaro; Richard A. Burkhart; William R. Burns; Brock Hewitt; Greg D. Sacks; Hjalmar C. van Santvoort; Marcel den Dulk; Freek Daams; J. Sven D. Mieog; Martijn W. J. Stommel; Gijs A. Patijn; Ignace de Hingh; Sebastiaan Festen; Maarten W. Nijkamp; Joost M. Klaase; Daan J. Lips; Jan H. Wijsman; Erwin van der Harst; Eric Manusama; Casper H. J. van Eijck; Bas Groot Koerkamp; Geert Kazemier; Olivier R. Busch; Izaak Quintus Molenaar; Lois A. Daamen; Marc G. Besselink; Jin He; Christopher L. Wolfgang; Ammar A. Javed; Asad Saulat Fatimi; Ingmar F. Rompen; Omar Mahmud; Iris W. J. M. van Goor; Joseph R. Habib; Paul Andel; Brady A. Campbell; Thijs J. Schouten; Fabio Bagante; Nabiha A. Mughal; Thomas F. Stoop; Kelly J. Lafaro; Richard A. Burkhart; William R. Burns; Brock Hewitt; Greg D. Sacks; Hjalmar C. van Santvoort; Marcel den Dulk; Freek Daams; J. Sven D. Mieog; Martijn W. J. Stommel; Gijs A. Patijn; Ignace de Hingh; Sebastiaan Festen; Maarten W. Nijkamp; Joost M. Klaase; Daan J. Lips; Jan H. Wijsman; Erwin van der Harst; Eric Manusama; Casper H. J. van Eijck; Bas Groot Koerkamp; Geert Kazemier; Olivier R. Busch; Izaak Quintus Molenaar; Lois A. Daamen; Marc G. Besselink; Jin He; Christopher L. Wolfgang

doi:10.1093/jnci/djaf196

Time-varying impact of established prognostic factors in resected pancreatic ductal adenocarcinoma

Ammar A. Javed
, Asad Saulat Fatimi
, Ingmar F. Rompen
, Omar Mahmud
, Iris W. J. M. van Goor
, Joseph R. Habib
, Paul Andel
, Brady A. Campbell
, Thijs J. Schouten
, Fabio Bagante
, Nabiha A. Mughal
, Thomas F. Stoop
, Kelly J. Lafaro
, Richard A. Burkhart
, William R. Burns
, Brock Hewitt
, Greg D. Sacks
, Hjalmar C. van Santvoort
, Marcel den Dulk
, Freek Daams

J. Sven D. Mieog, Martijn W. J. Stommel, Gijs A. Patijn, Ignace de Hingh, Sebastiaan Festen, Maarten W. Nijkamp, Joost M. Klaase, Daan J. Lips, Jan H. Wijsman, Erwin van der Harst, Eric Manusama, Casper H. J. van Eijck, Bas Groot Koerkamp, Geert Kazemier, Olivier R. Busch, Izaak Quintus Molenaar, Lois A. Daamen, Marc G. Besselink, Jin He, Christopher L. Wolfgang^*, Ammar A. Javed, Asad Saulat Fatimi, Ingmar F. Rompen, Omar Mahmud, Iris W. J. M. van Goor, Joseph R. Habib, Paul Andel, Brady A. Campbell, Thijs J. Schouten, Fabio Bagante, Nabiha A. Mughal, Thomas F. Stoop, Kelly J. Lafaro, Richard A. Burkhart, William R. Burns, Brock Hewitt, Greg D. Sacks, Hjalmar C. van Santvoort, Marcel den Dulk, Freek Daams, J. Sven D. Mieog, Martijn W. J. Stommel, Gijs A. Patijn, Ignace de Hingh, Sebastiaan Festen, Maarten W. Nijkamp, Joost M. Klaase, Daan J. Lips, Jan H. Wijsman, Erwin van der Harst, Eric Manusama, Casper H. J. van Eijck, Bas Groot Koerkamp, Geert Kazemier, Olivier R. Busch, Izaak Quintus Molenaar, Lois A. Daamen, Marc G. Besselink, Jin He, Christopher L. Wolfgang

