Alterations in Somatic Driver Genes Are Associated with Response to Neoadjuvant FOLFIRINOX in Patients with Localized Pancreatic Ductal Adenocarcinoma
Open accessAbstract
BACKGROUND: There is increased use of neoadjuvant fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers of treatment response. STUDY DESIGN: Consecutive patients (n = 196) with resectable, borderline resectable or locally advanced PDAC (2012–2019) receiving FOLFIRINOX as initial treatment and with targeted sequencing of a pretreatment biopsy were identified in a prospective institutional database. Genomic alterations were determined in the 4 driver mutations (KRAS, TP53, CDKN2A, SMAD4), and associations between genomic alterations and clinical outcomes were assessed. RESULTS: Alterations in KRAS (n = 172, 87.8%) and TP53 (n = 131, 66.8%) were common; alterations in CDKN2A (n = 49, 25.0%) and SMAD4 (n = 36, 18.4%) were less frequently observed. A total of 105 patients (53.6%) were able to undergo resection, of whom 8 (7.6%) had a complete/near-complete pathologic response. There were no somatic alterations associated with major pathologic response. Alterations in SMAD4 were associated with a lower rate of surgical resection (27.8% vs 59.4%, p < 0.001); this was additionally observed in a multivariable regression model accounting for resectability status (OR 0.35, 95% confidence interval [CI] 0.15–0.85). Thirty-three patients (16.8%) developed metastatic disease while on neoadjuvant therapy. SMAD4 alterations were associated with a significant risk of metastatic progression on therapy when controlling for resectability status (OR 3.31, 95% CI 1.44–7.60). CONCLUSIONS: SMAD4 alterations are associated with more frequent development of metastasis during neoadjuvant FOLFIRINOX and lower probability of reaching surgical resection. Evaluation of alternative chemotherapy regimens in patients with SMAD4 alterations will be important to distinguish whether this represents a prognostic or predictive biomarker.
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SMAD4 loss is associated with higher rates of metastatic dissemination during neoadjuvant therapy and terminal disease.
“is associated with higher rates of metastatic dissemination during neoadjuvant therapy and terminal disease55,56.”
From Pancreatic cancer: Advances and challenges (2023) · cites this paper as [56]
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Cites
Cerami, E., Gao, J., Dogrusoz, U., Gross, B. E., Sumer, S. O., Aksoy, B. A., Jacobsen, A., Byrne, C. J., Heuer, M. L., Larsson, E., et al. (2012) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0095 · Cited by 17,455 · see citing works
FOLFIRINOX versus Gemcitabine for Metastatic Pancreatic Cancer
Conroy, T., Desseigne, F., Ychou, M., Bouché, O., Guimbaud, R., Bécouarn, Y., Adenis, A., Raoul, J.-L., Gourgou-Bourgade, S., de la Fouchardière, C., et al. (2011) · New England Journal of Medicine · doi:10.1056/nejmoa1011923 · Cited by 7,810 · see citing works
Rahib, L., Smith, B. D., Aizenberg, R., Rosenzweig, A. B., Fleshman, J. M., & Matrisian, L. M. (2014) · Cancer Research · doi:10.1158/0008-5472.can-14-0155 · Cited by 7,094 · see citing works
Maftools: efficient and comprehensive analysis of somatic variants in cancerPreprint
Mayakonda, A., Lin, D., Assenov, Y., Plass, C., & Koeffler, H. P. (2018) · Genome Research · doi:10.1101/gr.239244.118 · Cited by 4,914 · see citing works
