Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy

Hunter C Gits; Amy H Tang; William S Harmsen; William R Bamlet; Rondell P Graham; Gloria M Petersen; Thomas C Smyrk; Amit Mahipal; Roman O Kowalchuk; Jonathan B Ashman; William G Rule; Dawn Owen; Michelle A Neben Wittich; Robert R McWilliams; Thorvardur Halfdanarson; Wen Wee Ma; Terence T Sio; Sean P Cleary; Mark J Truty; Michael G Haddock; Christopher L Hallemeier; Kenneth W Merrell

doi:10.21037/jgo-21-55

Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy

J Gastrointest Oncol. 2021 Oct;12(5):2275-2286. doi: 10.21037/jgo-21-55.

Authors

Hunter C Gits¹, Amy H Tang², William S Harmsen³, William R Bamlet³, Rondell P Graham⁴, Gloria M Petersen⁵, Thomas C Smyrk⁴, Amit Mahipal⁶, Roman O Kowalchuk¹, Jonathan B Ashman⁷, William G Rule⁷, Dawn Owen¹, Michelle A Neben Wittich¹, Robert R McWilliams⁶, Thorvardur Halfdanarson⁶, Wen Wee Ma⁶, Terence T Sio⁷, Sean P Cleary⁸, Mark J Truty⁸, Michael G Haddock¹, Christopher L Hallemeier¹, Kenneth W Merrell¹

Affiliations

¹ Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA.
² Leroy T. Canoles Jr. Cancer Research Center, Department of Microbiology and Molecular Cell Biology, Eastern Virginia Medical School, Norfolk, VA, USA.
³ Department of Biostatistics and Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁴ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁵ Department of Epidemiology and Health Sciences Research, Mayo Clinic, Rochester, MN, USA.
⁶ Department of Medical Oncology, Mayo Clinic, Rochester, MN, USA.
⁷ Department of Radiation Oncology, Mayo Clinic, Phoenix, AZ, USA.
⁸ Department of Hepatobiliary & Pancreas Surgery, Mayo Clinic, Rochester, MN, USA.

Abstract

Background: Previous reports suggest that intact SMAD4 expression is associated with a locally aggressive pancreas cancer phenotype. The objectives of this work were to determine the frequency of intact SMAD4 and its association with patterns of recurrence in patients with upfront resected pancreas cancer receiving adjuvant therapy.

Methods: A tissue microarray was constructed using resected specimens from patients who underwent upfront surgery and adjuvant gemcitabine with no neoadjuvant treatment for pancreas cancer. SMAD4 expression was determined by immunohistochemical staining. Associations of SMAD4 expression and clinicopathologic parameters with clinical outcomes were evaluated using Cox proportional hazard models.

Results: One hundred twenty-seven patients were included with a median follow up of 5.7 years. Most patients had stage ≥ pT3 tumors (75%) and pN1 (68%). All patients received adjuvant gemcitabine, and 79% of patients received adjuvant chemoradiotherapy. Ten (8%) patients had intact SMAD4 expression. Grade was the only clinicopathologic parameter statistically associated with SMAD4 expression (P=0.05). Median overall survival was 2.1 years. On univariate analysis, SMAD4 expression was associated with increased locoregional recurrence (hazard ratio 7.0, P<0.01, 95% confidence interval: 2.8-18.0) but not distant recurrence (P=0.06) or overall survival (P=0.73). On multivariable analysis, SMAD4 expression (hazard ratio 9.6, P<0.01, 95% confidence interval: 3.7-24.8) and adjuvant chemoradiotherapy (hazard ratio 0.3, P=0.01, 95% confidence interval: 0.1-0.8) were associated with higher and lower locoregional recurrence, respectively.

Conclusions: In patients with upfront resected pancreas cancer, SMAD4 expression was associated with an increased risk of locoregional recurrence. Prospective evaluation of the frequency of SMAD4 expression and validation of its predictive utility is warranted.

Keywords: Pancreas cancer; chemoradiotherapy (CRT); mothers against decapentaplegic homolog 4 (SMAD4); patterns of recurrence; tissue microarray (TMA).

Abstract

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