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

Background Prognostic factors in resected pancreatic ductal adenocarcinoma (PDAC) have been determined under the assumption that hazard ratios (HRs) remain static. However, PDAC is a dynamic disease with evolving conditional survival. The aim of this study was to determine if the impact of prognostic factors in PDAC is time-varying. Methods This was a multicenter, retrospective cohort study of the prospectively maintained Dutch Pancreatic Cancer Recurrence Database and New York University and Johns Hopkins Hospital Institutional Databases. Patients with complete macroscopic resection of histopathologically proven PDAC between 2014 and 2019 and available follow-up data were included. The time-varying impact of prognostic factors identified by univariable Cox regression was modeled using Aalen's Additive Regression Models (Aalen's models) and visualized as plots of cumulative hazard. Results In total, 3104 patients were included, of whom 938 (30.2%) received neoadjuvant therapy (NAT), whereas the rest underwent upfront surgery (US). A total of 201 (6.5%) patients achieved observed long-term survival (>5 years). Aalen's models showed that lymphovascular invasion, perineural invasion, and nodal disease were prognostic up to 2 years postoperatively. At varying points thereafter, these variables lost their impact in the NAT but not US patients. Similarly, during the fourth year of follow-up, American Society of Anesthesiology scores became impactful in the NAT but not in the US patients. Conclusion The impact of prognostic factors in resected PDAC across NAT and US patients is time-varying. Our results suggest that aggressive disease drives early mortality but, after NAT, tumor-biological factors lose prognostic importance to frailty and comorbidities over time.

Original language	English
Pages (from-to)	2526-2534
Number of pages	9
Journal	Journal of the National Cancer Institute
Volume	117
Issue number	12
DOIs	https://doi.org/10.1093/jnci/djaf196
Publication status	Published - 1 Dec 2025

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10.1093/jnci/djaf196

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Javed, A. A., Fatimi, A. S., Rompen, I. F., Mahmud, O., van Goor, I. W. J. M., Habib, J. R., Andel, P., Campbell, B. A., Schouten, T. J., Bagante, F., Mughal, N. A., Stoop, T. F., Lafaro, K. J., Burkhart, R. A., Burns, W. R., Hewitt, B., Sacks, G. D., van Santvoort, H. C., den Dulk, M., ... Wolfgang, C. L. (2025). Time-varying impact of established prognostic factors in resected pancreatic ductal adenocarcinoma. Journal of the National Cancer Institute, 117(12), 2526-2534. https://doi.org/10.1093/jnci/djaf196

@article{caa71c6b7d094a6bb9d689734ed5806b,

title = "Time-varying impact of established prognostic factors in resected pancreatic ductal adenocarcinoma",

abstract = "Background Prognostic factors in resected pancreatic ductal adenocarcinoma (PDAC) have been determined under the assumption that hazard ratios (HRs) remain static. However, PDAC is a dynamic disease with evolving conditional survival. The aim of this study was to determine if the impact of prognostic factors in PDAC is time-varying. Methods This was a multicenter, retrospective cohort study of the prospectively maintained Dutch Pancreatic Cancer Recurrence Database and New York University and Johns Hopkins Hospital Institutional Databases. Patients with complete macroscopic resection of histopathologically proven PDAC between 2014 and 2019 and available follow-up data were included. The time-varying impact of prognostic factors identified by univariable Cox regression was modeled using Aalen's Additive Regression Models (Aalen's models) and visualized as plots of cumulative hazard. Results In total, 3104 patients were included, of whom 938 (30.2\%) received neoadjuvant therapy (NAT), whereas the rest underwent upfront surgery (US). A total of 201 (6.5\%) patients achieved observed long-term survival (>5 years). Aalen's models showed that lymphovascular invasion, perineural invasion, and nodal disease were prognostic up to 2 years postoperatively. At varying points thereafter, these variables lost their impact in the NAT but not US patients. Similarly, during the fourth year of follow-up, American Society of Anesthesiology scores became impactful in the NAT but not in the US patients. Conclusion The impact of prognostic factors in resected PDAC across NAT and US patients is time-varying. Our results suggest that aggressive disease drives early mortality but, after NAT, tumor-biological factors lose prognostic importance to frailty and comorbidities over time.",