Zehir, A., Benayed, R., Shah, R. H., Syed, A., Middha, S., Kim, H. R., Srinivasan, P., Gao, J., Chakravarty, D., Devlin, S. M., et al. (2017) · Nature Medicine · doi:10.1038/nm.4333 · Cited by 3,380 · see citing works
FOLFIRINOX or Gemcitabine as Adjuvant Therapy for Pancreatic Cancer
Conroy, T., Hammel, P., Hebbar, M., Ben Abdelghani, M., Wei, A. C., Raoul, J.-L., Choné, L., Francois, E., Artru, P., Biagi, J. J., et al. (2018) · New England Journal of Medicine · doi:10.1056/nejmoa1809775 · Cited by 2,874 · see citing works
Self-citationOncoKB: A Precision Oncology Knowledge Base
Chakravarty, D., Gao, J., Phillips, S. M., Kundra, R., Zhang, H., Wang, J., Rudolph, J. E., Yaeger, R. D., Soumerai, T. E., Nissan, M. H., et al. (2017) · JCO Precision Oncology · doi:10.1200/po.17.00011 · Cited by 2,735 · see citing works
Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT)
Cheng, D. T., Mitchell, T. N., Zehir, A., Shah, R. H., Benayed, R., Syed, A., Chandramohan, R., Liu, Z. Y., Won, H. H., Scott, S. N., et al. (2015) · The Journal of Molecular Diagnostics · doi:10.1016/j.jmoldx.2014.12.006 · Cited by 2,119 · see citing works
Iacobuzio-Donahue, C. A., Fu, B., Yachida, S., Luo, M., Abe, H., Henderson, C. M., Vilardell, F., Wang, Z., Keller, J. W., Banerjee, P., et al. (2009) · Journal of Clinical Oncology · doi:10.1200/jco.2008.17.7188 · Cited by 1,081 · see citing works
Chang, M. T., Asthana, S., Gao, S. P., Lee, B. H., Chapman, J. S., Kandoth, C., Gao, J., Socci, N. D., Solit, D. B., Olshen, A. B., et al. (2016) · Nature Biotechnology · doi:10.1038/nbt.3391 · Cited by 808 · see citing works
Aung, K. L., Fischer, S. E., Denroche, R. E., Jang, G.-H., Dodd, A., Creighton, S., Southwood, B., Liang, S.-B., Chadwick, D., Zhang, A., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-2994 · Cited by 618 · see citing works
Murphy, J. E., Wo, J. Y.-L., Ryan, D. P., Jiang, W., Yeap, B. Y., Drapek, L. C., Blaszkowsky, L. S., Kwak, E. L., Allen, J. N., Clark, J. W., et al. (2018) · JAMA Oncology · doi:10.1001/jamaoncol.2018.0329 · Cited by 530 · see citing works
Multidisciplinary standards of care and recent progress in pancreatic ductal adenocarcinoma
Grossberg, A. J., Chu, L. C. H., Deig, C. R., Fishman, E. K., Hwang, W. L., Maitra, A., Marks, D. L., Mehta, A., Nabavizadeh, N., Simeone, D. M., et al. (2020) · CA A Cancer Journal for Clinicians · doi:10.3322/caac.21626 · Cited by 491 · see citing works
Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine
Aguirre, A. J., Nowak, J. A., Camarda, N. D., Moffitt, R. A., Ghazani, A. A., Hazar-Rethinam, M., Raghavan, S., Kim, J., Brais, L. K., Ragon, D., et al. (2018) · Cancer Discovery · doi:10.1158/2159-8290.cd-18-0275 · Cited by 367 · see citing works
(2001) · PubMed · Cited by 309 · see citing works
Crane, C. H., Varadhachary, G. R., Yordy, J. S., Staerkel, G. A., Javle, M. M., Safran, H., Haque, W., Hobbs, B. D., Krishnan, S., Fleming, J. B., et al. (2011) · Journal of Clinical Oncology · doi:10.1200/jco.2010.33.8038 · Cited by 288 · see citing works
Surgical Outcome Results From SWOG S1505
Ahmad, S. A., Duong, M. C., Sohal, D. P. S., Gandhi, N. S., Beg, M. S., Wang‐Gillam, A., Wade, J. L., Chiorean, E. G., Guthrie, K. A., Lowy, A. M., et al. (2020) · Annals of Surgery · doi:10.1097/sla.0000000000004155 · Cited by 239 · see citing works
3D clusters of somatic mutations in cancer reveal numerous rare mutations as functional targets
Gao, J., Chang, M. T., Johnsen, H. C., Gao, S. P., Sylvester, B. E., Sümer, S. O., Zhang, H., Solit, D. B., Taylor, B. S., Schultz, N. D., et al. (2017) · Genome Medicine · doi:10.1186/s13073-016-0393-x · Cited by 218 · see citing works
