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Predictors of Long-Term Survival in Pancreatic Ductal Adenocarcinoma after Pancreatectomy: TP53 and SMAD4 Mutation Scoring in Combination with CA19-9

  • Pancreatic Tumors
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Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Pancreatic ductal adenocarcinoma (PDA) is a fatal cancer for which even unfavorable clinicopathological factors occasionally fail to preclude long-term survival. We sought to establish a scoring system that utilizes measurable pre-intervention factors for predicting survival following surgical resection.

Methods

We retrospectively analyzed 34 patients who died from short-term recurrences and 32 long-term survivors among 310 consecutively resected patients with PDA. A logistic regression model was used to define factors related to clinical parameters, molecular profiles of 18 pancreatic cancer-associated genes, and aberrant expression of major tumor suppressors.

Results

Carbohydrate antigen 19-9 (CA19-9) had the best ability to classify patients with short-term recurrence and long-term survivors [odds ratio 21.04, 95% confidence interval (CI) 4.612–96.019], followed by SMAD4 and TP53 mutation scoring (odds ratio 41.322, 95% CI 3.156–541.035). Missense TP53 mutations were strongly associated with the nuclear expression of p53, whereas truncating mutations were associated with the absence of nuclear p53. The former subset was associated with a worse prognosis. The combination of aberrant SMAD4 and mutation types of TP53 exhibited a better resolution for distinguishing patients with short-term recurrences from long-term survivors (compared with the assessment of the number of mutated KRAS, CDKN2A, TP53, and SMAD4 genes). Calibration of mutation scores combined with CA19-9 in a logistic regression model setting demonstrated a practical effect in classifying long survivors and patients with early recurrence (c-statistic = 0.876).

Conclusions

Genetic information, i.e., TP53 mutation types and SMAD4 abnormalities, combined with CA19-9, will be a valuable tool for improving surgical strategies for pancreatic cancer.

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Acknowledgements

We would like to thank Atsuko Sumi and Munehiko Ogata (Sapporo Higashi Tokushukai Hospital) for technical support regarding genetic analyses. We thank other members of Gastroenterological Surgery II at Hokkaido Medical University and the laboratory staff of the Institute of Biomedical Research at Sapporo Higashi Tokushukai Hospital for helpful suggestions throughout the course of this project and critical reading of the manuscript. We are also very grateful to Osamu Takahashi (Thermo-Fisher Scientific) for technical support regarding the sequencing analyses. This work was supported by JSPS KAKENHI grant number 20K07671 (to Y. Ono), 21K08724 (to T.N.), and 20H03655 (to Y.M.).

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Authors and Affiliations

  1. Department of Gastroenterological Surgery II, Faculty of Medicine, Hokkaido University, Sapporo, Hokkaido, Japan

    Masato Ono MD, Toru Nakamura MD, PhD, Takahiro Tsuchikawa MD, PhD, Tomotaka Kuraya MD, Shota Kuwabara MD, PhD, Yoshitsugu Nakanishi MD, PhD, Toshimichi Asano MD, PhD, Aya Matsui MD, PhD, Kimitaka Tanaka MD, PhD, Yuma Ebihara MD, PhD, Yo Kurashima MD, PhD, Takehiro Noji MD, PhD, Soichi Murakami MD, PhD, Toshiaki Shichinohe MD, PhD & Satoshi Hirano MD, PhD

  2. Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Sapporo, Japan

    Yusuke Ono PhD, Yuko Omori MD, PhD, Mayumi Suzuki, Ayumu Sugitani, Hidenori Karasaki MD, PhD & Yusuke Mizukami MD, PhD

  3. Department of Medicine, Asahikawa Medical University, Asahikawa, Hokkaido, Japan

    Yusuke Ono PhD, Kenzui Taniue PhD & Yusuke Mizukami MD, PhD

  4. Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan

    Tomoko Mitsuhashi MD, PhD

  5. Department of Investigative Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan

    Yuko Omori MD, PhD & Toru Furukawa MD, PhD

  6. Isotope Science Center, The University of Tokyo, Tokyo, Japan

    Kenzui Taniue PhD

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Correspondence to Toru Nakamura MD, PhD or Yusuke Mizukami MD, PhD.

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Disclosure

Yusuke Ono and Yusuke Mizukami received funding from the Hitachi High-Tech Corporation. The other authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.

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Ono, M., Ono, Y., Nakamura, T. et al. Predictors of Long-Term Survival in Pancreatic Ductal Adenocarcinoma after Pancreatectomy: TP53 and SMAD4 Mutation Scoring in Combination with CA19-9. Ann Surg Oncol 29, 5007–5019 (2022). https://doi.org/10.1245/s10434-022-11630-0

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