author = "Javed, \{Ammar A.\} and Fatimi, \{Asad Saulat\} and Rompen, \{Ingmar F.\} and Omar Mahmud and \{van Goor\}, \{Iris W. J. M.\} and Habib, \{Joseph R.\} and Paul Andel and Campbell, \{Brady A.\} and Schouten, \{Thijs J.\} and Fabio Bagante and Mughal, \{Nabiha A.\} and Stoop, \{Thomas F.\} and Lafaro, \{Kelly J.\} and Burkhart, \{Richard A.\} and Burns, \{William R.\} and Brock Hewitt and Sacks, \{Greg D.\} and \{van Santvoort\}, \{Hjalmar C.\} and \{den Dulk\}, Marcel and Freek Daams and Mieog, \{J. Sven D.\} and Stommel, \{Martijn W. J.\} and Patijn, \{Gijs A.\} and \{de Hingh\}, Ignace and Sebastiaan Festen and Nijkamp, \{Maarten W.\} and Klaase, \{Joost M.\} and Lips, \{Daan J.\} and Wijsman, \{Jan H.\} and \{van der Harst\}, Erwin and Eric Manusama and \{van Eijck\}, \{Casper H. J.\} and Koerkamp, \{Bas Groot\} and Geert Kazemier and Busch, \{Olivier R.\} and Molenaar, \{Izaak Quintus\} and Daamen, \{Lois A.\} and Besselink, \{Marc G.\} and Jin He and Wolfgang, \{Christopher L.\} and Javed, \{Ammar A.\} and Fatimi, \{Asad Saulat\} and Rompen, \{Ingmar F.\} and Omar Mahmud and \{van Goor\}, \{Iris W. J. M.\} and Habib, \{Joseph R.\} and Paul Andel and Campbell, \{Brady A.\} and Schouten, \{Thijs J.\} and Fabio Bagante and Mughal, \{Nabiha A.\} and Stoop, \{Thomas F.\} and Lafaro, \{Kelly J.\} and Burkhart, \{Richard A.\} and Burns, \{William R.\} and Brock Hewitt and Sacks, \{Greg D.\} and \{van Santvoort\}, \{Hjalmar C.\} and \{den Dulk\}, Marcel and Freek Daams and Mieog, \{J. Sven D.\} and Stommel, \{Martijn W. J.\} and Patijn, \{Gijs A.\} and \{de Hingh\}, Ignace and Sebastiaan Festen and Nijkamp, \{Maarten W.\} and Klaase, \{Joost M.\} and Lips, \{Daan J.\} and Wijsman, \{Jan H.\} and \{van der Harst\}, Erwin and Eric Manusama and \{van Eijck\}, \{Casper H. J.\} and Koerkamp, \{Bas Groot\} and Geert Kazemier and Busch, \{Olivier R.\} and Molenaar, \{Izaak Quintus\} and Daamen, \{Lois A.\} and Besselink, \{Marc G.\} and Jin He and Wolfgang, \{Christopher L.\}",

note = "Publisher Copyright: {\textcopyright} 2025 The Author(s). Published by Oxford University Press. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site - for further information please contact [email protected].",