Wang, F., Xia, X., Yang, C., Shen, J., Mai, J., Kim, H.-C., Kirui, D., Kang, Y., Fleming, J. B., Koay, E. J., et al. (2018) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-17-3435 · Cited by 160 · see citing works
Lee, S. M., Katz, M. H. G., Liu, L., Sundar, M., Wang, H., Varadhachary, G. R., Wolff, R. A., Lee, J. E., Maitra, A., Fleming, J. B., et al. (2016) · The American Journal of Surgical Pathology · doi:10.1097/pas.0000000000000738 · Cited by 123 · see citing works
Huang, W., Navarro-Serer, B., Jeong, Y. J., Chianchiano, P. E., Xia, L., Luchini, C., Veronese, N., Dowiak, C., Ng, T., Trujillo, M. A. M., et al. (2020) · Cancer Research · doi:10.1158/0008-5472.can-19-1523 · Cited by 85 · see citing works
Implications of Selection Bias Due to Delayed Study Entry in Clinical Genomic Studies
Brown, S., Lavery, J. A., Shen, R., Martin, A. S., Kehl, K. L., Sweeney, S. M., Lepisto, E. M., Rizvi, H. A., McCarthy, C. G., Schultz, N. D., et al. (2021) · JAMA Oncology · doi:10.1001/jamaoncol.2021.5153 · Cited by 55 · see citing works
Tanaka, T., Watanabe, T., Kazama, Y., Tanaka, J., Kanazawa, T., Kazama, S., & Nagawa, H. (2006) · British Journal of Cancer · doi:10.1038/sj.bjc.6603460 · Cited by 50 · see citing works
The Landmark Series: Preoperative Therapy for Pancreatic Cancer
Patel, S. H., Katz, M. H. G., & Ahmad, S. A. (2021) · Annals of Surgical Oncology · doi:10.1245/s10434-021-10075-1 · Cited by 32 · see citing works
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1 of the 25 references couldn’t be matched to a known paper.
Cited by
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Pancreatic cancer: Advances and challenges
Halbrook, C. J., Lyssiotis, C. A., Pasca di Magliano, M., & Maitra, A. (2023) · Cell · doi:10.1016/j.cell.2023.02.014 · Cited by 1,321 · see citing works
Stoop, T. F., Theijse, R. T., Seelen, L. W. F., Koerkamp, B. G., van Eijck, C. H. J., Wolfgang, C. L., van Tienhoven, G., van Santvoort, H. C., Molenaar, I. Q., Wilmink, J. W., et al. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00856-2 · Cited by 206 · see citing works
Janssen, B. V., van Roessel, S. R., van Dieren, S., de Boer, O. J., Adsay, V. N., Baştürk, O., Brosens, L. A. A., Campbell, F., Chatterjee, D., Chou, A. S. Y., et al. (2022) · British journal of surgery · doi:10.1093/bjs/znac350 · Cited by 29 · see citing works
Ecker, B. L., Tao, A. J., Janssen, Q. P., Walch, H. S., Court, C. M., Balachandran, V. P., Crane, C. H., D'Angelica, M. I., Drebin, J. A., Kingham, T. P., et al. (2023) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-22-3089 · Cited by 26 · see citing works
Self-citationYao, H.-J., Luo, L., Li, R. Q., Zhao, Y., Zhang, L., Pešić, M., Cai, L., & Li, L. (2024) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2024.189220 · Cited by 19 · see citing works
Peng, J., Fang, S., Li, M., Liu, Y., Liang, X., Li, Z., Chen, G., Peng, L., Chen, N., Liu, L., et al. (2023) · Open Life Sciences · doi:10.1515/biol-2022-0652 · Cited by 17 · see citing works
Anatomical and Biological Considerations to Determine Resectability in Pancreatic Cancer
Rompen, I. F., Habib, J. R., Wolfgang, C. L., & Javed, A. A. (2024) · Cancers · doi:10.3390/cancers16030489 · Cited by 17 · see citing works
Racu, M.-L., Bernardi, D., Chaouche, A., Zindy, E., Navez, J., Loi, P., Maris, C., Closset, J., Laethem, J. V., Decaestecker, C., et al. (2023) · Cancers · doi:10.3390/cancers15153765 · Cited by 10 · see citing works
Greendyk, J. D., Allen, W. E., Alexander, H. R., Beninato, T., Eskander, M. F., Grandhi, M. S., Kennedy, T. J., Langan, R. C., Maggi, J. C., De, S., et al. (2023) · Biomedicines · doi:10.3390/biomedicines11113058 · Cited by 3 · see citing works
Self-citationMimori, K., Fujii, T., Sho, M., Endo, I., Shirabe, K., & Kitagawa, Y. (2024) · Annals of Gastroenterological Surgery · doi:10.1002/ags3.12882
Surgical Resection for Borderline and Locally Advanced Pancreatic Adenocarcinoma
Haque, O. J., & Warner, S. G. (2025) · Surgical Oncology Clinics of North America · doi:10.1016/j.soc.2025.02.001
Salcedo, M. T., Fusté, V., Zucchiatti, A., Piñol, T. S., Cuatrecasas, M., Archilla, I., Ortiz, M., Meléndez, C., Aula-Olivar, A., Martos, R. L., et al. (2026) · Gastroenterología y Hepatología · doi:10.1016/j.gastrohep.2026.502700
Salcedo, M. T., Fusté, V., Llanos, A. C. Z., Piñol, T. S., Cuatrecasas, M., Archilla, I., Ortiz, M. R., Muñoz, C. M., Aula-Olivar, A., Martos, R. L., et al. (2026) · Gastroenterología y Hepatología (English Edition) · doi:10.1016/j.gastre.2026.502700
- Authors
- Ecker, B. L., Court, C. M., Janssen, Q. P., Tao, A. J., D’Angelica, M. I., Drebin, J. A., Gonen, M., O’Reilly, E. M., Jarnagin, W. R., Wei, A. C., & for the David M Rubenstein Center for Pancreatic Cancer Research Group at Memorial Sloan Kettering Cancer Center
- Affiliations
- Memorial Sloan Kettering Cancer Center (US)
- From the Hepatopancreatobiliary Service, Department of Surgery (Ecker, Court, D’Angelica, Drebin, Jarnagin, Wei), Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Biostatistics (Gonen), Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine (O’Reilly), Memorial Sloan Kettering Cancer Center, New York, NY
- Corresponding author
- Wei, Alice C
- ORCID
- Venue
- Journal of the American College of Surgeons
- Published
- 2022-04-05
- Volume
- 235
- Issue
- 2
- Pages
- 342-349
- ISSN
- 1072-7515 (ISSN-L)
- PMC
- PMC9319357
- OpenAlex
- W4285504239
- Cited by
- 13
- References
- 25
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2023: 6 · 2022: 1
- FWCI
- 1.15
- Type
- journal article
- Language
- en
- Open access
- green
- pure.eur.nl
- Licence
- other-oa
- Locations
- Journal of the American College of Surgeons (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, other-oa)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- Funders
- Memorial Sloan-Kettering Cancer Center (CA008748, P30 CA008748)
- National Cancer Institute (CA008748, P30CA008748)
- Topics
- Health Sciences › Medicine › Oncology › Pancreatic and Hepatic Oncology Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer Genomics and Diagnostics
- Health Sciences › Medicine › Surgery › Cholangiocarcinoma and Gallbladder Cancer Studies
- Keywords
- pancreatic ductal adenocarcinoma, FOLFIRINOX, neoadjuvant chemotherapy, driver mutations, KRAS, TP53, CDKN2A, metastatic progression, surgical resection, pathological response, predictive biomarkers, metastasis risk stratification, borderline resectable pancreatic cancer, locally advanced pancreatic cancer
- MeSH terms
- Irinotecan, Oxaliplatin, Adenocarcinoma, Antineoplastic Combined Chemotherapy Protocols, Leucovorin, Fluorouracil, Humans, Neoplasm Staging, Pancreatic Neoplasms, Prospective Studies, Retrospective Studies, Proto-Oncogene Proteins p21(ras), Neoadjuvant Therapy, Carcinoma, Pancreatic Ductal
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