year = "2025",

month = dec,

day = "1",

doi = "10.1093/jnci/djaf196",

language = "English",

volume = "117",

pages = "2526--2534",

journal = "Journal of the National Cancer Institute",

issn = "0027-8874",

publisher = "Oxford University Press",

number = "12",

}

Javed, AA, Fatimi, AS, Rompen, IF, Mahmud, O, van Goor, IWJM, Habib, JR, Andel, P, Campbell, BA, Schouten, TJ, Bagante, F, Mughal, NA, Stoop, TF, Lafaro, KJ, Burkhart, RA, Burns, WR, Hewitt, B, Sacks, GD, van Santvoort, HC, den Dulk, M, Daams, F, Mieog, JSD, Stommel, MWJ, Patijn, GA, de Hingh, I, Festen, S, Nijkamp, MW, Klaase, JM, Lips, DJ, Wijsman, JH, van der Harst, E, Manusama, E, van Eijck, CHJ, Koerkamp, BG, Kazemier, G , Busch, OR, Molenaar, IQ, Daamen, LA, Besselink, MG, He, J, Wolfgang, CL, Javed, AA, Fatimi, AS, Rompen, IF, Mahmud, O, van Goor, IWJM, Habib, JR, Andel, P, Campbell, BA, Schouten, TJ, Bagante, F, Mughal, NA, Stoop, TF, Lafaro, KJ, Burkhart, RA, Burns, WR, Hewitt, B, Sacks, GD, van Santvoort, HC, den Dulk, M, Daams, F, Mieog, JSD, Stommel, MWJ, Patijn, GA, de Hingh, I, Festen, S, Nijkamp, MW, Klaase, JM, Lips, DJ, Wijsman, JH, van der Harst, E, Manusama, E, van Eijck, CHJ, Koerkamp, BG, Kazemier, G , Busch, OR, Molenaar, IQ, Daamen, LA, Besselink, MG, He, J & Wolfgang, CL 2025, 'Time-varying impact of established prognostic factors in resected pancreatic ductal adenocarcinoma', Journal of the National Cancer Institute, vol. 117, no. 12, pp. 2526-2534. https://doi.org/10.1093/jnci/djaf196

TY - JOUR

T1 - Time-varying impact of established prognostic factors in resected pancreatic ductal adenocarcinoma

AU - Javed, Ammar A.

AU - Fatimi, Asad Saulat

AU - Rompen, Ingmar F.

AU - Mahmud, Omar

AU - van Goor, Iris W. J. M.

AU - Habib, Joseph R.

AU - Andel, Paul

AU - Campbell, Brady A.

AU - Schouten, Thijs J.

AU - Bagante, Fabio

AU - Mughal, Nabiha A.

AU - Stoop, Thomas F.

AU - Lafaro, Kelly J.

AU - Burkhart, Richard A.

AU - Burns, William R.

AU - Hewitt, Brock

AU - Sacks, Greg D.

AU - van Santvoort, Hjalmar C.

AU - den Dulk, Marcel

AU - Daams, Freek

AU - Mieog, J. Sven D.

AU - Stommel, Martijn W. J.

AU - Patijn, Gijs A.

AU - de Hingh, Ignace

AU - Festen, Sebastiaan

AU - Nijkamp, Maarten W.

AU - Klaase, Joost M.

AU - Lips, Daan J.

AU - Wijsman, Jan H.

AU - van der Harst, Erwin

AU - Manusama, Eric

AU - van Eijck, Casper H. J.

AU - Koerkamp, Bas Groot

AU - Kazemier, Geert

AU - Busch, Olivier R.

AU - Molenaar, Izaak Quintus

AU - Daamen, Lois A.

AU - Besselink, Marc G.

AU - He, Jin

AU - Wolfgang, Christopher L.

AU - Javed, Ammar A.

AU - Fatimi, Asad Saulat

AU - Rompen, Ingmar F.

AU - Mahmud, Omar

AU - van Goor, Iris W. J. M.

AU - Habib, Joseph R.

AU - Andel, Paul

AU - Campbell, Brady A.

AU - Schouten, Thijs J.

AU - Bagante, Fabio

AU - Mughal, Nabiha A.

AU - Stoop, Thomas F.

AU - Lafaro, Kelly J.

AU - Burkhart, Richard A.

AU - Burns, William R.

AU - Hewitt, Brock

AU - Sacks, Greg D.

AU - van Santvoort, Hjalmar C.

AU - den Dulk, Marcel

AU - Daams, Freek

AU - Mieog, J. Sven D.

AU - Stommel, Martijn W. J.

AU - Patijn, Gijs A.

AU - de Hingh, Ignace

AU - Festen, Sebastiaan

AU - Nijkamp, Maarten W.

AU - Klaase, Joost M.

AU - Lips, Daan J.

AU - Wijsman, Jan H.

AU - van der Harst, Erwin

AU - Manusama, Eric

AU - van Eijck, Casper H. J.

AU - Koerkamp, Bas Groot

AU - Kazemier, Geert

AU - Busch, Olivier R.

AU - Molenaar, Izaak Quintus

AU - Daamen, Lois A.

AU - Besselink, Marc G.

AU - He, Jin

AU - Wolfgang, Christopher L.

N1 - Publisher Copyright: © 2025 The Author(s). Published by Oxford University Press. All rights reserved. For commercial re-use, please contact [email protected] for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site - for further information please contact [email protected].

PY - 2025/12/1

Y1 - 2025/12/1

N2 - Background Prognostic factors in resected pancreatic ductal adenocarcinoma (PDAC) have been determined under the assumption that hazard ratios (HRs) remain static. However, PDAC is a dynamic disease with evolving conditional survival. The aim of this study was to determine if the impact of prognostic factors in PDAC is time-varying. Methods This was a multicenter, retrospective cohort study of the prospectively maintained Dutch Pancreatic Cancer Recurrence Database and New York University and Johns Hopkins Hospital Institutional Databases. Patients with complete macroscopic resection of histopathologically proven PDAC between 2014 and 2019 and available follow-up data were included. The time-varying impact of prognostic factors identified by univariable Cox regression was modeled using Aalen's Additive Regression Models (Aalen's models) and visualized as plots of cumulative hazard. Results In total, 3104 patients were included, of whom 938 (30.2%) received neoadjuvant therapy (NAT), whereas the rest underwent upfront surgery (US). A total of 201 (6.5%) patients achieved observed long-term survival (>5 years). Aalen's models showed that lymphovascular invasion, perineural invasion, and nodal disease were prognostic up to 2 years postoperatively. At varying points thereafter, these variables lost their impact in the NAT but not US patients. Similarly, during the fourth year of follow-up, American Society of Anesthesiology scores became impactful in the NAT but not in the US patients. Conclusion The impact of prognostic factors in resected PDAC across NAT and US patients is time-varying. Our results suggest that aggressive disease drives early mortality but, after NAT, tumor-biological factors lose prognostic importance to frailty and comorbidities over time.

AB - Background Prognostic factors in resected pancreatic ductal adenocarcinoma (PDAC) have been determined under the assumption that hazard ratios (HRs) remain static. However, PDAC is a dynamic disease with evolving conditional survival. The aim of this study was to determine if the impact of prognostic factors in PDAC is time-varying. Methods This was a multicenter, retrospective cohort study of the prospectively maintained Dutch Pancreatic Cancer Recurrence Database and New York University and Johns Hopkins Hospital Institutional Databases. Patients with complete macroscopic resection of histopathologically proven PDAC between 2014 and 2019 and available follow-up data were included. The time-varying impact of prognostic factors identified by univariable Cox regression was modeled using Aalen's Additive Regression Models (Aalen's models) and visualized as plots of cumulative hazard. Results In total, 3104 patients were included, of whom 938 (30.2%) received neoadjuvant therapy (NAT), whereas the rest underwent upfront surgery (US). A total of 201 (6.5%) patients achieved observed long-term survival (>5 years). Aalen's models showed that lymphovascular invasion, perineural invasion, and nodal disease were prognostic up to 2 years postoperatively. At varying points thereafter, these variables lost their impact in the NAT but not US patients. Similarly, during the fourth year of follow-up, American Society of Anesthesiology scores became impactful in the NAT but not in the US patients. Conclusion The impact of prognostic factors in resected PDAC across NAT and US patients is time-varying. Our results suggest that aggressive disease drives early mortality but, after NAT, tumor-biological factors lose prognostic importance to frailty and comorbidities over time.

UR - https://www.scopus.com/pages/publications/105024118330

U2 - 10.1093/jnci/djaf196

DO - 10.1093/jnci/djaf196

M3 - Article

C2 - 40900668

SN - 0027-8874

VL - 117

SP - 2526

EP - 2534

JO - Journal of the National Cancer Institute

JF - Journal of the National Cancer Institute

IS - 12

ER -

Time-varying impact of established prognostic factors in resected pancreatic ductal adenocarcinoma

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